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Sample records for retinoblastoma susceptibility gene

  1. Human retinoblastoma susceptibility gene: cloning, identification, and sequence

    SciTech Connect

    Lee, W.; Bookstein, R.; Hong, F.; Young, L.; Shew, J.; Lee, E.Y.P.

    1987-03-13

    Recent evidence indicates the existence of a genetic locus in chromosome region 13q14 that confers susceptibility to retinoblastoma, a cancer of the eye in children. A gene encoding a messenger RNA of 4.6 kilobases (kb), located in the proximity of esterase D, was identified as the retinoblastoma susceptibility (RB) gene on the basis of chromosomal location, homozygous deletion, and tumor-specific alterations in expression. Transcription of this gene was abnormal in six of six retinoblastomas examined: in two tumors, RB mRNA was not detectable, while four others expressed variable quantities of RB mRNA with decreased molecular size of about 4.0 kb. In contrast, full-length RB mRNA was present in human fetal retina and placenta, and in other tumors such as neuroblastoma and medulloblastoma. DNA from retinoblastoma cells had a homozygous gene deletion in one case and hemizygous deletion in another case, while the remainder were not grossly different from normal human control DNA. The gene contains at least 12 exons distributed in a region of over 100 kb. Sequence analysis of complementary DNA clones yielded a single long open reading frame that could encode a hypothetical protein of 816 amino acids.

  2. Retinoblastoma

    MedlinePlus

    ... Stories Español Eye Health / Eye Health A-Z Retinoblastoma Sections What Is Retinoblastoma? Retinoblastoma Causes Retinoblastoma Symptoms Retinoblastoma Diagnosis Retinoblastoma Treatment What Is Retinoblastoma? Aug. 02, 2012 Retinoblastoma is cancer of the ...

  3. Retinoblastoma

    PubMed Central

    Aerts, Isabelle; Lumbroso-Le Rouic, Livia; Gauthier-Villars, Marion; Brisse, Hervé; Doz, François; Desjardins, Laurence

    2006-01-01

    Retinoblastoma is a rare eye tumor of childhood that arises in the retina. It is the most common intraocular malignancy of infancy and childhood; with an incidence of 1/15,000–20,000 live births. The two most frequent symptoms revealing retinoblastoma are leukocoria and strabismus. Iris rubeosis, hypopyon, hyphema, buphthalmia, orbital cellulites and exophthalmia may also be observed. Sixty per cent of retinoblastomas are unilateral and most of these forms are not hereditary (median age at diagnosis two years). Retinoblastoma is bilateral in 40% of cases (median age at diagnosis one year). All bilateral and multifocal unilateral forms are hereditary. Hereditary retinoblastoma constitutes a cancer predisposition syndrome: a subject constitutionally carrying an RB1 gene mutation has a greater than 90% risk of developing retinoblastoma but is also at increased risk of developing other types of cancers. Diagnosis is made by fundoscopy. Ultrasound, magnetic resonance imaging (MRI) and computed tomography (CT) scans may contribute to diagnosis. Management of patients with retinoblastoma must take into account the various aspects of the disease: the visual risk, the possibly hereditary nature of the disease, the life-threatening risk. Enucleation is still often necessary in unilateral disease; the decision for adjuvant treatment is taken according to the histological risk factors. Conservative treatment for at least one eye is possible in most of the bilateral cases. It includes laser alone or combined with chemotherapy, cryotherapy and brachytherapy. The indication for external beam radiotherapy should be restricted to large ocular tumors and diffuse vitreous seeding because of the risk of late effects, including secondary sarcoma. Vital prognosis, related to retinoblastoma alone, is now excellent in patients with unilateral or bilateral forms of retinoblastoma. Long term follow-up and early counseling regarding the risk of second primary tumors and transmission should

  4. Simian virus 40 T antigen can transcriptionally activate and mediate viral DNA replication in cells which lack the retinoblastoma susceptibility gene product.

    PubMed Central

    Trifillis, P; Picardi, J; Alwine, J C

    1990-01-01

    Simian virus 40 T antigen is a multifunctional protein which has recently been shown to form a complex with the retinoblastoma susceptibility gene product (Rb protein) (J.A. DeCaprio, J.W. Ludlow, J. Figge, J.-Y. Shaw, C.-M. Huang, W.-H. Lee, E. Marsilio, E. Paucha, and D.M. Livingston, Cell 54:275-283, 1988; P. Whyte, K.J. Buchkovich, J.M. Horowitz, S.H. Friend, M. Raybuck, R.A. Weinberg, and E. Harlow, Nature (London) 334:124-129, 1988). This interaction may facilitate some of the functions of T antigen. The ability of simian virus 40 T antigen to mediate transcriptional activation and viral DNA replication was tested in human osteosarcoma cell lines U-2OS and Saos-2, which are Rb positive and Rb negative, respectively. Both functions of T antigen were efficient in both cell lines. Hence, these functions can occur in the absence of Rb protein. Images PMID:2154611

  5. The retinoblastoma gene in human pituitary tumors

    SciTech Connect

    Cryns, V.L.; Arnold, A.; Alexander, J.M.; Klibanski, A. )

    1993-09-01

    Functional inactivation of the retinoblastoma (RB) tumor suppressor gene is important in the pathogenesis of many human tumors. Recently, the frequent occurrence of pituitary tumors was reported in mice genetically engineered to have one defective RB allele, a genetic background analogous to that of patients with familial retinoblastoma. The molecular pathogenesis of human pituitary tumors is largely unknown, and the potential role of RB gene inactivation in these neoplasms has not been examined. Consequently, the authors studied 20 human pituitary tumors (12 clinically nonfunctioning tumors, 4 somatotroph adenomas, 2 prolactinomas, and 2 corticotrophy adenomas) for tumor-specific allelic loss of the RB gene using a highly informative polymorphic locus within the gene. Control leukocyte DNA samples from 18 of these 20 patients were heterozygous at this locus, permitting genetic evaluation of their paired tumor specimens. In contrast to the pituitary tumors in the mouse model, none of these 18 human tumors exhibited RB allelic loss. These findings indicate that RB gene inactivation probably does not play an important role in the pathogenesis of common types of human pituitary tumors. 24 refs., 1 fig.

  6. Structure of the human retinoblastoma gene

    SciTech Connect

    Hong, F.D.; Huang, Hueijen S.; To, Hoang; Young, Lihjiuan S.; Oro, A.; Bookstein, R.; Lee, E.Y.H.P.; Lee, Wenhwa )

    1989-07-01

    Complete inactivation of the human retinoblastoma gene (RB) is believed to be an essential step in tumorigenesis of several different cancers. To provide a framework for understanding inactivation mechanisms, the structure of RB was delineated. The RB transcript is encoded in 27 exons dispersed over about 200 kilobases (kb) of genomic DNA. The length of individual exons ranges from 31 to 1,889 base pairs (bp). The largest intron spans >60 kb and the smallest one has only 80 bp. Deletion of exons 13-17 is frequently observed in various types of tumors, including retinoblastoma, breast cancer, and osteosarcoma, and the presence of a potential hot spot for recombination in the region is predicted. A putative leucine-zipper motif is exclusively encoded by exon 20. The detailed RB structure presented should prove useful in defining potential functional domains of its encoded protein. Transcription of RB is initiated at multiple positions and the sequences surrounding the initiation sites have a high G+C content. A typical upstream TATA box is not present. Localization of the RB promoter region was accomplished by utilizing a heterologous expression system containing a bacterial chloramphenicol acetyltransferase gene. Deletion analysis revealed that a region as small as 70 bp is sufficient for RB promoter activity, similar to other previously characterized G+C-rich gene promoters. Several direct repeats and possible stem-and-loop structures are found in the promoter region.

  7. Structure of the human retinoblastoma gene.

    PubMed Central

    Hong, F D; Huang, H J; To, H; Young, L J; Oro, A; Bookstein, R; Lee, E Y; Lee, W H

    1989-01-01

    Complete inactivation of the human retinoblastoma gene (RB) is believed to be an essential step in tumorigenesis of several different cancers. To provide a framework for understanding inactivation mechanisms, the structure of RB was delineated. The RB transcript is encoded in 27 exons dispersed over about 200 kilobases (kb) of genomic DNA. The length of individual exons ranges from 31 to 1889 base pairs (bp). The largest intron spans greater than 60 kb and the smallest one has only 80 bp. Deletion of exons 13-17 is frequently observed in various types of tumors, including retinoblastoma, breast cancer, and osteosarcoma, and the presence of a potential "hot spot" for recombination in the region is predicted. A putative "leucine-zipper" motif is exclusively encoded by exon 20. The detailed RB structure presented here should prove useful in defining potential functional domains of its encoded protein. Transcription of RB is initiated at multiple positions and the sequences surrounding the initiation sites have a high G + C content. A typical upstream TATA box is not present. Localization of the RB promoter region was accomplished by utilizing a heterologous expression system containing a bacterial chloramphenicol acetyltransferase gene. Deletion analysis revealed that a region as small as 70 bp is sufficient for RB promoter activity, similar to other previously characterized G + C-rich gene promoters. Several direct repeats and possible stem-and-loop structures are found in the promoter region. No enhancer element was detected within the 7.3 kb of upstream sequence studied. Several features of the RB promoter are reminiscent of the characteristics associated with many "housekeeping" genes, consistent with its ubiquitous expression pattern. Images PMID:2748600

  8. Retinoblastoma

    MedlinePlus

    ... It is especially important when more than 1 family member has had the disease, or if retinoblastoma occurs in both ... 8.1. Karcioglu ZA, Haik BG. Eye, orbit, and adnexal structures. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan ...

  9. Conditional haploinsufficiency of the retinoblastoma tumor suppressor gene

    PubMed Central

    Ishak, Charles A; Dick, Frederick A

    2015-01-01

    Recent work demonstrates that retention of a single functional retinoblastoma susceptibility (RB1) allele is insufficient to maintain genome stability. Haploinsufficiency of RB1 accelerates cancer pathogenesis in concert with inactivation of tumor protein p53. Collectively, multiple lines of evidence suggest revision of the ‘2-hit’ model to include conditional haploinsufficiency of RB1.

  10. [Genomic retinoblastoma perspectives: implications of tumor supressor gene RB1].

    PubMed

    Rodríguez-Cruz, Maricela; del Prado, Martha; Salcedo, Mauricio

    2005-01-01

    In order to define the molecular and cellular bases of the development of retinoblastomas it is necessary to know its etiology, and to apply the advances in genome technology to this kind of neoplasia. Retinoblastomas are childhood tumors of the eye with an average incidence of one case in every 15,000-20,000 live births, which occur in sporadic and hereditary forms. The sporadic form appears regularly as a unilateral tumor, while in the familial form of the disease, tumors may be unilateral and bilateral. This neoplasia is characterized by leukocoria, strabism, and heterochromia. The retinoblastoma gene (RB1) is a molecular marker of retinoblastoma tumors. This gene is located in chromosome 13q14.2 and encodes a nuclear phosphoprotein (pRB) of 110 KDa, which plays a major role in cell proliferation control through cell cycle-regulated phosphorylation/dephosphorylation cycles of this protein. The RB1 gene is mainly affected by point mutations, which occur most frequently in exons 3, 8, 18 and 20. At the end of the last century, DNA technology has improved notably, allowing for its application to the study of a vast array of diseases. The aim of this work is to show the molecular aspects involved in retinoblastoma which are currently deciphering; this is possible thanks to new technology platforms that have been developed. This will allow us in a near future, to offer tests for the early diagnoses, prognoses, and the determination of individual predisposition towards this neoplasia. PMID:16315642

  11. Molecular mechanism of retinoblastoma gene inactivation in retinoblastoma cell line Y79

    SciTech Connect

    Lee, E.Y.H.P.; Bookstein, R.; Young, Lihjiuan; Lin, Chijen; Rosenfeld, M.G.; Lee, Wenhwa )

    1988-08-01

    Formation of retinoblastoma, a cancer arising in the retinas of young children, is determined by mutational inactivation of an autosomal gene (RB), which has been molecularly cloned. Whereas all normal tissues and many tumor cells express an RB mRNA of 4.7 kilobases, six of six retinoblastomas were previously found either to lack RB gene expression or to have RB transcripts of abnormal (reduced) length. To further characterize the latter type of mutation, the authors chose to examine retinoblastoma cell line Y79, which expressed a shortened RB mRNA of about 4.0 kilobases. RB cDNA clones isolated from a library constructed with Y79 mRNA demonstrated an internal loss of 470 nucleotides near the 5{prime} end, which corresponded to a deletion of exons 2-6. Genomic clones containing the deletion junction were isolated from a library made with Y79 DNA, which allowed precise localization and sequencing of deletion endpoints in introns 1 and 6. These regions had no apparent homology to each other or to the Alu family of repetitive sequences, implying that the deletion must have occurred by a mechanism other than recombination of homologous sequences. Deletion of exons 2-6 would interrupt the open reading frame in RB mRNA and would result in premature termination of translation. Since no normal RB protein was detected by immunoprecipitation with specific antibody, the other, apparently normal RB allele in Y79 cells was necessarily inactivated by a different mutation.

  12. Retinoblastoma-like RRB gene of arabidopsis thaliana

    DOEpatents

    Durfee, Tim; Feiler, Heidi; Gruissem, Wilhelm; Jenkins, Susan; Roe, Judith; Zambryski, Patricia

    2004-02-24

    This invention provides methods and compositions for altering the growth, organization, and differentiation of plant tissues. The invention is based on the discovery that, in plants, genetically altering the levels of Retinoblastoma-related gene (RRB) activity produces dramatic effects on the growth, proliferation, organization, and differentiation of plant meristem.

  13. Amplification and characterization of the retinoblastoma gene VNTR by PCR.

    PubMed Central

    Scharf, S J; Bowcock, A M; McClure, G; Klitz, W; Yandell, D W; Erlich, H A

    1992-01-01

    VNTR regions are informative genetic markers for linkage mapping and individual identification. Using PCR, we have developed a procedure for the enzymatic amplification of the VNTR located in the 16th intron of the human retinoblastoma (RB1) gene. We have also prepared a nonisotopically labeled oligonucleotide probe which facilitates detection of the amplification products. In examining 250 individuals from four different populations, we have detected 11 alleles ranging from 650 to 1,800 bp in size. The core repeat is approximately 50 bp in length. On the basis of the observed allele frequencies for Caucasian, African-American, and Hispanic populations from the United States and for the Mexican Hispanic population, the heterozygosities have been calculated to be 62%, 75%, 61%, and 50%, respectively. The observed genotype frequencies do not deviate from the values expected under Hardy-Weinberg equilibrium. The effect of varying primer sequences, annealing temperature, and cycle number on the amplification are also discussed. Amplification of this marker may also prove useful for detecting the heterozygosity loss that is associated with tumor formation in retinoblastoma. Images Figure 4 Figure 2 Figure 3 Figure 5 PMID:1734717

  14. Identification of hub genes and pathways associated with retinoblastoma based on co-expression network analysis.

    PubMed

    Wang, Q L; Chen, X; Zhang, M H; Shen, Q H; Qin, Z M

    2015-01-01

    The objective of this paper was to identify hub genes and pathways associated with retinoblastoma using centrality analysis of the co-expression network and pathway-enrichment analysis. The co-expression network of retinoblastoma was constructed by weighted gene co-expression network analysis (WGCNA) based on differentially expressed (DE) genes, and clusters were obtained through the molecular complex detection (MCODE) algorithm. Degree centrality analysis of the co-expression network was performed to explore hub genes present in retinoblastoma. Pathway-enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Validation of hub gene expression in retinoblastoma was performed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. The co-expression network based on 221 DE genes between retinoblastoma and normal controls consisted of 210 nodes and 3965 edges, and 5 clusters of the network were evaluated. By assessing the centrality analysis of the co-expression network, 21 hub genes were identified, such as SNORD115-41, RASSF2, and SNORD115-44. According to RT-PCR analysis, 16 of the 21 hub genes were differently expressed, including RASSF2 and CDCA7, and 5 were not differently expressed in retinoblastoma compared to normal controls. Pathway analysis showed that genes in 2 clusters were enriched in 3 pathways: purine metabolism, p53 signaling pathway, and melanogenesis. In this study, we successfully identified 16 hub genes and 3 pathways associated with retinoblastoma, which may be potential biomarkers for early detection and therapy for retinoblastoma. PMID:26662407

  15. Hereditary Diffuse Infiltrating Retinoblastoma.

    PubMed

    Schedler, Katharina J E; Traine, Peter G; Lohmann, Dietmar R; Haritoglou, Christos; Metz, Klaus A; Rodrigues, Eduardo B

    2016-03-01

    Retinoblastoma is one of the most common childhood cancers. The diffuse infiltrating retinoblastoma is a rare subtype of this neoplasm. The majority of cases of diffuse infiltrating retinoblastoma are unilateral and occur sporadically. Herein we report on a family with three children affected by retinoblastoma, among them one girl with diffuse infiltrating retinoblastoma. This girl was diagnosed at the age of 8 years with a unilateral diffuse infiltrating retinoblastoma. By contrast, the two brothers became clinically apparent in the first 2 years of life with bilateral retinoblastoma. The parents were clinically unremarkable. Genetic analysis of RB1 gene was performed. The girl with diffuse infiltrating RB was found to be heterozygous for an oncogenic mutation in the RB1 gene that was also carried by both brothers and the father of the family. These results show that diffuse infiltrating retinoblastoma can develop on the background of a hereditary predisposition to retinoblastoma. PMID:24892564

  16. RNAi mediated Tiam1 gene knockdown inhibits invasion of retinoblastoma.

    PubMed

    Subramanian, Nithya; Navaneethakrishnan, Saranya; Biswas, Jyotirmay; Kanwar, Rupinder K; Kanwar, Jagat R; Krishnakumar, Subramanian

    2013-01-01

    T lymphoma invasion and metastasis protein (Tiam1) is up-regulated in variety of cancers and its expression level is related to metastatic potential of the type of cancer. Earlier, Tiam1 was shown to be overexpressed in retinoblastoma (RB) and we hypothesized that it was involved in invasiveness of RB. This was tested by silencing Tiam1 in RB cell lines (Y79 and Weri-Rb1) using siRNA pool, targeting different regions of Tiam1 mRNA. The cDNA microarray of Tiam1 silenced cells showed gene regulations altered by Tiam1 were predominantly on the actin cytoskeleton interacting proteins, apoptotic initiators and tumorogenic potential targets. The silenced phenotype resulted in decreased growth and increased apoptosis with non-invasive characteristics. Transfection of full length and N-terminal truncated construct (C1199) clearly revealed membrane localization of Tiam1 and not in the case of C580 construct. F-actin staining showed the interaction of Tiam1 with actin in the membrane edges that leads to ruffling, and also imparts varying invasive potential to the cell. The results obtained from our study show for the first time that Tiam1 modulates the cell invasion, mediated by actin cytoskeleton remodeling in RB. PMID:23950931

  17. Characterization and expression analysis of a Retinoblastoma-related gene from Chinese wild Vitis pseudoreticulata

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Retinoblastoma-related (RBR) genes, a conserved gene family in higher eukaryotes, plays an important role in cell differentiation, development and mammalian cell death in animals; however, little is known about its function in plants. In this study, an RBR gene was isolated from the Chinese wild gr...

  18. Alteration of the retinoblastoma gene locus in radium-exposed individuals

    SciTech Connect

    Hardwick, J.P.; Schlenker, R.; Huberman, E.

    1991-01-01

    This study was performed to determine if the retinoblastoma suppressor gene was altered in individuals exposed to radium. We analyzed the Rb gene in 30 individuals, 17 of whom were exposed to radium either occupationally or iatrogenically. In the kidney DNA from four of nine radium-exposed individuals, the Rb gene was deleted. Three of these alterations in the Rb gene were internal deletions, which resulted in the absence of Rb mRNA accumulation. These results imply that the Rb gene is susceptible to radium-induced damage and confirm previous showing that radiation preferentially causes genomic deletions. The pronounced alterations in the non-tumorigenic femurs from radium-exposed individuals suggests that in the many years of exposure there was a selection of cells with alterations, presumably because of their growth advantage. Also it implies that deletions of one of the Rb alleles can be one of the events (perhaps an initial one) in the progression of radium-induced sarcomas. 11 refs., 2 figs.

  19. Novel mutations in the RB1 gene from Chinese families with a history of retinoblastoma.

    PubMed

    Zhang, Leilei; Jia, Renbing; Zhao, Junyang; Fan, Jiayan; Zhou, YiXiong; Han, Bing; Song, Xin; Wu, Li; Zhang, He; Song, Huaidong; Ge, Shengfang; Fan, Xianqun

    2015-04-01

    Retinoblastoma is an aggressive eye cancer that develops during infancy and is divided into two clinical types, sporadic and heritable. RB1 has been identified as the only pathological gene responsible for heritable retinoblastoma. Here, we identified 11 RB1 germline mutations in the Han pedigrees of 17 bilateral retinoblastoma patients from China. Four mutations were nonsense mutations, five were splice site mutations, and two resulted in a frame shift due to an insertion or a deletion. Three of the mutations had not been previously reported, and the p.Q344L mutation occurred in two generations of retinoblastoma patients. We investigated phenotypic-genotypic relationships for the novel mutations and showed that these mutations affected the expression, location, and function of the retinoblastoma protein. Abnormal protein localization was observed after transfection of the mutant genes. In addition, changes in the cell cycle distribution and apoptosis rates were observed when the Saos-2 cell line was transfected with plasmids encoding the mutant RB1 genes. Our findings expand the spectrum of known RB1 mutations and will benefit the investigation of RB1 mutation hotspots. Genetic counseling can be offered to families with heritable RB1 mutations. PMID:25424699

  20. Alteration of plant meristem function by manipulation of the Retinoblastoma-like plant RRB gene

    DOEpatents

    Durfee, Tim; Feiler, Heidi; Gruissem, Wilhelm; Jenkins, Susan; Roe, Judith; Zambryski, Patricia

    2007-01-16

    This invention provides methods and compositions for altering the growth, organization, and differentiation of plant tissues. The invention is based on the discovery that, in plants, genetically altering the levels of Retinoblastoma-related gene (RRB) activity produces dramatic effects on the growth, proliferation, organization, and differentiation of plant meristem.

  1. Expression profile of genes regulated by curcumin in Y79 retinoblastoma cells.

    PubMed

    Sreenivasan, Seethalakshmi; Thirumalai, Karthiyaini; Krishnakumar, Subramanian

    2012-01-01

    Curcumin, a well-known chemopreventive agent from turmeric, inhibits the expression of several oncogenes and cell proliferation genes in tumor cells. This study aims to understand the precise molecular mechanism by which curcumin exerts its effects on retinoblastoma cells, by performing whole genome microarray analysis to determine the gene expression profiles altered by curcumin treatment. Curcumin suppressed cell viability and altered the cell cycle of retinoblastoma cells. We identified 903 downregulated genes and 1,319 upregulated genes when compared with the control cells after treatment with 20 μM curcumin concentration for 48 h. These genes were grouped into respective functional categories according to their biological function. We found that curcumin regulated the expression of genes that are involved in the regulation of apoptosis, tumor suppressor, cell-cycle arrest, transcription factor, and angiogenesis. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was used to validate the results of genome array, and the results were consistent with the obtained data. In conclusion, treatment of curcumin affects the expression of genes involved in various cellular functions and plays an important role in tumor metastasis and apoptosis. Thus, curcumin might be an effective chemopreventive agent for retinoblastoma cancer. PMID:22489823

  2. Multiple lipomas linked to an RB1 gene mutation in a large pedigree with low penetrance retinoblastoma.

    PubMed

    Genuardi, M; Klutz, M; Devriendt, K; Caruso, D; Stirpe, M; Lohmann, D R

    2001-09-01

    Hereditary predisposition to lipomas is observed in familial multiple lipomatosis (OMIM 151900) and benign cervical lipomatosis (OMIM 151800) and can also be associated with mutations in the MEN1 and PTEN genes (OMIM 131100 and 153480, respectively). In addition, a recent report indicates that a few patients with hereditary retinoblastoma also have lipomas. Here we report on an extended family segregating a splice site mutation in the RB1 gene. Almost all adult carriers of this mutation had multiple lipomas while penetrance for retinoblastoma was incomplete. In an unrelated pedigree, which was reported previously, the identical mutation was only associated with low-penetrance retinoblastoma but not lipomas. Our data indicate that lipoma predisposition in hereditary retinoblastoma is not associated with specific RB1 gene mutations but is influenced by modifying factors linked to this gene. PMID:11571558

  3. Quantification of the paternal allele bias for new germline mutations in the retinoblastoma gene

    SciTech Connect

    Morrow, J.F.; Rapaport, J.M.; Dryia, T.P.

    1994-09-01

    New germline mutations in the human retinoblastoma gene preferentially arise on a paternally derived allele. In nonhereditary retinoblastoma, the initial somatic mutation seems to have no such bias. The few previous reports of these phenomena included relatively few cases (less than a dozen new germline or initial somatic mutations), so that the magnitude of the paternal allele bias for new germline mutations is not known. Knowledge of the magnitude of the bias is valuable for genetic counseling, since, for example, patients with new germline mutations who reproduce transmit risk for retinoblastoma according to the risk that the transmitted allele has a germline mutation. We sought to quantitate the paternal allele bias and to determine whether paternal age is a factor possibly accounting for it. We studied 311 families with retinoblastoma (261 simplex, 50 multiplex) that underwent clinical genetic testing and 5 informative families recruited from earlier research. Using RFLPs and polymorphic microsatellites in the retinoblastoma gene, we could determine the parental origin of 45 new germline mutations and 44 probable initial somatic mutations. Thirty-seven of the 45 new germline mutations, or 82%, arose on a paternal allele while only 24 of the 44 initial somatic mutations (55%) did so. Increased paternal age does not appear to account for the excess of new paternal germline mutations, since the average age of fathers of children with new germline mutations (29.4 years, n=26, incomplete records on 11) was not significantly different from the average age of fathers of children with maternal germline mutations or somatic initial mutations (29.8 years, n=35, incomplete records on 17).

  4. Short, direct repeats at the breakpoints of deletions of the retinoblastoma gene

    SciTech Connect

    Canning, S.; Dryja, T.P. )

    1989-07-01

    The authors found deletions involving the retinoblastoma gene in 12 of 49 tumors from patients with retinoblastoma or osteosarcoma. After mapping the deletion breakpoints, they found that no two breakpoints coincided. Thus, the data do not support the conclusions of others regarding the existence of a hotspot for deletion breakpoints in this gene. In 4 of the tumors, they sequenced 200 base pairs surrounding each deletion breakpoint. Three deletions had termini within pairs of short, direct repeats ranging in size from 4 to 7 base pairs. These results indicate that the slipped mispairing mechanism may predominate in the generation of deletions at this locus. The review of deletion breakpoints at other genetic loci reveals that the nature of the sequences present at deletion breakpoints (short, direct repeats versus middle repetitive elements) varies according to the genetic locus under study.

  5. The retinoblastoma gene product RB stimulates Sp1-mediated transcription by liberating Sp1 from a negative regulator.

    PubMed Central

    Chen, L I; Nishinaka, T; Kwan, K; Kitabayashi, I; Yokoyama, K; Fu, Y H; Grünwald, S; Chiu, R

    1994-01-01

    Studies have demonstrated that the retinoblastoma susceptibility gene product, RB, can either positively or negatively regulate expression of several genes through cis-acting elements in a cell-type-dependent manner. The nucleotide sequence of the retinoblastoma control element (RCE) motif, GCCACC or CCACCC, and the Sp1 consensus binding sequence, CCGCCC, can confer equal responsiveness to RB. Here, we report that RB activates transcription of the c-jun gene through the Sp1-binding site within the c-jun promoter. Preincubation of crude nuclear extracts with monoclonal antibodies to RB results in reduction of Sp1 complexes in a mobility shift assay, while addition of recombinant RB in mobility shift assay mixtures with CCL64 cell extracts leads to an enhancement of DNA-binding activity of SP1. These results suggest that RB is directly or indirectly involved in Sp1-DNA binding activity. A mechanism by which RB regulates transactivation is indicated by our detection of a heat-labile and protease-sensitive Sp1 negative regulator(s) (Sp1-I) that specifically inhibits Sp1 binding to a c-jun Sp1 site. This inhibition is reversed by addition of recombinant RB proteins, suggesting that RB stimulates Sp1-mediated transactivation by liberating Sp1 from Sp1-I. Additional evidence for Sp1-I involvement in Sp1-mediated transactivation was demonstrated by cotransfection of RB, GAL4-Sp1, and a GAL4-responsive template into CV-1 cells. Finally, we have identified Sp1-I, a approximately 20-kDa protein(s) that inhibits the Sp1 complexes from binding to DNA and that is also an RB-associated protein. These findings provide evidence for a functional link between two distinct classes of oncoproteins, RB and c-Jun, that are involved in the control of cell growth, and also define a novel mechanism for the regulation of c-jun expression. Images PMID:8007947

  6. Susceptibility Genes in Thyroid Autoimmunity

    PubMed Central

    Ban, Yoshiyuki; Tomer, Yaron

    2005-01-01

    The autoimmune thyroid diseases (AITD) are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine) is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT) and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg). Most likely, these loci interact and their interactions may influence disease phenotype and severity. PMID:15712599

  7. Correlation between retinoblastoma gene expression and differentiation in human testicular tumors

    SciTech Connect

    Strohmeyer, T. Heinrich-Heine-Univ. of Duesseldorf ); Reissmann, P.; Slamon, D. ); Cordon-Cardo, C. ); Hartmann, M. ); Ackermann, R. )

    1991-08-01

    Inactivation of the retinoblastoma gene (RB gene) is associated with the development of several human malignancies including retinoblastomas, come osteo- and soft tissue sarcomas, small cell lung cancer, and possibly breast and bladder cancers. To the authors' knowledge, this gene has not been evaluated in human germ-cell malignancies. In this study 67 primary testicular germ-cell tumors and 4 testicular non-germ-cell malignancies were examined to determine the prevalence and nature of RB gene alterations. Decreased expression of RB gene mRNA was found in all testicular germ-cell tumors examined. The RB protein could not be detected by immunohistochemical analysis in the undifferentiated cells of any germ-cell tumors whereas the differentiated malignant cells present in 14/15 teratocarcinomas expressed the protein. No gross alterations of the RB gene were found at DNA level in any of the examined specimens. This and the presence of the RB protein in the more differentiated tumor cells of teratocarcinomas suggest that changes in transcript levels rather than mutation(s) of the gene may be responsible for the absent of decreased RB expression in human germ-cell tumors. To date studies on the mechanism of RB regulation have demonstrated that it occurs at the protein level by phosphorylation of the p105 gene product. The findings presented here indicate that additional regulation might occur at the transcript level.

  8. Molecular biology of retinoblastoma.

    PubMed

    Sábado Alvarez, C

    2008-07-01

    Retinoblastoma (Rb), the most common intraocular tumor in childhood, is caused by the loss of function of both retinoblastoma susceptibility gene (RB1 or Rb1) alleles. In 1971, Alfred Knudson proposed his "two-hit" theory based upon empiric observations of the clinical genetics of Rb, revealing the role of tumor-suppressor genes in human cancer. Knudson proposed that: "In the dominant inherited form of Rb, one mutation is inherited via germ line and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells." The Knudson hypothesis was validated later with the cloning of RB1, the first tumor-suppressor gene to be identified. A few years later, Harbour extended these findings to small-cell lung cancer, showing that the RB1 locus was disrupted in tumors other than Rb and osteosarcoma. Since then, it has been found that most, if not all, tumors have defects in their RB1 pathway through genetic lesions in the RB1 gene itself or other genes in the pathway. The history of Rb research highlights how basic research on a rare childhood cancer can have a much broader effect on a disease that affects millions of people each year worldwide. PMID:18628066

  9. Exclusion of the retinoblastoma gene and chromosome 13q as the site of a primary lesion for human breast cancer.

    PubMed Central

    Bowcock, A M; Hall, J M; Hebert, J M; King, M C

    1990-01-01

    Chromosome 13q has been suggested as the site of a gene predisposing to human breast cancer, because loss of heterozygosity of alleles on this chromosome has been observed in some ductal breast tumors and because two breast cancer lines are altered at the retinoblastoma gene (RB1) at 13q14. To test this possibility, linkage of breast cancer susceptibility to 14 loci on chromosome 13q loci was assessed in extended families in which breast cancer is apparently inherited as an autosomal dominant trait. RB1 was excluded as the site of a breast cancer gene by a lod score of Z = -7.60 at close linkage for 13 families. Multipoint analysis yielded negative lod scores throughout the region between 13q12 and 13q34; over most of this distance, Z less than -2.0. Therefore, chromosome 13q appears to be excluded as the site of primary lesion for breast cancer in these families. In addition, comparison of tumor versus normal tissues of nonfamilial breast cancer patients revealed an alteration at the 5' end of RB1 in a mucoid carcinoma but no alterations of RB1 in five informative ductal adenocarcinomas. Linkage data and comparisons of tumor and normal tissues suggest that changes in the RBI locus either are secondary alterations associated with progression of some tumors or occur by chance. Images Figure 2 PMID:2294744

  10. Characterization of the ATP-binding cassette transporter gene expression profile in Y79: a retinoblastoma cell line.

    PubMed

    Hendig, Doris; Langmann, Thomas; Zarbock, Ralf; Schmitz, Gerd; Kleesiek, Knut; Götting, Christian

    2009-08-01

    Chemotherapy failure was reported in treatment of retinoblastoma suggesting a role for ATP-binding cassette (ABC) proteins. Little is known about the expression pattern of ABC proteins in this cancer type. We investigated the gene expression profile of 47 ABC proteins in the human retinoblastoma cell line Y79 by TaqMan low-density array. Analysis revealed 31 ABC transporter genes expressed in this tumor cell line. Y79 cells demonstrate high gene expression of ABCA7, ABCA12, ABCB7, ABCB10, ABCC1, ABCC4, ABCD3, ABCE1, ABCF1, ABCF2, and ABCF3 (more than twofold compared to pooled RNA from different tissues). Moreover, we show that Y79 cells exhibit an active calcein efflux pointing to multidrug resistance protein (MRP)-like transporter activity. In summary, we present for the first time an ABC transporter gene expression profile in cells derived from retinoblastoma. Most of the highly expressed ABC transporter genes are typical markers of cancer cells and might exhibit potential targets for medical treatment of retinoblastoma. PMID:19266166

  11. Genomic imprinting of the human serotonin-receptor (HTR2) gene involved in development of retinoblastoma

    SciTech Connect

    Kato, Mitsuo V.; Nagayoshi, Mariko; Shimuzu, Takashi

    1996-11-01

    Epidemiological and genetic studies of retinoblastoma (RB) suggested that imprinted genes might be genetically linked to the RB gene. In this study, we found that the human serotonin-receptor, HTR2, gene, which had been mapped nearby the RB gene on chromosome 13, was expressed only in human fibroblasts with a maternal allele and not in cells without a maternal allele. The 5{prime} genomic region of the human HTR2 gene was cloned by PCR-mediated method. Only the 5{prime} region of the gene was methylated in cells with the maternal gene, and it was not methylated in cells without the maternal gene. A polymorphism of PvuII site of the gene was also found and useful for the segregation analysis in a family of an RB patient and for analysis of loss of heterozygosity on chromosome 13 in tumor and its parental origin. These results suggest that the human HTR2 gene might be affected by genomic imprinting and that exclusive expression of the maternal HTR2 gene may be associated with the delayed occurrence of RB, which had lost the maternal chromosome 13. 33 refs., 5 figs., 2 tabs.

  12. A Mouse Model for Imprinting of the Human Retinoblastoma Gene

    PubMed Central

    Tasiou, Vasiliki; Hiber, Michaela; Steenpass, Laura

    2015-01-01

    The human RB1 gene is imprinted due to integration of the PPP1R26P1 pseudogene into intron 2. PPP1R26P1 harbors the gametic differentially methylated region of the RB1 gene, CpG85, which is methylated in the female germ line. The paternally unmethylated CpG85 acts as promoter for the alternative transcript 2B of RB1, which interferes with expression of full-length RB1 in cis. In mice, PPP1R26P1 is not present in the Rb1 gene and Rb1 is not imprinted. Assuming that the mechanisms responsible for genomic imprinting are conserved, we investigated if imprinting of mouse Rb1 can be induced by transferring human PPP1R26P1 into mouse Rb1. We generated humanized Rb1_PPP1R26P1 knock-in mice that pass human PPP1R26P1 through the mouse germ line. We found that the function of unmethylated CpG85 as promoter for an alternative Rb1 transcript and as cis-repressor of the main Rb1 transcript is maintained in mouse tissues. However, CpG85 is not recognized as a gametic differentially methylated region in the mouse germ line. DNA methylation at CpG85 is acquired only in tissues of neuroectodermal origin, independent of parental transmission of PPP1R26P1. Absence of CpG85 methylation in oocytes and sperm implies a failure of imprint methylation establishment in the germ line. Our results indicate that site-specific integration of a proven human gametic differentially methylated region is not sufficient for acquisition of DNA methylation in the mouse germ line, even if promoter function of the element is maintained. This suggests a considerable dependency of DNA methylation induction on the surrounding sequence. However, our model is suited to determine the cellular function of the alternative Rb1 transcript. PMID:26275142

  13. A Meta-Analysis of Retinoblastoma Copy Numbers Refines the List of Possible Driver Genes Involved in Tumor Progression

    PubMed Central

    Kooi, Irsan E.; Mol, Berber M.; Massink, Maarten P. G.; de Jong, Marcus C.; de Graaf, Pim; van der Valk, Paul; Meijers-Heijboer, Hanne; Kaspers, Gertjan J. L.; Moll, Annette C.; te Riele, Hein; Cloos, Jacqueline; Dorsman, Josephine C.

    2016-01-01

    Background While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome-wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes. Methods We performed SCNA profiling of 45 primary retinoblastoma samples and eight retinoblastoma cell lines by high-resolution microarrays. We combined our data with genomic, clinical and histopathological data of ten published genome-wide SCNA studies, which strongly enhanced the power of our analyses (N = 310). Results Comprehensive recurrence analysis of SCNAs in all studies integrated with gene expression data allowed us to reduce candidate gene lists for 1q, 2p, 6p, 7q and 13q to a limited gene set. Besides the well-established driver genes RB1 (13q-loss) and MYCN (2p-gain) we identified CRB1 and NEK7 (1q-gain), SOX4 (6p-gain) and NUP205 (7q-gain) as novel retinoblastoma driver candidates. Depending on the sample subset and algorithms used, alternative candidates were identified including MIR181 (1q-gain) and DEK (6p gain). Remarkably, our study showed that copy number gains rarely exceeded change of one copy, even in pure tumor samples with 100% homozygosity at the RB1 locus (N = 34), which is indicative for intra-tumor heterogeneity. In addition, profound between-tumor variability was observed that was associated with age at diagnosis and differentiation grades. Interpretation Since focal alterations at commonly altered chromosome regions were rare except for 2p24.3 (MYCN), further functional validation of the oncogenic potential of the described candidate genes is now required. For further investigations, our study provides a refined and revised set

  14. [Effects of dibutyryl cyclic AMP on the gene expression during the differentiation of retinoblastoma cells (Y 79) in culture].

    PubMed

    Murakami, T; Takahashi, H; Akiya, S; Higashi, K

    1993-06-01

    Cultured human retinoblastoma cells (Y79) were induced to differentiate by dibutyryl cyclic AMP(Bt2cAMP). We examined the effects on the mRNA levels of several cellular genes when the induction of differentiation was monitored by observation of the cellular processes. Bt2cAMP(1mM) treatment produced significant extension of cellular process after 3 days. We examined the mRNA levels of N-myc gene(oncogene), Rb(anti-oncogene, retinoblastoma gene) and nucleolin (nucleolar protein) being linked with ribosome biosynthesis. The mRNA levels of all these genes decreased for 3 days after Bt2cAMP treatment. These results suggested the possibility that Y 79 cells were induced to differentiate by down-modulation of both N-myc gene expression and ribosome biosynthesis in the nucleolus following treatment of Bt2cAMP. Furthermore, the gene expression of the retinoblastoma gene is likely to be downregulated by this condition even if the product of mRNA is not functional. PMID:8392280

  15. Defining a new vision for the retinoblastoma gene: report from the 3rd International Rb Meeting.

    PubMed

    Rubin, Seth M; Sage, Julien

    2013-01-01

    The retinoblastoma tumor suppressor (Rb) pathway is mutated in most, if not all human tumors. In the G0/G1 phase, Rb and its family members p107 and p130 inhibit the E2F family of transcription factors. In response to mitogenic signals, Cyclin-dependent kinases (CDKs) phosphorylate Rb family members, which results in the disruption of complexes between Rb and E2F family members and in the transcription of genes essential for S phase progression. Beyond this role in early cell cycle decisions, Rb family members regulate DNA replication and mitosis, chromatin structure, metabolism, cellular differentiation, and cell death. While the RB pathway has been extensively studied in the past three decades, new investigations continue to provide novel insights into basic mechanisms of cancer development and, beyond cancer, help better understand fundamental cellular processes, from plants to mammals. This meeting report summarizes research presented at the recently held 3rd International Rb Meeting. PMID:24257515

  16. Defining a new vision for the retinoblastoma gene: report from the 3rd International Rb Meeting

    PubMed Central

    2013-01-01

    The retinoblastoma tumor suppressor (Rb) pathway is mutated in most, if not all human tumors. In the G0/G1 phase, Rb and its family members p107 and p130 inhibit the E2F family of transcription factors. In response to mitogenic signals, Cyclin-dependent kinases (CDKs) phosphorylate Rb family members, which results in the disruption of complexes between Rb and E2F family members and in the transcription of genes essential for S phase progression. Beyond this role in early cell cycle decisions, Rb family members regulate DNA replication and mitosis, chromatin structure, metabolism, cellular differentiation, and cell death. While the RB pathway has been extensively studied in the past three decades, new investigations continue to provide novel insights into basic mechanisms of cancer development and, beyond cancer, help better understand fundamental cellular processes, from plants to mammals. This meeting report summarizes research presented at the recently held 3rd International Rb Meeting. PMID:24257515

  17. Infrequent genomic rearrangement and normal expression of the putative RB1 gene in retinoblastoma tumors

    SciTech Connect

    Goddard, A.D.; Balakier, H.; Canton, M.; Dunn, J.; Squire, J.; Reyes, E.; Becker, A.; Phillips, R.A.; Gallie, B.L.

    1988-05-01

    Retinoblastoma (RB) tumors develop when both alleles of a gene (RB1) are mutated and unable to function normally. Recently, others reported the cloning of a gene, 4.7R, with some properties expected for the RB1 gene, namely, a high frequency (30%) of genomic rearrangements in tumors and absence of message in all RB tumors examined. To extend the characterization of this gene, the authors used 4.7R probes to search for genomic rearrangements of DNA and to study the expression of the 4.7R gene in RB tumors, osteosarcoma (OS) tumors arising in RB patients, and other normal and malignant tissues. In 34 previously unreported RB and OS tumors arising in RB patients, the authors observed only four (12%) with genomic abnormalities. Transcripts of 4.7R were present in 12 of 17 RB tumors, 2 of 2 OS tumors, and all non-RB tumors and normal tissues tested. They were unable to confirm the high frequency of truncated messages of 4.7R in RB tumors reported by others, but did not confirm the presence of a truncated transcription in the RB cell line Y79. Of the RB and RB-related OS tumors which appeared normal on Southern blots, 2 of 16 or 12% had abnormal transcripts, giving a combined frequency of 22% abnormalities in the 4.7R gene detectable by Southern and Northern (RNA) blot analyses.

  18. Time-course gene profiling and networks in demethylated retinoblastoma cell line

    PubMed Central

    Malusa, Federico; Taranta, Monia; Zaki, Nazar; Cinti, Caterina; Capobianco, Enrico

    2015-01-01

    Retinoblastoma, a very aggressive cancer of the developing retina, initiatiates by the biallelic loss of RB1 gene, and progresses very quickly following RB1 inactivation. While its genome is stable, multiple pathways are deregulated, also epigenetically. After reviewing the main findings in relation with recently validated markers, we propose an integrative bioinformatics approach to include in the previous group new markers obtained from the analysis of a single cell line subject to epigenetic treatment. In particular, differentially expressed genes are identified from time course microarray experiments on the WERI-RB1 cell line treated with 5-Aza-2′-deoxycytidine (decitabine; DAC). By inducing demethylation of CpG island in promoter genes that are involved in biological processes, for instance apoptosis, we performed the following main integrative analysis steps: i) Gene expression profiling at 48h, 72h and 96h after DAC treatment; ii) Time differential gene co-expression networks and iii) Context-driven marker association (transcriptional factor regulated protein networks, master regulatory paths). The observed DAC-driven temporal profiles and regulatory connectivity patterns are obtained by the application of computational tools, with support from curated literature. It is worth emphasizing the capacity of networks to reconcile multi-type evidences, thus generating testable hypotheses made available by systems scale predictive inference power. Despite our small experimental setting, we propose through such integrations valuable impacts of epigenetic treatment in terms of gene expression measurements, and then validate evidenced apoptotic effects. PMID:26143641

  19. Molecular Insights on Post-chemotherapy Retinoblastoma by Microarray Gene Expression Analysis

    PubMed Central

    Nalini, Venkatesan; Segu, Ramya; Deepa, Perinkulam Ravi; Khetan, Vikas; Vasudevan, Madavan; Krishnakumar, Subramanian

    2013-01-01

    Purpose Management of Retinoblastoma (RB), a pediatric ocular cancer is limited by drug-resistance and drug-dosage related side effects during chemotherapy. Molecular de-regulation in post-chemotherapy RB tumors was investigated. Materials and Methods cDNA microarray analysis of two post-chemotherapy and one pre-chemotherapy RB tumor tissues was performed, followed by Principle Component Analysis, Gene ontology, Pathway Enrichment analysis and Biological Analysis Network (BAN) modeling. The drug modulation role of two significantly up-regulated genes (p≤0.05) − Ect2 (Epithelial-cell-transforming-sequence-2), and PRAME (preferentially-expressed-Antigen-in-Melanoma) was assessed by qRT-PCR, immunohistochemistry and cell viability assays. Results Differential up-regulation of 1672 genes and down-regulation of 2538 genes was observed in RB tissues (relative to normal adult retina), while 1419 genes were commonly de-regulated between pre-chemotherapy and post- chemotherapy RB. Twenty one key gene ontology categories, pathways, biomarkers and phenotype groups harboring 250 differentially expressed genes were dys-regulated (EZH2, NCoR1, MYBL2, RB1, STAMN1, SYK, JAK1/2, STAT1/2, PLK2/4, BIRC5, LAMN1, Ect2, PRAME and ABCC4). Differential molecular expressions of PRAME and Ect2 in RB tumors with and without chemotherapy were analyzed. There was neither up- regulation of MRP1, nor any significant shift in chemotherapeutic IC50, in PRAME over-expressed versus non-transfected RB cells. Conclusion Cell cycle regulatory genes were dys-regulated post-chemotherapy. Ect2 gene was expressed in response to chemotherapy-induced stress. PRAME does not contribute to drug resistance in RB, yet its nuclear localization and BAN information, points to its possible regulatory role in RB. PMID:24092970

  20. The retinoblastoma gene functions as a growth and tumor suppressor in human bladder carcinoma cells

    SciTech Connect

    Takahashi, Rei; Hashimoto, Tomoko; Hongji Xu; Shixu Hu; Bigo-Marshall, H.; Benedict, W.F. ); Matsui, Toshimitsu Kobe Univ. School of Medicine ); Miki, Toru; Aaronson, S.A. )

    1991-06-15

    The product of the human retinoblastoma gene (RB) is a nuclear phosphoprotein that is thought to function as a tumor suppressor. Mutations of RB frequently occur in human bladder carcinoma. To investigate the significance of the functional loss of this gene in bladder cancer, an RB expression plasmid (pBARB) under control of the human {beta}-actin promoter was transfected into the bladder carcinoma cell line HTB9, which lacks RB expression. Marker-selected transfectants that expressed RB protein were identified by immunoblotting and immunohistochemical staining. In selected clones, stable RB expression has persisted over 1 yr under standard culture conditions with 10% serum. However, RB expression caused major alterations of HTB9 growth properties both in vitro and in vivo. RB{sup +} tranfectants lacked the ability to form colonies in semi-solid medium, and their growth rate was significantly decreased in 3% serum. In addition, the tumorigenicity of these transfectants was markedly decreased. Tumors that formed in nude mice were much smaller and had a longer latency period but were indistinguishable microscopically from those produced by parental cells. Slower growing tumors were RB{sup +}, as measured by nuclear staining of their RB protein and by a normal RB protein pattern on immunoblots. These findings support the concept that the RB gene acts as both a growth and tumor suppressor in bladder cancer cells.

  1. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines

    SciTech Connect

    Scheffner, M.; Muenger, K.; Byrne, J.C.; Howley, P.M. )

    1991-07-01

    Human cervical carcinoma cell lines that were either positive or negative for human papillomavirus (HPV) DNA sequences were analyzed for evidence of mutation of the p53 and retinoblastoma genes. Each of five HPV-positive cervical cancer cell lines expressed normal pRB and low levels of wild-type p53 proteins, which are presumed to be altered in function as a consequence of association with HPV E7 and E6 oncoproteins, respectively. In contrast, mutations were identified in the p53 and RB genes expressed in the C-33A and HT-3 cervical cancer cell lines, which lack HPV DNA sequences. Mutations in the p53 genes mapped to codon 273 and codon 245 in the C33-A and HT-3 cell lines, respectively, located in the highly conserved regions of p53, where mutations appear in a variety of human cancers. Mutations in RB occurred at splice junctions, resulting in in-frame deletions, affecting exons 13 and 20 in the HT-3 and C-33A cell lines, respectively. These mutations resulted in aberrant proteins that were not phosphorylated and were unable to complex with the adenovirus E1A oncoprotein. These results support the hypothesis that the inactivation of the normal functions of the tumor-suppressor proteins pRB and p53 are important steps in human cervical carcinogenesis, either by mutation or from complex formation with the HPV E6 and E7 oncoproteins.

  2. Retinoblastoma-associated protein 140 as a candidate for a novel etiological gene to hypertension.

    PubMed

    Crespo, Kimberley; Ménard, Annie; Deng, Alan Y

    2016-01-01

    Gene discovery in animal models may lead to the revelation of therapeutic targets for essential hypertension as well as mechanistic insights into blood pressure (BP) regulation. Our aim was to identify a disease-causing gene for a component of polygenic hypertension contrasting inbred hypertensive Dahl salt-sensitive (DSS) and normotensive Lewis rats. The chromosome segment harboring a quantitative trait locus (QTL), C16QTL, was first isolated from the rat genome via congenic strains. A candidate gene responsible for C16QTL causing a BP difference between DSS and Lewis rats was then identified using molecular analyses combining our independently-conducted total genome and gene-specific sequencings. The retinoblastoma-associated protein 140 (Rap140)/family with sequence similarity 208 member A (Fam208a) is the only candidate gene supported to be C16QTL among three genes in genome block 1 present in the C16QTL-residing interval. A mode of its actions could be to influence the expressions of genes that are downstream in a pathway potentially leading to BP regulation such as that encoding the solute carrier family 7 (cationic amino acid transporter, y+ system) member 12 (Slc7a12), which is specifically expressed in kidneys. Thus, Rap140/Fam208a probably encoding a transcription factor is the strongest candidate for a novel BP QTL that acts via a putative Rap140/Fam208a-Slc7a12-BP pathway. These data implicate a premier physiological role for Rap140/Fam208 beyond development and a first biological function for the Slc7a12 protein in any organism. PMID:27391979

  3. Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer.

    PubMed

    Parisi, T; Bronson, R T; Lees, J A

    2015-11-26

    The retinoblastoma gene (Rb) is mutated at significant frequency in various human epithelial tumors, including colorectal cancer, and is strongly associated with metastatic disease. However, sole inactivation of Rb in the mouse has so far failed to yield epithelial cancers. Here, we specifically inactivate Rb and/or p53 in the urogenital epithelium and the intestine. We find that the loss of both tumor suppressors is unable to yield tumors in the transitional epithelium lining the bladder, kidneys and ureters. Instead, these mice develop highly metastatic tumors of neuroendocrine, not epithelial, origin within the urogenital tract to give prostate cancer in the males and vaginal tumors in the females. Additionally, we discovered that the sole inactivation of Rb in the intestine was sufficient to induce formation of metastatic colorectal adenocarcinomas. These tumors closely mirror the human disease in regard to the age of onset, histological appearance, invasiveness and metastatic potential. Like most human colorectal carcinomas, our murine Rb-deficient tumors demonstrate genomic instability and they show activation of β-catenin. Deregulation of the Wnt/β-catenin pathway is specific to the intestinal tumors, as genomic instability but not activation of β-catenin was observed in the neuroendocrine tumors. To date, attempts to generate genetically engineered mouse models of colorectal cancer tumors have yielded mostly cancer of the small intestine, which rarely occurs in humans. Our system provides the opportunity to accurately model and study colorectal cancer in the mouse via a single gene mutation. PMID:25745996

  4. Genetics of Retinoblastoma.

    PubMed

    Mallipatna, Ashwin; Marino, Meghan; Singh, Arun D

    2016-01-01

    Retinoblastoma is a malignant retinal tumor that affects young children. Mutations in the RB1 gene cause retinoblastoma. Mutations in both RB1 alleles within the precursor retinal cell are essential, with one mutation that may be germline or somatic and the second one that is always somatic. Identification of the RB1 germline status of a patient allows differentiation between sporadic and heritable retinoblastoma variants. Application of this knowledge is crucial for assessing short-term (risk of additional tumors in the same eye and other eye) and long-term (risk of nonocular malignant tumors) prognosis and offering cost-effective surveillance strategies. Genetic testing and genetic counseling are therefore essential components of care for all children diagnosed with retinoblastoma. The American Joint Committee on Cancer has acknowledged the importance of detecting this heritable trait and has introduced the letter "H" to denote a heritable trait of all cancers, starting with retinoblastoma (in publication). In this article, we discuss the clinically relevant aspects of genetic testing and genetic counseling for a child with retinoblastoma. PMID:27488068

  5. Alterations in the RB1 gene in Pakistani patients with retinoblastoma using direct sequencing analysis

    PubMed Central

    Wasim, Muhammad; Afzal, Sibtain; Shahzad, Muhammad Saqib; Ramzan, Shaiqa; Awan, Ali Raza; Anjum, Aftab Ahmed; Ramzan, Khushnooda

    2015-01-01

    Purpose Retinoblastoma (RB) is a rare intraocular malignant tumor of the developing retina with an estimated incidence of 1:20,000 live births in children under the age of 5 years. In addition to the abnormal whitish appearance of the pupil or leukocoria, strabismus has also been reported as a clinical symptom of the disease. RB1 is the first cloned tumor suppressor gene, and mutational inactivation of this gene is responsible for the development of RB during early childhood. The purpose of this study was to identify mutational alterations in the RB1 gene in Pakistani patients with RB. Methods During this study, 70 clinically evaluated patients with RB were recruited from different regions of Pakistan. The cases included 23 sporadic bilateral (32.9%), 34 sporadic unilateral (48.6%), nine familial bilateral (12.8%), and four familial unilateral (5.7%) cases. Constitutional causative mutations in the RB1 gene were screened via direct sequencing of all RB1 exons and their flanking regions. Results In this report, genetic testing resulted in the identification of 18 mutations in 25 patients with RB including six novel RB1 mutations. Of the total mutations identified, 13 (72.22%) were found to be null mutations caused by nine nonsense, three deletions, and one insertion. Two (11.11%) missense, two (11.11%) splice site mutations, and one (5.55%) base substitution in the promoter region were also found. Moreover, ten intronic variants were identified, one of which is novel. Conclusions Molecular screening and identification of these mutations in Pakistani patients with RB provide the mutational variants of the RB1 gene in the Pakistani population. The detection of oncogenic mutations in patients with RB and genetically predisposed individuals is a major step in clinical management, prognosis, follow-up care, accurate genetic counseling, and presymptomatic diagnosis of RB. PMID:26396485

  6. [Molecular study of retinoblastoma in the Algerian population. Screening of Rb gene in constitutional and tumoral level].

    PubMed

    Boubekeur, Amina; Louhibi, Lotfi; Mahmoudi, Khadidja; Boudjema, Abdallah; Mehtar, Nadhira

    2012-02-01

    Inactivation of both alleles of the RB1 gene during normal retinal development initiates the formation of a retinoblastoma (RB) tumor. RB1 screening remains difficult, most of the alterations being unique and randomly distributed throughout the entire coding sequence. In this report, we present the results of a constitutionnal and tumoral RB1 analysis in Algerian population. The detection of RB1 gene deletion or mutation was performed by high performance liquid chromatography (HPLC) and sequence analyses in 21 patients. Germline abnormalities were found in 2/21 patients of sporadic unilateral retinoblastoma. The spectrum of germline and tumoral alterations included: three nonsense mutations; one mutation affecting splice site; one deletion and two polymorphisms. In general, for the 21 patients with no family history of the disease, we have identified mutations in germinal level in two of them showing that it is a transmissible form of retinoblastoma in these two cases known to be sporadic. A total of two mutations have not been previously reported. PMID:22265791

  7. Positive regulation of minichromosome maintenance gene expression, DNA replication, and cell transformation by a plant retinoblastoma gene

    PubMed Central

    Sabelli, Paolo A.; Hoerster, George; Lizarraga, Lucina E.; Brown, Sara W.; Gordon-Kamm, William J.; Larkins, Brian A.

    2009-01-01

    Retinoblastoma-related (RBR) genes inhibit the cell cycle primarily by repressing adenovirus E2 promoter binding factor (E2F) transcription factors, which drive the expression of numerous genes required for DNA synthesis and cell cycle progression. The RBR-E2F pathway is conserved in plants, but cereals such as maize are characterized by having a complex RBR gene family with at least 2 functionally distinct members, RBR1 and RBR3. Although RBR1 has a clear cell cycle inhibitory function, it is not known whether RBR3 has a positive or negative role. By uncoupling RBR3 from the negative regulation of RBR1 in cultured maize embryos through a combination of approaches, we demonstrate that RBR3 has a positive and critical role in the expression of E2F targets required for the initiation of DNA synthesis, DNA replication, and the efficiency with which transformed plants can be obtained. Titration of endogenous RBR3 activity through expression of a dominant-negative allele with a compromised pocket domain suggests that these RBR3 functions require an activity distinct from its pocket domain. Our results indicate a cell cycle pathway in maize, in which 2 RBR genes have specific and opposing functions. Thus, the paradigm that RBR genes are negative cell cycle regulators cannot be considered universal. PMID:19234120

  8. Breast cancer risk after radiotherapy for heritable and non-heritable retinoblastoma: a US–UK study

    PubMed Central

    Little, M P; Schaeffer, M L; Reulen, R C; Abramson, D H; Stovall, M; Weathers, R; de Vathaire, F; Diallo, I; Seddon, J M; Hawkins, M M; Tucker, M A; Kleinerman, R A

    2014-01-01

    Background: Retinoblastoma is a rare childhood eye cancer caused by germline or somatic mutations in the RB1 gene. Previous studies observed elevated breast cancer risk among retinoblastoma survivors. However, there has been no research on breast cancer risk in relation to radiation (primarily scatter radiation from the primary treatment) and genetic susceptibility of retinoblastoma survivors. Methods: Two groups of retinoblastoma survivors from the US and UK were selected, and breast cancer risk analysed using a case–control methodology, nesting within the respective cohorts, matching on heritability (that is to say, having bilateral retinoblastoma or being unilateral cases with at least one relative with retinoblastoma), and using exact statistical methods. There were a total of 31 cases and 77 controls. Results: Overall there was no significant variation of breast cancer risk with dose (P>0.5). However, there was a pronounced and significant (P=0.047) increase in the risk of breast cancer with increasing radiation dose for non-heritable retinoblastoma patients and a slight and borderline significant (P=0.072) decrease in risk of breast cancer with increasing radiation dose for heritable retinoblastoma patients, implying significant (P=0.024) heterogeneity in radiation risk between the heritable and non-heritable retinoblastoma groups; this was unaffected by the blindness status. There was no significant effect of any type of alkylating-agent chemotherapy on breast cancer risk (P>0.5). Conclusions: There is significant radiation-related risk of breast cancer for non-heritable retinoblastoma survivors but no excess risk for heritable retinoblastoma survivors, and no significant risk overall. However, these results are based on very small numbers of cases; therefore, they must be interpreted with caution. PMID:24755883

  9. Sensitive and Efficient Detection of RB1 Gene Mutations Enhances Care for Families with Retinoblastoma

    PubMed Central

    Richter, Suzanne; Vandezande, Kirk; Chen, Ning; Zhang, Katherine; Sutherland, Joanne; Anderson, Julie; Han, Liping; Panton, Rachel; Branco, Patricia; Gallie, Brenda

    2003-01-01

    Timely molecular diagnosis of RB1 mutations enables earlier treatment, lower risk, and better health outcomes for patients with retinoblastoma; empowers families to make informed family-planning decisions; and costs less than conventional surveillance. However, complexity has hindered clinical implementation of molecular diagnosis. The majority of RB1 mutations are unique and distributed throughout the RB1 gene, with no real hot spots. We devised a sensitive and efficient strategy to identify RB1 mutations that combines quantitative multiplex polymerase chain reaction (QM-PCR), double-exon sequencing, and promoter-targeted methylation-sensitive PCR. Optimization of test order by stochastic dynamic programming and the development of allele-specific PCR for four recurrent point mutations decreased the estimated turnaround time to <3 wk and decreased direct costs by one-third. The multistep method reported here detected 89% (199/224) of mutations in bilaterally affected probands and both mutant alleles in 84% (112/134) of tumors from unilaterally affected probands. For 23 of 27 exons and the promoter region, QM-PCR was a highly accurate measure of deletions and insertions (accuracy 95%). By revealing those family members who did not carry the mutation found in the related proband, molecular analysis enabled 97 at-risk children from 20 representative families to avoid 313 surveillance examinations under anesthetic and 852 clinic visits. The average savings in direct costs from clinical examinations avoided by children in these families substantially exceeded the cost of molecular testing. Moreover, health care savings continue to accrue, as children in succeeding generations avoid unnecessary repeated anaesthetics and examinations. PMID:12541220

  10. Tissue transglutaminase-dependent posttranslational modification of the retinoblastoma gene product in promonocytic cells undergoing apoptosis.

    PubMed Central

    Oliverio, S; Amendola, A; Di Sano, F; Farrace, M G; Fesus, L; Nemes, Z; Piredda, L; Spinedi, A; Piacentini, M

    1997-01-01

    The retinoblastoma gene product (pRB) plays an important role in controlling both cell release from the G1 phase and apoptosis. We show here that in the early phases of apoptosis, pRB is posttranslationally modified by a tissue transglutaminase (tTG)-catalyzed reaction. In fact, by employing a novel haptenized lysis synthetic substrate which allows the isolation of glutaminyl-tTG substrates in vivo, we identified pRB as a potential tTG substrate in U937 cells undergoing apoptosis. In keeping with this finding, we showed that apoptosis of U937 cells is characterized by the rapid disappearance of the 105,000- to 110,000-molecular-weight pRB forms concomitantly with the appearance of a smear of immunoreactive products with a molecular weight of greater than 250,000. The shift in pRB molecular weight was reproduced by adding exogenous purified tTG to extracts obtained from viable U937 cells and was prevented by dansylcadaverine, a potent enzyme inhibitor. The effect of the pRB posttranslational modification during apoptosis was investigated by determining the E2F-1 levels and by isolating and characterizing pRB-null clones from U937 cells. Notably, the lack of pRB in these U937-derived clones renders these p53-null cells highly resistant to apoptosis induced by serum withdrawal, calphostin C, and ceramide. Taken together, these data suggest that tTG, acting on the pRB protein, might play an important role in the cell progression through the death program. PMID:9315663

  11. Integrated Analysis of Dysregulated miRNA-gene Expression in HMGA2-silenced Retinoblastoma Cells

    PubMed Central

    Venkatesan, Nalini; Deepa, PR; Vasudevan, Madavan; Khetan, Vikas; Reddy, Ashwin M; Krishnakumar, Subramanian

    2014-01-01

    Retinoblastoma (RB) is a primary childhood eye cancer. HMGA2 shows promise as a molecule for targeted therapy. The involvement of miRNAs in genome-level molecular dys-regulation in HMGA2-silenced RB cells is poorly understood. Through miRNA expression microarray profiling, and an integrated array analysis of the HMGA2-silenced RB cells, the dysregulated miRNAs and the miRNA-target relationships were modelled. Loop network analysis revealed a regulatory association between the transcription factor (SOX5) and the deregulated miRNAs (miR-29a, miR-9*, miR-9-3). Silencing of HMGA2 deregulated the vital oncomirs (miR-7, miR-331, miR-26a, miR-221, miR-17~92 and miR-106b∼25) in RB cells. From this list, the role of the miR-106b∼25 cluster was examined further for its expression in primary RB tumor tissues (n = 20). The regulatory targets of miR-106b∼25 cluster namely p21 (cyclin-dependent kinase inhibitor) and BIM (pro-apoptotic gene) were elevated, and apoptotic cell death was observed, in RB tumor cells treated with the specific antagomirs of the miR-106b∼25 cluster. Thus, suppression of miR-106b∼25 cluster controls RB tumor growth. Taken together, HMGA2 mediated anti-tumor effect present in RB is, in part, mediated through the miR-106b∼25 cluster. PMID:25232279

  12. Retinoblastoma: An update.

    PubMed

    Delhiwala, Kushal S; Vadakkal, Indu P; Mulay, Kaustubh; Khetan, Vikas; Wick, Mark R

    2016-05-01

    Retinoblastoma is the most common ocular malignancy in children, and is initiated by mutation of the RB1 gene. The tumor may be unilateral or bilateral and can be inherited. Overall survival, eye salvage, and preservation of vision are largely dependent on the stage of disease at presentation. Despite a recently enhanced understanding of the etiology of retinoblastoma, the mortality associated with it remains high worldwide. This may relate to a continuing lack of awareness of the lesion by laypersons, and unavailability of modern treatment facilities. Adverse outcomes are also caused by the occurrence of secondary malignancies after treatment of retinoblastoma in childhood. Early diagnosis, multidisciplinary treatment, and genetic counseling are all priorities in the management of this tumor. PMID:26969537

  13. Transcriptional regulatory program in wild-type and retinoblastoma gene-deficient mouse embryonic fibroblasts during adipocyte differentiation

    PubMed Central

    2011-01-01

    Background Although many molecular regulators of adipogenesis have been identified a comprehensive catalogue of components is still missing. Recent studies showed that the retinoblastoma protein (pRb) was expressed in the cell cycle and late cellular differentiation phase during adipogenesis. To investigate this dual role of pRb in the early and late stages of adipogenesis we used microarrays to perform a comprehensive systems-level analysis of the common transcriptional program of the classic 3T3-L1 preadipocyte cell line, wild-type mouse embryonic fibroblasts (MEFs), and retinoblastoma gene-deficient MEFs (Rb-/- MEFs). Findings Comparative analysis of the expression profiles of 3T3-L1 cells and wild-type MEFs revealed genes involved specifically in early regulation of the adipocyte differentiation as well as secreted factors and signaling molecules regulating the later phase of differentiation. In an attempt to identify transcription factors regulating adipogenesis, bioinformatics analysis of the promoters of coordinately and highly expressed genes was performed. We were able to identify a number of high-confidence target genes for follow-up experimental studies. Additionally, combination of experimental data and computational analyses pinpointed a feedback-loop between Pparg and Foxo1. To analyze the effects of the retinoblastoma protein at the transcriptional level we chose a perturbated system (Rb-/- MEFs) for comparison to the transcriptional program of wild-type MEFs. Gene ontology analysis of 64 deregulated genes showed that the Rb-/- MEF model exhibits a brown(-like) adipocyte phenotype. Additionally, the analysis results indicate a different or additional role for pRb family member involvement in the lineage commitment. Conclusion In this study a number of commonly modulated genes during adipogenesis in 3T3-L1 cells and MEFs, potential transcriptional regulation mechanisms, and differentially regulated targets during adipocyte differentiation of Rb

  14. Chromatin remodelers HELLS and UHRF1 mediate the epigenetic deregulation of genes that drive retinoblastoma tumor progression

    PubMed Central

    Benavente, Claudia A.; Finkelstein, David; Johnson, Dianna A.; Marine, Jean-Christophe; Ashery-Padan, Ruth; Dyer, Michael A.

    2014-01-01

    The retinoblastoma (Rb) family of proteins are key regulators of cell cycle exit during development and their deregulation is associated with cancer. Rb is critical for normal retinal development and germline mutations lead to retinoblastoma making retinae an attractive system to study Rb family signaling. Rb coordinates proliferation and differentiation through the E2f family of transcription factors, a critical interaction for the role of Rb in retinal development and tumorigenesis. However, whether the roles of the different E2fs are interchangeable in controlling development and tumorigenesis in the retina or if they have selective functions remains unknown. In this study, we found that E2f family members play distinct roles in the development and tumorigenesis. In Rb;p107-deficient retinae, E2f1 and E2f3 inactivation rescued tumor formation but only E2f1 rescued the retinal development phenotype. This allowed the identification of key target genes for Rb/E2f family signaling contributing to tumorigenesis and those contributing to developmental defects. We found that Sox4 and Sox11 genes contribute to the developmental phenotype and Hells and Uhrf1 contribute to tumorigenesis. Using orthotopic human xenografts, we validated that upregulation of HELLS and UHRF1 is essential for the tumor phenotype. Also, these epigenetic regulators are important for the regulation of SYK. PMID:25338120

  15. Expression of genes involved in heme biosynthesis in the human retinoblastoma cell lines WERI-Rb-1 and Y79: implications for photodynamic therapy.

    PubMed

    Ruiz-Galindo, E; Arenas-Huertero, F; Ramón-Gallegos, E

    2007-06-01

    Photodynamic therapy (PDT), using protoporphyrin IX (PpIX) as a natural photosensitizer, may be a viable alternative therapy of retinoblastoma. In order to evaluate the potential value of PpIX, the expression profiles of genes involved in heme biosynthesis in human retinoblastoma WERI-Rb-1 and Y79 cells were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). Expression levels were highest in protoporphyrinogen oxidase (PPOX), uroporphyrinogen synthase and aminolevulinic acid synthase. Ferrochelatase expression showed a reduction compared to PPOX. PpIX levels were 15- and 18-fold higher in WERI-Rb-1 and Y79 cells, respectively, following induction by delta-aminolevulinic acid. PDT may thus be a promising treatment in vitro, at least in these two retinoblastoma cell lines. PMID:17725098

  16. Suppression of proliferative cholangitis in a rat model with direct adenovirus-mediated retinoblastoma gene transfer to the biliary tract.

    PubMed

    Terao, R; Honda, K; Hatano, E; Uehara, T; Yamamoto, M; Yamaoka, Y

    1998-09-01

    Proliferative cholangitis (PC) associated with hepatolithiasis develops the stricture of main bile ducts, and is the main cause of residual and/or recurrent stones after repeated treatments for hepatolithiasis. The aim of this study was to inhibit PC using the cytostatic gene therapy with direct adenovirus-mediated retinoblastoma (Rb) gene transfer to the biliary tract. PC was induced by introducing a fine nylon thread into the bile duct in a rat model. The adenovirus vector encoding a nonphosphorylatable, constitutively active form of retinoblastoma gene product (AdRb) was administered directly into the biliary tract. The adenovirus vector encoding beta-galactosidase (AdlacZ) was also given as a control. The bile duct wall thickness and 5'-bromodeoxyuridine (BrdU) labeling index were compared among uninfected, AdlacZ-infected, and AdRb-infected PC rats. The Rb expression in the bile duct was detected using reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemical study. AdRb-infected bile ducts showed inhibition of the epithelial and fibrous tissue proliferation and the peribiliary gland hyperplasia, resulting in a significant reduction of wall thickness compared with uninfected and AdlacZ-infected ones. The BrdU labeling index was 4.87% +/- 3.06% in the AdRb-infected bile ducts, while those of uninfected and AdlacZ-infected ones were 15.48% +/- 4.61% and 11.72% +/- 1.23%, respectively (P < .05). In conclusion, our cytostatic gene therapy approach using direct Rb gene transfer into the biliary tract suppressed PC in a rat model and may offer an effective therapeutic option for reducing recurrences following treatments against hepatolithiasis. PMID:9731547

  17. Nasopharyngeal carcinomas frequently lack the p16/MTS1 tumor suppressor protein but consistently express the retinoblastoma gene product.

    PubMed Central

    Gulley, M. L.; Nicholls, J. M.; Schneider, B. G.; Amin, M. B.; Ro, J. Y.; Geradts, J.

    1998-01-01

    The p16/MTS1 gene is altered by deletion, mutation, or hypermethylation in a wide variety of human cancers. As a result of deficient p16 protein, these cancers lack a critical mechanism for halting G1/S cell cycle progression. In the current study, 59 cases of nasopharyngeal carcinoma were evaluated for expression of the p16 tumor suppressor protein by immunohistochemical analysis of paraffin-embedded tissue. There was no detectable p16 in 38/59 cases (64%), which implies a very high rate of p16 inactivation in this type of cancer. On the other hand, the retinoblastoma gene product, which also regulates the G1 to S phase transition of the cell cycle, was consistently expressed in nasopharyngeal carcinomas by immunohistochemical analysis. These results implicate p16 inactivation but not Rb alteration in the stepwise progression of nasopharyngeal carcinogenesis. Images Figure 1 Figure 2 PMID:9546345

  18. Defective human retinoblastoma protein identified by lack of interaction with the E1A oncoprotein.

    PubMed

    Paggi, M G; Martelli, F; Fanciulli, M; Felsani, A; Sciacchitano, S; Varmi, M; Bruno, T; Carapella, C M; Floridi, A

    1994-02-15

    Inactivating mutations of the retinoblastoma susceptibility gene (Rb) are involved in the pathogenesis of hereditary and sporadic retinoblastoma. Alterations in the Rb gene have also been found in several other human tumors occurring with epidemiological incidence higher than that of retinoblastoma. Four human malignant glioma cell lines were examined for abnormalities in the retinoblastoma gene product (pRb), using a procedure based on the interaction of pRb with an in vitro-translated adenovirus E1A oncoprotein. In the CRS-A2 cell line, derived from a glioblastoma multiforme, pRb did not bind with the in vitro-translated E1A protein. Restriction analysis of the CRS-A2 Rb gene and Rb mRNA expression provided patterns that could not be distinguished from the other glioma cell lines. Further investigation revealed the presence of a truncated pRb in the CRS-A2 cell line, due to a nucleotide insertion in the coding sequence at position 2550. In addition, this truncated Rb protein was undetectable in phosphorylated form. The binding assay with the in vitro-translated E1A was also used to study other cell lines with known mutations in the Rb gene. This method, which evaluates the interaction between in vitro-translated E1A and the pRb, is proposed as a rapid screening for detecting functional alterations in the retinoblastoma protein. PMID:8313367

  19. What is Retinoblastoma?

    MedlinePlus

    ... are the key statistics about retinoblastoma? What is retinoblastoma? Cancer starts when cells begin to grow out ... visual cortex , allowing us to see. How does retinoblastoma develop? The eyes develop very early as babies ...

  20. Effect of restoration of retinoblastoma gene function on the radiosensitivity of cells of human tumor cell lines

    SciTech Connect

    Tsang, N.M.; Little, J.B.

    1994-11-01

    To assess the role of expression of the retinoblastoma (RB) gene on the sensitivity of cells to the cytotoxic effects of ionizing radiation, we transfected a normal RB gene into cells of RB{sup +} and RB{sup {minus}} osteosarcoma cell lines and an RB{sup {minus}} prostate carcinoma line and studied the radiosensitivity of the cells before and after transfection. Four transfected clones were isolated from the two RB{sup {minus}} tumor cell lines that expressed the product of the transfected normal RB gene and contained no mutations in the pocket and C-terminal regions by sequencing. A small increase in radiosensitivity was observed in cell lines transfected with the pDOL plasmid vector alone, containing the neo gene and a long terminal repeat (LTR) promoter. However, no significant change in radiosensitivity occurred in transfected cells expressing the normal RB gene compared to controls transfected with an RB{sup {minus}} plasmid. Based on this and other information, we conclude that RB gene function is not involved in the response of these human tumor cells to the cytotoxic effects of radiation. 38 refs., 5 figs., 4 tabs.

  1. Modulation of retinoblastoma gene in normal adult hematopoiesis: peak expression and functional role in advanced erythroid differentiation.

    PubMed Central

    Condorelli, G L; Testa, U; Valtieri, M; Vitelli, L; De Luca, A; Barberi, T; Montesoro, E; Campisi, S; Giordano, A; Peschle, C

    1995-01-01

    The retinoblastoma (RB) gene specifies a nuclear phosphoprotein (pRb 105), which is a prototype tumor suppressor inactivated in a variety of human tumors. Recent studies suggest that RB is also involved in embryonic development of murine central nervous and hematopoietic systems. We have investigated RB expression and function in human adult hematopoiesis--i.e., in liquid suspension culture of purified quiescent hematopoietic progenitor cells (HPCs) induced by growth factor stimulus to proliferation and unilinage differentiation/maturation through the erythroid or granulocytic lineage. In the initial HPC differentiation stages, the RB gene is gradually induced at the mRNA and protein level in both erythroid and granulopoietic cultures. In late HPC differentiation and then precursor maturation, RB gene expression is sustained in the erythroid lineage, whereas it is sharply downmodulated in the granulocytic series. Functional studies were performed by treatment of HPC differentiation culture with phosphorothioate antisense oligomer targeting Rb mRNA; coherent with the expression pattern, oligomer treatment of late HPCs causes a dose-dependent and selective inhibition of erythroid colony formation. These observations suggest that the RB gene plays an erythroid- and stage-specific functional role in normal adult hematopoiesis, particularly at the level of late erythroid HPCs. Images Fig. 2 Fig. 3 Fig. 4 PMID:7761404

  2. The genomic landscape of retinoblastoma: a review

    PubMed Central

    Thériault, Brigitte L; Dimaras, Helen; Gallie, Brenda L; Corson, Timothy W

    2013-01-01

    Retinoblastoma is a paediatric ocular tumour that continues to reveal much about the genetic basis of cancer development. Study of genomic aberrations in retinoblastoma tumours has exposed important mechanisms of cancer development, and identified oncogenes and tumour suppressors that offer potential points of therapeutic intervention. The recent development of next-generation genomic technologies has allowed further refinement of the genomic landscape of retinoblastoma at high resolution. In a relatively short period of time, a wealth of genetic and epigenetic data has emerged on a small number of tumour samples. These data highlight the inherent molecular complexity of this cancer, despite the fact that most retinoblastomas are initiated by the inactivation of a single tumour suppressor gene. Here, we review the current understanding of the genomic, genetic and epigenetic changes in retinoblastoma, highlighting recent genome-wide analyses that have identified exciting candidate genes worthy of further validation as potential prognostic and therapeutic targets. PMID:24433356

  3. Insights from mouse models into human retinoblastoma

    PubMed Central

    MacPherson, David

    2008-01-01

    Novel murine models of retinoblastoma based on Rb gene deletion in concert with inactivation of Rb family members have recently been developed. These new Rb knockout models of retinoblastoma provide excellent tools for pre-clinical studies and for the exploration of the genetics of tumorigenesis driven by RB inactivation. This review focuses on the developmental consequences of Rb deletion in the retina and the genetic interactions between Rb and the two other members of the pocket protein family, p107 (Rbl1) and p130 (Rbl2). There is increasing appreciation that homozygous RB mutations are insufficient for human retinoblastoma. Identifying and understanding secondary gene alterations that cooperate with RB inactivation in tumorigenesis may be facilitated by mouse models. Recent investigation of the p53 pathway in retinoblastoma, and evidence of spatial topology to early murine retinoblastoma are also discussed in this review. PMID:18489754

  4. Amino-terminal domains of c-myc and N-myc proteins mediate binding to the retinoblastoma gene product

    NASA Astrophysics Data System (ADS)

    Rustgi, Anil K.; Dyson, Nicholas; Bernards, Rene

    1991-08-01

    THE proteins encoded by the myc gene family are involved in the control of cell proliferation and differentiation, and aberrant expression of myc proteins has been implicated in the genesis of a variety of neoplasms1. In the carboxyl terminus, myc proteins have two domains that encode a basic domain/helix-loop-helix and a leucine zipper motif, respectively. These motifs are involved both in DNA binding and in protein dimerization2-5. In addition, myc protein family members share several regions of highly conserved amino acids in their amino termini that are essential for transformation6,7. We report here that an N-terminal domain present in both the c-myc and N-myc proteins mediates binding to the retinoblastoma gene product, pRb. We show that the human papilloma virus E7 protein competes with c-myc for binding to pRb, indicating that these proteins share overlapping binding sites on pRb. Furthermore, a mutant Rb protein from a human tumour cell line that carried a 35-amino-acid deletion in its C terminus failed to bind to c-myc. Our results suggest that c-myc and pRb cooperate through direct binding to control cell proliferation.

  5. Evaluation of SLE Susceptibility Genes in Malaysians

    PubMed Central

    Molineros, Julio E.; Chua, Kek Heng; Sun, Celi; Lian, Lay Hoong; Motghare, Prasenjeet; Kim-Howard, Xana; Nath, Swapan K.

    2014-01-01

    Systemic Lupus Erythematosus (SLE) is a clinically heterogeneous autoimmune disease with strong genetic and environmental components. Our objective was to replicate 25 recently identified SLE susceptibility genes in two distinct populations (Chinese (CH) and Malays (MA)) from Malaysia. We genotyped 347 SLE cases and 356 controls (CH and MA) using the ImmunoChip array and performed an admixture corrected case-control association analysis. Associated genes were grouped into five immune-related pathways. While CH were largely homogenous, MA had three ancestry components (average 82.3% Asian, 14.5% European, and 3.2% African). Ancestry proportions were significantly different between cases and controls in MA. We identified 22 genes with at least one associated SNP (P < 0.05). The strongest signal was at HLA-DRA (PMeta = 9.96 × 10−9; PCH = 6.57 × 10−8, PMA = 6.73 × 10−3); the strongest non-HLA signal occurred at STAT4 (PMeta = 1.67 × 10−7; PCH = 2.88 × 10−6, PMA = 2.99 × 10−3). Most of these genes were associated with B- and T-cell function and signaling pathways. Our exploratory study using high-density fine-mapping suggests that most of the established SLE genes are also associated in the major ethnicities of Malaysia. However, these novel SNPs showed stronger association in these Asian populations than with the SNPs reported in previous studies. PMID:24696779

  6. RECQL: a new breast cancer susceptibility gene

    PubMed Central

    Banerjee, Taraswi; Brosh, Robert M

    2015-01-01

    Identifying and characterizing novel genetic risk factors for BRCA1/2 negative breast cancers is highly relevant for early diagnosis and development of a management plan. Mutations in a number of DNA repair genes have been associated with genomic instability and development of breast and various other cancers. Whole exome sequencing efforts by 2 groups have led to the discovery in distinct populations of multiple breast cancer susceptibility mutations in RECQL, a gene that encodes a DNA helicase involved in homologous recombination repair and response to replication stress. RECQL pathogenic mutations were identified that truncated or disrupted the RECQL protein or introduced missense mutations in its helicase domain. RECQL mutations may serve as a useful biomarker for breast cancer. Targeting RECQL associated tumors with novel DNA repair inhibitors may provide a new strategy for anti-cancer therapy. PMID:26125302

  7. Melanoma susceptibility genes and risk assessment.

    PubMed

    Marzuka-Alcalá, Alexander; Gabree, Michele Jacobs; Tsao, Hensin

    2014-01-01

    Familial melanoma accounts for approximately a tenth of all melanoma cases. The most commonly known melanoma susceptibility gene is the highly penetrant CDKN2A (p16INK4a) locus, which is transmitted in an autosomal dominant fashion and accounts for approximately 20-50 % of familial melanoma cases. Mutated p16INK4a shows impaired capacity to inhibit the cyclin D1-CDK4 complex, allowing for unchecked cell cycle progression. Mutations in the second protein coded by CDKN2A, p14ARF, are much less common and result in proteasomal degradation of p53 with subsequent accumulation of DNA damage as the cell progresses through the cell cycle without a functional p53-mediated DNA damage response. Mutations in CDK4 that impair the inhibitory interaction with p16INK4a also increase melanoma risk but these mutations are extremely rare. Genes of the melanin biosynthetic pathway, including MC1R and MITF, have also been implicated in melanomagenesis. MC1R variants were traditionally thought to increase risk for melanoma secondary to intensified UV-mediated DNA damage in the setting of absent photoprotective eumelanin. Accumulation of pheomelanin, which appears to have a carcinogenic effect regardless of UV exposure, may be a more likely mechanism. Impaired SUMOylation of the E318K variant of MITF results in increased transcription of genes that confer melanocytes with a pro-malignant phenotype. Mutations in the tumor suppressor BAP1 enhance the metastatic potential of uveal melanoma and predispose to cutaneous/ocular melanoma, atypical melanocytic tumors, and other internal malignancies (COMMON syndrome). Genome-wide association studies have identified numerous low-risk alleles. Although several melanoma susceptibility genes have been identified, risk assessment tools have been developed only for the most common gene implicated with hereditary melanoma, CDKN2A. MelaPRO, a validated model that relies on Mendelian inheritance and Bayesian probability theories, estimates carrier

  8. Computational and in vitro Investigation of miRNA-Gene Regulations in Retinoblastoma Pathogenesis: miRNA Mimics Strategy

    PubMed Central

    Venkatesan, Nalini; Deepa, Perinkulam Ravi; Khetan, Vikas; Krishnakumar, Subramanian

    2015-01-01

    PURPOSE Retinoblastoma (RB), a primary pediatric intraocular tumor, arises from primitive retinal layers. Several novel molecular strategies are being developed for the clinical management of RB. miRNAs are known to regulate cancer-relevant biological processes. Here, the role of selected miRNAs, namely, miR-532-5p and miR-486-3p, has been analyzed for potential therapeutic targeting in RB. METHODS A comprehensive bioinformatic analysis was performed to predict the posttranscriptional regulators (miRNAs) of the select panel of genes [Group 1: oncogenes (HMGA2, MYCN, SYK, FASN); Group 2: cancer stem cell markers (TACSTD, ABCG2, CD133, CD44, CD24) and Group 3: cell cycle regulatory proteins (p53, MDM2)] using Microcosm, DIANALAB, miRBase v 18, and REFSEQ database, and RNA hybrid. The expressions of five miRNAs, namely, miR-146b-5p, miR-532-5p, miR-142-5p, miR-328, and miR-486-3p, were analyzed by qRT–PCR on primary RB tumor samples (n = 30; including 17 invasive RB tumors and 13 noninvasive RB tumors). Detailed complementary alignment between 5’ seed sequence of differentially expressed miRNAs and the sequence of target genes was determined. Based on minimum energy level and piCTAR scores, the gene targets were selected. Functional roles of these miRNA clusters were studied by using mimics in cultured RB (Y79, Weri Rb-1) cells in vitro. The gene targets (SYK and FASN) of the studied miRNAs were confirmed by qRT-PCR and western blot analysis. Cell proliferation and apoptotic studies were performed. RESULTS Nearly 1948 miRNAs were identified in the in silico analysis, From this list, only 9 upregulated miRNAs (miR-146b-5p, miR-305, miR-663b, miR-299, miR-532-5p, miR-892b, miR-501, miR-142-5p, and miR-513b) and 10 downregulated miRNAs (miR-1254, miR-328, miR-133a, miR-1287, miR-1299, miR-375, miR-486-3p, miR-720, miR-98, and miR-122*) were found to be common with the RB serum miRNA profile. Downregulation of five miRNAs (miR-146b-5p, miR-532-5p, miR-142-5p, miR-328

  9. Cyclin D1 is dispensable for G1 control in retinoblastoma gene-deficient cells independently of cdk4 activity.

    PubMed Central

    Lukas, J; Bartkova, J; Rohde, M; Strauss, M; Bartek, J

    1995-01-01

    To elucidate the regulator-versus-target relationship in the cyclin D1/cdk4/retinoblastoma protein (pRB) pathway, we examined fibroblasts from RB-1 gene-deficient and RB-1 wild-type littermate mouse embryos (ME) and in human tumor cell lines that differed in the status of the RB-1 gene. The RB+/+ and RB-/- ME fibroblasts expressed similar protein levels of D-type cyclins, cdk4, and cdk6, showed analogous spectra and abundance of cellular proteins complexed with cdk4 and/or cyclins D1 and D2, and exhibited comparable associated kinase activities. Of the two human cell lines established from the same sarcoma biopsy, the RB-positive SKUT1B cells contained cdk4 that was mainly associated with D-type cyclins, contrary to a predominant cdk4-p16INK4 complex in the RB-deficient SKUT1A cells. Antibody-mediated neutralization of cyclin D1 arrested the RB-positive ME and SKUT1B cells in G1, whereas this cyclin appeared dispensable in the RB-deficient ME and SKUT1A cells. Lack of requirement for cyclin D1 therefore correlated with absence of functional pRB, regardless of whether active cyclin D1/cdk4 holoenzyme was present in the cells under study. Consistent with a potential role of cyclin D/cdk4 in phosphorylation of pRB, monoclonal anti-cyclin D1 antibodies supporting the associated kinase activity failed to significantly affect proliferation of RB-positive cells, whereas the antibody DCS-6, unable to coprecipitate cdk4, efficiently inhibited G1 progression and prevented pRB phosphorylation in vivo. These data provide evidence for an upstream control function of cyclin D1/cdk4, and a downstream role for pRB, in the order of events regulating transition through late G1 phase of the mammalian cell division cycle. PMID:7739541

  10. Mapping susceptibility gene in systemic lupus erythematosus.

    PubMed

    Scofield, R Hal; Kaufman, Kenneth M

    2012-01-01

    Genome-wide association studies have identified many dozen genetic intervals that harbor single-nucleotide polymorphisms (SNPs) showing statistical association with systemic lupus erythematosus. Despite the wealth of data produced, there are limitations of these studies. The causal alleles at a given locus are not identified; only SNP is strong linkage disequilibrium with the putative causative alleles. In order to address identification of the causative SNPs for lupus susceptibility genes, we have initiated a candidate gene study for which more than 40 investigators have contributed patient and control samples. In addition, these investigators have designated SNPs to be placed on a custom array. In this way fine mapping of genetic association findings can occur in order to identify causal alleles. These efforts have thus far benefitted greatly from comparisons of different ethnicities. Work on about ten previously identified associations has been published using this resource. Genome-wide association studies cannot identify rare SNPs or mutations, which may impart greater relative risks than common variants. Much of the genetics of lupus may be from rare variants or mutations. In order to approach this aspect of lupus genetics, next-generation sequencing has begun in which all exons will be sequenced in controls and patients. This effort can also be used to identify causal alleles from association intervals not yet otherwise identified. PMID:22933063

  11. Human lung and bladder carcinoma tumors as compared to their adjacent normal tissue have elevated AP-1 activity associated with the retinoblastoma gene promoter.

    PubMed

    Linardopoulos, S; Papadakis, E; Delakas, D; Theodosiou, V; Cranidis, A; Spandidos, D A

    1993-01-01

    Examination of the nucleotide sequence of the retinoblastoma (Rb) promoter revealed the presence of a DNA region highly homologous to the recognition site for the cellular transcription factor AP-1. A pair of complementary oligonucleotides containing the AP-1 site was synthesized and used in gel retardation assays to determine the role of the AP-1 protein in the regulation of the Rb gene expression. Using nuclear extracts from Hela cells as well as from lung and bladder tumors, we found specific binding of the AP-1 protein to this oligonucleotide. This binding is elevated in Hela cells, in 10/13 lung and 3/8 bladder tumors as compared to adjacent normal tissue. These results suggest that AP-1 could be implicated in Rb gene transcriptional regulation through its interaction with the AP-1 binding site of the Rb gene promoter. PMID:8476221

  12. 5-Aza-2′'-deoxycytidine inhibits retinoblastoma cell by reactivating epigenetically silenced RASSF1A gene

    PubMed Central

    Liu, Ru; Zhang, Xiao-Huan; Zhang, Kun; Li, Wei; Wang, Wen-Jun; Luo, Di-Xian; Gao, Ling

    2014-01-01

    AIM To investigate the effect of 5-Aza-2′-deoxycytidine (5-Aza-CdR), a DNA methyltransferase (DNMT) inhibitor, on the growth and survival of the Chinese retinoblastoma (RB) cell line HXO-RB44. METHODS The DNA methylation status of the Ras association domain family (RASSF1A) promoter in the presence of 5-Aza-CdR at different concentrations was analyzed by methylation-specific polymerase chain reaction (MSP). RASSF1A mRNA and protein levels were measured by semiquantitative RT-PCR and immunohistochemistry staining, respectively, when cells were treated with 5.0µmol/L of 5-Aza-CdR. The effect of 5.0µmol/L 5-Aza-CdR on the proliferation and viability of HXO-RB44 cells was examined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. RESULTS 5-Aza-CdR efficiently induced cell cycle arrest at G0/G1 and apoptotic death in HXO-RB44 cells. MSP analysis showed that unmethylated RASSF1A DNA increased and methylated RASSF1A decreased in a dose-dependent manner in a range of 0.5-5.0µmol/L 5-Aza-CdR. Accordingly, RASSF1A expression was reactivated at both mRNA and protein levels. Incubation time of 5-Aza-CdR treatment also functioned as a factor for the demethylation status of RASSF1A promoter DNA, with a plateau on day four. 5-Aza-CdR at 5.0µmol/L completely demethylated the RASSF1A promoter in HXO-RB44 cells on day four, and as a result, RASSF1A expression increased significantly from day 4 to day 7. CONCLUSION 5-Aza-CdR inhibits the growth of the HXO-RB44 RB cell line and induces apoptosis by demethylating the RASSF1A gene. PMID:24634863

  13. Gene-gene interactions in breast cancer susceptibility.

    PubMed

    Turnbull, Clare; Seal, Sheila; Renwick, Anthony; Warren-Perry, Margaret; Hughes, Deborah; Elliott, Anna; Pernet, David; Peock, Susan; Adlard, Julian W; Barwell, Julian; Berg, Jonathan; Brady, Angela F; Brewer, Carole; Brice, Glen; Chapman, Cyril; Cook, Jackie; Davidson, Rosemarie; Donaldson, Alan; Douglas, Fiona; Greenhalgh, Lynn; Henderson, Alex; Izatt, Louise; Kumar, Ajith; Lalloo, Fiona; Miedzybrodzka, Zosia; Morrison, Patrick J; Paterson, Joan; Porteous, Mary; Rogers, Mark T; Shanley, Susan; Walker, Lisa; Ahmed, Munaza; Eccles, Diana; Evans, D Gareth; Donnelly, Peter; Easton, Douglas F; Stratton, Michael R; Rahman, Nazneen

    2012-02-15

    There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation. PMID:22072393

  14. A screen for new trithorax group genes identified little imaginal discs, the Drosophila melanogaster homologue of human retinoblastoma binding protein 2.

    PubMed Central

    Gildea, J J; Lopez, R; Shearn, A

    2000-01-01

    The proteins encoded by two groups of conserved genes, the Polycomb and trithorax groups, have been proposed to maintain, at the level of chromatin structure, the expression pattern of homeotic genes during Drosophila development. To identify new members of the trithorax group, we screened a collection of deficiencies for intergenic noncomplementation with a mutation in ash1, a trithorax group gene. Five of the noncomplementing deletions uncover genes previously classified as members of the Polycomb group. This evidence suggests that there are actually three groups of genes that maintain the expression pattern of homeotic genes during Drosophila development. The products of the third group appear to be required to maintain chromatin in both transcriptionally inactive and active states. Six of the noncomplementing deficiencies uncover previously unidentified trithorax group genes. One of these deficiencies removes 25D2-3 to 26B2-5. Within this region, there are two, allelic, lethal P-insertion mutations that identify one of these new trithorax group genes. The gene has been called little imaginal discs based on the phenotype of mutant larvae. The protein encoded by the little imaginal discs gene is the Drosophila homologue of human retinoblastoma binding protein 2. PMID:11014813

  15. cDNA sequence and chromosomal localization of a novel human protein, RBQ-1 (RBBP6), that binds to the retinoblastoma gene product

    SciTech Connect

    Sakai, Yoshihisa; Saijo, Masafumi; Taya, Yoichi

    1995-11-01

    We have previously isolated cDNA of a novel protein (RBQ-1, HGMW-approved symbol RBBP6) that binds to the retinoblastoma gene product (pRB). Total nucleotide sequence of the cDNA has now been determined. It encoded a protein of 140 kDa that consists of 948 amino acids and contains multiple repeated sequences like SRS, YRE, and VPPP. The region used for pRB binding was identified on a small region near the C-terminus. We have mapped this gene to 16p11.2-p12 using polymerase chain reaction analysis on a human-hamster hybrid cell panel and chromosomal fluorescence in situ hybridization. 24 refs., 3 figs.

  16. Molecular Karyotype of Sporadic Unilateral Retinoblastoma Tumors

    PubMed Central

    Ganguly, Arupa; Nichols, Kim E.; Grant, Gregory; Rappaport, Eric; Shields, Carol

    2009-01-01

    Background Retinoblastoma (RB) is a childhood ocular malignancy associated with mutations in RB1, a tumor susceptibility gene. Inactivation of both copies of the RB1 gene in a retinal cell is followed by the sequential acquisition of additional genetic changes that define the course to tumor formation. Methods To identify the genetic events that cooperate with loss of the RB1 gene function, we performed a whole genome sampling assay (WGSA) based on SNP genotyping. We used DNA isolated from 25 sporadic, unilateral RB tumors and matched blood samples. Results Genomic profiles were analyzed to identify regions of loss of heterozygosity (LOH) and/or amplification. Two major subclasses of RB tumors were defined by the presence (n=18) or absence (n=7) of LOH of chromosome 13. LOH in most cases was due to copy neutral events caused by mitotic recombination and mitotic non-disjunction. Tumors harbored novel regions of amplification at 1q44, 3p25, 11q14, 11q25, 14q23, 15q21, 16p13, 17p11.2, 19q13, and 20q13 while regions of loss included 6q22, 7q21and 21q2. Conclusion WGSA-based analysis of unilateral RB tumors revealed novel regions as significant. These minimum critical regions that are lost or amplified are expected to harbor genes that aid the process of tumorigenesis. PMID:19491728

  17. Cloning and expression of retinoblastoma-binding protein 4 gene in embryo diapause termination and in response to salinity stress from brine shrimp Artemia sinica.

    PubMed

    Wang, Xiaolu; Yao, Feng; Liang, Xiaoyu; Zhu, Xiaolin; Zheng, Ren; Jia, Baolin; Hou, Lin; Zou, Xiangyang

    2016-10-15

    Retinoblastoma binding protein 4 (RBBP4) is a nuclear protein with four WD-repeat sequences and thus belongs to a highly conserved subfamily of proteins with such domains. This retinoblastoma-binding protein plays an important role in nucleosome assembly and histone modification, which influences gene transcription and regulates cell cycle and proliferation. Artemia sinica (brine shrimp) undergoes an unusual diapause process under stress conditions of high salinity and low temperature. However, the role of RBBP4 in diapause termination of embryo development in A. sinica remains unknown. Here, the full-length cDNA of the As-rbbp4 gene was obtained from A. sinica and found to contain 1411 nucleotides, including a 1281 bp open reading frame (ORF), 63 bp 5'-untranslated region (UTR) and a 67-bp 3'-UTR, which encodes a 427 amino acid (48 kDa) protein. Bioinformatic analysis indicated As-RBBP4 to be mainly located in the nucleus, with a theoretical isoelectric point of 4.79. Protein sequence domain analysis showed that As-RBBP4 is a conserved protein, especially in the WD40 domain. No specificity in expression of this gene was observed in tissues or organs by in situ hybridization. Real-time quantitative PCR and Western blot analyses of As-RBBP4 gene and protein expression, respectively, showed notably high levels at 10 h and a subsequent downward trend. Obvious trends in upregulation of As-RBBP4 were observed under conditions of low temperature and high salinity stress. As-E2F1 and As-CyclinE also presented similar trends as that of As-RBBP4 in Western blots. Analysis of the RBBP4 expression in early embryonic development of A. sinica indicated that this protein plays an important role in diapause termination and cell cycle regulation. PMID:27267406

  18. The genetics of retinoblastoma, revisited.

    PubMed Central

    Naumova, A.; Sapienza, C.

    1994-01-01

    Our epidemiological and genetic analyses of sporadic and familial retinoblastoma indicate that an X-chromosome-linked gene is involved in the genesis of a significant fraction of new bilateral cases of the disease. The activity of this gene results in sex-ratio distortion in favor of males among patients with bilateral sporadic disease. Among the offspring of these males, both sex-ratio distortion in favor of males and transmission-ratio distortion in favor of affecteds are observed. We propose that these phenomena are due to the inability of these males to erase the genome imprint established on the half of the genome inherited from their mothers. PMID:8304343

  19. Gene regulatory mechanisms underpinning prostate cancer susceptibility.

    PubMed

    Whitington, Thomas; Gao, Ping; Song, Wei; Ross-Adams, Helen; Lamb, Alastair D; Yang, Yuehong; Svezia, Ilaria; Klevebring, Daniel; Mills, Ian G; Karlsson, Robert; Halim, Silvia; Dunning, Mark J; Egevad, Lars; Warren, Anne Y; Neal, David E; Grönberg, Henrik; Lindberg, Johan; Wei, Gong-Hong; Wiklund, Fredrik

    2016-04-01

    Molecular characterization of genome-wide association study (GWAS) loci can uncover key genes and biological mechanisms underpinning complex traits and diseases. Here we present deep, high-throughput characterization of gene regulatory mechanisms underlying prostate cancer risk loci. Our methodology integrates data from 295 prostate cancer chromatin immunoprecipitation and sequencing experiments with genotype and gene expression data from 602 prostate tumor samples. The analysis identifies new gene regulatory mechanisms affected by risk locus SNPs, including widespread disruption of ternary androgen receptor (AR)-FOXA1 and AR-HOXB13 complexes and competitive binding mechanisms. We identify 57 expression quantitative trait loci at 35 risk loci, which we validate through analysis of allele-specific expression. We further validate predicted regulatory SNPs and target genes in prostate cancer cell line models. Finally, our integrated analysis can be accessed through an interactive visualization tool. This analysis elucidates how genome sequence variation affects disease predisposition via gene regulatory mechanisms and identifies relevant genes for downstream biomarker and drug development. PMID:26950096

  20. Epigenomic elements enriched in the promoters of autoimmunity susceptibility genes.

    PubMed

    Dozmorov, Mikhail G; Wren, Jonathan D; Alarcón-Riquelme, Marta E

    2014-02-01

    Genome-wide association studies have identified a number of autoimmune disease-susceptibility genes. Whether or not these loci share any regulatory or functional elements, however, is an open question. Finding such common regulators is of considerable research interest in order to define systemic therapeutic targets. The growing amount of experimental genomic annotations, particularly those from the ENCODE project, provide a wealth of opportunities to search for such commonalities. We hypothesized that regulatory commonalities might not only delineate a regulatory landscape predisposing to autoimmune diseases, but also define functional elements distinguishing specific diseases. We further investigated if, and how, disease-specific epigenomic elements can identify novel genes yet to be associated with the diseases. We evaluated transcription factors, histone modifications, and chromatin state data obtained from the ENCODE project for statistically significant over- or under-representation in the promoters of genes associated with Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Systemic Sclerosis (SSc). We identified BATF, BCL11A, IRF4, NFkB, PAX5, and PU.1 as transcription factors over-represented in SLE- and RA-susceptibility gene promoters. H3K4me1 and H3K4me2 epigenomic marks were associated with SLE susceptibility genes, and H3K9me3 was common to both SLE and RA. In contrast to a transcriptionally active signature in SLE and RA, SSc-susceptibility genes were depleted in activating epigenomic elements. Using epigenomic elements enriched in SLE and RA, we identified additional immune and B cell signaling-related genes with the same elements in their promoters. Our analysis suggests common and disease-specific epigenomic elements that may define novel therapeutic targets for controlling aberrant activation of autoimmune susceptibility genes. PMID:24213554

  1. Genetics Home Reference: retinoblastoma

    MedlinePlus

    ... Arias VE. Trilateral retinoblastoma. Pediatr Blood Cancer. 2007 Mar;48(3):306-10. Review. Citation on PubMed ... for genetic counseling. Am J Hum Genet. 1998 Mar;62(3):610-9. Citation on PubMed or ...

  2. Chemotherapy in metastatic retinoblastoma.

    PubMed

    Kingston, J E; Hungerford, J L; Plowman, P N

    1987-03-01

    Eleven children with metastatic retinoblastoma diagnosed during the period 1970-1984 were treated with chemotherapy. Short-term complete responses were observed in three children treated with a four-drug combination which included cisplatinum, and in one child treated with vincristine and cyclophosphamide. The median duration of survival of the 11 children receiving chemotherapy was nine months, whilst the median survival of 13 children with metastatic retinoblastoma who were not given chemotherapy was only 2.3 months (p = 0.06). This suggests that retinoblastoma is a chemosensitive tumour and therefore adjuvant chemotherapy may have a role in children with retinoblastoma who at diagnosis are thought to be at high risk of developing metastatic disease. PMID:3587892

  3. Drugs Approved for Retinoblastoma

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for retinoblastoma. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  4. Genetic mapping of tumor susceptibility genes involved in mouse plasmacytomagenesis

    SciTech Connect

    Mock, B.A.; Krall, M.M.; Dosik, J.K. )

    1993-10-15

    Plasmacytomas (PCTs) were induced in 47% of BALB/cAnPt mice by the intraperitoneal injection of pristane, in 2% of (BALB/c [times] DBA/2N)F[sub 1], and in 11% of 773 BALB/cAnPt [times] (BALB/cAnPt [times] DBA/2N)F[sub 1]N[sub 2] backcross mice. This result indicates a multigenic mode of inheritance for PCT susceptibility. To locate genes controlling this complex genetic trait, tumor susceptibility in backcross progeny generated from BALB/c and DBA/2N (resistant) mice was correlated with alleles of 83 marker loci. The genotypes of the PCT-susceptible progeny displayed an excess homozygosity for BALB/c alleles with a 32-centimorgan stretch of mouse chromosome 4 (>95% probability of linkage) with minimal recombination (12%) near Gt10. Another susceptibility gene on mouse chromosome 1 may be linked to Fcgr2 (90% probability of linkage); there were excess heterozygotes for Fcgr2 among the susceptible progeny and excess homozygotes among the resistant progeny. Regions of mouse chromosomes 4 and 1 that are correlated with PCT susceptibility share extensive linkage homology with regions of human chromosome 1 that have been associated with cytogenetic abnormalities in multiple myeloma and lymphoid, breast, and endocrine tumors. 68 refs., 2 figs., 1 tab.

  5. [Susceptibility gene in multiple system atrophy (MSA)].

    PubMed

    Tsuji, Shoji

    2014-01-01

    To elucidate molecular bases of multiple system atrophy (MSA), we first focused on recently identified MSA multiplex families. Though linkage analyses followed by whole genome resequencing, we have identified a causative gene, COQ2, for MSA. We then conducted comprehensive nucleotide sequence analysis of COQ2 of sporadic MSA cases and controls, and found that functionally deleterious COQ2 variants confer a strong risk for developing MSA. COQ2 encodes an enzyme in the biosynthetic pathway of coenzyme Q10. Decreased synthesis of coenzyme Q10 is considered to be involved in the pathogenesis of MSA through decreased electron transport in mitochondria and increased vulnerability to oxidative stress. PMID:25672683

  6. The Epstein-Barr Virus Immediate-Early Gene Product, BRLF1, Interacts with the Retinoblastoma Protein during the Viral Lytic Cycle

    PubMed Central

    Zacny, Valerie L.; Wilson, Julie; Pagano, Joseph S.

    1998-01-01

    Retinoblastoma protein (Rb) is a key regulator of cellular proliferation, controlling entry into G1/S in the cell cycle, largely through its action in binding the cellular transcription factor E2F, which activates genes important in DNA synthesis. Small DNA tumor viruses encode gene products which can functionally inactivate Rb, promoting cellular proliferation and viral DNA synthesis. In this study, the Epstein-Barr virus (EBV) immediate-early lytic gene product, BRLF1 (R), is shown to bind Rb in vivo, shortly after induction of the viral lytic cycle in EBV-infected Akata cells. Furthermore, the temporal kinetics of R-Rb interaction correlate with displacement of E2F1 from Rb. Mapping of the domains required for the interaction of R and Rb proteins reveals that R binds specifically to the N terminus of Rb, outside the Rb pocket, and that the first 200 amino acids of R are required for this interaction. The interaction of R and Rb may initiate cell cycle progression and facilitate viral DNA synthesis during lytic replication. PMID:9733844

  7. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

    PubMed Central

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo. PMID:26870082

  8. Expression of p14ARF, MDM2, and MDM4 in human retinoblastoma.

    PubMed

    Guo, Ying; Pajovic, Sanja; Gallie, Brenda L

    2008-10-10

    It is still not clear whether the p53 pathway is altered in retinoblastoma development. We assessed the expression of the p53 pathway genes p14(ARF), mouse double minute 2 (MDM2), and mouse double minute 4 (MDM4) in human retinoblastoma compared to normal retina. Primary human retinoblastomas, retinoblastoma cell lines and normal retinas were assessed for p14(ARF) and MDM4 mRNA by quantitative RT-PCR. p14(ARF), MDM2, and MDM4 protein were measured by immunoblot and immunohistochemistry. Compared to retina, p14(ARF) mRNA expression was notably increased in retinoblastoma but p14(ARF) protein was undetectable. MDM2 and MDM4 proteins were expressed in 22/22 retinoblastomas. MDM2 was expressed in 3/10 retinas tested, and MDM4 in 10/10 retinas. The expression level of MDM2 protein in retinoblastomas and retina was comparable, while MDM4 protein was overexpressed in one retinoblastoma cell line Y79 and two primary retinoblastomas. We observe that overexpression of MDM2 and MDM4 is not a necessary step in retinoblastoma development. However, loss of detectable p14(ARF) protein and resultant lack of functional inactivation of these p53 inhibitors may contribute to retinoblastoma development by constitutive inhibition of p53. PMID:18644346

  9. Network Analysis of Human Genes Influencing Susceptibility to Mycobacterial Infections

    PubMed Central

    Lipner, Ettie M.; Garcia, Benjamin J.; Strong, Michael

    2016-01-01

    Tuberculosis and nontuberculous mycobacterial infections constitute a high burden of pulmonary disease in humans, resulting in over 1.5 million deaths per year. Building on the premise that genetic factors influence the instance, progression, and defense of infectious disease, we undertook a systems biology approach to investigate relationships among genetic factors that may play a role in increased susceptibility or control of mycobacterial infections. We combined literature and database mining with network analysis and pathway enrichment analysis to examine genes, pathways, and networks, involved in the human response to Mycobacterium tuberculosis and nontuberculous mycobacterial infections. This approach allowed us to examine functional relationships among reported genes, and to identify novel genes and enriched pathways that may play a role in mycobacterial susceptibility or control. Our findings suggest that the primary pathways and genes influencing mycobacterial infection control involve an interplay between innate and adaptive immune proteins and pathways. Signaling pathways involved in autoimmune disease were significantly enriched as revealed in our networks. Mycobacterial disease susceptibility networks were also examined within the context of gene-chemical relationships, in order to identify putative drugs and nutrients with potential beneficial immunomodulatory or anti-mycobacterial effects. PMID:26751573

  10. Progress in searching for the febrile seizure susceptibility genes.

    PubMed

    Nakayama, Junko

    2009-05-01

    Febrile seizures (FS) represent the most common form of childhood seizures. They affect 2-5% of infants in the Caucasian population and are even more common in the Japanese population, affecting 6-9% of infants. Some familial FS are associated with a wide variety of afebrile seizures. Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical FS (FS+) and afebrile seizures. A significant genetic component exists for susceptibility to FS and GEFS+: extensive genetic studies have shown that at least nine loci are responsible for FS. Furthermore, mutations in the voltage-gated sodium channel subunit genes (SCN1A, SCN2A and SCN1B) and the GABA(A) receptor subunit genes (GABRG2 and GABRD) have been identified in GEFS+. However, the causative genes have not been identified in most patients with FS or GEFS+. Common forms of FS are genetically complex disorders believed to be influenced by variations in several susceptibility genes. Recently, several association studies on FS have been reported, but the results vary among different groups and no consistent or convincing FS susceptibility gene has emerged. Herein, we review the genetic data reported in FS, including the linkage analysis, association studies, and genetic abnormalities found in the FS-related disorders such as GEFS+ and severe myoclonic epilepsy in infancy. PMID:19201561

  11. Genetic perspective of retinoblastoma: From present to future.

    PubMed

    Jagadeesan, Madhavan; Khetan, Vikas; Mallipatna, Ashwin

    2016-05-01

    Retinoblastoma (RB) is the most common malignant intraocular tumor in children. In the last decade, basic research has led to a better understanding of events after two hits in RB susceptibility gene (RB1), molecular mechanism of tumor growth, the cell of origin of RB, etc. This would pave way to identify biomarkers and molecular targeted therapy for better treatment option in the future. Furthermore, improvement in molecular techniques has led to enhanced diagnostic methods for early diagnosis, genetic counseling, and prevention of the disease. This review will help to understand the essence of basic research work conducted in recent times and its implication in the management of RB in the future. PMID:27380971

  12. Genetic perspective of retinoblastoma: From present to future

    PubMed Central

    Jagadeesan, Madhavan; Khetan, Vikas; Mallipatna, Ashwin

    2016-01-01

    Retinoblastoma (RB) is the most common malignant intraocular tumor in children. In the last decade, basic research has led to a better understanding of events after two hits in RB susceptibility gene (RB1), molecular mechanism of tumor growth, the cell of origin of RB, etc. This would pave way to identify biomarkers and molecular targeted therapy for better treatment option in the future. Furthermore, improvement in molecular techniques has led to enhanced diagnostic methods for early diagnosis, genetic counseling, and prevention of the disease. This review will help to understand the essence of basic research work conducted in recent times and its implication in the management of RB in the future. PMID:27380971

  13. Liver tumor formation by a mutant retinoblastoma protein in the transgenic mice is caused by an upregulation of c-Myc target genes

    SciTech Connect

    Wang, Bo; Hikosaka, Keisuke; Sultana, Nishat; Sharkar, Mohammad Tofael Kabir; Noritake, Hidenao; Kimura, Wataru; Wu, Yi-Xin; Kobayashi, Yoshimasa; Uezato, Tadayoshi; Miura, Naoyuki

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Fifty percent of the mutant Rb transgenic mice produced liver tumors. Black-Right-Pointing-Pointer In the tumor, Foxm1, Skp2, Bmi1 and AP-1 mRNAs were up-regulated. Black-Right-Pointing-Pointer No increase in expression of the Myc-target genes was observed in the non-tumorous liver. Black-Right-Pointing-Pointer Tumor formation depends on up-regulation of the Myc-target genes. -- Abstract: The retinoblastoma (Rb) tumor suppressor encodes a nuclear phosphoprotein that regulates cellular proliferation, apoptosis and differentiation. In order to adapt itself to these biological functions, Rb is subjected to modification cycle, phosphorylation and dephosphorylation. To directly determine the effect of phosphorylation-resistant Rb on liver development and function, we generated transgenic mice expressing phosphorylation-resistant human mutant Rb (mt-Rb) under the control of the rat hepatocyte nuclear factor-1 gene promoter/enhancer. Expression of mt-Rb in the liver resulted in macroscopic neoplastic nodules (adenomas) with {approx}50% incidence within 15 months old. Interestingly, quantitative reverse transcriptase-PCR analysis showed that c-Myc was up-regulated in the liver of mt-Rb transgenic mice irrespective of having tumor tissues or no tumor. In tumor tissues, several c-Myc target genes, Foxm1, c-Jun, c-Fos, Bmi1 and Skp2, were also up-regulated dramatically. We determined whether mt-Rb activated the Myc promoter in the HTP9 cells and demonstrated that mt-Rb acted as an inhibitor of wild-type Rb-induced repression on the Myc promoter. Our results suggest that continued upregulation of c-Myc target genes promotes the liver tumor formation after about 1 year of age.

  14. Retinoblastoma (RB1) gene product expression in breast carcinoma. Correlation with Ki-67 growth fraction and biopathological profile.

    PubMed Central

    Ceccarelli, C; Santini, D; Chieco, P; Taffurelli, M; Gamberini, M; Pileri, S A; Marrano, D

    1998-01-01

    AIMS: To investigate the expression of retinoblastoma protein (pRb) in invasive breast tumours and compare its expression with the major biopathological prognostic indicators to identify more aggressive subgroups. MATERIAL: Archival paraffin embedded tissues from 153 consecutive primary breast carcinomas. METHODS: pRb, Ki-67, and oestrogen receptor/progesterone receptor proteins were identified by immunohistochemistry and score values were recorded by image cytometric analysis; p53 and EGFr expression was also evaluated. RESULTS: pRb scores correlated strongly with proliferation activity as determined by Ki-67 staining. Positive relations were also observed between pRb scores, tumour size, nuclear and histological grade, and oestrogen receptor/progesterone receptor content, while abnormal p53 accumulation was not associated with pRb expression. Among the high proliferating carcinomas it was possible to identify 13 cases with loss of pRb expression. CONCLUSIONS: pRb expression paralleled proliferative activity in the majority of breast carcinomas examined, suggesting that in these cases the protein behaves normally in regulating the cell cycle. Conversely in cases with loss of pRb immunostaining, the combined expression of specific highly aggressive factors (EGFr and p53 expression, oestrogen receptor/progesterone receptor negative status, and high K67) seems to characterise a more aggressive phenotype showing growth advantage and cellular "progression" rather than significant nodal involvement. Images PMID:10193322

  15. Identification of Tuberculosis Susceptibility Genes with Human Macrophage Gene Expression Profiles

    PubMed Central

    Chau, Tran Thi Hong; Thorsson, Vesteinn; Simmons, Cameron P.; Quyen, Nguyen Than Ha; Thwaites, Guy E.; Thi Ngoc Lan, Nguyen; Hibberd, Martin; Teo, Yik Y.; Seielstad, Mark; Aderem, Alan; Farrar, Jeremy J.; Hawn, Thomas R.

    2008-01-01

    Although host genetics influences susceptibility to tuberculosis (TB), few genes determining disease outcome have been identified. We hypothesized that macrophages from individuals with different clinical manifestations of Mycobacterium tuberculosis (Mtb) infection would have distinct gene expression profiles and that polymorphisms in these genes may also be associated with susceptibility to TB. We measured gene expression levels of >38,500 genes from ex vivo Mtb-stimulated macrophages in 12 subjects with 3 clinical phenotypes: latent, pulmonary, and meningeal TB (n = 4 per group). After identifying differentially expressed genes, we confirmed these results in 34 additional subjects by real-time PCR. We also used a case-control study design to examine whether polymorphisms in differentially regulated genes were associated with susceptibility to these different clinical forms of TB. We compared gene expression profiles in Mtb-stimulated and unstimulated macrophages and identified 1,608 and 199 genes that were differentially expressed by >2- and >5-fold, respectively. In an independent sample set of 34 individuals and a subset of highly regulated genes, 90% of the microarray results were confirmed by RT-PCR, including expression levels of CCL1, which distinguished the 3 clinical groups. Furthermore, 6 single nucleotide polymorphisms (SNPs) in CCL1 were found to be associated with TB in a case-control genetic association study with 273 TB cases and 188 controls. To our knowledge, this is the first identification of CCL1 as a gene involved in host susceptibility to TB and the first study to combine microarray and DNA polymorphism studies to identify genes associated with TB susceptibility. These results suggest that genome-wide studies can provide an unbiased method to identify critical macrophage response genes that are associated with different clinical outcomes and that variation in innate immune response genes regulate susceptibility to TB. PMID:19057661

  16. A new rosette in retinoblastoma

    PubMed Central

    Das, Dipankar; Bhattacharjee, Kasturi; Barthakur, Sumita Sarma; Tahiliani, Prerana Sushil; Deka, Panna; Bhattacharjee, Harsha; Deka, Apurba; Paul, Rajashree

    2014-01-01

    Retinoblastoma, the most common primary malignant intraocular tumor of childhood is a great success story in pediatric and ocular oncology. Pathology of retinoblastoma is important to guide the treatment modalities. Differentiated retinoblastoma is commonly seen in younger age group. Since a hundred years, we have been observing two typical true rosettes in retinoblastoma in the form of Flexner-Wintersteiner (FW) and Homer Wright (HW) rosettes and in many occasions pseudorosettes have been documented. In the present case report, a third new type of rosette was identified in a differentiated retinoblastoma which had an unusual anterior segment involvement. PMID:24881618

  17. Postgenomics, uncertain futures, and the familiarization of susceptibility genes

    PubMed Central

    Chilibeck, Gillian; Lock, Margaret; Sehdev, Megha

    2016-01-01

    This paper draws on empirical findings from interview studies in the USA and Canada to interrogate the idea that expanding practices of genetic testing are likely to transform kin and family relations in fundamental ways. We argue that in connection with common adult onset disorders in which susceptibility genes with low predictive power are implicated it is unlikely that family relationships will be radically altered as a result of learning about either individual or family genotypes. Rather, pre-existing family dynamics and ideas about family susceptibilities for disease may be reinforced. The case of the ApoE gene and its relationship to Alzheimer’s disease is used as an illustrative example. We found that “postgenomic” thinking, in which complexity of disease causation is emphasized, is readily apparent in informant narratives. PMID:20570031

  18. Brg1 coordinates multiple processes during retinogenesis and is a tumor suppressor in retinoblastoma

    SciTech Connect

    Aldiri, Issam; Ajioka, Itsuki; Xu, Beisi; Zhang, Jiakun; Chen, Xiang; Benavente, Claudia; Finkelstein, David; Johnson, Dianna; Akiyama, Jennifer; Pennacchio, Len A.; Dyer, Michael A.

    2015-12-01

    Retinal development requires precise temporal and spatial coordination of cell cycle exit, cell fate specification, cell migration and differentiation. When this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. Here we explore the role of Brg1 (Smarca4) in retinal development and retinoblastoma in mice using molecular and cellular approaches. Brg1 was found to regulate retinal size by controlling cell cycle length, cell cycle exit and cell survival during development. Brg1 was not required for cell fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. Despite the hypocellularity, premature cell cycle exit, increased cell death and extended cell cycle length, retinal progenitor cells persisted in Brg1-deficient retinae, making them more susceptible to retinoblastoma. In conclusion, ChIP-Seq analysis suggests that Brg1 might regulate gene expression through multiple mechanisms.

  19. Brg1 coordinates multiple processes during retinogenesis and is a tumor suppressor in retinoblastoma.

    PubMed

    Aldiri, Issam; Ajioka, Itsuki; Xu, Beisi; Zhang, Jiakun; Chen, Xiang; Benavente, Claudia; Finkelstein, David; Johnson, Dianna; Akiyama, Jennifer; Pennacchio, Len A; Dyer, Michael A

    2015-12-01

    Retinal development requires precise temporal and spatial coordination of cell cycle exit, cell fate specification, cell migration and differentiation. When this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. Here we explore the role of Brg1 (Smarca4) in retinal development and retinoblastoma in mice using molecular and cellular approaches. Brg1 was found to regulate retinal size by controlling cell cycle length, cell cycle exit and cell survival during development. Brg1 was not required for cell fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. Despite the hypocellularity, premature cell cycle exit, increased cell death and extended cell cycle length, retinal progenitor cells persisted in Brg1-deficient retinae, making them more susceptible to retinoblastoma. ChIP-Seq analysis suggests that Brg1 might regulate gene expression through multiple mechanisms. PMID:26628093

  20. Brg1 coordinates multiple processes during retinogenesis and is a tumor suppressor in retinoblastoma

    DOE PAGESBeta

    Aldiri, Issam; Ajioka, Itsuki; Xu, Beisi; Zhang, Jiakun; Chen, Xiang; Benavente, Claudia; Finkelstein, David; Johnson, Dianna; Akiyama, Jennifer; Pennacchio, Len A.; et al

    2015-12-01

    Retinal development requires precise temporal and spatial coordination of cell cycle exit, cell fate specification, cell migration and differentiation. When this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. Here we explore the role of Brg1 (Smarca4) in retinal development and retinoblastoma in mice using molecular and cellular approaches. Brg1 was found to regulatemore » retinal size by controlling cell cycle length, cell cycle exit and cell survival during development. Brg1 was not required for cell fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. Despite the hypocellularity, premature cell cycle exit, increased cell death and extended cell cycle length, retinal progenitor cells persisted in Brg1-deficient retinae, making them more susceptible to retinoblastoma. In conclusion, ChIP-Seq analysis suggests that Brg1 might regulate gene expression through multiple mechanisms.« less

  1. Brg1 coordinates multiple processes during retinogenesis and is a tumor suppressor in retinoblastoma

    PubMed Central

    Aldiri, Issam; Ajioka, Itsuki; Xu, Beisi; Zhang, Jiakun; Chen, Xiang; Benavente, Claudia; Finkelstein, David; Johnson, Dianna; Akiyama, Jennifer; Pennacchio, Len A.; Dyer, Michael A.

    2015-01-01

    Retinal development requires precise temporal and spatial coordination of cell cycle exit, cell fate specification, cell migration and differentiation. When this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. Here we explore the role of Brg1 (Smarca4) in retinal development and retinoblastoma in mice using molecular and cellular approaches. Brg1 was found to regulate retinal size by controlling cell cycle length, cell cycle exit and cell survival during development. Brg1 was not required for cell fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. Despite the hypocellularity, premature cell cycle exit, increased cell death and extended cell cycle length, retinal progenitor cells persisted in Brg1-deficient retinae, making them more susceptible to retinoblastoma. ChIP-Seq analysis suggests that Brg1 might regulate gene expression through multiple mechanisms. PMID:26628093

  2. Factor-binding element in the human c-myc promoter involved in transcriptional regulation by transforming growth factor. beta. 1 and by the retinoblastoma gene product

    SciTech Connect

    Pietenpol, J.A.; Stein, R.W.; Moses, H.L. ); Muenger, K.; Howley, P.M. )

    1991-11-15

    Previous studies have shown that transforming growth factor {beta}1 (TGF-{beta}1) inhibition of keratinocyte proliferation involves suppression of c-myc transcription, and indirect evidence has suggested that the retinoblastoma gene product (pRB) may be involved in this process. In this study, transient expression of pRB in skin keratinocytes was shown to repress transcription of the human c-myc promoter region was required for regulation by both TGF-{beta}1 and pRB. These sequences, termed the TGF-{beta} control element (TCE), lie between positions {minus}86 and {minus}63 relative to the P1 transcription start site. Oligonucleotides containing the TCE bound to several nuclear factors in mobility-shift assays using extracts from cells with or without normal pRB. Binding of some factors was inhibited by TGF-{beta}1 treatment of TGF-{beta}-sensitive but not TGF-{beta}-insensitive cells. These data indicate that pRB can suppress c-myc transcription and growth inhibition.

  3. A Retinoblastoma Allele That Is Mutated at Its Common E2F Interaction Site Inhibits Cell Proliferation in Gene-Targeted Mice

    PubMed Central

    Cecchini, Matthew J.; Thwaites, Michael J.; Talluri, Srikanth; MacDonald, James I.; Passos, Daniel T.; Chong, Jean-Leon; Cantalupo, Paul; Stafford, Paul M.; Sáenz-Robles, M. Teresa; Francis, Sarah M.; Pipas, James M.; Leone, Gustavo; Welch, Ian

    2014-01-01

    The retinoblastoma protein (pRB) is best known for regulating cell proliferation through E2F transcription factors. In this report, we investigate the properties of a targeted mutation that disrupts pRB interactions with the transactivation domain of E2Fs. Mice that carry this mutation endogenously (Rb1ΔG) are defective for pRB-dependent repression of E2F target genes. Except for an accelerated entry into S phase in response to serum stimulation, cell cycle regulation in Rb1ΔG/ΔG mouse embryonic fibroblasts (MEFs) strongly resembles that of the wild type. In a serum deprivation-induced cell cycle exit, Rb1ΔG/ΔG MEFs display a magnitude of E2F target gene derepression similar to that of Rb1−/− cells, even though Rb1ΔG/ΔG cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1ΔG/ΔG MEFs is responsive to p16 expression and gamma irradiation, indicating that alternate mechanisms can be activated in G1 to arrest proliferation. Some Rb1ΔG/ΔG mice die neonatally with a muscle degeneration phenotype, while the others live a normal life span with no evidence of spontaneous tumor formation. Most tissues appear histologically normal while being accompanied by derepression of pRB-regulated E2F targets. This suggests that non-E2F-, pRB-dependent pathways may have a more relevant role in proliferative control than previously identified. PMID:24662053

  4. Multiplex screening for RB1 germline mutations in 106 patients with hereditary retinoblastoma

    SciTech Connect

    Lohmann, D.R.; Brandt, B.; Passarge, E.

    1994-09-01

    The identification of germline mutations in the retinoblastoma susceptibility gene (RB1) is important for genetic counseling in hereditary retinoblastoma. Due to the complex genomic organization of this gene and the heterogeneity of mutations, efficient screening procedures are important for rapid mutation detection. We have developed methods based on simultaneous analysis of multiple regions of this gene in an ABI automated DNA fragment analyzer to examine 106 patients with hereditary retinoblastoma in which no alteration was identified by Southern blot hybridization. Primers for the amplification of all 27 exons of the RB1 gene as well as the promoter and poly(A) signal sequences were labelled with distinct fluorescent dyes (FAM, HEX, TAMRA) to enable simultaneous electrophoretic analysis of PCR products with similar mobility. PCR fragments distinguishable by size or color were co-amplified by multiplex PCR and analyzed for length by GENESCAN analysis. Using this approach, small deletions ranging from 1 bp to 22 bp were identified in 24 patients (23%). Short sequence repeats or polypyrimidine runs were present in the vicinity of most of these deletions. In 4 patients (4%), insertions from 1 bp to 4 bp were found. The majority of length mutations resulted in a truncated gene product due to frameshift and premature termination. No mutation was identified in exons 25 to 27 possibly indicating that the encoded protein domains have minor functional importance. In order to screen for base substitutions that are not detectable by fragment length analysis, we adapted heteroduplex analysis for the use in the DNA fragment analyzer. During the optimization of this method we detected 10 single base substitutions most of which generated stop codons. Intriguingly, two identical missense mutations were identified in two unrelated families with a low-penetrance phenotype.

  5. Chromosome damage in G0 X-irradiated lymphocytes from patients with hereditary retinoblastoma

    SciTech Connect

    Morten, J.E.; Harnden, D.G.; Taylor, A.M.

    1981-09-01

    The amount of chromosome damage in peripheral blood lymphocytes following 400 rads G0 X-irradiation in 10 of 11 hereditary retinoblastoma patients was shown to be intermediate between that in normals and damage in trisomy 21 patients. The difference between normals and hereditary retinoblastoma patients was small, it varied between hereditary retinoblastoma patients, and no difference was detected following 200 rads G0 X-irradiation. No difference was found in levels of spontaneous chromosome damage in hereditary retinoblastoma patients, trisomy 21 patients, and normals. These results suggest that, although sensitivity to ionizing radiation may be associated with hereditary retinoblastoma, the observed difference is so small that it is probably not the major effect of the gene predisposing to retinoblastoma.

  6. Intelligence of Retinoblastoma Patients and Their Siblings

    ERIC Educational Resources Information Center

    Levitt, Eugene A.; And Others

    1972-01-01

    It was concluded that while retinoblastoma per se is not associated with intellectual superiority or inferiority, retinoblastoma associated with blindness may result in selective cognitive superiority. (Authors)

  7. Minimal 16q genomic loss implicates cadherin-11 in retinoblastoma.

    PubMed

    Marchong, Mellone N; Chen, Danian; Corson, Timothy W; Lee, Cheong; Harmandayan, Maria; Bowles, Ella; Chen, Ning; Gallie, Brenda L

    2004-09-01

    Retinoblastoma is initiated by loss of both RB1 alleles. Previous studies have shown that retinoblastoma tumors also show further genomic gains and losses. We now define a 2.62 Mbp minimal region of genomic loss of chromosome 16q22, which is likely to contain tumor suppressor gene(s), in 76 retinoblastoma tumors, using loss of heterozygosity (30 of 76 tumors) and quantitative multiplex PCR (71 of 76 tumors). The sequence-tagged site WI-5835 within intron 2 of the cadherin-11 (CDH11) gene showed the highest frequency of loss (54%, 22 of 41 samples tested). A second hotspot for loss (39%, 9 of 23 samples tested) was detected within intron 2 of the cadherin-13 (CDH13) gene. Furthermore, deletion of the exons of CDH11 and/or WI-5835 was shown by quantitative multiplex PCR in 17 of 30 (57%) of previously untested tumors. Immunoblot analyses revealed that 91% (20 of 22) retinoblastoma exhibited either a complete loss or a decrease of the intact form of CDH11 and 8 of 13 showed a prevalent band suggestive of the variant form. Copy number of WI-5835 for these samples correlated with CDH11 protein expression. CDH11 staining was evident in the inner nuclear layer in early mouse retinal development and in small transgenic murine SV40 large T antigen-induced retinoblastoma tumors, but advanced tumors frequently showed loss of CDH11 expression by reverse transcription-PCR, suggestive of a role for CDH11 in tumor progression or metastasis. CDH13 protein and mRNA were consistently expressed in all human and murine retinoblastoma compared with normal adult human retina. Our analyses implicate CDH11, but not CDH13, as a potential tumor suppressor gene in retinoblastoma. PMID:15383628

  8. Is MSH2 a breast cancer susceptibility gene?

    PubMed

    Wong, Ee Ming; Tesoriero, Andrea A; Pupo, Gulietta M; McCredie, Margaret R E; Giles, Graham G; Hopper, John L; Mann, Graham J; Goldgar, David E; Southey, Melissa C

    2008-01-01

    Mutations in the DNA mismatch repair gene MSH2 lead to increased replication error and microsatellite instability and account for a substantial proportion of hereditary non-polyposis colorectal cancer (Lynch syndrome). A recent international collaborative genome-wide linkage scan (GWS) for breast cancer susceptibility loci found some evidence for there being a breast cancer susceptibility gene in a genomic region on chromosome 2p close to MSH2. We sought to investigate the possibility that mutations in MSH2 might explain the multiple cases of breast cancer in some families that were included in the international GWS. DNA samples from the affected probands of 59 multiple-case breast cancer families, many of whom gave LOD scores >0.5 in the MSH2 region, were screened for large genomic alterations in MSH2 via the Multiplex Ligation-dependent Probe Amplification (MLPA) assay and for coding region mutations via exonic sequencing. Several of the families also contained cases of colorectal cancer in addition to breast cancer and had been included in the GWS that had identified a positive LOD score on chromosome 2p. Using MLPA, c.1236C > T was identified in one proband but this variant was not predicted to create an alternate acceptor/donor site within exon 7 MSH2 using in silico analyses. A c.1734T > C was identified in a second proband via exonic sequencing but testing of the variant in other family members did not support segregation of this variant with disease. Extensive screening of 59 multiple-case breast cancer families did not identify any coding region mutations or larger genomic alterations in MSH2 that might implicate MSH2 as a breast cancer susceptibility gene. PMID:17922223

  9. Growing up with Retinoblastoma

    ERIC Educational Resources Information Center

    Maley, Tom

    2005-01-01

    An account is given of growing up as a child blinded as a result of a cancer of the eye known as retinoblastoma. The role of his mother is brought out, variously as a source of objective knowledge, of one's personal worth, and of the worth of other people in one's community. The strengths and weaknesses of his first school in his home area and…

  10. Polymorphisms in Autophagy Genes and Susceptibility to Tuberculosis

    PubMed Central

    Alisjahbana, Bachti; Sahiratmadja, Edhyana; Parwati, Ida; Oosting, Marije; Plantinga, Theo S.; Joosten, Leo A. B.; Netea, Mihai G.; Ottenhoff, Tom H. M.; van de Vosse, Esther; van Crevel, Reinout

    2012-01-01

    Recent data suggest that autophagy is important for intracellular killing of Mycobacterium tuberculosis, and polymorphisms in the autophagy gene IRGM have been linked with susceptibility to tuberculosis (TB) among African-Americans, and with TB caused by particular M. tuberculosis genotypes in Ghana. We compared 22 polymorphisms of 14 autophagy genes between 1022 Indonesian TB patients and 952 matched controls, and between patients infected with different M. tuberculosis genotypes, as determined by spoligotyping. The same autophagy polymorphisms were studied in correlation with ex-vivo production of TNF, IL-1β, IL-6, IL-8, IFN-γ and IL-17 in healthy volunteers. No association was found between TB and polymorphisms in the genes ATG10, ATG16L2, ATG2B, ATG5, ATG9B, IRGM, LAMP1, LAMP3, P2RX7, WIPI1, MTOR and ATG4C. Associations were found between polymorphisms in LAMP1 (p = 0.02) and MTOR (p = 0.02) and infection with the successful M. tuberculosis Beijing genotype. The polymorphisms examined were not associated with M. tuberculosis induced cytokines, except for a polymorphism in ATG10, which was linked with IL-8 production (p = 0.04). All associations found lost statistical significance after correction for multiple testing. This first examination of a broad set of polymorphisms in autophagy genes fails to show a clear association with TB, with M. tuberculosis Beijing genotype infection or with ex-vivo pro-inflammatory cytokine production. PMID:22879892

  11. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients

    PubMed Central

    van Wezel, Tom; Jagmohan-Changur, Shantie C.; Ruano, Dina; van der Klift, Heleen M.; van den Akker, Brendy E. W. M.; Laros, Jeroen F. J.; van Galen, Michiel; Wagner, Anja; Letteboer, Tom G. W.; Gómez-García, Encarna B.; Tops, Carli M. J.; Vasen, Hans F.; Devilee, Peter; Hes, Frederik J.; Morreau, Hans; Wijnen, Juul T.

    2016-01-01

    Background and Aims Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history. Methods Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants. Results Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG). Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29%) cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32%) with one pathogenic somatic variant (n = 8) or one VUS predicted to be pathogenic (n = 1). Conclusions This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes. PMID:27300758

  12. Adenocarcinoma of the ethmoid following radiotherapy for bilateral retinoblastoma

    SciTech Connect

    Rowe, L.D.; Lane, R.; Snow, J.B. Jr.

    1980-01-01

    Adenocarcinoma of the ethmoid sinus is rare, representing only 4 to 8% of malignancies of the paranasal sinuses. An extraordinary case of papillary adenocarcinoma of the ethmoid sinus arising 30 years following high-dose radiotherapy for bilateral retinoblastoma is presented. Second fatal mesenchymal and epithelial primaries have been described in 8.5% of patients with bilateral retinoblastomas previously treated with radiotherapy; however, papillary adenocarcinoma arising within the paranasal sinuses has not been reported. Aggressive treatment including partial maxillectomy, radical pansinusectomy, radical neck dissection followed by regional radiotherapy and systemic chemotherapy failed to prevent the development of fatal hepatic metastases. The high incidence of second fatal primary neoplasms in patients with bilateral retinoblastomas receiving radiation suggests an innate susceptibility that may add to the risk of radiotherapy.

  13. Lentivirus-Mediated Knockdown of Astrocyte Elevated Gene-1 Inhibits Growth and Induces Apoptosis through MAPK Pathways in Human Retinoblastoma Cells

    PubMed Central

    Chang, Ying; Li, Bin; Xu, Xiaolin; Shen, Ling; Bai, Haixia; Gao, Fei; Zhang, Zhibao; Jonas, Jost B.

    2016-01-01

    Purpose To explore expression and function of astrocyte elevated gene-1 (AEG-1) in human retinoblastoma (RB). Methods The expression of AEG-1 in histological sections of human RBs and in RB cell lines was examined using immunohistochemical staining and RT-PCR and Western blotting respectively. We knocked down AEG-1 gene levels by AEG-1-siRNA lentivirus transfection of human RB cell lines SO-RB50 and Y79, and using an MTT assay, we assessed the role of AEG-1 on RB cell proliferation. The biological significance of lentivirus transfection induced AEG-1 down-regulation was examined by assessing the apoptosis rate in the transfected RB cells by Annexin V-APC staining and flow cytometry. We additionally measured the expression of Bcl-2, Bax, cleaved-caspase-3 and caspase-3, and the phosphorylation and non-phosphorylation alternation of MAPKs. Results AEG-1 expression was detected to be strongly positive in the histological slides of 35 out of 54 (65%) patients with RB. AEG-1 expression increased significantly (P<0.05) with tumor stage. In the RB cell lines SO-RB50, Y79 and WERI-RB1 as compared with retinal pigment epithelium cells, expression of AEG-1 mRNA and AEG-1 protein was significantly higher. In AEG-1-siRNA lentivirus transfected cell cultures as compared with negative control lentivirus transfected cell cultures, levels of AEG-1 mRNA and of AEG-1 protein (P<0.05) and cell growth rates (P<0.01) were significantly lower, and apoptosis rate (P<0.001), Bax/Bcl-2 ratio and cleaved-caspase-3 protein level were significantly increased. The P-ERK/ERK ratio was significantly decreased in the AEG-1-siRNA lentivirus transfected cell lines. Conclusions Expression of AEG-1 was associated with RB, in histological slides of patients and in cell culture experiments. Lentivirus transfection induced knockdown of AEG-1 had a tumor suppressive effect, potentially by tumor cell apoptosis induction through inhibition of ERK. PMID:26894431

  14. Prioritization of Susceptibility Genes for Ectopic Pregnancy by Gene Network Analysis

    PubMed Central

    Liu, Ji-Long; Zhao, Miao

    2016-01-01

    Ectopic pregnancy is a very dangerous complication of pregnancy, affecting 1%–2% of all reported pregnancies. Due to ethical constraints on human biopsies and the lack of suitable animal models, there has been little success in identifying functionally important genes in the pathogenesis of ectopic pregnancy. In the present study, we developed a random walk–based computational method named TM-rank to prioritize ectopic pregnancy–related genes based on text mining data and gene network information. Using a defined threshold value, we identified five top-ranked genes: VEGFA (vascular endothelial growth factor A), IL8 (interleukin 8), IL6 (interleukin 6), ESR1 (estrogen receptor 1) and EGFR (epidermal growth factor receptor). These genes are promising candidate genes that can serve as useful diagnostic biomarkers and therapeutic targets. Our approach represents a novel strategy for prioritizing disease susceptibility genes. PMID:26840308

  15. Prioritization of Susceptibility Genes for Ectopic Pregnancy by Gene Network Analysis.

    PubMed

    Liu, Ji-Long; Zhao, Miao

    2016-01-01

    Ectopic pregnancy is a very dangerous complication of pregnancy, affecting 1%-2% of all reported pregnancies. Due to ethical constraints on human biopsies and the lack of suitable animal models, there has been little success in identifying functionally important genes in the pathogenesis of ectopic pregnancy. In the present study, we developed a random walk-based computational method named TM-rank to prioritize ectopic pregnancy-related genes based on text mining data and gene network information. Using a defined threshold value, we identified five top-ranked genes: VEGFA (vascular endothelial growth factor A), IL8 (interleukin 8), IL6 (interleukin 6), ESR1 (estrogen receptor 1) and EGFR (epidermal growth factor receptor). These genes are promising candidate genes that can serve as useful diagnostic biomarkers and therapeutic targets. Our approach represents a novel strategy for prioritizing disease susceptibility genes. PMID:26840308

  16. Treating psoriasis by targeting its susceptibility gene Rel.

    PubMed

    Fan, Tingting; Wang, Shaowen; Yu, Linjiang; Yi, Huqiang; Liu, Ruiling; Geng, Wenwen; Wan, Xiaochun; Ma, Yifan; Cai, Lintao; Chen, Youhai H; Ruan, Qingguo

    2016-04-01

    Psoriasis is a chronic inflammatory disorder of the skin. Accumulating evidence indicates that the Rel gene, a member of the NF-κB family, is a risk factor for the disease. We sought to investigate whether psoriasis can be prevented by directly targeting the Rel gene transcript, i.e., the c-Rel mRNA. Using chemically-modified c-Rel specific siRNA (siRel) and poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) micelles, we successfully knocked down the expression of c-Rel, and showed that the expression of cytokine IL-23, a direct target of c-Rel that can drive the development of IL-17-producing T cells, was markedly inhibited. More importantly, treating mice with siRel not only prevented but also ameliorated imiquimod (IMQ)-induced psoriasis. Mechanistic studies showed that siRel treatment down-regulated the expression of multiple inflammatory cytokines. Taken together, these results indicate that the susceptibility gene Rel can be targeted to treat and prevent psoriasis. PMID:26993753

  17. Molecular cloning of cellular genes encoding retinoblastoma-associated proteins: identification of a gene with properties of the transcription factor E2F.

    PubMed Central

    Shan, B; Zhu, X; Chen, P L; Durfee, T; Yang, Y; Sharp, D; Lee, W H

    1992-01-01

    The retinoblastoma protein interacts with a number of cellular proteins to form complexes which are probably crucial for its normal physiological function. To identify these proteins, we isolated nine distinct clones by direct screening of cDNA expression libraries using purified RB protein as a probe. One of these clones, Ap12, is expressed predominantly at the G1-S boundary and in the S phase of the cell cycle. The nucleotide sequence of Ap12 has features characteristic of transcription factors. The C-terminal region binds to unphosphorylated RB in regions similar to those to which T antigen binds and contains a transactivation domain. A region containing a potential leucine zipper flanked by basic residues is able to bind an E2F recognition sequence specifically. Expression of Ap12 in mammalian cells significantly enhances E2F-dependent transcriptional activity. These results suggest that Ap12 encodes a protein with properties known to be characteristic of transcription factor E2F. Images PMID:1448092

  18. Gene--gene interaction among cytokine polymorphisms influence susceptibility to aggressive periodontitis.

    PubMed

    Scapoli, C; Mamolini, E; Carrieri, A; Guarnelli, M E; Annunziata, M; Guida, L; Romano, F; Aimetti, M; Trombelli, L

    2011-09-01

    Aggressive periodontitis (AgP) is a multifactorial disease. The distinctive aspect of periodontitis is that this disease must deal with a large number of genes interacting with one another and forming complex networks. Thus, it is reasonable to expect that gene-gene interaction may have a crucial role. Therefore, we carried out a pilot case-control study to identify the association of candidate epistatic interactions between genetic risk factors and susceptibility to AgP, by using both conventional parametric analyses and a higher order interactions model, based on the nonparametric Multifactor Dimensionality Reduction algorithm. We analyzed 122 AgP patients and 246 appropriate periodontally healthy individuals, and genotyped 28 polymorphisms, located within 14 candidate genes, chosen among the principal genetic variants pointed out from literature and having a role in inflammation and immunity. Our analyses provided significant evidence for gene--gene interactions in the development of AgP, in particular, present results: (a) indicate a possible role of two new polymorphisms, within SEPS1 and TNFRSF1B genes, in determining host individual susceptibility to AgP; (b) confirm the potential association between of IL-6 and Fc γ- receptor polymorphisms and the disease; (c) exclude an essential contribution of IL-1 cluster gene polymorphisms to AgP in our Caucasian-Italian population. PMID:21593780

  19. Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease

    PubMed Central

    Harold, Denise; Jones, Lesley; Holmans, Peter; Gerrish, Amy; Vedernikov, Alexey; Richards, Alexander; DeStefano, Anita L.; Lambert, Jean-Charles; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca; Jun, Gyungah; Bis, Joshua C.; Beecham, Gary W.; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A.; Denning, Nicola; Smith, Albert V.; Chouraki, Vincent; Thomas, Charlene; Ikram, M. Arfan; Zelenika, Diana; Vardarajan, Badri N.; Kamatani, Yoichiro; Lin, Chiao-Feng; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L.; Vronskaya, Maria; Johnson, Andrew D.; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Hanon, Olivier; Fitzpatrick, Annette L.; Buxbaum, Joseph D.; Campion, Dominique; Crane, Paul K.; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L.; De Jager, Philip L.; Deramecourt, Vincent; Johnston, Janet A.; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Hernández, Isabel; Rubinsztein, David C.; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M.; Fiévet, Nathalie; Huentelman, Matthew J.; Gill, Michael; Brown, Kristelle; Kamboh, M. Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B.; Myers, Amanda J.; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; George-Hyslop, Peter St; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W.; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petra; Collinge, John; Sorbi, Sandro; Garcia, Florentino Sanchez; Fox, Nick C.; Hardy, John; Naranjo, Maria Candida Deniz; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Scarpini, Elio; Bonuccelli, Ubaldo; Mancuso, Michelangelo; Siciliano, Gabriele; Moebus, Susanne; Mecocci, Patrizia; Zompo, Maria Del; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Frank-García, Ana; Panza, Francesco; Solfrizzi, Vincenzo; Caffarra, Paolo; Nacmias, Benedetta; Perry, William; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M.; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G.; Coto, Eliecer; Hamilton-Nelson, Kara L.; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J.; Faber, Kelley M.; Jonsson, Palmi V.; Combarros, Onofre; O'Donovan, Michael C.; Cantwell, Laura B.; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H.; Bennett, David A.; Harris, Tamara B.; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee F. A. G.; Passmore, Peter; Montine, Thomas J.; Bettens, Karolien; Rotter, Jerome I.; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M.; Kukull, Walter A.; Hannequin, Didier; Powell, John F.; Nalls, Michael A.; Ritchie, Karen; Lunetta, Kathryn L.; Kauwe, John S. K.; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R.; Schmidt, Reinhold; Rujescu, Dan; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M.; Graff, Caroline; Psaty, Bruce M.; Haines, Jonathan L.; Lathrop, Mark; Pericak-Vance, Margaret A.; Launer, Lenore J.; Van Broeckhoven, Christine; Farrer, Lindsay A.; van Duijn, Cornelia M.; Ramirez, Alfredo

    2014-01-01

    Background Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci. Significance The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease. PMID:24922517

  20. Impact of ESR1 Gene Polymorphisms on Migraine Susceptibility

    PubMed Central

    Li, Li; Liu, Ruozhuo; Dong, Zhao; Wang, Xiaolin; Yu, Shengyuan

    2015-01-01

    Abstract An increasing number of studies have explored genetic associations between the functionally important polymorphisms in estrogen receptor 1 (ESR1) gene and migraine susceptibility. The previously reported associations have nevertheless been inconsistent. The present work incorporating the published data derived from 8 publications was performed to assess the impact of these polymorphisms on incident migraine. Strength of the genetic risk was estimated by means of an odds ratio along with the 95% confidence interval (OR and 95% CI). From the results, we found individuals who harbored the 325-GG genotype, compared with those harboring the CC genotype or CG and CC combined genotypes, had almost 50% greater risk of migraine. The same genetic models showed notable associations in subgroups of Caucasians and migraine with aura (MA). For 594G>A, a moderately increased risk of migraine was seen under AG versus GG. The AA + AG versus GG model, however, showed a borderline association with migraine. Subgroup analyses according to ethnicity and subtype of migraine provided statistical evidence of significantly increased risk of migraine in Caucasians and of a marginal association with MA, respectively. Both 325C>G and 594G>A polymorphisms showed no major effects either in males or in females. Based on the statistical data, we conclude some of the ESR1 gene polymorphisms may have major contributions to the pathogenesis of migraine in Caucasian populations. PMID:26334887

  1. Dyslexia susceptibility genes influence brain atrophy in frontotemporal dementia

    PubMed Central

    Paternicó, Donata; Premi, Enrico; Alberici, Antonella; Archetti, Silvana; Bonomi, Elisa; Gualeni, Vera; Gasparotti, Roberto; Padovani, Alessandro

    2015-01-01

    Objective: In this study, we evaluated whether variations within genes specifically associated with dyslexia, namely KIAA0319, DCDC2, and CNTNAP2, were associated with greater damage of language-related regions in patients with frontotemporal dementia (FTD) and primary progressive aphasia (PPA) in particular. Methods: A total of 118 patients with FTD, 84 with the behavioral variant of FTD (bvFTD) and 34 with PPA, underwent neuropsychological examination, genetic analyses, and brain MRI. KIAA0319 rs17243157 G/A, DCDC2 rs793842 A/G, and CNTNAP2 rs17236239 A/G genetic variations were assessed. Patients were grouped according to clinical phenotype and genotype status (GA/AA or GG). Gray matter (GM) and white matter (WM) differences were assessed by voxel-based morphometry and structural intercorrelation pattern analyses. Results: Patients carrying KIAA0319 A* (GA or AA) showed greater GM and WM atrophy in the left middle and inferior temporal gyri, as compared with KIAA0319 GG (p < 0.001). The effect of KIAA0319 polymorphism was mainly reported in patients with PPA. In patients with PPA carrying at-risk polymorphism, temporal damage led to loss of interhemispheric and intrahemispheric GM and WM structural association. No effect of DCDC2 and CNTNAP2 was found. Conclusions: Genes involved in dyslexia susceptibility, such as KIAA0319, result in language network vulnerability in FTD, and in PPA in particular. PMID:27066561

  2. IL18 Gene Variants Influence the Susceptibility to Chagas Disease

    PubMed Central

    Leon Rodriguez, Daniel A; Carmona, F. David; Echeverría, Luis Eduardo; González, Clara Isabel; Martin, Javier

    2016-01-01

    Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC). Interleukin 18 (IL18) encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and CCC (n = 401), were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77), rs360719 (P = 1.49E-03, OR = 0.76), rs2043055 (P = 2.52E-03, OR = 1.29), and rs1946518 (P = 0.0162, OR = 1.22). However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control. PMID:27027876

  3. Differential Gene Susceptibility to Sperm DNA Damage: Analysis of Developmental Key Genes in Trout

    PubMed Central

    González-Rojo, Silvia; Fernández-Díez, Cristina; Guerra, Susana M.; Robles, Vanesa; Herraez, Maria Paz

    2014-01-01

    Sperm chromatin in mammals is packaged in different blocks associated to protamines (PDNA), histones (HDNA), or nuclear matrix proteins. Differential packaging has been related to early or late transcription and also to differential susceptibility to genotoxic damage. Genes located in the more accessible HDNA could be more susceptible to injuries than those located in PDNA, being potential biomarkers of paternal DNA damage. Fish sperm chromatin organization is much diversified, some species lacking protamines and some others totally depleted of histones. Analyzing genotoxic damage in a species homogeneously compacted with some sperm nuclear basic protein type, could help in deciphering the clues of differential susceptibility to damage. In the present study we analyzed in rainbow trout the differential susceptibility of nine genes to UV irradiation and H2O2 treatment. The absence of histones in the sperm nuclei was confirmed by Western blot. The chromatin fractionation in sensitive and resistant regions to PvuII (presumably HDNA-like and PDNA-like, respectively) revealed that the nine genes locate in the same resistant region. The number of lesions promoted was quantified using a qPCR approach. Location of 8-hydroxyguanosine (8-OHdG) was analyzed by immunocytochemistry and confocal microscopy. UV irradiation promoted similar number of lesions in all the analyzed genes and a homogenous distribution of 8-OHdG within the nuclei. 8-OHdG was located in the peripheral area of the nucleus after H2O2 treatment, which promoted a significantly higher number of lesions in developmental-related genes (8.76–10.95 lesions/10 kb) than in rDNA genes (1.05–1.67 lesions/10 kb). We showed for the first time, that differential susceptibility to damage is dependent on the genotoxic mechanism and relies on positional differences between genes. Sensitive genes were also analyzed in cryopreserved sperm showing a lower number of lesions than the previous treatments and a predominant

  4. Liver X Receptor Gene Polymorphisms in Tuberculosis: Effect on Susceptibility

    PubMed Central

    Liu, Li-rong; Yue, Jun; Zhao, Yan-lin; Xiao, He-ping

    2014-01-01

    Objectives The Liver X receptors (LXRs), Liver X receptor A (LXRA) and Liver X receptor B (LXRB), regulate lipid metabolism and antimicrobial response. LXRs have a crucial role in the control of Mycobacterium tuberculosis (M.tb). Lacking LXRs mice is more susceptibility to infection M.tb, developing higher bacterial burdens and an increase in the size and number of granulomatous lesions. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRs and risk of tuberculosis. Methods We sequenced the LXRs genes to detect SNPs and to examine genotypic frequencies in 600 patients and 620 healthy controls to investigate for associations with tuberculosis (TB) in the Chinese Han population. DNA re-sequencing revealed eight common variants in the LXRs genes. Results The G allele of rs1449627 and the T allele of rs1405655 demonstrated an increased risk of developing TB (p<0.001, p = 0.002), and the T allele of rs3758673, the T allele of rs2279238, and the C allele of rs1449626 in LXRA and the C allele of rs17373080, the G allele of rs2248949, and the C allele of rs1052677 in LXRB were protective against TB patients compared to healthy controls (p = 0.0002, p = 0.006, p<0.001, p = 0.004, p = 0.008, p = 0.003, respectively). All SNP genotypes were significantly associated with TB. An estimation of the frequencies of haplotypes revealed two potential risk haplotypes,GGCG in LXRB (p = 0.004,) and TTCG in LXRA (p<0.001, p = 0.004). Moreover, three protective haplotypes, TTAT and CCAT in LXRA and CATC in LXRB, were significantly “protective” (p = 0.008, p<0.001, p = 0.031) for TB. Furthermore, we determined that the LXRs SNPs were nominally associated with the clinical pattern of disease. Conclusions Our study data supported that LXRs play a fundamental role in the genetic susceptibility to TB and to different clinical patterns of disease. Thus, further investigation is required in larger populations and in

  5. Susceptibility Genes for Multiple Sclerosis Identified in a Gene-Based Genome-Wide Association Study

    PubMed Central

    Lin, Xiang; Deng, Fei-Yan; Lu, Xin

    2015-01-01

    Background and Purpose Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system. The aim of this study was to identify more genes associated with MS. Methods Based on the publicly available data of the single-nucleotide polymorphism-based genome-wide association study (GWAS) from the database of Genotypes and Phenotypes, we conducted a powerful gene-based GWAS in an initial sample with 931 family trios, and a replication study sample with 978 cases and 883 controls. For interesting genes, gene expression in MS-related cells between MS cases and controls was examined by using publicly available datasets. Results A total of 58 genes was identified, including 20 "novel" genes significantly associated with MS (p<1.40×10-4). In the replication study, 44 of the 58 identified genes had been genotyped and 35 replicated the association. In the gene-expression study, 21 of the 58 identified genes exhibited differential expressions in MS-related cells. Thus, 15 novel genes were supported by replicated association and/or differential expression. In particular, four of the novel genes, those encoding myelin oligodendrocyte glycoprotein (MOG), coiled-coil alpha-helical rod protein 1 (CCHCR1), human leukocyte antigen complex group 22 (HCG22), and major histocompatibility complex, class II, DM alpha (HLA-DMA), were supported by the evidence of both. Conclusions The results of this study emphasize the high power of gene-based GWAS in detecting the susceptibility genes of MS. The novel genes identified herein may provide new insights into the molecular genetic mechanisms underlying MS. PMID:26320842

  6. Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus

    PubMed Central

    Hughes, Travis; Adler, Adam; Kelly, Jennifer A.; Kaufman, Kenneth M.; Williams, Adrienne; Langefeld, Carl D.; Brown, Elizabeth E.; Alarcón, Graciela S.; Kimberly, Robert P.; Edberg, Jeffrey C.; Ramsey-Goldman, Rosalind; Petri, Michelle; Boackle, Susan A.; Stevens, Anne M.; Reveille, John D.; Sanchez, Elena; Martin, Javier; Niewold, Timothy B.; Vilá, Luis M.; Scofield, R Hal; Gilkeson, Gary S.; Gaffney, Patrick M.; Criswell, Lindsey A.; Moser, Kathy L.; Merrill, Joan T.; Jacob, Chaim O.; Tsao, Betty P.; James, Judith A.; Vyse, Timothy J.; Alarcón-Riquelme, Marta E.; Harley, John B.; Richardson, Bruce C.; Sawalha, Amr H.

    2011-01-01

    Objective Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis is established in lupus. We test for gene-gene interactions in a number of known lupus susceptibility loci. Methods Eighteen SNPs tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 lupus patients and 3,818 normal healthy controls of European descent. Epistasis was tested using a 2-step approach utilizing both parametric and non-parametric methods. The false discovery rate (FDR) method was used to correct for multiple testing. Results We detected and confirmed gene-gene interactions between the HLA region and CTLA4, IRF5, and ITGAM, and between PDCD1 and IL21 in lupus patients. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (Interaction odds ratio=1.19, z-score= 3.95, P= 7.8×10−5 (FDR≤0.05), PMDR= 5.9×10−45). Importantly, our data suggest that in lupus patients the presence of the HLA lupus-risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus-risk allele in IRF5 (rs2070197) by 17% and 16%, respectively (P= 0.0028 and 0.0047). Conclusion We provide evidence for gene-gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability. PMID:21952918

  7. TERT gene harbors multiple variants associated with pancreatic cancer susceptibility.

    PubMed

    Campa, Daniele; Rizzato, Cosmeri; Stolzenberg-Solomon, Rachael; Pacetti, Paola; Vodicka, Pavel; Cleary, Sean P; Capurso, Gabriele; Bueno-de-Mesquita, H B As; Werner, Jens; Gazouli, Maria; Butterbach, Katja; Ivanauskas, Audrius; Giese, Nathalia; Petersen, Gloria M; Fogar, Paola; Wang, Zhaoming; Bassi, Claudio; Ryska, Miroslav; Theodoropoulos, George E; Kooperberg, Charles; Li, Donghui; Greenhalf, William; Pasquali, Claudio; Hackert, Thilo; Fuchs, Charles S; Mohelnikova-Duchonova, Beatrice; Sperti, Cosimo; Funel, Niccola; Dieffenbach, Aida Karina; Wareham, Nicholas J; Buring, Julie; Holcátová, Ivana; Costello, Eithne; Zambon, Carlo-Federico; Kupcinskas, Juozas; Risch, Harvey A; Kraft, Peter; Bracci, Paige M; Pezzilli, Raffaele; Olson, Sara H; Sesso, Howard D; Hartge, Patricia; Strobel, Oliver; Małecka-Panas, Ewa; Visvanathan, Kala; Arslan, Alan A; Pedrazzoli, Sergio; Souček, Pavel; Gioffreda, Domenica; Key, Timothy J; Talar-Wojnarowska, Renata; Scarpa, Aldo; Mambrini, Andrea; Jacobs, Eric J; Jamroziak, Krzysztof; Klein, Alison; Tavano, Francesca; Bambi, Franco; Landi, Stefano; Austin, Melissa A; Vodickova, Ludmila; Brenner, Hermann; Chanock, Stephen J; Delle Fave, Gianfranco; Piepoli, Ada; Cantore, Maurizio; Zheng, Wei; Wolpin, Brian M; Amundadottir, Laufey T; Canzian, Federico

    2015-11-01

    A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 × 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D' = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10(-5) ), rs4583925 (p = 4.0 × 10(-5) ) and rs2735948 (p = 5.0 × 10(-5) ). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. PMID:25940397

  8. Schizophrenia susceptibility gene locus at Xp22.3.

    PubMed

    Milunsky, J; Huang, X L; Wyandt, H E; Milunsky, A

    1999-06-01

    Multiple genetic loci have been implicated in the search for schizophrenia susceptibility genes, none having been proven as causal. Genetic heterogeneity is probable in the polygenic etiology of schizophrenia. We report on two unrelated Caucasian women with paranoid schizophrenia (meeting Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria) who have an Xp22.3 overlapping deletion characterized by fluorescence in situ hybridization (FISH). Patient 1 was previously reported by us (Wyandt HE, Bugeau-Michaud L, Skare JC, Milunsky A. Partial duplication of Xp: a case report and review of previously reported cases. Amer J Med Genet 1991: 40: 280-283) to have a de novo partial duplication of Xp. At that time, she was a 24-year-old woman with short stature, irregular menses, other abnormalities suggestive of Turner syndrome, and paranoid schizophrenia. Recently, FISH analysis demonstrated that she has an inverted duplication (X)(p22.1p11.2) and a microscopic deletion (X)(p22.2p22.3) between DXS1233 and DXS7108 spanning approximately 16-18 cM. Patient 2 is a 14-year-old girl with short stature, learning disabilities, and paranoid schizophrenia. High-resolution chromosome analysis revealed a de novo deletion involving Xp22. FISH analysis showed that the deletion (X)(p22.2p22.3) spanned 10-12 cM between AFMB290XG5 and DXS1060. Given that deletions of Xp22 are not common events, the occurrence of two unrelated schizophrenia patients with an overlapping deletion of this region would be extraordinarily rare. Hence, the deletion within Xp22.3 almost certainly contains a gene involved in the pathogenesis of paranoid schizophrenia. PMID:10450863

  9. Adult onset retinoblastoma.

    PubMed

    Sengupta, Sabyasachi; Pan, Utsab; Khetan, Vikas

    2016-07-01

    Retinoblastoma (RB) is the most common primary malignant intraocular tumor of childhood presenting usually before 5 years of age. RB in adults older than 20 years is extremely rare. A literature search using PubMed/PubMed Central, Scopus, Google Scholar, EMBASE, and Cochrane databases revealed only 45 cases till date. Over the past decade, there has been a significant increase in the number of such reports, indicating heightened level of suspicion among ophthalmologists. Compared to its pediatric counterpart, adult onset RB poses unique challenges in diagnosis and treatment. This article summarizes available literature on adult onset RB and its clinical and pathologic profile, genetics, association with retinocytoma, diagnostics, treatment, and outcomes. PMID:27609158

  10. Kif14 overexpression accelerates murine retinoblastoma development.

    PubMed

    O'Hare, Michael; Shadmand, Mehdi; Sulaiman, Rania S; Sishtla, Kamakshi; Sakisaka, Toshiaki; Corson, Timothy W

    2016-10-15

    The mitotic kinesin KIF14 has an essential role in the recruitment of proteins required for the final stages of cytokinesis. Genomic gain and/or overexpression of KIF14 has been documented in retinoblastoma and a number of other cancers, such as breast, lung and ovarian carcinomas, strongly suggesting its role as an oncogene. Despite evidence of oncogenic properties in vitro and in xenografts, Kif14's role in tumor progression has not previously been studied in a transgenic cancer model. Using a novel Kif14 overexpressing, simian virus 40 large T-antigen retinoblastoma (TAg-RB) double transgenic mouse model, we aimed to determine Kif14's role in promoting retinal tumor formation. Tumor initiation and development in double transgenics and control TAg-RB littermates were documented in vivo over a time course by optical coherence tomography, with subsequent ex vivo quantification of tumor burden. Kif14 overexpression led to an accelerated initiation of tumor formation in the TAg-RB model and a significantly decreased tumor doubling time (1.8 vs. 2.9 weeks). Moreover, overall percentage tumor burden was also increased by Kif14 overexpression. These data provide the first evidence that Kif14 can promote tumor formation in susceptible cells in vivo. PMID:27270502

  11. Gene expression profiling of Naïve sheep genetically resistant and susceptible to gastrointestinal nematodes

    PubMed Central

    Keane, Orla M; Zadissa, Amonida; Wilson, Theresa; Hyndman, Dianne L; Greer, Gordon J; Baird, David B; McCulloch, Alan F; Crawford, Allan M; McEwan, John C

    2006-01-01

    Background Gastrointestinal nematodes constitute a major cause of morbidity and mortality in grazing ruminants. Individual animals or breeds, however, are known to differ in their resistance to infection. Gene expression profiling allows us to examine large numbers of transcripts simultaneously in order to identify those transcripts that contribute to an animal's susceptibility or resistance. Results With the goal of identifying genes with a differential pattern of expression between sheep genetically resistant and susceptible to gastrointestinal nematodes, a 20,000 spot ovine cDNA microarray was constructed. This array was used to interrogate the expression of 9,238 known genes in duodenum tissue of four resistant and four susceptible female lambs. Naïve animals were used in order to look at genes that were differentially expressed in the absence of infection with gastrointestinal nematodes. Forty one unique known genes were identified that were differentially expressed between the resistant and susceptible animals. Northern blotting of a selection of the genes confirmed differential expression. The differentially expressed genes had a variety of functions, although many genes relating to the stress response and response to stimulus were more highly expressed in the susceptible animals. Conclusion We have constructed the first reported ovine microarray and used this array to examine gene expression in lambs genetically resistant and susceptible to gastrointestinal nematode infection. This study indicates that susceptible animals appear to be generating a hyper-sensitive immune response to non-nematode challenges. The gastrointestinal tract of susceptible animals is therefore under stress and compromised even in the absence of gastrointestinal nematodes. These factors may contribute to the genetic susceptibility of these animals. PMID:16515715

  12. Candidate genes and late-onset type 2 diabetes mellitus. Susceptibility genes or common polymorphisms?

    PubMed

    Hansen, Lars

    2003-11-01

    985Met variant in the insulin receptor is associated with type 2 diabetes or that the Met326Val of the p85 alpha regulatory subunit of the phosphoinositide-3 kinase is associated with insulin resistance. We found no coding mutations (missense) in the insulin signalling protein kinases but we confirmed that the 5 bp deletion (PP1ARE) in the 3'-end of the PPP1R3 gene that encodes the glycogen-associated regulatory subunit of protein phosphatase-1 (PP1G) is associated with insulin resistance estimated as insulin mediated glucose uptake. In contrast to protein kinases in skeletal muscles the genes encoding beta-cell transcription factors (IPF-1, NeuroD1/BETA2, and Neurogenin 3) are polymorphic but we could not confirm that the Asp76Asn of IPF-1 is a susceptibility gene for late-onset type 2 diabetes. On the other hand we confirmed that the Ala45Thr variant in NeuroD1/BETA2 may represent a susceptibility gene for type 1 diabetes but none of these genes revealed any MODY-specific mutations. Also the gene encoding the ATP-regulatable potassium channels of the beta-cell (Kir6.2) is polymorphic but none of these polymorphisms associated with changes in glucose-induced insulin secretion. Reviewed in context of the existing data our studies support the candidate gene approach as a feasible method for directly either identifying or excluding any gene as a diabetes-susceptibility gene ("diabetogene"). PMID:14694850

  13. Genetic dissection of susceptibility to radiation-induced apoptosis of thymocytes and mapping of Rapop1, a novel susceptibility gene

    SciTech Connect

    Mori, Nobuko; Okumoto, Masaaki; Esaki, Kozaburo

    1995-02-10

    Genetic dissection of susceptibility to radiation-induced apoptosis of thymocytes was performed by counting dead cells in histologically processed thymuses after 0.5 Gy of whole-body X-irradiation, using recombinant congenic (CcS/Dem) strains derived from inbred mouse strains BALB/cHeA (susceptible) and STS/A (resistant). A high (8/20) number of strains with lower dead cell scores than BALB/cHeA among CcS/Dem recombinant congenic strains (RCS), which contain 12.5% of STS/A genome in the genetic background of BALB/cHeA strain, indicates that the difference between BALB/cHeA and STS/A is caused by several genes and that susceptibility probably requires BALB/ cHeA alleles at more than one locus. Similar results were obtained with CXS/Hg recombinant inbred (CXS/ Hg) strains. Analysis of F{sub 2} hybrids between BALB/ cHeA and CcS-7, one of the CcS/Dem strains that showed lower dead cell scores than BALB/cHeA, demonstrated that a novel gene (Rapop1, radiation-induced apoptosis 1) controlling susceptibility to radiation-induced apoptosis in the thymus is located in the proximal region of mouse chromosome 16. 40 refs., 2 figs., 2 tabs.

  14. Retinoblastoma: One World, One Vision

    PubMed Central

    Rodriguez-Galindo, Carlos; Wilson, Mathew W.; Chantada, Guillermo; Fu, Ligia; Qaddoumi, Ibrahim; Antonelli, Célia; Leal-Leal, Carlos; Sharma, Tarum; Barnoya, Margarita; Epelman, Sidnei; Pizzarello, Louis; Kane, Javier R.; Barfield, Ray; Merchant, Thomas E.; Robison, Leslie L.; Murphree, A. Linn; Chevez-Barrios, Patricia; Dyer, Michael A.; O′Brien, Joan; Ribeiro, Raul C.; Hungerford, John; Helveston, Eugene M.; Haik, Barrett G.; Wilimas, Judith

    2009-01-01

    Retinoblastoma is curable when diagnosed early and treated appropriately; however, the prognosis is dismal when the basic elements in diagnosis and treatment are lacking. In developing countries, poor education, lower socioeconomic conditions, and inefficient health care systems result in delayed diagnosis and suboptimal care. Furthermore, the complexity of multidisciplinary care required is seldom possible. While ocular salvage is a priority in the Western world, death from retinoblastoma is still a major problem in developing countries. To bring the two ends of this spectrum together and provide a forum for discussion, the One World, One Vision symposium was organized, where clinicians and researchers from various cultural, geographic, and socioeconomic backgrounds converged to discuss their experiences. Strategies for early diagnosis in developing countries were discussed. Elements in the development of retinoblastoma centers in developing countries were discussed, and examples of successful programs were highlighted. An important component in this process is twinning between centers in developing countries and mentor institutions in high-income countries. Global initiatives by nongovernmental organizations such as the International Network for Cancer Treatment and Research, Orbis International, and the International Agency for Prevention of Blindness were presented. Treatment of retinoblastoma in developing countries remains a challenge. However, it is possible to coordinate efforts at multiple levels, including public administrations and nonprofit organizations, to improve the diagnosis and treatment of retinoblastoma and to improve the outcome for these children. PMID:18762512

  15. Glucocorticoid Genes and the Developmental Origins of Asthma Susceptibility and Treatment Response

    PubMed Central

    Kho, Alvin T.; Chhabra, Divya; Qiu, Weiliang; Gaedigk, Roger; Vyhlidal, Carrie A.; Leeder, J. Steven; Barraza-Villarreal, Albino; London, Stephanie J.; Gilliland, Frank; Raby, Benjamin A.; Weiss, Scott T.; Tantisira, Kelan G.

    2015-01-01

    Antenatal corticosteroids enhance lung maturation. However, the importance of glucocorticoid genes on early lung development, asthma susceptibility, and treatment response remains unknown. We investigated whether glucocorticoid genes are important during lung development and their role in asthma susceptibility and treatment response. We identified genes that were differentially expressed by corticosteroids in two of three genomic datasets: lymphoblastoid cell lines of participants in the Childhood Asthma Management Program, a glucocorticoid chromatin immunoprecipitation/RNA sequencing experiment, or a murine model; these genes made up the glucocorticoid gene set (GCGS). Using gene expression profiles from 38 human fetal lungs and C57BL/6J murine fetal lungs, we identified developmental genes that were in the top 5% of genes contributing to the top three principal components (PCs) most highly associated with post-conceptional age. Glucocorticoid genes that were enriched in this set of developmental genes were then included in the developmental glucocorticoid gene set (DGGS). We then investigated whether glucocorticoid genes are important during lung development, and their role in asthma susceptibility and treatment response. A total of 232 genes were included in the GCGS. Analysis of gene expression demonstrated that glucocorticoid genes were enriched in lung development (P = 7.02 × 10−26). The developmental GCGS was enriched for genes that were differentially expressed between subjects with asthma and control subjects (P = 4.26 × 10−3) and were enriched after treatment of subjects with asthma with inhaled corticosteroids (P < 2.72 × 10−4). Our results show that glucocorticoid genes are overrepresented among genes implicated in fetal lung development. These genes influence asthma susceptibility and treatment response, suggesting their involvement in the early ontogeny of asthma. PMID:25192440

  16. Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.

    PubMed

    Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel; Lorsch, Zachary S; Walker, Deena M; Wang, Junshi; Huang, Xiaojie; Schlüter, Oliver M; Maze, Ian; Peña, Catherine J; Heller, Elizabeth A; Issler, Orna; Wang, Minghui; Song, Won-Min; Stein, Jason L; Liu, Xiaochuan; Doyle, Marie A; Scobie, Kimberly N; Sun, Hao Sheng; Neve, Rachael L; Geschwind, Daniel; Dong, Yan; Shen, Li; Zhang, Bin; Nestler, Eric J

    2016-06-01

    Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery. PMID:27181059

  17. COMPARATIVE MICROARRAY EXPRESSION ANALYSIS OF SELECTED CANCER RELEVANT GENES IN HYPERTENSIVE RESISTANT VERSUS SUSCEPTIBLE RODENT STRAINS

    EPA Science Inventory

    Hypertension and cancer are prevalent diseases. Epidemiological studies suggest that hypertension may increase the long term risk of cancer. Identification of resistance and/or susceptibility genes using rodent models could provide important insights into the management and treat...

  18. Genome-Wide Transcriptome Directed Pathway Analysis of Maternal Pre-Eclampsia Susceptibility Genes

    PubMed Central

    Yong, Hannah E. J.; Melton, Phillip E.; Johnson, Matthew P.; Freed, Katy A.; Kalionis, Bill; Murthi, Padma; Brennecke, Shaun P.; Keogh, Rosemary J.; Moses, Eric K.

    2015-01-01

    Background Preeclampsia (PE) is a serious hypertensive pregnancy disorder with a significant genetic component. Numerous genetic studies, including our own, have yielded many susceptibility genes from distinct functional groups. Additionally, transcriptome profiling of tissues at the maternal-fetal interface has likewise yielded many differentially expressed genes. Often there is little overlap between these two approaches, although genes identified in both approaches are significantly associated with PE. We have thus taken a novel integrative bioinformatics approach of analysing pathways common to the susceptibility genes and the PE transcriptome. Methods Using Illumina Human Ht12v4 and Wg6v3 BeadChips, transcriptome profiling was conducted on n = 65 normotensive and n = 60 PE decidua basalis tissues collected at delivery. The R software package libraries lumi and limma were used to preprocess transcript data for pathway analysis. Pathways were analysed and constructed using Pathway Studio. We examined ten candidate genes, which are from these functional groups: activin/inhibin signalling—ACVR1, ACVR1C, ACVR2A, INHA, INHBB; structural components—COL4A1, COL4A2 and M1 family aminopeptidases—ERAP1, ERAP2 and LNPEP. Results/Conclusion Major common regulators/targets of these susceptibility genes identified were AGT, IFNG, IL6, INHBA, SERPINE1, TGFB1 and VEGFA. The top two categories of pathways associated with the susceptibility genes, which were significantly altered in the PE decidual transcriptome, were apoptosis and cell signaling (p < 0.001). Thus, susceptibility genes from distinct functional groups share similar downstream pathways through common regulators/targets, some of which are altered in PE. This study contributes to a better understanding of how susceptibility genes may interact in the development of PE. With this knowledge, more targeted functional analyses of PE susceptibility genes in these key pathways can be performed to examine their

  19. Prion permissive pathways: extracellular matrix genes control susceptibility to prion infection

    PubMed Central

    Imberdis, Thibaut; Harris, David A

    2014-01-01

    There are wide variations in the susceptibility of humans, animals, and cultured cell lines to infection by prions. In this issue of The EMBO Journal, Marbiah et al (2014) identified a gene regulatory network that regulates the susceptibility of cultured cells to prion infection. Surprisingly, a number of these genes impact the structure of the extracellular matrix. These results have important implications for understanding mechanisms of prion infection and also suggest new therapeutic targets. PMID:24952893

  20. Susceptibility genes in the pathogenesis of murine lupus

    PubMed Central

    2002-01-01

    Chapter summary Systemic lupus erythematosus (SLE) is the paradigm of a multisystem autoimmune disease in which genetic factors strongly influence susceptibility. Through genome scans and congenic dissection, numerous loci associated with lupus susceptibility have been defined and the complexity of the inheritance of this disease has been revealed. In this review, we provide a brief description of animal models of SLE, both spontaneous models and synthetic models, with an emphasis on the B6 congenic model derived from analyses of the NZM2410 strain. A hypothetical model of disease progression that organizes many of the identified SLE susceptibility loci in three distinct biological pathways that interact to mediate disease pathogenesis is also described. We finally discuss our recent fine mapping analysis, which revealed a cluster of loci that actually comprise the Sle1 locus. PMID:12110145

  1. Linkage proof for PTPN22, a rheumatoid arthritis susceptibility gene and a human autoimmunity gene

    PubMed Central

    Michou, Laëtitia; Lasbleiz, Sandra; Rat, Anne-Christine; Migliorini, Paola; Balsa, Alejandro; Westhovens, René; Barrera, Pilar; Alves, Helena; Pierlot, Céline; Glikmans, Elodie; Garnier, Sophie; Dausset, Jean; Vaz, Carlos; Fernandes, Manuela; Petit-Teixeira, Elisabeth; Lemaire, Isabelle; Pascual-Salcedo, Dora; Bombardieri, Stefano; Dequeker, Jan; Radstake, Timothy R.; Van Riel, Piet; van de Putte, Leo; Lopes-Vaz, Antonio; Prum, Bernard; Bardin, Thomas; Dieudé, Philippe; Cornélis, François

    2007-01-01

    The tyrosine phosphatase PTPN22 allele 1858T has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. RA is the most frequent of those multifactorial diseases. The RA association was usually restricted to serum rheumatoid factor positive disease (RF+). No interaction was shown with HLA-DRB1, the first RA gene. Many case-control studies replicated the RA association, showing an allele frequency increase of ≈5% on average and large variations of population allele frequencies (2.1–15.5%). In multifactorial diseases, the final proof for a new susceptibility allele is provided by departure from Mendel's law (50% transmission from heterozygous parents). For PTPN22–1858T allele, convincing linkage proof was available only for type 1 diabetes. We aimed at providing this proof for RA. We analyzed 1,395 West European Caucasian individuals from 465 “trio” families. We replicated evidence for linkage, demonstrating departure from Mendel's law in this subset of early RA onset patients. We estimated the overtransmission of the 1858T allele in RF+ families: T = 63%, P < 0.0007. The 1858T allele frequency increased from 11.0% in controls to 17.4% in RF+ RA for the French Caucasian population and the susceptibility genotype (1858T/T or T/C) from 20.2% to 31.6% [odds ratio (OR) = 1.8 (1.2–2.8)]. In conclusion, we provided the linkage proof for the PTPN22–1858T allele and RF+ RA. With diabetes and RA, PTPN22 is therefore a “linkage-proven” autoimmunity gene. PTPN22 accounting for ≈1% of the RA familial aggregation, many new genes could be expected that are as many leads to definitive therapy for autoimmune diseases. PMID:17237219

  2. Adenocarcinoma of the ethmoid following radiotherapy for bilateral retinoblastoma

    SciTech Connect

    Rowe, L.D.; Lane, R.; Snow, J.B. Jr.

    1980-01-01

    Adenocarcinoma of the ethmoid sinus is rare, representing only 4 to 8% of malignancies of the paranasal sinuses. An extraordinary case of papillary adenocarcinoma of the ethmoid sinus arising 30 years following high-dose radiotherapy for bilateral retinoblastoma is presented. Histologically, the findings of a papillary pattern of poorly differentiated, mucicarmine-staining cells enclosing gland-like spaces, and the absence of pseudorosettes, melanin, mesenchymal and peripheral neural elements supports an epithelial origin of this tumor. The high incidence of second fatal primary neoplasms in patients with bilateral retinoblastomas receiving radiation suggests an innate susceptibility that may add to the risk of radiotherapy. Careful long-term head and neck surveillance is mandatory if early aggressive management of these extremely lethal tumors is to be successful.

  3. Fluconazole susceptibility and ERG11 gene expression in vaginal candida species isolated from Lagos Nigeria.

    PubMed

    Pam, Victoria K; Akpan, Juliet U; Oduyebo, Oyinlola O; Nwaokorie, Francisca O; Fowora, Muinah A; Oladele, Rita O; Ogunsola, Folasade T; Smith, Stella I

    2012-01-01

    Fluconazole resistance is an important type of resistance in Candida because in most countries, fluconazole is the drug of choice for vulvovaginal candidiasis. Candida species resist fluconazole by various mechanisms but there is paucity of data on these in our environment. Such mechanisms include among others, over-expression of the ERG11 gene, which codes for synthesis of the target enzymes in the fungus. The aim of this study was to screen Candida spp. resistant to fluconazole for the expression of ERG11 gene. Fluconazole susceptibility test was performed on 28 clinical strains of Candida species previously obtained from students of a School of Nursing in Lagos, Nigeria. They were identified by API Candida, CHROMagar candida and germ tube test. Using 25 mcg discs, fluconazole susceptibility was determined by the disc diffusion method and results were interpreted in accordance with the Clinical Laboratory Standard Institute (CLSI) criteria; sensitive (S), resistant (R) and susceptible dose dependent (SDD). The R and SDD isolates were subsequently evaluated for the presence of ERG11 gene. Of the 28 clinical isolates, 14 were identified as C. albicans and six as C. tropicalis. The remaining isolates were identified as C. glabrata (2), C. famata (2) C. kefyr (2) one each of C. parapsilosis and C. guilliermondii respectively. In this study, 18 were susceptible (S) to fluconazole, eight were SDD and two were resistant to the antifungal agent. Out of the 14 C. albicans isolates, 12 were susceptible, one showed high level resistance and similar number showed susceptible dose dependence. ERG11 was detected in three susceptible dose dependent Candida species. This analysis demonstrates that susceptible dose dependence should not be overlooked as it may be associated with the presence of ERG11 gene and resistance to fluconazole. There is a need to consider routine antifungal susceptibility testing for Candida species causing vulvovaginitis. PMID:22493755

  4. Methionine synthase A2756G variation is associated with the risk of retinoblastoma in Iranian children.

    PubMed

    Akbari, Mohammad Taghi; Naderi, Asieh; Saremi, Leila; Sayad, Arezou; Irani, Shiva; Ahani, Ali

    2015-12-01

    Association of epigenetic modifications with cancer has been widely studied. Gene-specific hypermethylation and global DNA hypomethylation are the most frequently observed patterns in great number of tumors. The methionine synthase (MTR) gene plays key role in maintaining adequate intracellular folate, methionine and normal homocysteine concentrations and, its polymorphism have been associated with the risk of retinoblastoma and other neoplasms. We evaluated the association of MTR A2756G polymorphism with the risk of retinoblastoma in an Iranian population. Totally, 150 retinoblastoma patients and 300 individuals with no family history of cancer as control were included in this study. Genotyping of the A2756G polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) using the restriction enzymes HaeIII. Our results showed that the "G" was the minor allele with a frequency of 31.7% and 20.3% in both retinoblastoma and control groups, respectively. The frequency of the 2756GG genotype (P=0.023) and 2756G allele (P=0.0001) were significantly higher in the patients than control group, respectively. Individual with the 2756GG genotype had a 2.99 fold increased risk for retinoblastoma. According to our results, the MTR A2756G polymorphism was associated with the risk of retinoblastoma in Iranian patients. PMID:26595280

  5. New genes linked to lung cancer susceptibility in Asian women

    Cancer.gov

    An international group of scientists has identified three genes that predispose Asian women who have never smoked to lung cancer. The discovery of specific genetic variations, which have not previously been associated with lung cancer risk in other popul

  6. Retinoblastoma: concerning its initiation and treatment.

    PubMed

    Luo, Chang; Deng, Ying-Ping

    2013-01-01

    Retinoblastoma (RB) is the most common intraocular cancer of infancy and childhood. This cancer is initiated by mutation on RB1, the tumor suppressor gene that is responsible for the regulation of both cell cycle and gnome stability in retinal cells. Patients with a constitutional mutation on RB1 can be inherited. RB occurs approximately 1 in every 15 000-20 000 live births. The worldwide mortality for this cancer is about 5%-11%. However, this rate rises to about 40%-70% in developing countries due to a delay in diagnosis. A wide variety of options are available for the treatment, but often a combination of therapies is adopted to optimize individualized care. PMID:23826540

  7. Ferritin2 gene in paraquat-susceptible and resistant biotypes of horseweed Conyza canadensis (L.) Cronq.

    PubMed

    Soós, Vilmos; Jóri, Balázs; Páldi, Emil; Szego, Dóra; Szigeti, Zoltán; Rácz, Ilona; Lásztity, Demeter

    2006-09-01

    Ferritins, the multimeric iron storage proteins, are the main regulators of the cellular level of uncomplexed iron. Ferritins are encoded by small gene families and expressed differentially under various developmental conditions depending on iron availability, effect of hormones or oxygen radical generating agents. In the present work the primary structure of the ferritin2 gene from resistant and susceptible biotypes of horseweed Conyza canadensis was determined. This gene was found to exhibit great similarity and possess all the structural characteristics of known plant ferritin2 genes. The C. canadensis ferritin2 genes had identical primary structure in the two biotypes and were upregulated by paraquat (Pq) in both susceptible and resistant plants. The enhanced expression level was probably connected with defence reactions in the plants after Pq treatment. PMID:16949961

  8. The Epigenetic Modifications of Genes Associated with Tuberculosis Susceptibility and Implications for Epi-Drugs.

    PubMed

    Zeng, Jie; Xie, Longxiang; Luo, Hongping; Xie, Jianping

    2015-01-01

    Epigenetics of genes associated with tuberculosis susceptibility such as DNA methylation, posttranslational histone modifications, and non-coding RNA remain largely untapped field for better tuberculosis control. Many genes involved in tuberculosis susceptibility (e.g., NRAMP1 (SLC11A1), IFNG, NOS2A, VDR, ISG15, TACO, TLR1, TLR, IL18R1, chemokines, PADI, DUSP14, MBL, and MASP-2) have been subjected to epigenetic modification. Our summary of these modifications provides fresh insights into the pathogenesis of tuberculosis and inspires targets discovery for host-derived therapy. PMID:26559095

  9. Combination of hearing screening and genetic screening for deafness-susceptibility genes in newborns

    PubMed Central

    YAO, GEN-DONG; LI, SHOU-XIA; CHEN, DING-LI; FENG, HAI-QIN; ZHAO, SU-BIN; LIU, YONG-JIE; GUO, LI-LI; YANG, ZHI-MING; ZHANG, XIAO-FANG; SUN, CAI-XIA; WANG, ZE-HUI; ZHANG, WEI-YONG

    2014-01-01

    The aim of this study was to determine the clinical significance of the results of screening of newborn hearing and the incidence of deafness-susceptibility genes. One thousand newborn babies in the Handan Center Hospital (Handan, China) underwent screening of hearing and deafness-susceptibility genes. The first screening test was carried out using otoacoustic emissions (OAEs). Babies with hearing loss who failed to pass the initial screening were scheduled for rescreening at 42 days after birth. Cord blood was used for the screening of deafness-susceptibility genes, namely the GJB2, SLC26A4 and mitochondrial 12S rRNA (MTRNR1) genes. Among the 1,000 neonates that underwent the first hearing screening, 25 exhibited left-sided hearing loss, 21 exhibited right-sided hearing loss and 15 cases had binaural hearing loss. After rescreening 42 days later, only one of the initial 61 cases exhibited hearing loss under OAE testing. The neonatal deafness gene tests showed two cases with 1555A>G mutation and two cases with 1494C>T mutation of the MTRNR1 gene. In the SLC26A4 gene screening, four cases exhibited the heterozygous IVS7-2A>G mutation and one case exhibited heterozygous 1226G>A mutation. In the GJB2 gene screening, two cases exhibited the homozygous 427C>T mutation and 10 exhibited the heterozygous 235delC mutation. The genetic screening revealed 21 newborns with mutations in the three deafness-susceptibility genes. The overall carrier rate was 2.1% (21/1,000). The association of hearing and gene screening may be the promising screening strategy for the diagnosis of hearing loss. PMID:24348793

  10. Conservative treatment modalities in retinoblastoma

    PubMed Central

    Chawla, Bhavna; Jain, Amit; Azad, Rajvardhan

    2013-01-01

    Retinoblastoma is the most common primary intraocular malignancy of childhood. A potentially curable cancer, its treatment has improved significantly over the last few decades. The purpose of this article is to review the literature on various conservative treatment modalities available for the treatment of retinoblastoma and their effectiveness, when used alone or in combination. Pubmed, Medline, Embase, and the Cochrane library were searched through 2012 for published peer reviewed data on conservative treatment modalities for retinoblastoma. Various studies show that while enucleation remains the standard of care for advanced intraocular tumors, conservative modalities that can result in globe salvage and preservation of useful vision are being increasingly employed. Such modalities include systemic chemotherapy, focal consolidation with transpupillary thermotherapy, laser photocoagulation and cryotherapy, plaque brachytherapy, and delivery of local chemotherapy using subconjunctival, sub-tenon, or intra-arterial routes. When used alone or in combination, these treatment modalities can help in avoidance of external beam radiotherapy or enucleation, thus reducing the potential for long-term side effects, while salvaging useful vision. Radioactive plaque brachytherapy has an established role in selected patients with intraocular retinoblastoma. Local injections of chemotherapeutic agents via the sub-tenon or sub-conjunctival route have been used with varying degrees of success, usually as an adjunct to systemic chemotherapy. Intra-arterial ophthalmic artery delivery of melphalan has shown promising results. It is important to recognize that today, several treatment options are available that can obviate the need for enucleation, and cure the cancer with preservation of functional vision. A thorough knowledge and understanding of these conservative treatment modalities is essential for appropriate management. PMID:24104705

  11. Congenic mapping and candidate sequencing of susceptibility genes for Type 1 diabetes in the NOD mouse.

    PubMed

    Ikegami, Hiroshi; Fujisawa, Tomomi; Makino, Susumu; Ogihara, Toshio

    2003-11-01

    Inheritance of type 1 diabetes is polygenic with a major susceptibility gene located in the major histocompatibility complex (MHC). In addition to MHC-linked susceptibility, a number of susceptibility genes have been mapped outside the MHC in both humans and animal models. In order to localize and identify susceptibility genes for type 1 diabetes, we have developed a series of congenic strains in which either susceptibility intervals from the NOD mouse, a mouse model of type 1 diabetes, were introgressed onto control background genes or protective intervals from control strains were introgressed onto NOD background genes. NOD. CTS-H-2 congenic mice, which possess recombinant MHC with NOD alleles at class II A and E genes, which are candidates for Idd1, revealed that Idd1 consists of multiple components, one in class II (Idd1) and the other adjacent to, but distinct from, Idd1 (Idd16). Phenotypes of NOD. IIS-Idd3 congenic mice, which share the same alleles at both Il2 and Il21 as the NOD mouse, were indistinguishable from the NOD parental strain, indicating that both Il2 and Il21 are candidates for Idd3. In contrast, NOD. IIS-Idd10 congenic mice, which share the same alleles at Fcgr1, a previous candidate for Idd10, as the NOD mouse, were protected from type 1 diabetes, suggesting that Fcgr1 may not be responsible for the Idd10 effect. These data suggest that the use of strain colony closely related to a disease model to find the same candidate mutation on different haplotypes and make congenic strains with this recombinant chromosome, termed ancestral haplotype congenic mapping, is an effective strategy for fine mapping and identification of genes responsible for complex traits. PMID:14679059

  12. The role of ERBB2 gene polymorphisms in leprosy susceptibility.

    PubMed

    Rêgo, Jamile Leão; Oliveira, Joyce Moura; Santana, Nadja de Lima; Machado, Paulo Roberto Lima; Castellucci, Léa Cristina

    2015-01-01

    Mycobacterium leprae infects skin and peripheral nerves causing deformities and disability. The M. leprae bacterium binds to ErbB2 on the Schwann cell surface causing demyelination and favoring spread of the bacilli and causing nerve injury. Polymorphisms at the ERBB2 gene were previously investigated as genetic risk factors for leprosy in two Brazilian populations but with inconsistent results. Herein we extend the analysis of ERBB2 variants to a third geographically distinct population in Brazil. Our results show that there is no association between the genotyped SNPs and the disease (p>0.05) in this population. A gene set or pathway analysis under the genomic region of ERBB2 will be necessary to clarify its regulation under M. leprae stimulus. PMID:25636184

  13. Testing candidate genes that may affect susceptibility to leprosy.

    PubMed

    Cervino, A C; Curnow, R N

    1997-12-01

    Several statistical methods have been used to search familial data sets for marker alleles associated with the occurrence of a disease. In the present paper, a recently developed method is used to re-analyze published data on leprosy and candidate genes at the HLA loci. This new method of analysis, the randomization transmission disequilibrium test (TDT), confirmed previous conclusions that there was no significant evidence against random transmission at the HLA-A locus but significant positive association with the HLA-DR2 allele. The randomization TDT detected significant protective associations, that had not previously been found, with alleles HLA-B8 in Egyptian families and HLA-B21 (current nomenclature B x 4901, 5001-5002) in South Indian families, highlighting a major advantage of permutation tests in analyzing candidate gene loci with rare alleles. These findings provide evidence that HLA class I restricted T lymphocytes may be of protective importance in leprosy. PMID:9465154

  14. Genome Screen to Detect Linkage to Intracranial Aneurysm Susceptibility Genes

    PubMed Central

    Foroud, Tatiana; Sauerbeck, Laura; Brown, Robert; Anderson, Craig; Woo, Daniel; Kleindorfer, Dawn; Flaherty, Matthew L.; Deka, Ranjan; Hornung, Richard; Meissner, Irene; Bailey-Wilson, Joan E.; Rouleau, Guy; Sander Connolly, E.; Lai, Dongbing; Koller, Daniel L.; Huston, John; Broderick, Joseph P.

    2008-01-01

    Background and Purpose Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA. Methods Multiplex families having at least 2 individuals with “definite” or “probable” IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a gene×smoking (pack-years) interaction. Results The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P=0.03), 7 (LOD=4.1; P=0.01) and 12 (LOD=3.6; P=0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking. Conclusions We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a gene×smoking interaction with 3 of the loci. PMID:18323491

  15. Analysis on the susceptibility genes in two chinese pedigrees with familial Parkinson's disease.

    PubMed

    Xu, Changshui; Xu, Jun; Zhang, Yanmin; Ma, Jianjun; Kawakami, Hideshi; Maruyama, Hirofumi; Kamada, Masaki

    2010-01-01

    Objective. To screen the susceptibility genes in Chinese pedigrees with early-onset familial Parkinson's disease (FPD). Methods. Fifty-one genomic DNA samples extracted from two Chinese pedigrees with FPD, the alpha-synuclein genes (SNCA), the leucine-rich repeat kinase 2(LRRK2), PINK1(PTEN-induced putative kinase 1), PARK7(Protein DJ1), PARK2(Parkinson juvenile disease protein 2), the glucocerebrosidase (GBA), and ATP(Ezrin-binding protein PACE-1), were sequenced by the use of polymerase chain reaction (PCR) technique. The gene dose of SNCA was checked. Results. There were only two missense mutations observed, respectively, at exon 5 of LRRK2 and exon 10 of PARK2, and both were enrolled in SNPs. Conclusion. No meaningful mutations could be detected, and other susceptibility genes should be detected in FDP patients in China. PMID:21188226

  16. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1

    SciTech Connect

    Miki, Y.; Swenson, J.; Yakumo, K.; Lewis, C.; Neuhausen, S.; Goldgar, D.; Shattuck-Eidens, D.; Harshman, K.; Tavtigian, S.; Liu, Q.

    1994-10-07

    A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.

  17. Germline melanoma susceptibility and prognostic genes: a review of the literature.

    PubMed

    Ward, Katherine A; Lazovich, DeAnn; Hordinsky, Maria K

    2012-11-01

    In recent years, there have been increasing efforts to identify germline genetic variants that may alter melanoma susceptibility and prognosis. The findings of these studies have indicated the presence of rare, high-penetrance alleles with large effects, such as CDKN2A and CDK4, more common, moderately penetrant genes like MC1R, and very common, low-penetrance polymorphisms with small effects that are related to pigmentation, nevus count, immune responses, DNA repair, metabolism, and the vitamin D receptor. The study of these low-penetrance single nucleotide polymorphisms is relatively new; thus many of them are termed 'candidate melanoma susceptibility or prognostic genes.' This review summarizes the research on germline polymorphisms that have been implicated in melanoma susceptibility and prognosis in order to provide a framework for additional studies to meet the ultimate goal of predicting a patient's risk of, and prognosis in, cutaneous malignant melanoma. PMID:22583682

  18. Dopaminergic genes predict individual differences in susceptibility to confirmation bias

    PubMed Central

    Doll, Bradley B.; Hutchison, Kent E.; Frank, Michael J.

    2011-01-01

    The striatum is critical for the incremental learning of values associated with behavioral actions. The pre-frontal cortex (PFC) represents abstract rules and explicit contingencies to support rapid behavioral adaptation in the absence of cumulative experience. Here we test two alternative models of the interaction between these systems, and individual differences thereof, when human subjects are instructed with prior information about reward contingencies that may or may not be accurate. Behaviorally, subjects are overly influenced by prior instructions, at the expense of learning true reinforcement statistics. Computational analysis found that this pattern of data is best accounted for by a confirmation bias mechanism in which prior beliefs - putatively represented in PFC - influence the learning that occurs in the striatum such that reinforcement statistics are distorted. We assessed genetic variants affecting prefrontal and striatal dopaminergic neurotransmission. A polymorphism in the COMT gene (rs4680), associated with prefrontal dopaminergic function, was predictive of the degree to which participants persisted in responding in accordance with prior instructions even as evidence against their veracity accumulated. Polymorphisms in genes associated with striatal dopamine function (DARPP-32, rs907094, and DRD2, rs6277), were predictive of learning from positive and negative outcomes. Notably, these same variants were predictive of the degree to which such learning was overly inflated or neglected when outcomes are consistent or inconsistent with prior instructions. These findings indicate dissociable neurocomputational and genetic mechanisms by which initial biases are strengthened by experience. PMID:21508242

  19. Dopaminergic genes predict individual differences in susceptibility to confirmation bias.

    PubMed

    Doll, Bradley B; Hutchison, Kent E; Frank, Michael J

    2011-04-20

    The striatum is critical for the incremental learning of values associated with behavioral actions. The prefrontal cortex (PFC) represents abstract rules and explicit contingencies to support rapid behavioral adaptation in the absence of cumulative experience. Here we test two alternative models of the interaction between these systems, and individual differences thereof, when human subjects are instructed with prior information about reward contingencies that may or may not be accurate. Behaviorally, subjects are overly influenced by prior instructions, at the expense of learning true reinforcement statistics. Computational analysis found that this pattern of data is best accounted for by a confirmation bias mechanism in which prior beliefs--putatively represented in PFC--influence the learning that occurs in the striatum such that reinforcement statistics are distorted. We assessed genetic variants affecting prefrontal and striatal dopaminergic neurotransmission. A polymorphism in the COMT gene (rs4680), associated with prefrontal dopaminergic function, was predictive of the degree to which participants persisted in responding in accordance with prior instructions even as evidence against their veracity accumulated. Polymorphisms in genes associated with striatal dopamine function (DARPP-32, rs907094, and DRD2, rs6277) were predictive of learning from positive and negative outcomes. Notably, these same variants were predictive of the degree to which such learning was overly inflated or neglected when outcomes are consistent or inconsistent with prior instructions. These findings indicate dissociable neurocomputational and genetic mechanisms by which initial biases are strengthened by experience. PMID:21508242

  20. Global Gene Expression Profiles of Resistant and Susceptible Genotypes of Glycine tomentella During Phakopsora pachyrhizi Infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soybean rust, caused by Phakopsora pachyrhizi, is a destructive foliar disease that occurs in many soybean-producing countries. Towards the goal of identifying genes controlling resistance to soybean rust, transcriptome profiling was conducted in resistant and susceptible Glycine tomentella genotype...

  1. A Unique Wheat Disease Resistance-like Gene Governs Effector-Induced Susceptibility to Necrotrophic pathogens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plant disease resistance is often conferred by genes with nucleotide binding site and leucine-rich repeat NBS-LRR) or serine/threonine protein kinase (S/TPK) domains. Much less is known about mechanisms of susceptibility, particularly to necrotrophic fungal pathogens. The pathogens that cause the di...

  2. Major Histocompatibility Complex and Background Genes in Chickens Influence Susceptibility to High Pathogenicity Avian Influenza Virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The chicken’s major histocompatibility complex (MHC) haplotype has profound influence on the resistance or susceptibility to certain pathogens such as B21 MHC haplotype confers resistance to Marek’s disease (MD). However, non-MHC genes are also important in disease resistance. For example, both line...

  3. ALTERED HEPATIC GENE EXPRESSION IN MORBIDLY OBESE WOMEN AND ITS IMPLICATIONS FOR SUSCEPTIBILITY TO OTHER DISEASES

    EPA Science Inventory

    The objective of this study was to determine the molecular bases of disordered hepatic function and disease susceptibility in obesity. We compared global gene expression in liver biopsies from morbidly obese (MO) women undergoing gastric bypass (GBP) surgery with that of women un...

  4. Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil

    PubMed Central

    Castellucci, Léa; Jamieson, Sarra E; Almeida, Lucas; Oliveira, Joyce; Guimarães, Luiz Henrique; Lessa, Marcus; Fakiola, Michaela; de Jesus, Amélia Ribeiro; Miller, E. Nancy; Carvalho, Edgar M

    2012-01-01

    Leishmania braziliensis causes cutaneous (CL) and mucosal (ML) leishmaniasis. In the mouse, Fli1 was identified as a gene influencing enhanced wound healing and resistance to CL caused by L. major. Polymorphism at FLI1 is associated with CL caused by L. braziliensis in humans, with an inverse association observed for ML disease. Here we extend the analysis to look at other wound healing genes, including CTGF, TGFB1, TGFBR1/2, SMADS 2/3/4/7 and FLII, all functionally linked along with FLI1 in the TGF beta pathway. Haplotype tagging single nucleotide polymorphisms (tag-SNPs) were genotyped using Taqman technology in 325 nuclear families (652 CL cases; 126 ML cases) from Brazil. Robust case-pseudocontrol (CPC) conditional logistic regression analysis showed associations between CL and SNPs at CTGF (SNP rs6918698; CC genotype; OR 1.67; 95%CI 1.10–2.54; P=0.016), TGFBR2 (rs1962859; OR 1.50; 95%CI 1.12–1.99; P=0.005), SMAD2 (rs1792658; OR 1.57; 95%CI 1.04–2.38; P=0.03), SMAD7 (rs4464148; AA genotype; OR 2.80; 95%CI 1.00–7.87; P=0.05) and FLII (rs2071242; OR 1.60; 95%CI 1.14–2.24; P=0.005), and between ML and SNPs at SMAD3 (rs1465841; OR 2.15; 95%CI 1.13–4.07; P=0.018) and SMAD7 (rs2337107; TT genotype; OR 3.70; 95%CI 1.27–10.7; P=0.016). Stepwise logistic regression analysis showed that all SNPs associated with CL at FLI1, CTGF, TGFBR2, and FLII showed independent effects from each other, but SNPs at SMAD2 and SMAD7 did not add independent effects to SNPs from other genes. These results suggest that TGFβ signalling via SMAD2 is important in directing events that contribute to CL, whereas signalling via SMAD3 is important in ML. Both are modulated by the inhibitory SMAD7 that acts upstream of SMAD2 and SMAD3 in this signalling pathway. Along with the published FLI1 association, these data further contribute to the hypothesis that wound healing processes are important determinants of pathology associated with cutaneous forms of leishmaniasis. PMID:22554650

  5. The genetic basis of aminoglycoside ototoxicity: The search for susceptibility genes

    SciTech Connect

    Prezant, T.R.; Fischel-Ghodsian, F.

    1994-09-01

    The susceptibility to aminoglycoside ototoxicity appears to be genetically determined. Recently we identified a mutation in the small ribosomal RNA gene of the mitochondrial DNA that can cause deafness after aminoglycoside treatment in families with maternally-inherited susceptibility to the ototoxic effect of these antibiotics. The mutation produces a structural change in the 12S rRNA, which allows increased binding of aminoglycosides, mistranslation of mitochondrial proteins, decreased energy production, and cell death. Because only a minority of sporadic patients have mutations in the 12S rRNA gene, we anticipate the involvement of other genes in ototoxic deafness. We have developed a model system in the yeast Saccharomyces cerevisiae to functionally identify genes whose products interact with aminoglycosides. Besides its small genome size and well-developed genetic tools, a unique advantage of using this haploid organism is that recessive drug-responsive mutations will not be missed. An additional advantage is that yeast can be grown in either fermentative or respiratory media, allowing the functional categorization of mutants. Over 100 antibiotic-resistant mutants have now been isolated. The majority of these mutations (69%) are dominant and are being sorted by segregation tests. The 31% of mutations that are recessive have been sorted into two major complementation groups, indicating that two genes appear to be responsible for most of the recessive cases. Our strategy is to isolate the yeast genes that most commonly acquire mutations, clone the human homologs, and screen patients for susceptibility mutations.

  6. Differential gene expression of two extreme honey bee (Apis mellifera) colonies showing varroa tolerance and susceptibility.

    PubMed

    Jiang, S; Robertson, T; Mostajeran, M; Robertson, A J; Qiu, X

    2016-06-01

    Varroa destructor, an ectoparasitic mite of honey bees (Apis mellifera), is the most serious pest threatening the apiculture industry. In our honey bee breeding programme, two honey bee colonies showing extreme phenotypes for varroa tolerance/resistance (S88) and susceptibility (G4) were identified by natural selection from a large gene pool over a 6-year period. To investigate potential defence mechanisms for honey bee tolerance to varroa infestation, we employed DNA microarray and real time quantitative (PCR) analyses to identify differentially expressed genes in the tolerant and susceptible colonies at pupa and adult stages. Our results showed that more differentially expressed genes were identified in the tolerant bees than in bees from the susceptible colony, indicating that the tolerant colony showed an increased genetic capacity to respond to varroa mite infestation. In both colonies, there were more differentially expressed genes identified at the pupa stage than at the adult stage, indicating that pupa bees are more responsive to varroa infestation than adult bees. Genes showing differential expression in the colony phenotypes were categorized into several groups based on their molecular functions, such as olfactory signalling, detoxification processes, exoskeleton formation, protein degradation and long-chain fatty acid metabolism, suggesting that these biological processes play roles in conferring varroa tolerance to naturally selected colonies. Identification of differentially expressed genes between the two colony phenotypes provides potential molecular markers for selecting and breeding varroa-tolerant honey bees. PMID:26919127

  7. STAT3 inhibition suppresses proliferation of retinoblastoma through down-regulation of positive feedback loop of STAT3/miR-17-92 clusters

    PubMed Central

    Jo, Dong Hyun; Kim, Jin Hyoung; Cho, Chang Sik; Cho, Young-Lai; Jun, Hyoung Oh; Yu, Young Suk; Min, Jeong-Ki; Kim, Jeong Hun

    2014-01-01

    Retinoblastoma, the most common intraocular malignant tumor in children, is characterized by the loss of both functional alleles of RB1 gene, which however alone cannot maintain malignant characteristics of retinoblastoma cells. Nevertheless, the investigation of other molecular aberrations such as matrix metalloproteinases (MMPs) and miRNAs is still lacking. In this study, we demonstrate that STAT3 is activated in retinoblastoma cells, Ki67-positive areas of in vivo orthotopic tumors in BALB/c nude mice, and human retinoblastoma tissues of the advanced stage. Furthermore, target genes of STAT3 including BCL2, BCL2L1, BIRC5, and MMP9 are up-regulated in retinoblastoma cells compared to other retinal constituent cells. Interestingly, STAT3 inhibition by targeted siRNA suppresses the proliferation of retinoblastoma cells and the formation of in vivo orthotopic tumors. In line with these results, STAT3 siRNA effectively induces down-regulation of target genes of STAT3. In addition, miRNA microarray analysis and further real-time PCR experiments with STAT3 siRNA treatment show that STAT3 activation is related to the up-regulation of miR-17-92 clusters in retinoblastoma cells via positive feedback loop between them. In conclusion, we suggest that STAT3 inhibition could be a potential therapeutic approach in retinoblastoma through the suppression of tumor proliferation. PMID:25359779

  8. STAT3 inhibition suppresses proliferation of retinoblastoma through down-regulation of positive feedback loop of STAT3/miR-17-92 clusters.

    PubMed

    Jo, Dong Hyun; Kim, Jin Hyoung; Cho, Chang Sik; Cho, Young-Lai; Jun, Hyoung Oh; Yu, Young Suk; Min, Jeong-Ki; Kim, Jeong Hun

    2014-11-30

    Retinoblastoma, the most common intraocular malignant tumor in children, is characterized by the loss of both functional alleles of RB1 gene, which however alone cannot maintain malignant characteristics of retinoblastoma cells. Nevertheless, the investigation of other molecular aberrations such as matrix metalloproteinases (MMPs) and miRNAs is still lacking. In this study, we demonstrate that STAT3 is activated in retinoblastoma cells, Ki67-positive areas of in vivo orthotopic tumors in BALB/c nude mice, and human retinoblastoma tissues of the advanced stage. Furthermore, target genes of STAT3 including BCL2, BCL2L1, BIRC5, and MMP9 are up-regulated in retinoblastoma cells compared to other retinal constituent cells. Interestingly, STAT3 inhibition by targeted siRNA suppresses the proliferation of retinoblastoma cells and the formation of in vivo orthotopic tumors. In line with these results, STAT3 siRNA effectively induces down-regulation of target genes of STAT3. In addition, miRNA microarray analysis and further real-time PCR experiments with STAT3 siRNA treatment show that STAT3 activation is related to the up-regulation of miR-17-92 clusters in retinoblastoma cells via positive feedback loop between them. In conclusion, we suggest that STAT3 inhibition could be a potential therapeutic approach in retinoblastoma through the suppression of tumor proliferation. PMID:25359779

  9. Gene Expression Analysis of Plum pox virus (Sharka) Susceptibility/Resistance in Apricot (Prunus armeniaca L.).

    PubMed

    Rubio, Manuel; Ballester, Ana Rosa; Olivares, Pedro Manuel; Castro de Moura, Manuel; Dicenta, Federico; Martínez-Gómez, Pedro

    2015-01-01

    RNA-Seq has proven to be a very powerful tool in the analysis of the Plum pox virus (PPV, sharka disease)/Prunus interaction. This technique is an important complementary tool to other means of studying genomics. In this work an analysis of gene expression of resistance/susceptibility to PPV in apricot is performed. RNA-Seq has been applied to analyse the gene expression changes induced by PPV infection in leaves from two full-sib apricot genotypes, "Rojo Pasión" and "Z506-7", resistant and susceptible to PPV, respectively. Transcriptomic analyses revealed the existence of more than 2,000 genes related to the pathogen response and resistance to PPV in apricot. These results showed that the response to infection by the virus in the susceptible genotype is associated with an induction of genes involved in pathogen resistance such as the allene oxide synthase, S-adenosylmethionine synthetase 2 and the major MLP-like protein 423. Over-expression of the Dicer protein 2a may indicate the suppression of a gene silencing mechanism of the plant by PPV HCPro and P1 PPV proteins. On the other hand, there were 164 genes involved in resistance mechanisms that have been identified in apricot, 49 of which are located in the PPVres region (scaffold 1 positions from 8,050,804 to 8,244,925), which is responsible for PPV resistance in apricot. Among these genes in apricot there are several MATH domain-containing genes, although other genes inside (Pleiotropic drug resistance 9 gene) or outside (CAP, Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis-related 1 protein; and LEA, Late embryogenesis abundant protein) PPVres region could also be involved in the resistance. PMID:26658051

  10. Gene Expression Analysis of Plum pox virus (Sharka) Susceptibility/Resistance in Apricot (Prunus armeniaca L.)

    PubMed Central

    Rubio, Manuel; Ballester, Ana Rosa; Olivares, Pedro Manuel; Castro de Moura, Manuel; Dicenta, Federico; Martínez-Gómez, Pedro

    2015-01-01

    RNA-Seq has proven to be a very powerful tool in the analysis of the Plum pox virus (PPV, sharka disease)/Prunus interaction. This technique is an important complementary tool to other means of studying genomics. In this work an analysis of gene expression of resistance/susceptibility to PPV in apricot is performed. RNA-Seq has been applied to analyse the gene expression changes induced by PPV infection in leaves from two full-sib apricot genotypes, “Rojo Pasión” and “Z506-7”, resistant and susceptible to PPV, respectively. Transcriptomic analyses revealed the existence of more than 2,000 genes related to the pathogen response and resistance to PPV in apricot. These results showed that the response to infection by the virus in the susceptible genotype is associated with an induction of genes involved in pathogen resistance such as the allene oxide synthase, S-adenosylmethionine synthetase 2 and the major MLP-like protein 423. Over-expression of the Dicer protein 2a may indicate the suppression of a gene silencing mechanism of the plant by PPV HCPro and P1 PPV proteins. On the other hand, there were 164 genes involved in resistance mechanisms that have been identified in apricot, 49 of which are located in the PPVres region (scaffold 1 positions from 8,050,804 to 8,244,925), which is responsible for PPV resistance in apricot. Among these genes in apricot there are several MATH domain-containing genes, although other genes inside (Pleiotropic drug resistance 9 gene) or outside (CAP, Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis-related 1 protein; and LEA, Late embryogenesis abundant protein) PPVres region could also be involved in the resistance. PMID:26658051

  11. Retinoblastoma. Fifty Years of Progress. The LXXI Edward Jackson Memorial Lecture

    PubMed Central

    Grossniklaus, Hans E.

    2014-01-01

    Purpose To review the progress made in understanding the genetic basis, molecular pathology, and treatment of retinoblastoma since the previous Jackson lecture on the topic was published 50 years ago. Design Perspective based on personal experience and the literature. Methods The literature regarding retinoblastoma was reviewed since 1963. Advances in understanding the biology and treatment of retinoblastoma provided context through the author’s clinical, pathological and research experiences. Results Retinoblastoma was first identified in the 1500s and defined as a unique clinicopathologic entity in 1809. Until the mid-1900s, knowledge advanced sporadically, with technological developments of ophthalmoscopy and light microscopy, and with the introduction of surgical enucleation, chemotherapy and radiation therapy. During the last 50 years, research and treatment have progressed at an unprecedented rate due to innovations in molecular biology and the development of targeted therapies. During this time period, the retinoblastoma gene was discovered; techniques for genetic testing for retinoblastoma were developed; and plaque brachytherapy, chemoreduction, intraarterial chemotherapy, and intraocular injections of chemotherapeutic agents were successfully introduced. Conclusions Nearly all patients with retinoblastoma in developed countries can now be cured of their primary cancer- a remarkable achievement for a childhood cancer that once was uniformly fatal. Much of this success is owed to deciphering the role of the Rb gene, and the benefits of targeted therapies, such as chemoreduction with consolidation as well as intra-arterial and intravitreal chemotherapies. Going forward, the main challenge will be ensuring that access to care is available for all children, particularly those in developing countries. PMID:25065496

  12. Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer.

    PubMed

    Smith, Alyssa L; Alirezaie, Najmeh; Connor, Ashton; Chan-Seng-Yue, Michelle; Grant, Robert; Selander, Iris; Bascuñana, Claire; Borgida, Ayelet; Hall, Anita; Whelan, Thomas; Holter, Spring; McPherson, Treasa; Cleary, Sean; Petersen, Gloria M; Omeroglu, Atilla; Saloustros, Emmanouil; McPherson, John; Stein, Lincoln D; Foulkes, William D; Majewski, Jacek; Gallinger, Steven; Zogopoulos, George

    2016-01-28

    The genetic basis underlying the majority of hereditary pancreatic adenocarcinoma (PC) is unknown. Since DNA repair genes are widely implicated in gastrointestinal malignancies, including PC, we hypothesized that there are novel DNA repair PC susceptibility genes. As germline DNA repair gene mutations may lead to PC subtypes with selective therapeutic responses, we also hypothesized that there is an overall survival (OS) difference in mutation carriers versus non-carriers. We therefore interrogated the germline exomes of 109 high-risk PC cases for rare protein-truncating variants (PTVs) in 513 putative DNA repair genes. We identified PTVs in 41 novel genes among 36 kindred. Additional genetic evidence for causality was obtained for 17 genes, with FAN1, NEK1 and RHNO1 emerging as the strongest candidates. An OS difference was observed for carriers versus non-carriers of PTVs with early stage (≤IIB) disease. This adverse survival trend in carriers with early stage disease was also observed in an independent series of 130 PC cases. We identified candidate DNA repair PC susceptibility genes and suggest that carriers of a germline PTV in a DNA repair gene with early stage disease have worse survival. PMID:26546047

  13. Loss of photoreceptorness and gain of genomic alterations in retinoblastoma reveal tumor progression

    PubMed Central

    Kooi, Irsan E.; Mol, Berber M.; Moll, Annette C.; van der Valk, Paul; de Jong, Marcus C.; de Graaf, Pim; van Mil, Saskia E.; Schouten-van Meeteren, Antoinette Y.N.; Meijers-Heijboer, Hanne; Kaspers, Gertjan L.; te Riele, Hein; Cloos, Jacqueline; Dorsman, Josephine C.

    2015-01-01

    Background Retinoblastoma is a pediatric eye cancer associated with RB1 loss or MYCN amplification (RB1+/+MYCNA). There are controversies concerning the existence of molecular subtypes within RB1−/− retinoblastoma. To test whether these molecular subtypes exist, we performed molecular profiling. Methods Genome-wide mRNA expression profiling was performed on 76 primary human retinoblastomas. Expression profiling was complemented by genome-wide DNA profiling and clinical, histopathological, and ex vivo drug sensitivity data. Findings RNA and DNA profiling identified major variability between retinoblastomas. While gene expression differences between RB1+/+MYCNA and RB1−/− tumors seemed more dichotomous, differences within the RB1−/− tumors were gradual. Tumors with high expression of a photoreceptor gene signature were highly differentiated, smaller in volume and diagnosed at younger age compared with tumors with low photoreceptor signature expression. Tumors with lower photoreceptor expression showed increased expression of genes involved in M-phase and mRNA and ribosome synthesis and increased frequencies of somatic copy number alterations. Interpretation Molecular, clinical and histopathological differences between RB1−/− tumors are best explained by tumor progression, reflected by a gradual loss of differentiation and photoreceptor expression signature. Since copy number alterations were more frequent in tumors with less photoreceptorness, genomic alterations might be drivers of tumor progression. Research in context Retinoblastoma is an ocular childhood cancer commonly caused by mutations in the RB1 gene. In order to determine optimal treatment, tumor subtyping is considered critically important. However, except for very rare retinoblastomas without an RB1 mutation, there are controversies as to whether subtypes of retinoblastoma do exist. Our study shows that retinoblastomas are highly diverse but rather than reflecting distinct tumor types with

  14. Retinoblastoma genetics in India: From research to implementation.

    PubMed

    Dimaras, Helen

    2015-03-01

    Retinoblastoma is the prototypic genetic cancer. India carries the biggest burden of retinoblastoma globally, with an estimated 1500 new cases annually. Recent advances in retinoblastoma genetics are reviewed, focusing specifically on information with clinical significance to patients. The Indian literature on retinoblastoma clinical genetics is also highlighted, with a comment on challenges and future directions. The review concludes with recommendations to help clinicians implement and translate retinoblastoma genetics to their practice. PMID:25971166

  15. Association Analysis Suggests SOD2 as a Newly Identified Candidate Gene Associated With Leprosy Susceptibility.

    PubMed

    Ramos, Geovana Brotto; Salomão, Heloisa; Francio, Angela Schneider; Fava, Vinícius Medeiros; Werneck, Renata Iani; Mira, Marcelo Távora

    2016-08-01

    Genetic studies have identified several genes and genomic regions contributing to the control of host susceptibility to leprosy. Here, we test variants of the positional and functional candidate gene SOD2 for association with leprosy in 2 independent population samples. Family-based analysis revealed an association between leprosy and allele G of marker rs295340 (P = .042) and borderline evidence of an association between leprosy and alleles C and A of markers rs4880 (P = .077) and rs5746136 (P = .071), respectively. Findings were validated in an independent case-control sample for markers rs295340 (P = .049) and rs4880 (P = .038). These results suggest SOD2 as a newly identified gene conferring susceptibility to leprosy. PMID:27132285

  16. Social Environmental Variation, Plasticity Genes, and Aggression: Evidence for the Differential Susceptibility Hypothesis

    PubMed Central

    Simons, Ronald L.; Lei, Man Kit; Beach, Steven R.H.; Brody, Gene H.; Philibert, Robert A.; Gibbons, Frederick X.

    2011-01-01

    Although G×E studies are typically based on the assumption that some individuals possess genetic variants that enhance their vulnerability to environmental adversity, the differential susceptibility perspective posits that these individuals are simply more susceptible to environmental influence than others. An important implication of this model is that those persons most vulnerable to adverse social environments are the same ones who reap the most benefit from environmental support. The present study tested several implications of this proposition. Using longitudinal data from a sample of several hundred African Americans, we found that relatively common variants of the dopamine receptor gene and the serotonin transporter gene interact with social environmental conditions to predict aggression in a manner consonant with differential susceptibility. When the social environment was adverse, individuals with these genetic variants manifested more aggression than other genotypes, whereas when the environment was supportive they demonstrated less aggression than other genotypes. Further, we found that these genetic variants interact with environmental conditions to foster various cognitive schemas and emotions in a manner consistent with differential susceptibility and that a latent construct formed by these schemas and emotions mediated the effect of gene by environment interaction on aggression. PMID:22199399

  17. Lateral organ boundaries 1 is a disease susceptibility gene for citrus bacterial canker disease.

    PubMed

    Hu, Yang; Zhang, Junli; Jia, Hongge; Sosso, Davide; Li, Ting; Frommer, Wolf B; Yang, Bing; White, Frank F; Wang, Nian; Jones, Jeffrey B

    2014-01-28

    Citrus bacterial canker (CBC) disease occurs worldwide and incurs considerable costs both from control measures and yield losses. Bacteria that cause CBC require one of six known type III transcription activator-like (TAL) effector genes for the characteristic pustule formation at the site of infection. Here, we show that Xanthomonas citri subspecies citri strain Xcc306, with the type III TAL effector gene pthA4 or with the distinct yet biologically equivalent gene pthAw from strain XccA(w), induces two host genes, CsLOB1 and CsSWEET1, in a TAL effector-dependent manner. CsLOB1 is a member of the Lateral Organ Boundaries (LOB) gene family of transcription factors, and CsSWEET1 is a homolog of the SWEET sugar transporter and rice disease susceptibility gene. Both TAL effectors drive expression of CsLOB1 and CsSWEET1 promoter reporter gene fusions when coexpressed in citrus or Nicotiana benthamiana. Artificially designed TAL effectors directed to sequences in the CsLOB1 promoter region, but not the CsSWEET1 promoter, promoted pustule formation and higher bacterial leaf populations. Three additional distinct TAL effector genes, pthA*, pthB, and pthC, also direct pustule formation and expression of CsLOB1. Unlike pthA4 and pthAw, pthB and pthC do not promote the expression of CsSWEET1. CsLOB1 expression was associated with the expression of genes associated with cell expansion. The results indicate that CBC-inciting species of Xanthomonas exploit a single host disease susceptibility gene by altering the expression of an otherwise developmentally regulated gene using any one of a diverse set of TAL effector genes in the pathogen populations. PMID:24474801

  18. Lateral organ boundaries 1 is a disease susceptibility gene for citrus bacterial canker disease

    PubMed Central

    Hu, Yang; Zhang, Junli; Jia, Hongge; Sosso, Davide; Li, Ting; Frommer, Wolf B.; Yang, Bing; White, Frank F.; Wang, Nian; Jones, Jeffrey B.

    2014-01-01

    Citrus bacterial canker (CBC) disease occurs worldwide and incurs considerable costs both from control measures and yield losses. Bacteria that cause CBC require one of six known type III transcription activator-like (TAL) effector genes for the characteristic pustule formation at the site of infection. Here, we show that Xanthomonas citri subspecies citri strain Xcc306, with the type III TAL effector gene pthA4 or with the distinct yet biologically equivalent gene pthAw from strain XccAw, induces two host genes, CsLOB1 and CsSWEET1, in a TAL effector-dependent manner. CsLOB1 is a member of the Lateral Organ Boundaries (LOB) gene family of transcription factors, and CsSWEET1 is a homolog of the SWEET sugar transporter and rice disease susceptibility gene. Both TAL effectors drive expression of CsLOB1 and CsSWEET1 promoter reporter gene fusions when coexpressed in citrus or Nicotiana benthamiana. Artificially designed TAL effectors directed to sequences in the CsLOB1 promoter region, but not the CsSWEET1 promoter, promoted pustule formation and higher bacterial leaf populations. Three additional distinct TAL effector genes, pthA*, pthB, and pthC, also direct pustule formation and expression of CsLOB1. Unlike pthA4 and pthAw, pthB and pthC do not promote the expression of CsSWEET1. CsLOB1 expression was associated with the expression of genes associated with cell expansion. The results indicate that CBC-inciting species of Xanthomonas exploit a single host disease susceptibility gene by altering the expression of an otherwise developmentally regulated gene using any one of a diverse set of TAL effector genes in the pathogen populations. PMID:24474801

  19. Transgenic Models in Retinoblastoma Research

    PubMed Central

    Nair, Rohini M.; Vemuganti, Geeta K.

    2015-01-01

    Understanding the mechanism of retinoblastoma (Rb) tumor initiation, development, progression and metastasis in vivo mandates the use of animal models that mimic this intraocular tumor in its genetic, anatomic, histologic and ultrastructural features. An early setback for developing mouse Rb models was that Rb mutations did not cause tumorigenesis in murine retinas. Subsequently, the discovery that the p107 protein takes over the role of pRb in mice led to the development of several animal models that phenotypically and histologically resemble the human form. This paper summarizes the transgenic models that have been developed over the last three decades. PMID:27171579

  20. Transgenic Models in Retinoblastoma Research.

    PubMed

    Nair, Rohini M; Vemuganti, Geeta K

    2015-04-01

    Understanding the mechanism of retinoblastoma (Rb) tumor initiation, development, progression and metastasis in vivo mandates the use of animal models that mimic this intraocular tumor in its genetic, anatomic, histologic and ultrastructural features. An early setback for developing mouse Rb models was that Rb mutations did not cause tumorigenesis in murine retinas. Subsequently, the discovery that the p107 protein takes over the role of pRb in mice led to the development of several animal models that phenotypically and histologically resemble the human form. This paper summarizes the transgenic models that have been developed over the last three decades. PMID:27171579

  1. Analysis of retinoblastoma age incidence data using a fully stochastic cancer model

    PubMed Central

    Little, Mark P.; Kleinerman, Ruth A.; Stiller, Charles A.; Li, Guangquan; Kroll, Mary E.; Murphy, Michael F.G.

    2011-01-01

    Retinoblastoma (RB) is an important ocular malignancy of childhood. It has been commonly accepted for some time that knockout of the two alleles of the RB1 gene is the principal molecular target associated with the occurrence of RB. In this paper, we examine the validity of the two-hit theory for retinoblastoma by comparing the fit of a stochastic model with two or more mutational stages. Unlike many such models, our model assumes a fully stochastic stem cell compartment, which is crucial to its behavior. Models are fitted to a population-based dataset comprising 1,553 cases of retinoblastoma for the period 1962–2000 in Great Britain (England, Scotland, Wales). The population incidence of retinoblastoma is best described by a fully stochastic model with two stages, although models with a deterministic stem cell compartment yield equivalent fit; models with three or more stages fit much less well. The results strongly suggest that knockout of the two alleles of the RB1 gene is necessary and may be largely sufficient for the development of retinoblastoma, in support of Knudson’s two-hit hypothesis. PMID:21387305

  2. Some retinoblastomas, osteosarcomas, and soft tissue sarcomas may share a common etiology

    SciTech Connect

    Weichselbaum, R.R.; Beckett, M.; Diamond, A. )

    1988-04-01

    DNA and RNA were extracted from primary human osteosarcomas and soft tissue sarcomas obtained from patients without retinoblastoma and were analyzed by hybridization with a cDNA probe for RB mRNA; absence or alterations of the RB gene are associated with development of retinoblastoma. Most of the osteosarcomas or soft tissue sarcomas examined by the authors did not express detectable levels of RB mRNA, whereas normal cells and epithelial tumor cells did. One osteosarcoma expressed a 2.4-kilobase transcript in addition to a normal 4.7-kilobase species. The data suggest that transcriptional inactivation or post-transcriptional down-regulation of the RB gene may be important in the etiology of some osteosarcomas and soft tissue sarcomas as well as retinoblastomas.

  3. Genes Expressed Differentially in Hessian Fly Larvae Feeding in Resistant and Susceptible Plants.

    PubMed

    Chen, Ming-Shun; Liu, Sanzhen; Wang, Haiyan; Cheng, Xiaoyan; El Bouhssini, Mustapha; Whitworth, R Jeff

    2016-01-01

    The Hessian fly, Mayetiola destructor, is a destructive pest of wheat worldwide and mainly controlled by deploying resistant cultivars. In this study, we investigated the genes that were expressed differentially between larvae in resistant plants and those in susceptible plants through RNA sequencing on the Illumina platform. Informative genes were 11,832, 14,861, 15,708, and 15,071 for the comparisons between larvae in resistant versus susceptible plants for 0.5, 1, 3, and 5 days, respectively, after larvae had reached the feeding site. The transcript abundance corresponding to 5401, 6902, 8457, and 5202 of the informative genes exhibited significant differences (p ≤ 0.05) in the respective paired comparisons. Overall, genes involved in nutrient metabolism, RNA and protein synthesis exhibited lower transcript abundance in larvae from resistant plants, indicating that resistant plants inhibited nutrient metabolism and protein production in larvae. Interestingly, the numbers of cytochrome P450 genes with higher transcript abundance in larvae from resistant plants were comparable to, or higher than those with lower transcript abundance, indicating that toxic chemicals from resistant plants may have played important roles in Hessian fly larval death. Our study also identified several families of genes encoding secreted salivary gland proteins (SSGPs) that were expressed at early stage of 1(st) instar larvae and with more genes with higher transcript abundance in larvae from resistant plants. Those SSGPs are candidate effectors with important roles in plant manipulation. PMID:27529231

  4. Genes Expressed Differentially in Hessian Fly Larvae Feeding in Resistant and Susceptible Plants

    PubMed Central

    Chen, Ming-Shun; Liu, Sanzhen; Wang, Haiyan; Cheng, Xiaoyan; El Bouhssini, Mustapha; Whitworth, R. Jeff

    2016-01-01

    The Hessian fly, Mayetiola destructor, is a destructive pest of wheat worldwide and mainly controlled by deploying resistant cultivars. In this study, we investigated the genes that were expressed differentially between larvae in resistant plants and those in susceptible plants through RNA sequencing on the Illumina platform. Informative genes were 11,832, 14,861, 15,708, and 15,071 for the comparisons between larvae in resistant versus susceptible plants for 0.5, 1, 3, and 5 days, respectively, after larvae had reached the feeding site. The transcript abundance corresponding to 5401, 6902, 8457, and 5202 of the informative genes exhibited significant differences (p ≤ 0.05) in the respective paired comparisons. Overall, genes involved in nutrient metabolism, RNA and protein synthesis exhibited lower transcript abundance in larvae from resistant plants, indicating that resistant plants inhibited nutrient metabolism and protein production in larvae. Interestingly, the numbers of cytochrome P450 genes with higher transcript abundance in larvae from resistant plants were comparable to, or higher than those with lower transcript abundance, indicating that toxic chemicals from resistant plants may have played important roles in Hessian fly larval death. Our study also identified several families of genes encoding secreted salivary gland proteins (SSGPs) that were expressed at early stage of 1st instar larvae and with more genes with higher transcript abundance in larvae from resistant plants. Those SSGPs are candidate effectors with important roles in plant manipulation. PMID:27529231

  5. Antioxidant defense enzyme genes and asthma susceptibility: gender-specific effects and heterogeneity in gene-gene interactions between pathogenetic variants of the disease.

    PubMed

    Polonikov, Alexey V; Ivanov, Vladimir P; Bogomazov, Alexey D; Freidin, Maxim B; Illig, Thomas; Solodilova, Maria A

    2014-01-01

    Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants plays an important role in the pathogenesis of asthma. The present study tested the hypothesis that genetic susceptibility to allergic and nonallergic variants of asthma is determined by complex interactions between genes encoding antioxidant defense enzymes (ADE). We carried out a comprehensive analysis of the associations between adult asthma and 46 single nucleotide polymorphisms of 34 ADE genes and 12 other candidate genes of asthma in Russian population using set association analysis and multifactor dimensionality reduction approaches. We found for the first time epistatic interactions between ADE genes underlying asthma susceptibility and the genetic heterogeneity between allergic and nonallergic variants of the disease. We identified GSR (glutathione reductase) and PON2 (paraoxonase 2) as novel candidate genes for asthma susceptibility. We observed gender-specific effects of ADE genes on the risk of asthma. The results of the study demonstrate complexity and diversity of interactions between genes involved in oxidative stress underlying susceptibility to allergic and nonallergic asthma. PMID:24895604

  6. Antioxidant Defense Enzyme Genes and Asthma Susceptibility: Gender-Specific Effects and Heterogeneity in Gene-Gene Interactions between Pathogenetic Variants of the Disease

    PubMed Central

    Polonikov, Alexey V.; Ivanov, Vladimir P.; Bogomazov, Alexey D.; Freidin, Maxim B.; Illig, Thomas; Solodilova, Maria A.

    2014-01-01

    Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants plays an important role in the pathogenesis of asthma. The present study tested the hypothesis that genetic susceptibility to allergic and nonallergic variants of asthma is determined by complex interactions between genes encoding antioxidant defense enzymes (ADE). We carried out a comprehensive analysis of the associations between adult asthma and 46 single nucleotide polymorphisms of 34 ADE genes and 12 other candidate genes of asthma in Russian population using set association analysis and multifactor dimensionality reduction approaches. We found for the first time epistatic interactions between ADE genes underlying asthma susceptibility and the genetic heterogeneity between allergic and nonallergic variants of the disease. We identified GSR (glutathione reductase) and PON2 (paraoxonase 2) as novel candidate genes for asthma susceptibility. We observed gender-specific effects of ADE genes on the risk of asthma. The results of the study demonstrate complexity and diversity of interactions between genes involved in oxidative stress underlying susceptibility to allergic and nonallergic asthma. PMID:24895604

  7. A candidate gene approach for the genetic analysis of susceptibility to tuberculosis

    SciTech Connect

    Morgan, K.; Liu, J.; Boothroyd, L.

    1994-09-01

    Tuberculosis is the most frequent and severe human disease caused by mycobacteria. In the mouse a candidate gene for innate resistance to mycobacteria (Bcg) was recently isolated and termed Nramp. We used SSCA and DNA sequencing to identify mutations in the human homologue, NRAMP, in chromosome region 2q35 in order to test if NRAMP contributes to susceptibility to tuberculosis. We have identified 16 sequence variants in or near NRAMP and defined haplotypes segregating in multiplex tuberculosis families from Canada, Columbia and Hong Kong. We defined a recessive susceptibility model for linkage analysis with four liability classes which take into account clinical status, age, exposure, and BCG vaccination. Our preliminary results support a role of NRAMP in tuberculosis susceptibility in an epidemic situation. This research was supported by grants from the Medical Research Council of Canada and the Canadian Genetic Diseases Network.

  8. Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q

    SciTech Connect

    Tomfohrde, J.; Barnes, R.; Bowcock, A.; Fernandez-Vina, M.A.; Stastny, P.; Silverman, A.; Young, M.; Lory, D.; Morris, L.; Menter, A.

    1994-05-20

    A gene involved in psoriasis susceptibility was localized to the distal region of human chromosomes 17q as a result of a genome-wide linkage analysis with polymorphic microsatellites and eight multiply affected psoriasis kindreds. In the family which showed the strongest evidence for linkage, the recombination fraction between a psoriasis susceptibility locus and D17S784 was 0.04 with a maximum two-point lod score of 5.33. There was also evidence for genetic heterogeneity and although none of the linked families showed any association with HLA-Cw6, two unlinked families showed weak levels of association. This study demonstrates that is some families, psoriasis susceptibility is due to variation at a single major genetic locus other than the human lymphocyte antigen locus. 28 refs., 2 figs., 1 tab.

  9. Evidence From Human and Zebrafish That GPC1 Is a Biliary Atresia Susceptibility Gene

    PubMed Central

    Cui, Shuang; Leyva-Vega, Melissa; Tsai, Ellen A.; Eauclaire, Steven F.; Glessner, Joseph T.; Hakonarson, Hakon; Devoto, Marcella; Haber, Barbara A.; Spinner, Nancy B.; Matthews, Randolph P.

    2013-01-01

    BACKGROUND & AIMS Biliary atresia (BA) is a progressive fibroinflammatory disorder of infants involving the extrahepatic and intrahepatic biliary tree. Its etiology is unclear but is believed to involve exposure of a genetically susceptible individual to certain environmental factors. BA occurs exclusively in the neonatal liver, so variants of genes expressed during hepatobiliary development could affect susceptibility. Genome-wide association studies previously identified a potential region of interest at 2q37. We continued these studies to narrow the region and identify BA susceptibility genes. METHODS We searched for copy number variants that were increased among patients with BA (n = 61) compared with healthy individuals (controls; n = 5088). After identifying a candidate gene, we investigated expression patterns of orthologues in zebrafish liver and the effects of reducing expression, with morpholino antisense oligonucleotides, on biliary development, gene expression, and signal transduction. RESULTS We observed a statistically significant increase in deletions at 2q37.3 in patients with BA that resulted in deletion of one copy of GPC1, which encodes glypican 1, a heparan sulfate proteoglycan that regulates Hedgehog signaling and inflammation. Knockdown of gpc1 in zebrafish led to developmental biliary defects. Exposure of the gpc1 morphants to cyclopamine, a Hedgehog antagonist, partially rescued the gpc1-knockdown phenotype. Injection of zebrafish with recombinant Sonic Hedgehog led to biliary defects similar to those of the gpc1 morphants. Liver samples from patients with BA had reduced levels of apical GPC1 in cholangiocytes compared with samples from controls. CONCLUSIONS Based on genetic analysis of patients with BA and zebrafish, GPC1 appears to be a BA susceptibility gene. These findings also support a role for Hedgehog signaling in the pathogenesis of BA. PMID:23336978

  10. Role of key-regulator genes in melanoma susceptibility and pathogenesis among patients from South Italy

    PubMed Central

    2009-01-01

    Background Several genetic alterations have been demonstrated to contribute to the development and progression of melanoma. In this study, we further investigated the impact of key-regulator genes in susceptibility and pathogenesis of such a disease. Methods A large series (N = 846) of sporadic and familial cases originating from South Italy was screened for germline mutations in p16CDKN2A, BRCA2, and MC1R genes by DHPLC analysis and automated DNA sequencing. Paired primary melanomas and lymph node metastases from same patients (N = 35) as well as melanoma cell lines (N = 18) were analyzed for somatic mutations in NRAS, BRAF, and p16CDKN2A genes. Results For melanoma susceptibility, investigations at germline level indicated that p16CDKN2A was exclusively mutated in 16/545 (2.9%) non-Sardinian patients, whereas BRCA2 germline mutations were observed in 4/91 (4.4%) patients from North Sardinia only. Two MC1R germline variants, Arg151Cys and Asp294His, were significantly associated with melanoma in Sardinia. Regarding genetic events involved in melanoma pathogenesis at somatic level, mutually-exclusive mutations of NRAS and BRAF genes were observed at quite same rate (about two thirds) in cultured and in vivo melanomas (either primary or metastatic lesions). Conversely, p16CDKN2A gene alterations were observed at increased rates moving from primary to metastatic melanomas and melanoma cell lines. Activation of the ERK gene product was demonstrated to be consistently induced by a combination of molecular alterations (NRAS/BRAF mutations and p16CDKN2A silencing). Conclusion Our findings further clarified that: a) mutation prevalence in melanoma susceptibility genes may vary within each specific geographical area; b) multiple molecular events are accumulating during melanomagenesis. PMID:19799798

  11. Knockdown of MLO genes reduces susceptibility to powdery mildew in grapevine.

    PubMed

    Pessina, Stefano; Lenzi, Luisa; Perazzolli, Michele; Campa, Manuela; Dalla Costa, Lorenza; Urso, Simona; Valè, Giampiero; Salamini, Francesco; Velasco, Riccardo; Malnoy, Mickael

    2016-01-01

    Erysiphe necator is the causal agent of powdery mildew (PM), one of the most destructive diseases of grapevine. PM is controlled by sulfur-based and synthetic fungicides, which every year are dispersed into the environment. This is why PM-resistant varieties should become a priority for sustainable grapevine and wine production. PM resistance can be achieved in other crops by knocking out susceptibility S-genes, such as those residing at genetic loci known as MLO (Mildew Locus O). All MLO S-genes of dicots belong to the phylogenetic clade V, including grapevine genes VvMLO7, 11 and 13, which are upregulated during PM infection, and VvMLO6, which is not upregulated. Before adopting a gene-editing approach to knockout candidate S-genes, the evidence that loss of function of MLO genes can reduce PM susceptibility is necessary. This paper reports the knockdown through RNA interference of VvMLO6, 7, 11 and 13. The knockdown of VvMLO6, 11 and 13 did not decrease PM severity, whereas the knockdown of VvMLO7 in combination with VvMLO6 and VvMLO11 reduced PM severity up to 77%. The knockdown of VvMLO7 and VvMLO6 seemed to be important for PM resistance, whereas a role for VvMLO11 does not seem likely. Cell wall appositions (papillae) were present in both resistant and susceptible lines in response to PM attack. Thirteen genes involved in defense were less upregulated in infected mlo plants, highlighting the early mlo-dependent disruption of PM invasion. PMID:27390621

  12. Knockdown of MLO genes reduces susceptibility to powdery mildew in grapevine

    PubMed Central

    Pessina, Stefano; Lenzi, Luisa; Perazzolli, Michele; Campa, Manuela; Dalla Costa, Lorenza; Urso, Simona; Valè, Giampiero; Salamini, Francesco; Velasco, Riccardo; Malnoy, Mickael

    2016-01-01

    Erysiphe necator is the causal agent of powdery mildew (PM), one of the most destructive diseases of grapevine. PM is controlled by sulfur-based and synthetic fungicides, which every year are dispersed into the environment. This is why PM-resistant varieties should become a priority for sustainable grapevine and wine production. PM resistance can be achieved in other crops by knocking out susceptibility S-genes, such as those residing at genetic loci known as MLO (Mildew Locus O). All MLO S-genes of dicots belong to the phylogenetic clade V, including grapevine genes VvMLO7, 11 and 13, which are upregulated during PM infection, and VvMLO6, which is not upregulated. Before adopting a gene-editing approach to knockout candidate S-genes, the evidence that loss of function of MLO genes can reduce PM susceptibility is necessary. This paper reports the knockdown through RNA interference of VvMLO6, 7, 11 and 13. The knockdown of VvMLO6, 11 and 13 did not decrease PM severity, whereas the knockdown of VvMLO7 in combination with VvMLO6 and VvMLO11 reduced PM severity up to 77%. The knockdown of VvMLO7 and VvMLO6 seemed to be important for PM resistance, whereas a role for VvMLO11 does not seem likely. Cell wall appositions (papillae) were present in both resistant and susceptible lines in response to PM attack. Thirteen genes involved in defense were less upregulated in infected mlo plants, highlighting the early mlo-dependent disruption of PM invasion. PMID:27390621

  13. GNL3 and SKA3 are novel prostate cancer metastasis susceptibility genes.

    PubMed

    Lee, Minnkyong; Williams, Kendra A; Hu, Ying; Andreas, Jonathan; Patel, Shashank J; Zhang, Suiyuan; Crawford, Nigel P S

    2015-12-01

    Prostate cancer (PC) is very common in developed countries. However, the molecular determinants of PC metastasis are unclear. Previously, we reported that germline variation influences metastasis in the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of PC. These mice develop prostate tumors similar to a subset of poor outcome, treatment-associated human PC tumors. Here, we used TRAMP mice to nominate candidate genes and validate their role in aggressive human PC in PC datasets and cell lines. Candidate metastasis susceptibility genes were identified through quantitative trait locus (QTL) mapping in 201 (TRAMP × PWK/PhJ) F2 males. Two metastasis-associated QTLs were identified; one on chromosome 12 (LOD = 5.86), and one on chromosome 14 (LOD = 4.41). Correlation analysis using microarray data from (TRAMP × PWK/PhJ) F2 prostate tumors identified 35 metastasis-associated transcripts within the two loci. The role of these genes in susceptibility to aggressive human PC was determined through in silico analysis using multiple datasets. First, analysis of candidate gene expression in two human PC datasets demonstrated that five candidate genes were associated with an increased risk of aggressive disease and lower disease-free survival. Second, four of these genes (GNL3, MAT1A, SKA3, and ZMYM5) harbored SNPs associated with aggressive tumorigenesis in the PLCO/CGEMS GWAS of 1172 PC patients. Finally, over-expression of GNL3 and SKA3 in the PC-3 human PC cell line decreased in vitro cell migration and invasion. This novel approach demonstrates how mouse models can be used to identify metastasis susceptibility genes, and gives new insight into the molecular mechanisms of fatal PC. PMID:26429724

  14. SRGAP1 Is a Candidate Gene for Papillary Thyroid Carcinoma Susceptibility

    PubMed Central

    He, Huiling; Bronisz, Agnieszka; Liyanarachchi, Sandya; Nagy, Rebecca; Li, Wei; Huang, Yungui; Akagi, Keiko; Saji, Motoyasu; Kula, Dorota; Wojcicka, Anna; Sebastian, Nikhil; Wen, Bernard; Puch, Zbigniew; Kalemba, Michal; Stachlewska, Elzbieta; Czetwertynska, Malgorzata; Dlugosinska, Joanna; Dymecka, Kinga; Ploski, Rafal; Krawczyk, Marek; Morrison, Patrick J.; Ringel, Matthew D.; Kloos, Richard T.; Jazdzewski, Krystian; Symer, David E.; Vieland, Veronica J.; Ostrowski, Michael; Jarząb, Barbara

    2013-01-01

    Background: Papillary thyroid carcinoma (PTC) shows high heritability, yet efforts to find predisposing genes have been largely negative. Objectives: The objective of this study was to identify susceptibility genes for PTC. Methods: A genome-wide linkage analysis was performed in 38 families. Targeted association study and screening were performed in 2 large cohorts of PTC patients and controls. Candidate DNA variants were tested in functional studies. Results: Linkage analysis and association studies identified the Slit-Robo Rho GTPase activating protein 1 gene (SRGAP1) in the linkage peak as a candidate gene. Two missense variants, Q149H and A275T, localized in the Fes/CIP4 homology domain segregated with the disease in 1 family each. One missense variant, R617C, located in the RhoGAP domain occurred in 1 family. Biochemical assays demonstrated that the ability to inactivate CDC42, a key function of SRGAP1, was severely impaired by the Q149H and R617C variants. Conclusions: Our findings suggest that SRGAP1 is a candidate gene in PTC susceptibility. SRGAP1 is likely a low-penetrant gene, possibly of a modifier type. PMID:23539728

  15. Identification of ITPA on chromosome 20 as a susceptibility gene for young-onset tuberculosis

    PubMed Central

    Nakauchi, Ayaka; Wong, Jing Hao; Mahasirimongkol, Surakameth; Yanai, Hideki; Yuliwulandari, Rika; Mabuchi, Akihiko; Liu, Xiaoxi; Mushiroda, Taisei; Wattanapokayakit, Sukanya; Miyagawa, Taku; Keicho, Naoto; Tokunaga, Katsushi

    2016-01-01

    Tuberculosis (TB) is a complex disease, and both genetic and environmental factors contribute to disease progression. A previous genome-wide linkage study in Thailand determined that chromosome 20p13-12.3 may contain risk factors for young-onset disease. The present study aimed to identify novel susceptibility genes for young-onset TB within a 1-Mbp target region adjacent to the top-ranking risk marker in Chr.20p13-12.3. We performed next-generation sequencing (NGS) of the region in 13 young patients from multi-case families in Thailand. We then selected the functionally interesting single-nucleotide polymorphisms as candidates for subsequent analyses. The detected candidates rs13830 and rs1127354 in ITPA showed an association with young (<45 years old) TB patients. However, there was no association in old (⩾45 years old) patients. These findings confirm that stratifying patients based on age of TB onset can be important for identifying genetic risk factors for TB susceptibility. In addition, in silico expression quantitative trait loci analyses indicated that ITPA expression was associated with rs13830 genotype. This is the first study to use NGS resequencing to gain insight into host genetic factors associated with TB and to report a significant association for ITPA with host susceptibility in young-onset TB. The study also demonstrated the effectiveness of NGS in identifying susceptibility genes in common diseases. PMID:27081565

  16. Bipolar disorder: idioms of susceptibility and disease and the role of 'genes' in illness explanations.

    PubMed

    Baart, Ingrid; Widdershoven, Guy

    2013-11-01

    This qualitative study explores (1) how members of the Dutch Association for People with Bipolar Disorder explain the affliction of bipolar disorder; (2) the relationship between genetic, environmental and personal factors in these explanations and (3) the relationship between illness explanations, self-management and identity. A total of 40 participants took part in seven different focus group discussions. The results demonstrate that there are two different explanatory idioms, each one centred around an opposing concept, that is, susceptibility and disease. Individuals who construct explanations around the concept of 'disease' attach more importance to 'genes and chemicals' than to environmental components in the onset of the disorder, whereas individuals adhering to the central concept of 'susceptibility' tend to do this much less. Compared with individuals using the 'susceptibility' idiom, those who use a 'disease' idiom tend to observe fewer possibilities for self-management and are less inclined to construct normalcy through a quest for personal growth. Stories of suffering seem more integral to the 'disease' idiom than to the 'susceptibility' idiom. The 'disease' idiom seems less integrated in a contemporary surveillance psychiatric discourse than the 'susceptibility' idiom; however, both vocabularies can offer normative constraints. PMID:23382566

  17. Matrix metalloproteinase gene polymorphisms and periodontitis susceptibility: a meta-analysis involving 6,162 individuals

    PubMed Central

    Weng, Hong; Yan, Yan; Jin, Ying-Hui; Meng, Xiang-Yu; Mo, Yuan-Yuan; Zeng, Xian-Tao

    2016-01-01

    We aimed to systematically investigate the potential association of matrix metalloproteinase (MMP)-9, -3, -2, and -8 gene polymorphisms with susceptibility to periodontitis using meta-analysis. A literature search in PubMed, Embase, and Web of Sciencewas conducted to obtain relevant publications. Finally a total of 16 articles with 24 case-control studies (nine on MMP-9-1562 C/T, seven on MMP-3-1171 A5/A6, four on MMP-2-753C/T, and four on MMP-8-799 C/T) were considered in this meta-analysis. The results based on 2,724 periodontitis patients and 3,438 controls showed that MMP-9-1562C/T, MMP-3-1171 A5/A6, and MMP-8-799C/T polymorphisms were associated with periodontitis susceptibility. No significant association was found between MMP-2-753 C/T and periodontitis susceptibility. Subgroup analyses suggested that the MMP-9-1562 C/T polymorphism reduced chronic periodontitis susceptibility and MMP-3-1171 A5/A6polymorphism increased chronic periodontitis susceptibility. In summary, current evidence demonstrated that MMP-9-753 C/Tpolymorphism reduced the risk of periodontitis, MMP-3-1171 5A/6A and MMP-8-799 C/Tpolymorphisms increased the risk of periodontitis, and MMP-2-753 C/T was not associated with risk of periodontitis. PMID:27095260

  18. Integrating genomic and clinical medicine: Searching for susceptibility genes in complex lung diseases

    PubMed Central

    DESAI, ANKIT A.; HYSI, PIRRO; GARCIA, JOE G. N.

    2011-01-01

    The integration of molecular, genomic, and clinical medicine in the post-genome era provides the promise of novel information on genetic variation and pathophysiologic cascades. The current challenge is to translate these discoveries rapidly into viable biomarkers that identify susceptible populations and into the development of precisely targeted therapies. In this article, we describe the application of comparative genomics, microarray platforms, genetic epidemiology, statistical genetics, and bioinformatic approaches within examples of complex pulmonary pathobiology. Our search for candidate genes, which are gene variations that drive susceptibility to and severity of enigmatic acute and chronic lung disorders, provides a logical framework to understand better the evolution of genomic medicine. The dissection of the genetic basis of complex diseases and the development of highly individualized therapies remain lofty but achievable goals. PMID:18355765

  19. Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

    PubMed Central

    Crampton, Steve P.; Morawski, Peter A.; Bolland, Silvia

    2014-01-01

    Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS) and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease. PMID:25147296

  20. CARD15 Gene Polymorphisms Are Associated with Tuberculosis Susceptibility in Chinese Holstein Cows

    PubMed Central

    Liu, Tong; Tu, Wenji; Li, Wengui; Dong, Guodong; Xu, Cong; Qin, Bo; Liu, Kaihua; Yang, Jie; Chai, Jun; Shi, Xianwei; Zhang, Yifang

    2015-01-01

    Bovine tuberculosis (BTB) is a significant veterinary and financial problem in many parts of the world. Associations between specific host genes and susceptibility to mycobacterial infections, such as tuberculosis, have been reported in several species. The objective of this study was to identify and evaluate the relationship of single-nucleotide polymorphisms (SNPs) in the CARD15 gene with susceptibility to BTB in Chinese Holstein cows. DNA samples from 201 Chinese Holstein cows (103 cases and 98 controls) were collected from Kunming City, Yuxi City, and Dali City in China. SNPs in the CARD15 gene were assessed using polymerase chain reaction (PCR) and restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). Case-control association testing and statistical analysis identified six SNPs associated with susceptibility to BTB in Chinese Holstein cows. The frequency of genotypes C/T, A/G, A/G, A/G, C/T, and A/G in E4 (-37), 208, 1644, 1648, 1799, and E10 (+107), respectively, was significantly higher in cases than in controls, and also the alleles C, A, A, G, T, and A, respectively, were associated with a greater relative risk in cases than in controls. The distribution of two haplotypes, TGGACA and CAGACA, was significantly different between cases and controls. Overall, this case-control study suggested that E4 (-37)(C/T), 208(A/G), 1644(A/G), 1648(A/G), 1799(C/T), and E10 (+107)(A/G) in the CARD15 gene were significantly associated with susceptibility to BTB in Chinese Holstein cows and that haplotypes TGGACA and CAGACA could be used as genetic markers in marker-assisted breeding programs for breeding cows with high resistance to BTB. PMID:26244859

  1. CARD15 Gene Polymorphisms Are Associated with Tuberculosis Susceptibility in Chinese Holstein Cows.

    PubMed

    Wang, Youtao; Wang, Shengkui; Liu, Tong; Tu, Wenji; Li, Wengui; Dong, Guodong; Xu, Cong; Qin, Bo; Liu, Kaihua; Yang, Jie; Chai, Jun; Shi, Xianwei; Zhang, Yifang

    2015-01-01

    Bovine tuberculosis (BTB) is a significant veterinary and financial problem in many parts of the world. Associations between specific host genes and susceptibility to mycobacterial infections, such as tuberculosis, have been reported in several species. The objective of this study was to identify and evaluate the relationship of single-nucleotide polymorphisms (SNPs) in the CARD15 gene with susceptibility to BTB in Chinese Holstein cows. DNA samples from 201 Chinese Holstein cows (103 cases and 98 controls) were collected from Kunming City, Yuxi City, and Dali City in China. SNPs in the CARD15 gene were assessed using polymerase chain reaction (PCR) and restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). Case-control association testing and statistical analysis identified six SNPs associated with susceptibility to BTB in Chinese Holstein cows. The frequency of genotypes C/T, A/G, A/G, A/G, C/T, and A/G in E4 (-37), 208, 1644, 1648, 1799, and E10 (+107), respectively, was significantly higher in cases than in controls, and also the alleles C, A, A, G, T, and A, respectively, were associated with a greater relative risk in cases than in controls. The distribution of two haplotypes, TGGACA and CAGACA, was significantly different between cases and controls. Overall, this case-control study suggested that E4 (-37)(C/T), 208(A/G), 1644(A/G), 1648(A/G), 1799(C/T), and E10 (+107)(A/G) in the CARD15 gene were significantly associated with susceptibility to BTB in Chinese Holstein cows and that haplotypes TGGACA and CAGACA could be used as genetic markers in marker-assisted breeding programs for breeding cows with high resistance to BTB. PMID:26244859

  2. TGFβ receptor 1: an immune susceptibility gene in HPV-associated cancer.

    PubMed

    Levovitz, Chaya; Chen, Dan; Ivansson, Emma; Gyllensten, Ulf; Finnigan, John P; Alshawish, Sara; Zhang, Weijia; Schadt, Eric E; Posner, Marshal R; Genden, Eric M; Boffetta, Paolo; Sikora, Andrew G

    2014-12-01

    Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein-protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFβR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFβR1 containing p38-MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV(+) head and neck cancer tumors. These concordant analyses implicate TGFβR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFβR1/TGFβ signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer. PMID:25273091

  3. TGFβ Receptor 1: An Immune Susceptibility Gene in HPV-Associated Cancer

    PubMed Central

    Levovitz, Chaya; Chen, Dan; Ivansson, Emma; Gyllensten, Ulf; Finnigan, John P.; Alshawish, Sara; Zhang, Weijia; Schadt, Eric E.; Posner, Marshal R.; Genden, Eric M.; Boffetta, Paolo; Sikora, Andrew G.

    2015-01-01

    Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein–protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFβR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFβR1 containing p38–MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV+ head and neck cancer tumors. These concordant analyses implicate TGFβR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFβR1/TGFβ signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer. PMID:25273091

  4. Gene expression profiling in the thiamethoxam resistant and susceptible B-biotype sweetpotato whitefly, Bemisia tabaci.

    PubMed

    Xie, Wen; Yang, Xin; Wang, Shao-Ii; Wu, Qing-jun; Yang, Ni-na; Li, Ru-mei; Jiao, Xiao-guo; Pan, Hui-peng; Liu, Bai-ming; Feng, Yun-tao; Xu, Bao-yun; Zhou, Xu-guo; Zhang, You-jun

    2012-01-01

    Thiamethoxam has been used as a major insecticide to control the B-biotype sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). Due to its excessive use, a high level of resistance to thiamethoxam has developed worldwide over the past several years. To better understand the molecular mechanisms underlying this resistance in B. tabaci, gene profiles between the thiamethoxam-resistant and thiamethoxam-susceptible strains were investigated using the suppression subtractive hybridization (SSH) library approach. A total of 72 and 52 upand down-regulated genes were obtained from the forward and reverse SSH libraries, respectively. These expressed sequence tags (ESTs) belong to several functional categories based on their gene ontology annotation. Some categories such as cell communication, response to abiotic stimulus, lipid particle, and nuclear envelope were identified only in the forward library of thiamethoxam-resistant strains. In contrast, categories such as behavior, cell proliferation, nutrient reservoir activity, sequence-specific DNA binding transcription factor activity, and signal transducer activity were identified solely in the reverse library. To study the validity of the SSH method, 16 differentially expressed genes from both forward and reverse SSH libraries were selected randomly for further analyses using quantitative realtime PCR (qRT-PCR). The qRT-PCR results were fairly consistent with the SSH results; however, only 50% of the genes showed significantly different expression profiles between the thiamethoxam-resistant and thiamethoxam-susceptible whiteflies. Among these genes, a putative NAD-dependent methanol dehydrogenase was substantially over-expressed in the thiamethoxamresistant adults compared to their susceptible counterparts. The distributed profiles show that it was highly expressed during the egg stage, and was most abundant in the abdomen of adult females. PMID:22957505

  5. Gene Expression Profiling in the Thiamethoxam Resistant and Susceptible B-biotype Sweetpotato Whitefly, Bemisia tabaci

    PubMed Central

    Xie, Wen; Yang, Xin; Wang, Shao-Ii; Wu, Qing-jun; Yang, Ni-na; Li, Ru-mei; Jiao, Xiaoguo; Pan, Hui-peng; Liu, Bai-ming; Feng, Yun-tao; Xu, Bao-yun; Zhou, Xu-guo; Zhang, You-jun

    2012-01-01

    Thiamethoxam has been used as a major insecticide to control the B-biotype sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). Due to its excessive use, a high level of resistance to thiamethoxam has developed worldwide over the past several years. To better understand the molecular mechanisms underlying this resistance in B. tabaci, gene profiles between the thiamethoxam-resistant and thiamethoxam-susceptible strains were investigated using the suppression subtractive hybridization (SSH) library approach. A total of 72 and 52 upand down-regulated genes were obtained from the forward and reverse SSH libraries, respectively. These expressed sequence tags (ESTs) belong to several functional categories based on their gene ontology annotation. Some categories such as cell communication, response to abiotic stimulus, lipid particle, and nuclear envelope were identified only in the forward library of thiamethoxam-resistant strains. In contrast, categories such as behavior, cell proliferation, nutrient reservoir activity, sequence-specific DNA binding transcription factor activity, and signal transducer activity were identified solely in the reverse library. To study the validity of the SSH method, 16 differentially expressed genes from both forward and reverse SSH libraries were selected randomly for further analyses using quantitative realtime PCR (qRT-PCR). The qRT-PCR results were fairly consistent with the SSH results; however, only 50% of the genes showed significantly different expression profiles between the thiamethoxam-resistant and thiamethoxam-susceptible whiteflies. Among these genes, a putative NAD-dependent methanol dehydrogenase was substantially over-expressed in the thiamethoxamresistant adults compared to their susceptible counterparts. The distributed profiles show that it was highly expressed during the egg stage, and was most abundant in the abdomen of adult females. PMID:22957505

  6. Expression of Phenylalanine Ammonia Lyase Genes in Maize Lines Differing in Susceptibility to Meloidogyne incognita

    PubMed Central

    Yang, W.; Yan, Y.; Crutcher, F.; Kolomiets, M.

    2014-01-01

    Maize is a well-known host for Meloidogyne incognita, and there is substantial variation in host status among maize genotypes. In previous work it was observed that nematode reproduction increased in the moderately susceptible maize inbred line B73 when the ZmLOX3 gene from oxylipid metabolism was knocked out. Additionally, in this mutant line, use of a nonspecific primer for phenyl alanine ammonialyase (PAL) genes indicated that expression of these genes was reduced in the mutant maize plants whereas expression of several other defense related genes was increased. In this study, we used more specific gene primers to examine the expression of six PAL genes in three maize genotypes that were good, moderate, and poor hosts for M. incognita, respectively. Of the six PAL genes interrogated, two (ZmPAL3 and ZmPAL6) were not expressed in either M. incognita–infected or noninfected roots. Three genes (ZmPAL1, ZmPAL2, and ZmPAL5) were strongly expressed in all three maize lines, in both nematode-infected and noninfected roots, between 2 and 16 d after inoculation (DAI). In contrast, ZmPAL4 was most strongly expressed in the most-resistant maize line W438, was not detected in the most-susceptible maize line CML, and was detected only at 8 DAI in the maize line B73 that supported intermediate levels of reproduction by M. incognita. These observations are consistent with at least one PAL gene playing a role in modulating host status of maize toward M. incognita and suggest a need for additional research to further elucidate this association. PMID:25580029

  7. CREB1 gene polymorphisms combined with environmental risk factors increase susceptibility to major depressive disorder (MDD)

    PubMed Central

    Wang, Peng; Yang, Yanjie; Yang, Xiuxian; Qiu, Xiaohui; Qiao, Zhengxue; Wang, Lin; Zhu, Xiongzhao; Sui, Hong; Ma, Jingsong

    2015-01-01

    Major depressive disorder (MDD) is one of the most severe psychiatric disorders. The objective of this study was to explore the effects of CREB1 gene polymorphisms on risk of developing MDD and the joint effects of gene-environment interactions. Genotyping was performed by Taqman allelic discrimination assay among 586 patients and 586 healthy controls. A significant impact on rs6740584 genotype distribution was found for childhood trauma (P = 0.015). We did not find an association of CREB1 polymorphisms with MDD susceptibility. However, we found a significantly increased risk associated with the interactions of CREB1 polymorphisms and drinking (OR = 11.67, 95% CI = 2.52-54.18; OR = 11.52, 95% CI = 2.55-51.95 for rs11904814; OR = 4.18, 95% CI = 1.87-9.38; OR = 5.02, 95% CI = 2.27-11.14 for rs6740584; OR = 7.58, 95% CI = 2.05-27.98; OR = 7.59, 95% CI = 2.12-27.14 for rs2553206; OR = 8.37, 95% CI = 3.02-23.23; OR = 7.84, 95% CI = 2.93-20.98 for rs2551941). We also noted that CREB polymorphisms combined with family harmony and childhood trauma conferred increased susceptibility for MDD. In conclusion, polymorphisms in the CREB gene may not be independently associated with MDD risk, but they are likely to confer increased susceptibility by interacting with environmental risk factors in the Chinese population. PMID:25755794

  8. Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain

    PubMed Central

    Richards, Alexander L; Jones, Lesley; Moskvina, Valentina; Kirov, George; Gejman, Pablo V; Levinson, Douglas F; Sanders, Alan R; Purcell, Shaun; Visscher, Peter M; Craddock, Nick; Owen, Michael J; Holmans, Peter; O’Donovan, Michael C

    2016-01-01

    It is widely thought that alleles that influence susceptibility to common diseases, including schizophrenia, will frequently do so through effects on gene expression. Since only a small proportion of the genetic variance for schizophrenia has been attributed to specific loci, this remains an unproven hypothesis. The International Schizophrenia Consortium (ISC) recently reported a substantial polygenic contribution to that disorder, and that schizophrenia risk alleles are enriched among SNPs selected for marginal evidence for association (p<0.5) from genome wide association studies (GWAS). It follows that if schizophrenia susceptibility alleles are enriched for those that affect gene expression, those marginally associated SNPs which are also eQTLs should carry more true association signals compared with SNPs which are not. To test this, we identified marginally associated (p<0.5) SNPs from two of the largest available schizophrenia GWAS datasets. We assigned eQTL status to those SNPs based upon an eQTL dataset derived from adult human brain. Using the polygenic score method of analysis reported by the ISC, we observed and replicated the observation that higher probability cis-eQTLs predicted schizophrenia better than those with a lower probability for being a cis-eQTL. Our data support the hypothesis that alleles conferring risk of schizophrenia are enriched among those that affect gene expression. Moreover, our data show that notwithstanding the likely developmental origin of schizophrenia, studies of adult brain tissue can in principle allow relevant susceptibility eQTLs to be identified. PMID:21339752

  9. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity.

    PubMed

    Buxbaum, J D; Silverman, J M; Smith, C J; Kilifarski, M; Reichert, J; Hollander, E; Lawlor, B A; Fitzgerald, M; Greenberg, D A; Davis, K L

    2001-06-01

    Although there is considerable evidence for a strong genetic component to idiopathic autism, several genomewide screens for susceptibility genes have been performed with limited concordance of linked loci, reflecting either numerous genes of weak effect and/or sample heterogeneity. Because decreasing sample heterogeneity would increase the power to identify genes, the effect on evidence for linkage of restricting a sample of autism-affected relative pairs to those with delayed onset (at age >36 mo) of phrase speech (PSD, for phrase speech delay) was studied. In the second stage of a two-stage genome screen for susceptibility loci involving 95 families with two or more individuals with autism or related disorders, a maximal multipoint heterogeneity LOD score (HLOD) of 1.96 and a maximal multipoint nonparametric linkage (NPL) score of 2.39 was seen on chromosome 2q. Restricting the analysis to the subset of families (n=49) with two or more individuals having a narrow diagnosis of autism and PSD generated a maximal multipoint HLOD score of 2.99 and an NPL score of 3.32. The increased scores in the restricted sample, together with evidence for heterogeneity in the entire sample, indicate that the restricted sample comprises a population that is more genetically homogeneous, which could therefore increase the likelihood of positional cloning of susceptibility loci. PMID:11353400

  10. Association of TAP1 and TAP2 genes with susceptibility to pulmonary tuberculosis in Koreans.

    PubMed

    Roh, Eun Youn; Yoon, Jong Hyun; Shin, Sue; Song, Eun Young; Park, Myoung Hee

    2015-06-01

    Tuberculosis remains an important public health problem in Koreans. However, very few studies have reported on the genetic factors associated with TB susceptibility in Koreans. The aim of this study was to elucidate the genetic factors associated with susceptibility to pulmonary tuberculosis (PTB). We investigated the transporter associated with antigen processing -1 (TAP1) and TAP2 gene polymorphisms in 160 Korean PTB patients (categorized according to extent of lesion and TB medication history) and 210 controls. TAP2*C/E frequency was significantly increased in the PTB (pc = 0.004, OR = 2.28). TAP2*Bky2/C/E were enriched in the retreated, far-advanced and total PTB compared with the controls (pc = 0.015, OR = 3.27; pc = 0.019, OR = 2.56; pc = 2.8 × 10(-4) , OR = 2.42, respectively). In the comparison of TAP2 gene with the DRB1*08:03, which is associated with TAP2*Bky2 and PTB in Koreans, we demonstrated the hierarchy of these association factors. TAP2*C/E is independent factors as strong as DRB1*08:03, and TAP2*C/E interacts with DRB1*08:03, resulting in a striking combined association. Our results suggest that TAP2 gene has an association with PTB susceptibility, the extent of the lesion or recurrence. These associations are independent from and additive with DRB1*08:03. PMID:25846714

  11. Novel miRNA-31 and miRNA-200a-Mediated Regulation of Retinoblastoma Proliferation.

    PubMed

    Montoya, Vanessa; Fan, Hanli; Bryar, Paul J; Weinstein, Joanna L; Mets, Marilyn B; Feng, Gang; Martin, Joshua; Martin, Alissa; Jiang, Hongmei; Laurie, Nikia A

    2015-01-01

    Retinoblastoma is the most common intraocular tumor in children. Current management includes broad-based treatments such as chemotherapy, enucleation, laser therapy, or cryotherapy. However, therapies that target specific pathways important for retinoblastoma progression could provide valuable alternatives for treatment. MicroRNAs are short, noncoding RNA transcripts that can regulate the expression of target genes, and their aberrant expression often facilitates disease. The identification of post-transcriptional events that occur after the initiating genetic lesions could further define the rapidly aggressive growth displayed by retinoblastoma tumors. In this study, we used two phenotypically different retinoblastoma cell lines to elucidate the roles of miRNA-31 and miRNA-200a in tumor proliferation. Our approach confirmed that miRNAs-31 and -200a expression is significantly reduced in human retinoblastomas. Moreover, overexpression of these two miRNAs restricts the expansion of a highly proliferative cell line (Y79), but does not restrict the growth rate of a less aggressive cell line (Weri1). Gene expression profiling of miRNA-31 and/or miRNA-200a-overexpressing cells identified differentially expressed mRNAs associated with the divergent response of the two cell lines. This work has the potential to enhance the development of targeted therapeutic approaches for retinoblastoma and improve the efficacy of treatment. PMID:26379276

  12. Novel miRNA-31 and miRNA-200a-Mediated Regulation of Retinoblastoma Proliferation

    PubMed Central

    Montoya, Vanessa; Fan, Hanli; Bryar, Paul J.; Weinstein, Joanna L.; Mets, Marilyn B.; Feng, Gang; Martin, Joshua; Martin, Alissa; Jiang, Hongmei; Laurie, Nikia A.

    2015-01-01

    Retinoblastoma is the most common intraocular tumor in children. Current management includes broad-based treatments such as chemotherapy, enucleation, laser therapy, or cryotherapy. However, therapies that target specific pathways important for retinoblastoma progression could provide valuable alternatives for treatment. MicroRNAs are short, noncoding RNA transcripts that can regulate the expression of target genes, and their aberrant expression often facilitates disease. The identification of post-transcriptional events that occur after the initiating genetic lesions could further define the rapidly aggressive growth displayed by retinoblastoma tumors. In this study, we used two phenotypically different retinoblastoma cell lines to elucidate the roles of miRNA-31 and miRNA-200a in tumor proliferation. Our approach confirmed that miRNAs-31 and -200a expression is significantly reduced in human retinoblastomas. Moreover, overexpression of these two miRNAs restricts the expansion of a highly proliferative cell line (Y79), but does not restrict the growth rate of a less aggressive cell line (Weri1). Gene expression profiling of miRNA-31 and/or miRNA-200a-overexpressing cells identified differentially expressed mRNAs associated with the divergent response of the two cell lines. This work has the potential to enhance the development of targeted therapeutic approaches for retinoblastoma and improve the efficacy of treatment. PMID:26379276

  13. Somatic genomic alterations in retinoblastoma beyond RB1 are rare and limited to copy number changes.

    PubMed

    Kooi, Irsan E; Mol, Berber M; Massink, Maarten P G; Ameziane, Najim; Meijers-Heijboer, Hanne; Dommering, Charlotte J; van Mil, Saskia E; de Vries, Yne; van der Hout, Annemarie H; Kaspers, Gertjan J L; Moll, Annette C; Te Riele, Hein; Cloos, Jacqueline; Dorsman, Josephine C

    2016-01-01

    Retinoblastoma is a rare childhood cancer initiated by RB1 mutation or MYCN amplification, while additional alterations may be required for tumor development. However, the view on single nucleotide variants is very limited. To better understand oncogenesis, we determined the genomic landscape of retinoblastoma. We performed exome sequencing of 71 retinoblastomas and matched blood DNA. Next, we determined the presence of single nucleotide variants, copy number alterations and viruses. Aside from RB1, recurrent gene mutations were very rare. Only a limited fraction of tumors showed BCOR (7/71, 10%) or CREBBP alterations (3/71, 4%). No evidence was found for the presence of viruses. Instead, specific somatic copy number alterations were more common, particularly in patients diagnosed at later age. Recurrent alterations of chromosomal arms often involved less than one copy, also in highly pure tumor samples, suggesting within-tumor heterogeneity. Our results show that retinoblastoma is among the least mutated cancers and signify the extreme sensitivity of the childhood retina for RB1 loss. We hypothesize that retinoblastomas arising later in retinal development benefit more from subclonal secondary alterations and therefore, these alterations are more selected for in these tumors. Targeted therapy based on these subclonal events might be insufficient for complete tumor control. PMID:27126562

  14. Somatic genomic alterations in retinoblastoma beyond RB1 are rare and limited to copy number changes

    PubMed Central

    Kooi, Irsan E.; Mol, Berber M.; Massink, Maarten P. G.; Ameziane, Najim; Meijers-Heijboer, Hanne; Dommering, Charlotte J.; van Mil, Saskia E.; de Vries, Yne; van der Hout, Annemarie H.; Kaspers, Gertjan J. L.; Moll, Annette C.; te Riele, Hein; Cloos, Jacqueline; Dorsman, Josephine C.

    2016-01-01

    Retinoblastoma is a rare childhood cancer initiated by RB1 mutation or MYCN amplification, while additional alterations may be required for tumor development. However, the view on single nucleotide variants is very limited. To better understand oncogenesis, we determined the genomic landscape of retinoblastoma. We performed exome sequencing of 71 retinoblastomas and matched blood DNA. Next, we determined the presence of single nucleotide variants, copy number alterations and viruses. Aside from RB1, recurrent gene mutations were very rare. Only a limited fraction of tumors showed BCOR (7/71, 10%) or CREBBP alterations (3/71, 4%). No evidence was found for the presence of viruses. Instead, specific somatic copy number alterations were more common, particularly in patients diagnosed at later age. Recurrent alterations of chromosomal arms often involved less than one copy, also in highly pure tumor samples, suggesting within-tumor heterogeneity. Our results show that retinoblastoma is among the least mutated cancers and signify the extreme sensitivity of the childhood retina for RB1 loss. We hypothesize that retinoblastomas arising later in retinal development benefit more from subclonal secondary alterations and therefore, these alterations are more selected for in these tumors. Targeted therapy based on these subclonal events might be insufficient for complete tumor control. PMID:27126562

  15. TOP2 gene disruption reduces drug susceptibility by increasing intracellular ergosterol biosynthesis in Candida albicans.

    PubMed

    Zheng, Hao; Jiang, Yuan-Ying; Wang, Yan; Jia, Xin-Ming; Yan, Tian-Hua; Gao, Ping-Hui; Yan, Lan; Jiang, Ling-Huo; Ji, Hui; Cao, Yong-Bing

    2010-07-01

    In this study the role of the TOP2 gene in fungal drug susceptibility was investigated by disrupting and overexpressing the gene in Candida albicans. MIC determination and a spot assay showed that a top2Delta/Delta null mutant (strain T2bc) was more resistant to the antifungals tested than the wild-type (strain CAI4). Real-time RT-PCR and rhodamine 6G efflux examination showed that TOP2 did not influence the activity of drug efflux pumps. Sterol analysis with GC/high-resolution MS indicated that the intracellular ergosterol composition of the top2Delta/Delta mutant was significantly increased. Subsequently, fluorescence polarization measurements also revealed that Top2-deprived cells displayed a decrease in membrane fluidity, resulting in enhanced passive diffusion of the drugs. Quantitative real-time RT-PCR analysis further confirmed that the ERG11 gene, an essential gene in ergosterol biosynthesis, was upregulated. These results demonstrate a close relationship between the TOP2 gene and drug susceptibility in C. albicans. PMID:20223895

  16. Association of Common Variants in the Glucocerebrosidase Gene with High Susceptibility to Parkinson's Disease among Chinese.

    PubMed

    Zhang, Xiong; Bao, Qiong-Qiong; Zhuang, Xiao-Sai; Gan, Shi-Rui; Zhao, Dan; Liu, Yun; Hu, Qiao; Chen, Ying; Zhu, Feiyan; Wang, Lian; Wang, Ning

    2012-12-31

    The genetic variants in glucocerebrosidase (GBA) gene have been previously examined as potential susceptibility factors for Parkinson's disease (PD). Although of great interest, possible role of GBA gene in PD has not been well investigated in eastern Chinese population. To explore this association, we conducted a genetic screen of three common GBA variants (p.L444P, p.N370S, and p.R120W) in a casecontrol cohort comprised of 638 subjects of Chinese ethnicity. In order to provide a more precise estimate of this association, a meta-analysis was performed. We found that the GBA p.L444P allele was significantly more frequent (P = 0.001) in the PD patients (6/195 = 3.08%) than in the controls (0/443). The p.L444P mutation, but not p.N370S and p.R120W, was found to be associated with PD. Combined analysis including all previously published ancestral Chinese data yielded a highly significant association between the GBA gene and an increased risk for PD (OR = 8.13, 95% CI, 4.43-14.92, P < 0.00001). Our study suggests that the GBA gene may be a susceptibility gene for PD in the Chinese population. Efforts to elucidate in detail this interesting and biologically plausible genetic association are warranted. PMID:23286447

  17. [Antimicrobial susceptibilities of clinical Nocardia isolates identified by 16S rRNA gene sequence analysis].

    PubMed

    Uner, Mahmut Celalettin; Hasçelik, Gülşen; Müştak, Hamit Kaan

    2016-01-01

    Nocardia species are ubiquitous in the environment and responsible for various human infections such as pulmonary, cutaneous, central nervous system and disseminated nocardiosis. Since the clinical pictures and antimicrobial susceptibilities of Nocardia species exhibit variability, susceptibility testing is recommended for every Nocardia isolates. The aims of this study was to determine the antimicrobial susceptibilities of Nocardia clinical isolates and to compare the results of broth microdilution and disc diffusion susceptibility tests. A total of 45 clinical Nocardia isolates (isolated from 17 respiratory tract, 8 brain abscess, 7 pus, 3 skin, 3 conjunctiva, 2 blood, 2 tissue, 2 pleural fluid and 1 cerebrospinal fluid samples) were identified by using conventional methods and 16S rRNA gene sequence analysis. Susceptibility testing was performed for amikacin, ciprofloxacin, ceftriaxone, linezolid and trimethoprim-sulfamethoxazole (TMP-SMX) by broth microdilution method according to the Clinical and Laboratory Standards Institute (CLSI) criteria recommended in 2011 approved standard (M24-A2) and disk diffusion method used as an alternative comparative susceptibility testing method. Among the 45 Nocardia strains, N.cyriacigeorgica (n: 26, 57.8%) was the most common species, followed by N.farcinica (n: 12, 26.7%), N.otitiscaviarum (n: 4, 8.9%), N.asteroides (n: 1, 2.2%), N.neocaledoniensis (n: 1, 2.2%) and N.abscessus (n: 1, 2.2%). Amikacin and linezolid were the only two antimicrobials to which all isolates were susceptible for both broth microdilution and disk diffusion tests. In broth microdilution test, resistance rates to TMP-SMX, ceftriaxone and ciprofloxacin were found as 15.6%, 37.8% and 84.4% respectively, whereas in the disk diffusion test, the highest resistance rate was observed against ciprofloxacin (n: 33, 73.3%), followed by TMP-SMX (n: 22, 48.9%) and ceftriaxone (n: 15, 33.3%). In both of these tests, N.cyriacigeorgica was the species with the

  18. Beta-lactamase genes of the penicillin-susceptible Bacillus anthracis Sterne strain.

    PubMed

    Chen, Yahua; Succi, Janice; Tenover, Fred C; Koehler, Theresa M

    2003-02-01

    Susceptibility to penicillin and other beta-lactam-containing compounds is a common trait of Bacillus anthracis. Beta-lactam agents, particularly penicillin, have been used worldwide to treat anthrax in humans. Nonetheless, surveys of clinical and soil-derived strains reveal penicillin G resistance in 2 to 16% of isolates tested. Bacterial resistance to beta-lactam agents is often mediated by production of one or more types of beta-lactamases that hydrolyze the beta-lactam ring, inactivating the antimicrobial agent. Here, we report the presence of two beta-lactamase (bla) genes in the penicillin-susceptible Sterne strain of B. anthracis. We identified bla1 by functional cloning with Escherichia coli. bla1 is a 927-nucleotide (nt) gene predicted to encode a protein with 93.8% identity to the type I beta-lactamase gene of Bacillus cereus. A second gene, bla2, was identified by searching the unfinished B. anthracis chromosome sequence database of The Institute for Genome Research for open reading frames (ORFs) predicted to encode beta-lactamases. We found a partial ORF predicted to encode a protein with significant similarity to the carboxy-terminal end of the type II beta-lactamase of B. cereus. DNA adjacent to the 5' end of the partial ORF was cloned using inverse PCR. bla2 is a 768-nt gene predicted to encode a protein with 92% identity to the B. cereus type II enzyme. The bla1 and bla2 genes confer ampicillin resistance to E. coli and Bacillus subtilis when cloned individually in these species. The MICs of various antimicrobial agents for the E. coli clones indicate that the two beta-lactamase genes confer different susceptibility profiles to E. coli; bla1 is a penicillinase, while bla2 appears to be a cephalosporinase. The beta-galactosidase activities of B. cereus group species harboring bla promoter-lacZ transcriptional fusions indicate that bla1 is poorly transcribed in B. anthracis, B. cereus, and B. thuringiensis. The bla2 gene is strongly expressed in B

  19. A gene for familial psoriasis susceptibility maps to the distal end of human chromosome 17q

    SciTech Connect

    Bowcock, A.; Tomfohrde, J.; Barnes, R.

    1994-09-01

    Psoriasis is a chronic inflammatory dermatosis that affects approximately 2% of the population. A gene for psoriasis susceptibility was localized to the distal region of human chromosome 17q as a result of a genome wide linkage-analysis with polymorphic microsatellites and eight multiply affected psoriasis kindreds. With one large kindred a maximum two-point lod score with D17S784 was 5.70 at 15% recombination. Heterogeneity testing indicated that psoriasis susceptibility in 50% of the families was linked to distal 17q. Susceptibility to psoriasis has repeatedly been found to be associated with HLA-Cw6 and associated HLA alleles. We therefore genotyped the families for loci within and flanking HLA; these included PCR assays for susceptibility alleles. By lod score analysis no evidence of linkage of psoriasis susceptibility to HLA was detected. The distribution of HLA-Cw6 and HLA-Class II alleles showed that HLA-Cw6 was frequent among patients, particularly in 4 of the 5 unlinked families. All affected members of two of these unlinked families carried HLA-Cw6 (empirical P values of 0.027 and 0.004). In 2 other families 4 of 6 and 6 of 7 had HLA-Cw6. In some of these families, an inability to detect linkage to HLA may have been due to the occurrence of multiple haplotypes carrying the psoriasis associated allele, HLA-Cw6. Contrasting with these findings, we observed a lack of association between HLA-Cw6 and psoriasis in the 3 families in which 17q markers were linked to susceptibility. The ability to detect linkage to 17q confirms that some forms of familial psoriasis are due to molecular defects at a single major genetic locus other than HLA.

  20. A unique wheat disease resistance-like gene governs effector-triggered susceptibility to necrotrophic pathogens

    PubMed Central

    Faris, Justin D.; Zhang, Zengcui; Lu, Huangjun; Lu, Shunwen; Reddy, Leela; Cloutier, Sylvie; Fellers, John P.; Meinhardt, Steven W.; Rasmussen, Jack B.; Xu, Steven S.; Oliver, Richard P.; Simons, Kristin J.; Friesen, Timothy L.

    2010-01-01

    Plant disease resistance is often conferred by genes with nucleotide binding site (NBS) and leucine-rich repeat (LRR) or serine/threonine protein kinase (S/TPK) domains. Much less is known about mechanisms of susceptibility, particularly to necrotrophic fungal pathogens. The pathogens that cause the diseases tan spot and Stagonospora nodorum blotch on wheat produce effectors (host-selective toxins) that induce susceptibility in wheat lines harboring corresponding toxin sensitivity genes. The effector ToxA is produced by both pathogens, and sensitivity to ToxA is governed by the Tsn1 gene on wheat chromosome arm 5BL. Here, we report the cloning of Tsn1, which was found to have disease resistance gene-like features, including S/TPK and NBS-LRR domains. Mutagenesis revealed that all three domains are required for ToxA sensitivity, and hence disease susceptibility. Tsn1 is unique to ToxA-sensitive genotypes, and insensitive genotypes are null. Sequencing and phylogenetic analysis indicated that Tsn1 arose in the B-genome diploid progenitor of polyploid wheat through a gene-fusion event that gave rise to its unique structure. Although Tsn1 is necessary to mediate ToxA recognition, yeast two-hybrid experiments suggested that the Tsn1 protein does not interact directly with ToxA. Tsn1 transcription is tightly regulated by the circadian clock and light, providing further evidence that Tsn1-ToxA interactions are associated with photosynthesis pathways. This work suggests that these necrotrophic pathogens may thrive by subverting the resistance mechanisms acquired by plants to combat other pathogens. PMID:20624958

  1. Antimicrobial Susceptibility of Bordetella bronchiseptica Isolates from Swine and Companion Animals and Detection of Resistance Genes

    PubMed Central

    Prüller, Sandra; Rensch, Ulrike; Meemken, Diana; Kaspar, Heike; Kopp, Peter A.; Klein, Günter; Kehrenberg, Corinna

    2015-01-01

    Bordetella bronchiseptica causes infections of the respiratory tract in swine and other mammals and is a precursor for secondary infections with Pasteurella multocida. Treatment of B. bronchiseptica infections is conducted primarily with antimicrobial agents. Therefore it is essential to get an overview of the susceptibility status of these bacteria. The aim of this study was to comparatively analyse broth microdilution susceptibility testing according to CLSI recommendations with an incubation time of 16 to 20 hours and a longer incubation time of 24 hours, as recently proposed to obtain more homogenous MICs. Susceptibility testing against a panel of 22 antimicrobial agents and two fixed combinations was performed with 107 porcine isolates from different farms and regions in Germany and 43 isolates obtained from companion animals in Germany and other European countries. Isolates with increased MICs were investigated by PCR assays for the presence of resistance genes. For ampicillin, all 107 porcine isolates were classified as resistant, whereas only a single isolate was resistant to florfenicol. All isolates obtained from companion animals showed elevated MICs for β-lactam antibiotics and demonstrated an overall low susceptibility to cephalosporines. Extension of the incubation time resulted in 1–2 dilution steps higher MIC50 values of porcine isolates for seven antimicrobial agents tested, while isolates from companion animals exhibited twofold higher MIC50/90 values only for tetracycline and cefotaxime. For three antimicrobial agents, lower MIC50 and MIC90 values were detected for both, porcine and companion animal isolates. Among the 150 isolates tested, the resistance genes blaBOR-1 (n = 147), blaOXA-2, (n = 4), strA and strB (n = 17), sul1 (n = 10), sul2 (n = 73), dfrA7 (n = 3) and tet(A) (n = 8) were detected and a plasmid localisation was identified for several of the resistance genes. PMID:26275219

  2. Comparison of gene activation by two TAL effectors from Xanthomonas axonopodis pv. manihotis reveals candidate host susceptibility genes in cassava.

    PubMed

    Cohn, Megan; Morbitzer, Robert; Lahaye, Thomas; Staskawicz, Brian J

    2016-08-01

    Xanthomonas axonopodis pv. manihotis (Xam) employs transcription activator-like (TAL) effectors to promote bacterial growth and symptom formation during infection of cassava. TAL effectors are secreted via the bacterial type III secretion system into plant cells, where they are directed to the nucleus, bind DNA in plant promoters and activate the expression of downstream genes. The DNA-binding activity of TAL effectors is carried out by a central domain which contains a series of repeat variable diresidues (RVDs) that dictate the sequence of bound nucleotides. TAL14Xam668 promotes virulence in Xam strain Xam668 and has been shown to activate multiple cassava genes. In this study, we used RNA sequencing to identify the full target repertoire of TAL14Xam668 in cassava, which includes over 50 genes. A subset of highly up-regulated genes was tested for activation by TAL14CIO151 from Xam strain CIO151. Although TAL14CIO151 and TAL14Xam668 differ by only a single RVD, they display differential activation of gene targets. TAL14CIO151 complements the TAL14Xam668 mutant defect, implying that shared target genes are important for TAL14Xam668 -mediated disease susceptibility. Complementation with closely related TAL effectors is a novel approach to the narrowing down of biologically relevant susceptibility genes of TAL effectors with multiple targets. This study provides an example of how TAL effector target activation by two strains within a single species of Xanthomonas can be dramatically affected by a small change in RVD-nucleotide affinity at a single site, and reflects the parameters of RVD-nucleotide interaction determined using designer TAL effectors in transient systems. PMID:26575863

  3. A Novel Differential Susceptibility Gene: "CHRNA4" and Moderation of the Effect of Maltreatment on Child Personality

    ERIC Educational Resources Information Center

    Grazioplene, Rachael G.; DeYoung, Colin G.; Rogosch, Fred A.; Cicchetti, Dante

    2013-01-01

    Background: The differential susceptibility hypothesis states that some genetic variants that confer risk in adverse environments are beneficial in normal or nurturing environments. The cholinergic system is promising as a source of susceptibility genes because of its involvement in learning and neural plasticity. The cholinergic receptor gene…

  4. The IL-33 gene is related to increased susceptibility to systemic sclerosis.

    PubMed

    Koca, Suleyman Serdar; Pehlivan, Yavuz; Kara, Murat; Alibaz-Oner, Fatma; Oztuzcu, Serdar; Yilmaz, Neslihan; Cetin, Gozde Yildirim; Kisacik, Bunyamin; Ozgen, Metin; Pamuk, Omer Nuri; Direskeneli, Haner; Sayarlioglu, Mehmet; Onat, Ahmet Mesut

    2016-04-01

    Systemic sclerosis (SSc) is a chronic inflammatory disease characterized by widespread fibrosis of the skin and several visceral organs. The pro-fibrotic potential of interleukin (IL)-33 has been demonstrated by in both in vitro and in vivo settings; moreover, increased level of IL-33 has also been reported in patients with SSc. Therefore, the aim of the present study was to detect the potential association of IL-33 gene polymorphisms on the susceptibility of SSc. A total of 300 SSc patients and 280 healthy controls (HC) were enrolled in this multicentric preliminary candidate gene study. DNA samples were harvested using an appropriate commercial DNA isolation kit. Four single nucleotide polymorphisms (SNPs) of IL-33 gene (rs7044343, rs1157505, rs11792633 and rs1929992) were genotyped using the appropriate commercial primer/probe sets on real-time PCR. There was no significant difference in terms of the allelic distributions and minor allele frequencies of evaluated four IL-33 polymorphisms between the SSc and HC groups (P > 0.05 for all). Moreover, the genotypic distributions of rs1157505, rs11792633 and rs1929992 polymorphisms were not significantly different (P > 0.05 for all). However, CC genotype of rs7044343 SNP was significantly higher in the SSc group compared to the HC group (P = 0.013, OR 1.75, 95 % CI 1.12-2.72). This preliminary candidate gene study demonstrates that rs7044343 polymorphism of IL-33 gene is associated with the susceptibility to the SSc in Turkish population. It may be suggested that IL-33 gene may be a candidate gene to research in SSc. PMID:26743213

  5. Variants of the SFTPA1 and SFTPA2 genes and susceptibility to tuberculosis in Ethiopia.

    PubMed

    Malik, S; Greenwood, C M T; Eguale, T; Kifle, A; Beyene, J; Habte, A; Tadesse, A; Gebrexabher, H; Britton, S; Schurr, E

    2006-02-01

    Lungs are the central organ affected and targeted by Mycobacterium tuberculosis and immune processes in the lung are of critical importance in the pathogenesis of tuberculosis. A major lung defense against invading pathogens is provided by surfactant protein A, a multi-chain protein encoded by the SFTPA1 and SFTPA2 genes. Here, we investigated polymorphisms in the SFTPA1 and SFTPA2 genes for association with tuberculosis in 181 Ethiopian families comprising 226 tuberculosis cases. Four polymorphisms, SFTPA1 307A, SFTPA1 776T, SFTPA2 355C, and SFTPA2 751C, were associated with tuberculosis (P=0.00008; P=0.019, P=0.029 and P=0.042, respectively). Additional subgroup analysis in male, female and more severely affected patients provided evidence for SFTPA1/2-covariate interaction. Finally, out of five intragenic haplotypes identified in the SFTPA1 gene and nine identified in the SFTPA2 gene, 1A(3) was most significantly associated with tuberculosis susceptibility (P=0.026). These findings suggest that SFTPA1 and SFTPA2 modify the risk of tuberculosis susceptibility and that this risk is influenced by additional covariates. PMID:16292672

  6. Outbreak of vancomycin-susceptible Enterococcus faecium containing the wild-type vanA gene.

    PubMed

    Szakacs, Tom A; Kalan, Lindsay; McConnell, Michael J; Eshaghi, Alireza; Shahinas, Dea; McGeer, Allison; Wright, Gerry D; Low, Donald E; Patel, Samir N

    2014-05-01

    Accurate detection of vancomycin-resistant enterococci (VRE) is essential in preventing transmission in health care settings. Chromogenic media are widely used for screening VRE because of fast turnaround times (TAT) and high sensitivity. We report an outbreak of Enterococcus faecium bearing vanA yet susceptible to vancomycin (vancomycin-variable Enterococcus [VVE]). Between October 2009 to March 2011, clinical and screening specimens (n=14,747) were screened for VRE using VRE-selective medium and/or PCR. VVE isolates were genotyped to determine relatedness. Plasmids from these isolates were characterized by sequencing. Overall, 52 VVE isolates were identified, comprising 15% of all VRE isolates identified. Isolates demonstrated growth on Brilliance VRE agar (Oxoid) at 24 h of incubation but did not grow on brain heart infusion agar with 6 μg/ml vancomycin (Oxoid) or bile esculin azide agar with 6 μg/ml vancomycin (Oxoid) and were susceptible to vancomycin. Genotyping of 20 randomly selected VVE isolates revealed that 15/20 were identical, while 5 were highly related. PCR of the VVE transposon confirmed the presence of vanHAXY gene cluster; however, vanS (sensor) and vanR (regulator) genes were absent. The outbreak was controlled through routine infection control measures. We report an emergence of a fit strain of E. faecium containing vanA yet susceptible to vancomycin. Whether this new strain represents VRE has yet to be determined; however, unique testing procedures are required for reliable identification of VVE. PMID:24523464

  7. SPINK1 Is a Susceptibility Gene for Fibrocalculous Pancreatic Diabetes in Subjects from the Indian Subcontinent

    PubMed Central

    Hassan, Zahid; Mohan, Viswananthan; Ali, Liaquat; Allotey, Rebecca; Barakat, Khalid; Faruque, M. Omar; Deepa, Raj; McDermott, Michael F.; Jackson, Alan E.; Cassell, Paul; Curtis, David; Gelding, Susan V.; Vijayaravaghan, Shanti; Gyr, Niklaus; Whitcomb, David C.; Khan, A. K. Azad; Hitman, Graham A.

    2002-01-01

    Fibrocalculous pancreatic diabetes (FCPD) is a secondary cause of diabetes due to chronic pancreatitis. Since the N34S variant of the SPINK1 trypsin inhibitor gene has been found to partially account for genetic susceptibility to chronic pancreatitis, we used a family-based and case-control approach in two separate ethnic groups from the Indian subcontinent, to determine whether N34S was associated with susceptibility to FCPD. Clear excess transmission of SPINK1 N34S to the probands with FCPD in 69 Bangladeshi families was observed (P<.0001; 20 transmissions and 2 nontransmissions). In the total study group (Bangladeshi and southern Indian) the N34S variant was present in 33% of 180 subjects with FCPD, 4.4% of 861 nondiabetic subjects (odds ratio 10.8; P<.0001 compared with FCPD), 3.7% of 219 subjects with type 2 diabetes, and 10.6% of 354 subjects with early-onset diabetes (aged <30 years) (P=.02 compared with the ethnically matched control group). These results suggest that the N34S variant of SPINK1 is a susceptibility gene for FCPD in the Indian subcontinent, although, by itself, it is not sufficient to cause disease. PMID:12187509

  8. The IFN-gamma +874T/A gene polymorphism is associated with retinochoroiditis toxoplasmosis susceptibility.

    PubMed

    Albuquerque, Maíra Cavalcanti de; Aleixo, Ana Luisa Quintella do Couto; Benchimol, Eliezer Israel; Leandro, Ana Cristina Câmara S; das Neves, Leandro Batista; Vicente, Regiane Trigueiro; Bonecini-Almeida, Maria da Glória; Amendoeira, Maria Regina Reis

    2009-05-01

    Toxoplasmosis is a worldwide zoonosis that generally produces an asymptomatic infection. In some cases, however, toxoplasmosis infection can lead to ocular damage. The immune system has a crucial role in both the course of the infection and in the evolution of toxoplasmosis disease. In particular, IFN-gamma plays an important role in resistance to toxoplasmosis. Polymorphisms in genes encoding cytokines have been shown to have an association with susceptibility to parasitic diseases. The aim of this work was to analyse the occurrence of polymorphisms in the gene encoding IFN-gamma (+874T/A) among Toxoplasma gondii seropositive individuals, including those with ocular lesions caused by the parasite, from a rural population of Santa Rita de Cássia, Barra Mansa, state of Rio de Janeiro, Brazil. Further, we verified which of these polymorphisms could be related to susceptibility to the development of ocular toxoplasmosis. This study included 34 individuals with ocular toxoplasmosis (ocular group) and 134 without ocular lesions (control group). The differences between A and T allele distributions were not statistically significant between the two groups. However, we observed that a higher frequency of individuals from the ocular group possessed the A/A genotype, when compared with the control group, suggesting that homozygocity for the A allele could enhance susceptibility to ocular toxoplasmosis in T. gondii infection. PMID:19547871

  9. A Genomewide Search for Type 2 Diabetes–Susceptibility Genes in Indigenous Australians

    PubMed Central

    Busfield, Frances; Duffy, David L.; Kesting, Janine B.; Walker, Shelley M.; Lovelock, 1 Paul K.; Good, 1 David; Tate, Heather; Watego, Denise; Marczak, Maureen; Hayman, Noel; Shaw, Joanne T. E.

    2002-01-01

    The prevalence of type 2 diabetes among Australian residents is 7.5%; however, prevalence rates up to six times higher have been reported for indigenous Australian communities. Epidemiological evidence implicates genetic factors in the susceptibility of indigenous Australians to type 2 diabetes and supports the hypothesis of the “thrifty genotype,” but, to date, the nature of the genetic predisposition is unknown. We have ascertained clinical details from a community of indigenous Australian descent in North Stradbroke Island, Queensland. In this population, the phenotype is characterized by severe insulin resistance. We have conducted a genomewide scan, at an average resolution of 10 cM, for type 2 diabetes–susceptibility genes in a large multigeneration pedigree from this community. Parametric linkage analysis undertaken using FASTLINK version 4.1p yielded a maximum two-point LOD score of +2.97 at marker D2S2345. Multipoint analysis yielded a peak LOD score of +3.9 <1 cM from marker D2S2345, with an 18-cM 3-LOD support interval. Secondary peak LOD scores were noted on chromosome 3 (+1.8 at recombination fraction [θ] 0.05, at marker D3S1311) and chromosome 8 (+1.77 at θ=0.0, at marker D8S549). These chromosomal regions are likely to harbor novel susceptibility genes for type 2 diabetes in the indigenous Australian population. PMID:11742441

  10. A genomewide search for type 2 diabetes-susceptibility genes in indigenous Australians.

    PubMed

    Busfield, Frances; Duffy, David L; Kesting, Janine B; Walker, Shelley M; Lovelock, Paul K; Good, David; Tate, Heather; Watego, Denise; Marczak, Maureen; Hayman, Noel; Shaw, Joanne T E

    2002-02-01

    The prevalence of type 2 diabetes among Australian residents is 7.5%; however, prevalence rates up to six times higher have been reported for indigenous Australian communities. Epidemiological evidence implicates genetic factors in the susceptibility of indigenous Australians to type 2 diabetes and supports the hypothesis of the "thrifty genotype," but, to date, the nature of the genetic predisposition is unknown. We have ascertained clinical details from a community of indigenous Australian descent in North Stradbroke Island, Queensland. In this population, the phenotype is characterized by severe insulin resistance. We have conducted a genomewide scan, at an average resolution of 10 cM, for type 2 diabetes-susceptibility genes in a large multigeneration pedigree from this community. Parametric linkage analysis undertaken using FASTLINK version 4.1p yielded a maximum two-point LOD score of +2.97 at marker D2S2345. Multipoint analysis yielded a peak LOD score of +3.9 <1 cM from marker D2S2345, with an 18-cM 3-LOD support interval. Secondary peak LOD scores were noted on chromosome 3 (+1.8 at recombination fraction [theta] 0.05, at marker D3S1311) and chromosome 8 (+1.77 at theta=0.0, at marker D8S549). These chromosomal regions are likely to harbor novel susceptibility genes for type 2 diabetes in the indigenous Australian population. PMID:11742441

  11. Profiles of epigenetic histone post-translational modifications at type 1 diabetes susceptible genes.

    PubMed

    Miao, Feng; Chen, Zhuo; Zhang, Lingxiao; Liu, Zheng; Wu, Xiwei; Yuan, Yate-Ching; Natarajan, Rama

    2012-05-11

    Both genetic and environmental factors are implicated in type 1 diabetes (T1D). Because environmental factors can trigger epigenetic changes, we hypothesized that variations in histone post-translational modifications (PTMs) at the promoter/enhancer regions of T1D susceptible genes may be associated with T1D. We therefore evaluated histone PTM variations at known T1D susceptible genes in blood cells from T1D patients versus healthy nondiabetic controls, and explored their connections to T1D. We used the chromatin immunoprecipitation-linked to microarray approach to profile key histone PTMs, including H3-lysine 4 trimethylation (H3K4me3), H3K27me3, H3K9me3, H3K9 acetylation (H3K9Ac), and H4K16Ac at genes within the T1D susceptible loci in lymphocytes, and H3K4me3, H3K9me2, H3K9Ac, and H4K16Ac at the insulin-dependent diabetes mellitus 1 region in monocytes of T1D patients and healthy controls separately. We screened for potential variations in histone PTMs using computational methods to compare datasets from T1D and controls. Interestingly, we observed marked variations in H3K9Ac levels at the upstream regions of HLA-DRB1 and HLA-DQB1 within the insulin-dependent diabetes mellitus 1 locus in T1D monocytes relative to controls. Additional experiments with THP-1 monocytes demonstrated increased expression of HLA-DRB1 and HLA-DQB1 in response to interferon-γ and TNF-α treatment that were accompanied by changes in H3K9Ac at the same promoter regions as that seen in the patient monocytes. These results suggest that the H3K9Ac status of HLA-DRB1 and HLA-DQB1, two genes highly associated with T1D, may be relevant to their regulation and transcriptional response toward external stimuli. Thus, the promoter/enhancer architecture and chromatin status of key susceptible loci could be important determinants in their functional association to T1D susceptibility. PMID:22431725

  12. Regulation of the retinoblastoma-E2F pathway by the ubiquitin-proteasome system.

    PubMed

    Sengupta, Satyaki; Henry, R William

    2015-10-01

    The retinoblastoma tumor suppressor (RB) and its related family members p107 and p130 regulate cell proliferation through the transcriptional repression of genes involved in cellular G1 to S phase transition. However, RB proteins are functionally versatile, and numerous genetic and biochemical studies point to expansive roles in cellular growth control, pluripotency, and apoptotic response. For the vast majority of genes, RB family members target the E2F family of transcriptional activators as an integral component of its gene regulatory mechanism. These interactions are regulated via reversible phosphorylation by Cyclin/Cyclin-dependent kinase (Cdk) complexes, a major molecular mechanism that regulates transcriptional output of RB/E2F target genes. Recent studies indicate an additional level of regulation involving the ubiquitin-proteasome system that renders pervasive control over each component of the RB pathway. Disruption of the genetic circuitry for proteasome-mediated targeting of the RB pathway has serious consequences on development and cellular transformation, and is associated with several forms of human cancer. In this review, we discuss the role of the ubiquitin-proteasome system in proteolytic control of RB-E2F pathway components, and recent data that points to surprising non-proteolytic roles for the ubiquitin-proteasome system in novel transcriptional regulatory mechanisms. PMID:26319102

  13. Identification of MAMDC1 as a Candidate Susceptibility Gene for Systemic Lupus Erythematosus (SLE)

    PubMed Central

    Hellquist, Anna; Zucchelli, Marco; Lindgren, Cecilia M.; Saarialho-Kere, Ulpu; Järvinen, Tiina M.; Koskenmies, Sari; Julkunen, Heikki; Onkamo, Päivi; Skoog, Tiina; Panelius, Jaana; Räisänen-Sokolowski, Anne; Hasan, Taina; Widen, Elisabeth; Gunnarson, Iva; Svenungsson, Elisabet; Padyukov, Leonid; Assadi, Ghazaleh; Berglind, Linda; Mäkelä, Ville-Veikko; Kivinen, Katja; Wong, Andrew; Cunningham Graham, Deborah S.; Vyse, Timothy J.; D'Amato, Mauro; Kere, Juha

    2009-01-01

    Background Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with multiple susceptibility genes. We have previously reported suggestive linkage to the chromosomal region 14q21-q23 in Finnish SLE families. Principal Findings Genetic fine mapping of this region in the same family material, together with a large collection of parent affected trios from UK and two independent case-control cohorts from Finland and Sweden, indicated that a novel uncharacterized gene, MAMDC1 (MAM domain containing glycosylphosphatidylinositol anchor 2, also known as MDGA2, MIM 611128), represents a putative susceptibility gene for SLE. In a combined analysis of the whole dataset, significant evidence of association was detected for the MAMDC1 intronic single nucleotide polymorphisms (SNP) rs961616 (P –value = 0.001, Odds Ratio (OR) = 1.292, 95% CI 1.103–1.513) and rs2297926 (P –value = 0.003, OR = 1.349, 95% CI 1.109–1.640). By Northern blot, real-time PCR (qRT-PCR) and immunohistochemical (IHC) analyses, we show that MAMDC1 is expressed in several tissues and cell types, and that the corresponding mRNA is up-regulated by the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) in THP-1 monocytes. Based on its homology to known proteins with similar structure, MAMDC1 appears to be a novel member of the adhesion molecules of the immunoglobulin superfamily (IgCAM), which is involved in cell adhesion, migration, and recruitment to inflammatory sites. Remarkably, some IgCAMs have been shown to interact with ITGAM, the product of another SLE susceptibility gene recently discovered in two independent genome wide association (GWA) scans. Significance Further studies focused on MAMDC1 and other molecules involved in these pathways might thus provide new insight into the pathogenesis of SLE. PMID:19997561

  14. Functional evaluation of the type 1 diabetes (T1D) susceptibility candidate genes.

    PubMed

    Park, Yongsoo

    2007-09-01

    Progress has been made in investigating the genetic factors involved in type 1 diabetes (T1D) development for the past few years. While Linkage disequilibrium (LD) mapping has been useful for both the confirmation and fine-mapping of susceptibility intervals, as well as identification of etiological mutations, identification of specific disease genes has been a challenge and limited to known candidate genes. The overall risk for T1D from the HLA DR and DQ molecules (IDDM1) is determined by combinations of polymorphic alleles. Functional studies indicate that the susceptible and protective HLA-DR and -DQ bind and present non-overlapping peptides. Although consistent linkage evidence was reported for the susceptibility intervals IDDM2, IDDM5 and IDDM12, evidence for most other intervals varies in different data sets. The variable number of tandem repeats at the 5' end of the insulin gene (IDDM2) regulates insulin expression in the thymus. Studies on IDDM5 have led to the discovery of a novel polymorphism 163 A-->G (M55V) in SUMO4 gene, which was found to be associated with T1D patients with Asian origin. Functionally SUMO4 conjugates to IkBalpha and negatively regulates NFkB transcriptional pathway. The M55V substitution reduces the sumoylation activity of the V55 variant, which resulted in higher NFkB dependent transcriptional activity. The polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4, IDDM12) encoding a regulatory molecule in the immune system associate with T1D and autoimmune thyroid diseases (ATD). The 3' untranslated region of this gene determines the level of soluble CTLA-4. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as evidenced by quantitative alterations of candidate genes contributing to autoimmune tissue destruction. Moreover, the identification of two transcription factors that, when mutated, are responsible for severe autoimmune disease is leading to a better understanding

  15. A polymorphism in the nuclear receptor coactivator 7 gene and breast cancer susceptibility.

    PubMed

    Süllner, Julia; Lattrich, Claus; Häring, Julia; Görse, Regina; Ortmann, Olaf; Treeck, Oliver

    2012-01-01

    The nuclear receptor coactivator 7 (NCoA7) gene codes for an estrogen receptor-associated protein that plays a significant role in the cellular response to estrogens. Given that NCoA7 is expressed in the mammary gland, alterations in this gene may affect breast cancer risk. In this study, we compared the genotype and allele frequencies of the missense single nucleotide polymorphism (SNP) rs1567, located in the coding region of the NCoA7 gene and resulting in an amino acid exchange from asparagine to glutamine, in 305 women with sporadic breast cancer and 346 women without any malignancy. Statistical analysis of the observed frequencies did not reveal a significant difference between the cancer and control groups, nor did a comparison between histological breast cancer subgroups. In conclusion, the results of our phenotype-genotype association study indicate that NCoA7 SNP rs1567 does not affect breast cancer susceptibility. PMID:22740868

  16. A polymorphism in the nuclear receptor coactivator 7 gene and breast cancer susceptibility

    PubMed Central

    SÜLLNER, JULIA; LATTRICH, CLAUS; HÄRING, JULIA; GÖRSE, REGINA; ORTMANN, OLAF; TREECK, OLIVER

    2012-01-01

    The nuclear receptor coactivator 7 (NCoA7) gene codes for an estrogen receptor-associated protein that plays a significant role in the cellular response to estrogens. Given that NCoA7 is expressed in the mammary gland, alterations in this gene may affect breast cancer risk. In this study, we compared the genotype and allele frequencies of the missense single nucleotide polymorphism (SNP) rs1567, located in the coding region of the NCoA7 gene and resulting in an amino acid exchange from asparagine to glutamine, in 305 women with sporadic breast cancer and 346 women without any malignancy. Statistical analysis of the observed frequencies did not reveal a significant difference between the cancer and control groups, nor did a comparison between histological breast cancer subgroups. In conclusion, the results of our phenotype-genotype association study indicate that NCoA7 SNP rs1567 does not affect breast cancer susceptibility. PMID:22740868

  17. Susceptibility to renal carcinoma in the Eker rat involves a tumor suppressor gene on chromosome 10.

    PubMed Central

    Yeung, R S; Buetow, K H; Testa, J R; Knudson, A G

    1993-01-01

    Germ-line mutations of tumor suppressor genes confer strong predisposition to tumor formation. In the rat, a form of dominantly inherited renal carcinoma (RC) results in multiple chromophobe cell tumors that resemble the human disease, and heterozygous carriers (RC/+) are highly susceptible to environmental agents (radiation and chemical carcinogens), making it a desirable model to study epithelial carcinogenesis. By linkage analysis, the locus of the inherited RC mutation was mapped to rat chromosomal band 10q12, near the protamine locus (logarithm of odds score = 17.96). Renal tumors also showed a loss of heterozygosity at this locus, lending support to the recessive nature of this putative tumor suppressor gene. Our result suggested that the human homolog of the RC gene may reside on human chromosome 16, not known to be altered commonly in human RC. Images Fig. 1 Fig. 3 Fig. 4 PMID:8103600

  18. Retinoblastoma

    MedlinePlus

    ... NEI Office of Science Communications, Public Liaison, and Education. Technical questions about this website can be addressed to the NEI Website Manager . Department of Health and Human Services | The National ...

  19. Susceptibility to Acute Rheumatic Fever Based on Differential Expression of Genes Involved in Cytotoxicity, Chemotaxis, and Apoptosis

    PubMed Central

    Smyth, Gordon K.; Gooding, Travis; Oshlack, Alicia; Harrington, Zinta; Currie, Bart; Carapetis, Jonathan R.; Robins-Browne, Roy; Curtis, Nigel

    2014-01-01

    It is unknown why only some individuals are susceptible to acute rheumatic fever (ARF). We investigated whether there are differences in the immune response, detectable by gene expression, between individuals who are susceptible to ARF and those who are not. Peripheral blood mononuclear cells (PBMCs) from 15 ARF-susceptible and 10 nonsusceptible (control) adults were stimulated with rheumatogenic (Rh+) group A streptococci (GAS) or nonrheumatogenic (Rh−) GAS. RNA from stimulated PBMCs from each subject was cohybridized with RNA from unstimulated PBMCs on oligonucleotide arrays to compare gene expression. Thirty-four genes were significantly differentially expressed between ARF-susceptible and control groups after stimulation with Rh+ GAS. A total of 982 genes were differentially expressed between Rh+ GAS- and Rh− GAS-stimulated samples from ARF-susceptible individuals. Thirteen genes were differentially expressed in the same direction (predominantly decreased) between the two study groups and between the two stimulation conditions, giving a strong indication of their involvement. Seven of these were immune response genes involved in cytotoxicity, chemotaxis, and apoptosis. There was variability in the degree of expression change between individuals. The high proportion of differentially expressed apoptotic and immune response genes supports the current model of autoimmune and cytokine dysregulation in ARF. This study also raises the possibility that a “failed” immune response, involving decreased expression of cytotoxic and apoptotic genes, contributes to the immunopathogenesis of ARF. PMID:24478089

  20. Susceptibility to acute rheumatic fever based on differential expression of genes involved in cytotoxicity, chemotaxis, and apoptosis.

    PubMed

    Bryant, Penelope A; Smyth, Gordon K; Gooding, Travis; Oshlack, Alicia; Harrington, Zinta; Currie, Bart; Carapetis, Jonathan R; Robins-Browne, Roy; Curtis, Nigel

    2014-02-01

    It is unknown why only some individuals are susceptible to acute rheumatic fever (ARF). We investigated whether there are differences in the immune response, detectable by gene expression, between individuals who are susceptible to ARF and those who are not. Peripheral blood mononuclear cells (PBMCs) from 15 ARF-susceptible and 10 nonsusceptible (control) adults were stimulated with rheumatogenic (Rh+) group A streptococci (GAS) or nonrheumatogenic (Rh-) GAS. RNA from stimulated PBMCs from each subject was cohybridized with RNA from unstimulated PBMCs on oligonucleotide arrays to compare gene expression. Thirty-four genes were significantly differentially expressed between ARF-susceptible and control groups after stimulation with Rh+ GAS. A total of 982 genes were differentially expressed between Rh+ GAS- and Rh- GAS-stimulated samples from ARF-susceptible individuals. Thirteen genes were differentially expressed in the same direction (predominantly decreased) between the two study groups and between the two stimulation conditions, giving a strong indication of their involvement. Seven of these were immune response genes involved in cytotoxicity, chemotaxis, and apoptosis. There was variability in the degree of expression change between individuals. The high proportion of differentially expressed apoptotic and immune response genes supports the current model of autoimmune and cytokine dysregulation in ARF. This study also raises the possibility that a "failed" immune response, involving decreased expression of cytotoxic and apoptotic genes, contributes to the immunopathogenesis of ARF. PMID:24478089

  1. Prion protein gene sequence and chronic wasting disease susceptibility in white-tailed deer (Odocoileus virginianus)

    PubMed Central

    Brandt, Adam L; Kelly, Amy C; Green, Michelle L; Shelton, Paul; Novakofski, Jan; Mateus-Pinilla, Nohra E

    2015-01-01

    ABSTRACT The sequence of the prion protein gene (PRNP) affects susceptibility to spongiform encephalopathies, or prion diseases in many species. In white-tailed deer, both coding and non-coding single nucleotide polymorphisms have been identified in this gene that correlate to chronic wasting disease (CWD) susceptibility. Previous studies examined individual nucleotide or amino acid mutations; here we examine all nucleotide polymorphisms and their combined effects on CWD. A 626 bp region of PRNP was examined from 703 free-ranging white-tailed deer. Deer were sampled between 2002 and 2010 by hunter harvest or government culling in Illinois and Wisconsin. Fourteen variable nucleotide positions were identified (4 new and 10 previously reported). We identified 68 diplotypes comprised of 24 predicted haplotypes, with the most common diplotype occurring in 123 individuals. Diplotypes that were found exclusively among positive or negative animals were rare, each occurring in less than 1% of the deer studied. Only one haplotype (C, odds ratio 0.240) and 2 diplotypes (AC and BC, odds ratios of 0.161 and 0.108 respectively) has significant associations with CWD resistance. Each contains mutations (one synonymous nucleotide 555C/T and one nonsynonymous nucleotide 286G/A) at positions reported to be significantly associated with reduced CWD susceptibility. Results suggest that deer populations with higher frequencies of haplotype C or diplotypes AC and BC might have a reduced risk for CWD infection – while populations with lower frequencies may have higher risk for infection. Understanding the genetic basis of CWD has improved our ability to assess herd susceptibility and direct management efforts within CWD infected areas. PMID:26634768

  2. Prion protein gene sequence and chronic wasting disease susceptibility in white-tailed deer (Odocoileus virginianus).

    PubMed

    Brandt, Adam L; Kelly, Amy C; Green, Michelle L; Shelton, Paul; Novakofski, Jan; Mateus-Pinilla, Nohra E

    2015-01-01

    The sequence of the prion protein gene (PRNP) affects susceptibility to spongiform encephalopathies, or prion diseases in many species. In white-tailed deer, both coding and non-coding single nucleotide polymorphisms have been identified in this gene that correlate to chronic wasting disease (CWD) susceptibility. Previous studies examined individual nucleotide or amino acid mutations; here we examine all nucleotide polymorphisms and their combined effects on CWD. A 626 bp region of PRNP was examined from 703 free-ranging white-tailed deer. Deer were sampled between 2002 and 2010 by hunter harvest or government culling in Illinois and Wisconsin. Fourteen variable nucleotide positions were identified (4 new and 10 previously reported). We identified 68 diplotypes comprised of 24 predicted haplotypes, with the most common diplotype occurring in 123 individuals. Diplotypes that were found exclusively among positive or negative animals were rare, each occurring in less than 1% of the deer studied. Only one haplotype (C, odds ratio 0.240) and 2 diplotypes (AC and BC, odds ratios of 0.161 and 0.108 respectively) has significant associations with CWD resistance. Each contains mutations (one synonymous nucleotide 555C/T and one nonsynonymous nucleotide 286G/A) at positions reported to be significantly associated with reduced CWD susceptibility. Results suggest that deer populations with higher frequencies of haplotype C or diplotypes AC and BC might have a reduced risk for CWD infection--while populations with lower frequencies may have higher risk for infection. Understanding the genetic basis of CWD has improved our ability to assess herd susceptibility and direct management efforts within CWD infected areas. PMID:26634768

  3. CHD7 Gene Polymorphisms Are Associated with Susceptibility to Idiopathic Scoliosis

    PubMed Central

    Gao, Xiaochong; Gordon, Derek; Zhang, Dongping; Browne, Richard; Helms, Cynthia; Gillum, Joseph; Weber, Samuel; Devroy, Shonn; Swaney, Saralove; Dobbs, Matthew; Morcuende, Jose; Sheffield, Val; Lovett, Michael; Bowcock, Anne; Herring, John; Wise, Carol

    2007-01-01

    Idiopathic scoliosis (IS) is the most common spinal deformity in children, and its etiology is unknown. To refine the search for genes underlying IS susceptibility, we ascertained a new cohort of 52 families and conducted a follow-up study of genomewide scans that produced evidence of linkage and association with 8q12 loci (multipoint LOD 2.77; P=.0028). Further fine mapping in the region revealed significant evidence of disease-associated haplotypes (P<1.0×10-4) centering over exons 2–4 of the CHD7 gene associated with the CHARGE (coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness) syndrome of multiple developmental anomalies. Resequencing CHD7 exons and conserved intronic sequence blocks excluded coding changes but revealed at least one potentially functional polymorphism that is overtransmitted (P=.005) to affected offspring and predicts disruption of a caudal-type (cdx) transcription-factor binding site. Our results identify the first gene associated with IS susceptibility and suggest etiological overlap between the rare, early-onset CHARGE syndrome and common, later-onset IS. PMID:17436250

  4. Identification of Susceptibility Genes of Adult Asthma in French Canadian Women

    PubMed Central

    Bérubé, Jean-Christophe; Gaudreault, Nathalie; Lavoie-Charland, Emilie; Sbarra, Laura; Henry, Cyndi; Madore, Anne-Marie; Paré, Peter D.; van den Berge, Maarten; Nickle, David; Laviolette, Michel; Laprise, Catherine; Boulet, Louis-Philippe; Bossé, Yohan

    2016-01-01

    Susceptibility genes of asthma may be more successfully identified by studying subgroups of phenotypically similar asthma patients. This study aims to identify single nucleotide polymorphisms (SNPs) associated with asthma in French Canadian adult women. A pooling-based genome-wide association study was performed in 240 allergic asthmatic and 120 allergic nonasthmatic women. The top associated SNPs were selected for individual genotyping in an extended cohort of 349 asthmatic and 261 nonasthmatic women. The functional impact of asthma-associated SNPs was investigated in a lung expression quantitative trait loci (eQTL) mapping study (n = 1035). Twenty-one of the 38 SNPs tested by individual genotyping showed P values lower than 0.05 for association with asthma. Cis-eQTL analyses supported the functional contribution of rs17801353 associated with C3AR1 (P = 7.90E − 10). The asthma risk allele for rs17801353 is associated with higher mRNA expression levels of C3AR1 in lung tissue. In silico functional characterization of the asthma-associated SNPs also supported the contribution of C3AR1 and additional genes including SYNE1, LINGO2, and IFNG-AS1. This pooling-based GWAS in French Canadian adult women followed by lung eQTL mapping suggested C3AR1 as a functional locus associated with asthma. Additional susceptibility genes were suggested in this homogenous subgroup of asthma patients.

  5. GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.

    PubMed

    Armstrong, D L; Zidovetzki, R; Alarcón-Riquelme, M E; Tsao, B P; Criswell, L A; Kimberly, R P; Harley, J B; Sivils, K L; Vyse, T J; Gaffney, P M; Langefeld, C D; Jacob, C O

    2014-09-01

    In a genome-wide association study (GWAS) of individuals of European ancestry afflicted with systemic lupus erythematosus (SLE) the extensive utilization of imputation, step-wise multiple regression, lasso regularization and increasing study power by utilizing false discovery rate instead of a Bonferroni multiple test correction enabled us to identify 13 novel non-human leukocyte antigen (HLA) genes and confirmed the association of four genes previously reported to be associated. Novel genes associated with SLE susceptibility included two transcription factors (EHF and MED1), two components of the NF-κB pathway (RASSF2 and RNF114), one gene involved in adhesion and endothelial migration (CNTN6) and two genes involved in antigen presentation (BIN1 and SEC61G). In addition, the strongly significant association of multiple single-nucleotide polymorphisms (SNPs) in the HLA region was assigned to HLA alleles and serotypes and deconvoluted into four primary signals. The novel SLE-associated genes point to new directions for both the diagnosis and treatment of this debilitating autoimmune disease. PMID:24871463

  6. Alu Elements as Novel Regulators of Gene Expression in Type 1 Diabetes Susceptibility Genes?

    PubMed Central

    Kaur, Simranjeet; Pociot, Flemming

    2015-01-01

    Despite numerous studies implicating Alu repeat elements in various diseases, there is sparse information available with respect to the potential functional and biological roles of the repeat elements in Type 1 diabetes (T1D). Therefore, we performed a genome-wide sequence analysis of T1D candidate genes to identify embedded Alu elements within these genes. We observed significant enrichment of Alu elements within the T1D genes (p-value < 10e−16), which highlights their importance in T1D. Functional annotation of T1D genes harboring Alus revealed significant enrichment for immune-mediated processes (p-value < 10e−6). We also identified eight T1D genes harboring inverted Alus (IRAlus) within their 3' untranslated regions (UTRs) that are known to regulate the expression of host mRNAs by generating double stranded RNA duplexes. Our in silico analysis predicted the formation of duplex structures by IRAlus within the 3'UTRs of T1D genes. We propose that IRAlus might be involved in regulating the expression levels of the host T1D genes. PMID:26184322

  7. A Polymorphism in RNF213 Is a Susceptibility Gene for Intracranial Atherosclerosis

    PubMed Central

    Bang, Oh Young; Chung, Jong-Won; Cha, Jihoon; Lee, Mi Ji; Yeon, Je Young; Ki, Chang-Seok; Jeon, Pyoung; Kim, Jong-Soo; Hong, Seung Chyul

    2016-01-01

    Background Both intracranial atherosclerotic stenosis (ICAS) and moyamoya disease (MMD) are prevalent in Asians. We hypothesized that the Ring Finger protein 213 gene polymorphism (RNF213), a susceptibility locus for MMD in East Asians, is also a susceptibility gene for ICAS in patients whose diagnosis had been confirmed by conventional angiography (absence of basal collaterals) and high-resolution MRI (HR-MRI, presence of plaque). Methods We analyzed 532 consecutive patients with ischemic events in the middle cerebral artery (MCA) distribution and relevant stenotic lesion on the distal internal carotid artery or proximal MCA, but no demonstrable carotid or cardiac embolism sources. Additional angiography was performed on 370 (69.5%) patients and HR-MRI on 283 (53.2%) patients. Results Based on angiographic and HR-MRI findings, 234 patients were diagnosed with ICAS and 288 with MMD. The RNF213 variant was observed in 50 (21.4%) ICAS patients and in 119 (69.1%) MMD patients. The variant was observed in 25.2% of patients with HR-MRI-confirmed ICAS. Similarly, 15.8% of ICAS patients in whom MMD was excluded by angiography had this variant. Among the ICAS patients, RNF213 variant carriers were younger and more likely to have a family history of MMD than non-carriers were. Multivariate testing showed that only the age of ICAS onset was independently associated with the RNF213 variant (odds ratio, 0.97; 95% CI, 0.944–0.99). Conclusions RNF213 is a susceptibility gene not only for MMD but also for ICAS in East Asians. Further studies are needed on RNF213 variants in ICAS patients outside East Asian populations. PMID:27253870

  8. Association Study between Polycystic Ovarian Syndrome and the Susceptibility Genes Polymorphisms in Hui Chinese Women

    PubMed Central

    Ha, Lingxia; Shi, Yuhua; Zhao, Junli; Li, Tao; Chen, Zi-Jiang

    2015-01-01

    Introduction Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders. Evidence of familial aggregation analysis and different clinical traits among different regions and ethnicities indicated that the pathogenesis of PCOS is associated with multiple genetic and environmental factors. Our previous research had identified three susceptibility loci (rs2479106, DENND1A; rs13405728, LHCGR; rs13429458, THADA) for PCOS in Han Chinese women. The overall aim of this study was to investigate the relationship between three susceptibility gene polymorphisms and PCOS in Hui ethnic women. Methods 151 patients with PCOS (case group) and 99 healthy women (control group) were recruited from the Reproductive Medicine Center of the General Hospital of Ningxia Medical University. Clinical data and serum hormone characteristics of case and control groups were collected and analyzed. The three susceptibility single-nucleotide polymorphisms have been replicated in both case and control groups. Gene polymorphisms were detected by direct sequencing after polymerase chain reaction. Results The Body Mass Index, LH, LH/FSH ratio and total testosterone were significantly elevated in PCOS patients compared to control group (P<0.05). The frequencies of genotype and allele in rs13405728 were significantly different between the PCOS and the control groups (P<0.05). Of the SNP rs13405728, the PCOS cases with TT genotype stayed at a higher level of total testosterone, TG and LDL than those with the CC and CT genotypes. In contrary, there was no statistical difference between the two groups for SNP rs13429458 and rs2479106 (P>0.05). Conclusion The present study suggested that the SNP rs13405728 in the LHCGR gene was associated with PCOS in Hui ethnic women, and its TT genotype characterized with higher level of TT, TG and LDL. PMID:25978310

  9. Acute non-lymphocytic leukemia following multimodality therapy for retinoblastoma

    SciTech Connect

    White, L.; Ortega, J.A.; Ying, K.L.

    1985-02-01

    The genetic form of retinoblastoma carries a high risk of secondary malignant neoplasm, apparently not related to the use of chemotherapy. A child with unilateral non-genetic retinoblastoma who had received chemotherapy and radiation therapy and developed acute non-lymphocytic leukemia (ANLL) is reported. The occurrence of ANLL and retinoblastoma has not been previously reported.

  10. Retinoblastoma Registry report--Hospital Kuala Lumpur experience.

    PubMed

    Jamalia, R; Sunder, R; Alagaratnam, J; Goh, P P

    2010-06-01

    Retinoblastoma is a childhood ocular cancer. The aim of this paper is to describe the clinical and epidemiological characteristics of patients with retinoblastoma in a major paediatric ophthalmology center in the country. Retrospective information was collected through the retinoblastoma registry. Late presentation with advanced staging is a major problem. PMID:21488473

  11. The retinoblastoma protein physically associates with the human cdc2 kinase.

    PubMed Central

    Hu, Q J; Lees, J A; Buchkovich, K J; Harlow, E

    1992-01-01

    The protein product (pRB) of the retinoblastoma susceptibility gene functions as a negative regulator of cell proliferation, and its activity appears to be modulated by phosphorylation. Using a new panel of anti-human pRB monoclonal antibodies, we have investigated the biochemical properties of this protein. These antibodies have allowed us to detect a pRB-associated kinase that has been identified as the cell cycle-regulating kinase p34cdc2 or a closely related enzyme. Since this associated kinase phosphorylates pRB at most of the sites used in vivo, these results suggest that this kinase is one of the major regulators of pRB. The associated kinase activity follows the pattern of phosphorylation seen for pRB in vivo. The associated kinase activity is not seen in the G1 phase but appears in the S phase, and the levels continue to increase throughout the remainder of the cell cycle. Images PMID:1545827

  12. Structural Insights into the Mechanism of Phosphoregulation of the Retinoblastoma Protein

    PubMed Central

    Lamber, Ekaterina P.; Beuron, Fabienne; Morris, Edward P.; Svergun, Dmitri I.; Mittnacht, Sibylle

    2013-01-01

    The retinoblastoma susceptibility protein RB1 is a key regulator of cell proliferation and fate. RB1 operates through nucleating the formation of multi-component protein complexes involved in the regulation of gene transcription, chromatin structure and protein stability. Phosphorylation of RB1 by cyclin-dependent kinases leads to conformational alterations and inactivates the capability of RB1 to bind partner protein. Using small angle X-ray scattering in combination with single particle analysis of transmission electron microscope images of negative-stained material we present the first three-dimensional reconstruction of non-phosphorylated RB1 revealing an extended architecture and deduce the domain arrangement within the molecule. Phosphorylation results in an overt alteration of the molecular shape and dimensions, consistent with the transition to a compact globular architecture. The work presented provides what is to our knowledge the first description of the relative domain arrangement in active RB1 and predicts the molecular movement that leads to RB1 inactivation following protein phosphorylation. PMID:23516486

  13. Early Differential Gene Expression in Haemocytes from Resistant and Susceptible Biomphalaria glabrata Strains in Response to Schistosoma mansoni

    PubMed Central

    Lockyer, Anne E.; Emery, Aidan M.; Kane, Richard A.; Walker, Anthony J.; Mayer, Claus D.; Mitta, Guillaume; Coustau, Christine; Adema, Coen M.; Hanelt, Ben; Rollinson, David; Noble, Leslie R.; Jones, Catherine S.

    2012-01-01

    The outcome of infection in the host snail Biomphalaria glabrata with the digenean parasite Schistosoma mansoni is determined by the initial molecular interplay occurring between them. The mechanisms by which schistosomes evade snail immune recognition to ensure survival are not fully understood, but one possibility is that the snail internal defence system is manipulated by the schistosome enabling the parasite to establish infection. This study provides novel insights into the nature of schistosome resistance and susceptibility in B. glabrata at the transcriptomic level by simultaneously comparing gene expression in haemocytes from parasite-exposed and control groups of both schistosome-resistant and schistosome-susceptible strains, 2 h post exposure to S. mansoni miracidia, using an novel 5K cDNA microarray. Differences in gene expression, including those for immune/stress response, signal transduction and matrix/adhesion genes were identified between the two snail strains and tests for asymmetric distributions of gene function also identified immune-related gene expression in resistant snails, but not in susceptible. Gene set enrichment analysis revealed that genes involved in mitochondrial electron transport, ubiquinone biosynthesis and electron carrier activity were consistently up-regulated in resistant snails but down-regulated in susceptible. This supports the hypothesis that schistosome-resistant snails recognize schistosomes and mount an appropriate defence response, while in schistosome-susceptible snails the parasite suppresses this defence response, early in infection. PMID:23300533

  14. CYP19 gene variant confers susceptibility to endometriosis-associated infertility in Chinese women

    PubMed Central

    Wang, Ledan; Lu, Xiaosheng; Wang, Danhan; Qu, Wanglei; Li, Wenju; Xu, Xiaowen; Huang, Qiusui; Han, Xueying; Lv, Jieqiang

    2014-01-01

    An aromatase encoded by the CYP19 gene catalyzes the final step in the biosynthesis of estrogens, which is related to endometriosis development. To assess the association of CYP19 gene polymorphisms with the risks of endometriosis, chocolate cysts and endometriosis-related infertility, a case–control study was conducted in Chinese Han women by recruiting 225 healthy control females, 146 patients with endometriosis, 94 endometriosis women with chocolate cyst and 65 women with infertility resulting from endometriosis, as diagnosed by both pathological and laparoscopic findings. Individual genotypes at rs2236722:T>C, rs700518:A>G, rs10046:T>C and [TTTA]n polymorphisms were identified. Allelic and genotypic frequencies were compared between the control group and case groups by chi-square analysis. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined by logistic regression analysis to predict the association of CYP19 gene polymorphisms with the risk of endometriosis, the related chocolate cysts and infertility. The genotype distributions of the tested CYP19 gene polymorphisms were not significantly different between the healthy control group and the endometriosis/endometriosis with the chocolate cyst group. However, the CYP19 rs700518AA genotype was significantly associated with an increased risk of endometriosis-related infertility (55.4% in the infertility group vs 25.3% in the control group, P<0.001; OR (95% CI): 3.66 (2.06–6.50)) under the recessive form of the A allele. Therefore, we concluded that in Chinese Han females CYP19 gene polymorphisms are not associated with susceptibility to endometriosis or chocolate cysts, whereas CYP19 rs700518AA genotype confers genetic susceptibility to endometriosis-related infertility. PMID:24968701

  15. Gastric precancerous lesions are associated with gene variants in Helicobacter pylori-susceptible ethnic Malays

    PubMed Central

    Maran, Sathiya; Lee, Yeong Yeh; Xu, Shuhua; Rajab, Nur-Shafawati; Hasan, Norhazrini; Syed Abdul Aziz, Syed Hassan; Majid, Noorizan Abdul; Zilfalil, Bin Alwi

    2013-01-01

    AIM: To identify genes associated with gastric precancerous lesions in Helicobacter pylori (H. pylori)-susceptible ethnic Malays. METHODS: Twenty-three Malay subjects with H. pylori infection and gastric precancerous lesions identified during endoscopy were included as “cases”. Thirty-seven Malay subjects who were H. pylori negative and had no precancerous lesions were included as “controls”. Venous blood was collected for genotyping with Affymetrix 50K Xba1 kit. Genotypes with call rates < 90% for autosomal single nucleotide polymorphisms (SNPs) were excluded. For each precancerous lesion, associated SNPs were identified from Manhattan plots, and only SNPs with a χ2 P value < 0.05 and Hardy Weinberg Equilibrium P value > 0.5 was considered as significant markers. RESULTS: Of the 23 H. pylori-positive subjects recruited, one sample was excluded from further analysis due to a low genotyping call rate. Of the 22 H. pylori-positive samples, atrophic gastritis only was present in 50.0%, complete intestinal metaplasia was present in 18.25%, both incomplete intestinal metaplasia and dysplasia was present in 22.7%, and dysplasia only was present in 9.1%. SNPs rs9315542 (UFM1 gene), rs6878265 (THBS4 gene), rs1042194 (CYP2C19 gene) and rs10505799 (MGST1 gene) were significantly associated with atrophic gastritis, complete intestinal metaplasia, incomplete metaplasia with foci of dysplasia and dysplasia, respectively. Allele frequencies in “cases” vs “controls” for rs9315542, rs6878265, rs1042194 and rs10505799 were 0.4 vs 0.06, 0.6 vs 0.01, 0.6 vs 0.01 and 0.5 vs 0.02, respectively. CONCLUSION: Genetic variants possibly related to gastric precancerous lesions in ethnic Malays susceptible to H. pylori infection were identified for testing in subsequent trials. PMID:23801863

  16. 16S rRNA gene mutations associated with decreased susceptibility to tetracycline in Mycoplasma bovis.

    PubMed

    Amram, E; Mikula, I; Schnee, C; Ayling, R D; Nicholas, R A J; Rosales, R S; Harrus, S; Lysnyansky, I

    2015-02-01

    Mycoplasma bovis isolates with decreased susceptibilities to tetracyclines are increasingly reported worldwide. The acquired molecular mechanisms associated with this phenomenon were investigated in 70 clinical isolates of M. bovis. Sequence analysis of the two 16S rRNA-encoding genes (rrs3 and rrs4 alleles) containing the primary binding pocket for tetracycline (Tet-1 site) was performed on isolates with tetracycline hydrochloride MICs of 0.125 to 16 μg/ml. Mutations at positions A965T, A967T/C (Escherichia coli numbering) of helix 31, U1199C of helix 34, and G1058A/C were identified. Decreased susceptibilities to tetracycline (MICs, ≥2 μg/ml) were associated with mutations present at two (A965 and A967) or three positions (A965, A967, and G1058) of the two rrs alleles. No tet(M), tet(O), or tet(L) determinants were found in the genome of any of the 70 M. bovis isolates. The data presented correlate (P<0.0001) the mutations identified in the Tet-1 site of clinical isolates of M. bovis with decreased susceptibility to tetracycline. PMID:25403668

  17. Functional polymorphisms in the IL-10 gene with susceptibility to esophageal, nasopharyngeal, and oral cancers.

    PubMed

    Li, Yu-Fen; Yang, Pei-Zhen; Li, Hua-Feng

    2016-03-18

    Emerging evidence showed that functional polymorphisms in the IL-10 gene may have effects on individuals' susceptibility to nasopharyngeal, oral and esophageal cancers, yet individually published findings are inconsistent. We therefore designed the meta-analysis to investigate the correlations of IL-10 genetic polymorphisms with susceptibility to nasopharyngeal, oral and esophageal cancers. The EMBASE, MEDLINE, CINAHL, Web of Science and the Chinese Biomedical Database (CBM) databases were searched with no language restrictions. We use Comprehensive Meta-analysis 2.0 software to carry out statistical analysis. Ten case-control studies with a number of 1,883 patients and 2,857 healthy subjects were enrolled. Our results revealed that IL-10 rs1800872 T>G and rs1800896 A>G polymorphisms has a significantly association with the increased risk of esophageal cancer under the allele and dominant models; rs1800871 T>G, rs1800872 T>G and rs1800896 A>G under allele and dominant models could increase the risk of nasopharyngeal cancer; rs1800871T>G, rs1800872T>G and rs1800896 A>G SNPs under allele model were closely related to the susceptibility to oral cancer. Our findings support the point that IL-10 genetic polymorphisms may play essential role in identifying esophageal cancer, nasopharyngeal cancer and oral cancer at early stage. PMID:27002767

  18. 16S rRNA Gene Mutations Associated with Decreased Susceptibility to Tetracycline in Mycoplasma bovis

    PubMed Central

    Amram, E.; Mikula, I.; Schnee, C.; Ayling, R. D.; Nicholas, R. A. J.; Rosales, R. S.; Harrus, S.

    2014-01-01

    Mycoplasma bovis isolates with decreased susceptibilities to tetracyclines are increasingly reported worldwide. The acquired molecular mechanisms associated with this phenomenon were investigated in 70 clinical isolates of M. bovis. Sequence analysis of the two 16S rRNA-encoding genes (rrs3 and rrs4 alleles) containing the primary binding pocket for tetracycline (Tet-1 site) was performed on isolates with tetracycline hydrochloride MICs of 0.125 to 16 μg/ml. Mutations at positions A965T, A967T/C (Escherichia coli numbering) of helix 31, U1199C of helix 34, and G1058A/C were identified. Decreased susceptibilities to tetracycline (MICs, ≥2 μg/ml) were associated with mutations present at two (A965 and A967) or three positions (A965, A967, and G1058) of the two rrs alleles. No tet(M), tet(O), or tet(L) determinants were found in the genome of any of the 70 M. bovis isolates. The data presented correlate (P < 0.0001) the mutations identified in the Tet-1 site of clinical isolates of M. bovis with decreased susceptibility to tetracycline. PMID:25403668

  19. Adult onset retinoblastoma: A diagnostic dilemma.

    PubMed

    Raj, Amit; Arya, Sudesh Kumar; Punia, Rajpal Singh; Kohli, Piyush

    2016-01-01

    Retinoblastoma is the most common intraocular tumor of childhood. About 95% of retinoblastoma cases are diagnosed before the age of 5 years. Not more than 30 cases of Adult-onset retinoblastoma have been reported in literature. A 32 year old male presented with a painful blind eye. There was sudden loss of vision accompanied by severe pain and redness in right eye about 1 year ago, for which some surgery was done with neither a gain in vision nor any relief from pain. Then he was put on maximum tolerable medical therapy, later cyclocryotherapy was done. Now he presented to us with complains of extreme pain and bleeding from right eye since 2 days. There is no history of any ocular trauma. Right eye had no perception of light & showed anterior staphyloma with perforation. Right eye evisceration was done & material sent for histopathological examination, which revealed an adult-onset retinoblastoma. CECT scan revealed thickening of optic nerve throughout its entire length with contrast enhancement. He was further taken up for enucleation of residual sclera with maximum optic nerve stump removal to reconfirm the diagnosis. Histopathological examination revealed tumor deposits present in orbital soft tissue, resection margins and optic nerve cut end.Retinoblastoma presenting in adult age creates a diagnostic dilemma because of its low frequency and atypical features. We want to highlight the importance of high clinical suspicion and imaging modalities before taking any patient for evisceration with unexplained vision loss. One should send the eviscerated material for histopathological examination. PMID:26709674

  20. A Major Susceptibility Gene for Asthma Maps to Chromosome 14q24

    PubMed Central

    Hakonarson, Hakon; Bjornsdottir, Unnur S.; Halapi, Eva; Palsson, Snaebjorn; Adalsteinsdottir, Elva; Gislason, David; Finnbogason, Gudmundur; Gislason, Thorarinn; Kristjansson, Kristleifur; Arnason, Thor; Birkisson, Illugi; Frigge, Michael L.; Kong, Augustine; Gulcher, Jeffrey R.; Stefansson, Kari

    2002-01-01

    Asthma is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. Numerous loci and candidate genes have been reported to show linkage and association to asthma and atopy. Although some studies reporting these observations are compelling, no gene has been mapped that confers a sufficiently high risk of asthma to meet the stringent criteria for genomewide significance. Using 175 extended Icelandic families that included 596 patients with asthma, we performed a genomewide scan with 976 microsatellite markers. The families were identified by cross-matching a list of patients with asthma from the Department of Allergy/Pulmonary Medicine of the National University Hospital of Iceland with a genealogy database of the entire Icelandic nation. We detected linkage of asthma to chromosome 14q24, with an allele-sharing LOD score of 2.66. After we increased the marker density within the locus to an average of one microsatellite every 0.2 cM, the LOD score rose to 4.00. We designate this locus “asthma locus one” (AS1). Taken together, these results provide evidence of a novel susceptibility gene for asthma on chromosome 14q24. PMID:12119603

  1. Vitamin D receptor gene ApaI polymorphism and breast cancer susceptibility: a meta-analysis.

    PubMed

    Luo, Shayang; Guo, Lei; Li, Yan; Wang, Shouman

    2014-01-01

    Vitamin D receptor (VDR) principally mediates the anticancer activities of vitamin D. Many studies investigated the association between VDR gene ApaI polymorphism and breast cancer, but the results were inconclusive. We performed this meta-analysis to evaluate the association between VDR gene ApaI polymorphism and breast cancer. Twelve studies with a total of 8,254 subjects were identified from PubMed and Wanfang databases. The pooled odds ratio (OR) and confidence intervals (95% CI) were used to assess the association. The meta-analysis indicated that VDR gene ApaI polymorphism was not associated with risk of breast cancer (a vs. A: OR = 0.97, 95% CI 0.91-1.04, P = 0.378; aa vs. AA: OR = 0.97, 95% CI 0.85-1.10, P = 0.618; aa vs. AA + Aa: OR = 1.00, 95% CI 0.89-1.12, P = 0.972; aa + Aa vs. AA: OR = 0.95, 95% CI 0.82-1.11, P = 0.550). Subgroup analysis by ethnicity further showed that VDR gene ApaI polymorphism was not associated with risk of breast cancer in both Asians and Caucasians. These data from the meta-analysis indicate that VDR gene ApaI polymorphism is not associated with breast cancer susceptibility. PMID:24048755

  2. Dopamine transporter gene susceptibility to methylation is associated with impulsivity in nonhuman primates

    PubMed Central

    Rajala, Abigail Z.; Zaitoun, Ismail; Henriques, Jeffrey B.; Converse, Alexander K.; Murali, Dhanabalan; Epstein, Miles L.

    2014-01-01

    Impulsivity, the predisposition to act without regard for negative consequences, is a characteristic of several psychiatric disorders and is thought to result in part from genetic variation in the untranslated region of the dopamine transporter (DAT) gene. As the exact link between genetic mutations and impulsivity has not been established, we used oculomotor behavior to characterize rhesus monkeys as impulsive or calm and genetic/epigenetic analysis and positron emission tomography (PET) to correlate phenotype to DAT genotype, DAT gene methylation, and DAT availability. We found three single nucleotide polymorphisms (SNPs) in the 3′-UTR of the DAT gene, one of which provided a potential site for methylation in the impulsive group. Bisulfite analysis showed that the DNA of the impulsive but not the calm subjects was methylated at one SNP. Because genetic/epigenetic modifications could lead to differences in protein expression, we measured DAT availability using [18F]2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane ([18F]FECNT) PET and found higher DAT availability in the internal globus pallidus, an output nucleus of the basal ganglia, of the impulsive group. Higher DAT availability lowers dopamine levels, potentially altering neuronal circuits involved in the initiation of action, thus contributing to the impulsive phenotype. The association between increased methylation in the DAT gene and greater DAT availability suggests that mutations to the regulatory portion of the DAT gene lead to a susceptibility to epigenetic modification resulting in a discrete behavioral phenotype. PMID:25122707

  3. HLA-D region genes and rheumatoid arthritis (RA): importance of DR and DQ genes in conferring susceptibility to RA.

    PubMed Central

    Singal, D P; Green, D; Reid, B; Gladman, D D; Buchanan, W W

    1992-01-01

    The distribution of HLA-D region antigens was studied in three groups (I, IIa, and IIb) of patients with rheumatoid arthritis (RA): group I comprised 43 patients with mild, non-progressive RA, controlled by non-steroidal anti-inflammatory drugs without progression or erosions; group II comprised 94 patients with severe disease, who had earlier been treated with non-steroidal anti-inflammatory drugs and all had incomplete response requiring treatment with gold (sodium aurothiomalate). Of these, 46 patients (group IIa) responded to gold and the disease was well controlled, and the remaining 48 patients (group IIb) did not respond to gold and developed gold induced toxic reactions, including thrombocytopenia or proteinuria, or both. HLA-D region antigens were defined by serological and molecular (Southern blot analysis and oligonucleotide typing) techniques. The results show that DR4 was significantly increased in all three groups of patients. The prevalence of DR1, or DR1 in DR4 negative patients, and DR3 and DR4 associated DQw7 specificities, however, showed differences in these three groups of patients. The prevalence of DR1 and of DR1 in DR4 negative patients was increased only in patients with mild (group I) RA, but not in patients with severe (groups IIa and IIb) disease. On the other hand, the prevalence of DR4 associated DQw7 was significantly increased in patients with severe disease, but not in patients with mild RA. In addition, DR3 was significantly increased only in patients with severe disease who developed gold induced toxic reactions (group IIb). These data suggest that the HLA-D region genes which cause susceptibility to mild RA may be different from those causing susceptibility to severe RA. The results suggest that both DR and DQ (A, B) genes may be important in conferring susceptibility to RA: DR in mild disease and DQ in severe RA. Images PMID:1371662

  4. Pharmacogenetics of drug dependence: role of gene variations in susceptibility and treatment.

    PubMed

    Khokhar, Jibran Y; Ferguson, Charmaine S; Zhu, Andy Z X; Tyndale, Rachel F

    2010-01-01

    Drug dependency is a highly prevalent mental health disorder that imposes a significant burden on those directly affected, health care systems, and society in general. There is substantial heritability in the susceptibility to drug addiction, which indicates that there are genetic risk factors. Variation in the human genome is abundant and can directly affect drug dependency phenotypes, for example, by altering the function of a gene product or by altering gene expression. Pharmacogenetic studies can assess the effects of genetic variation on the risk for a particular phenotype (e.g., being an alcoholic). In addition, pharmacogenetic variability in treatment efficacy and adverse reactions can be investigated to identify particular genetic variants associated with altered responses. This review highlights examples of genetic variations that are important in the development and maintenance of specific drug dependencies as well as those that affect the response to treatment. PMID:20055697

  5. Identification of AF4/FMR2 family, member 3 (AFF3) as a novel rheumatoid arthritis susceptibility locus and confirmation of two further pan-autoimmune susceptibility genes

    PubMed Central

    Barton, Anne; Eyre, Steve; Ke, Xiayi; Hinks, Anne; Bowes, John; Flynn, Edward; Martin, Paul; Wilson, Anthony G.; Morgan, Ann W.; Emery, Paul; Steer, Sophia; Hocking, Lynne J.; Reid, David M.; Harrison, Pille; Wordsworth, Paul; Thomson, Wendy; Worthington, Jane

    2009-01-01

    The concept of susceptibility genes common to different autoimmune diseases is now firmly established with previous studies demonstrating overlap of loci conferring susceptibility to type 1 diabetes (T1D) with both Coeliac disease and multiple sclerosis. Rheumatoid arthritis (RA) is an archetypal autoimmune disease and we, therefore, targeted putative T1D susceptibility loci for genotyping in UK RA cases and unrelated controls. A novel RA susceptibility locus at AFF3 was identified with convincing evidence for association in a combined sample cohort of 6819 RA cases and 12 650 controls [OR 1.12 95% confidence intervals (CI) 1.07–1.17, P = 2.8 × 10−7]. Association of two previously described loci (CTLA-4 and 4q27) with RA was also replicated (OR 0.87, 95% CI 0.82–0.94, P = 1.1 × 10−4 and OR 0.86, 95% CI 0.79–0.94, P = 5.4 × 10−4, respectively). These findings take the number of established RA susceptibility loci to 13, only one of which has not been associated with other autoimmune diseases. PMID:19359276

  6. MiR-433 inhibits retinoblastoma malignancy by suppressing Notch1 and PAX6 expression.

    PubMed

    Li, Xiaohua; Yang, Lan; Shuai, Tianjiao; Piao, Tianhua; Wang, Rui

    2016-08-01

    Retinoblastoma (RB) is the most frequent primary intraocular cancer. It has been demonstrated by previous studies that retinoblastoma is initiated primarily by the inactivation of the retinoblastoma Rb1 gene in retinal cells. However, additional genetic alterations than Rb1 mutation could play important roles in the process of transforming benign retinal cells into retinoblastoma tumor cells. In this study, we identified that microRNA miR-433 is one of such genetic factors. We found that the expression levels of miR-433 were downregulated in RB tissues. We also determined that miR-433 negatively regulated RB cell proliferation, migration and invasion, and induced cell cycle arrest and apoptosis of RB cells. We used bioinformatics method to predict and confirmed that Notch1 and PAX6 were miR-433 target genes in RB cells. Importantly, we demonstrated that restoration of Notch1 and PAX6 expression partially rescued the inhibition of cell proliferation and metastasis induced by miR-433 overexpression, suggesting that miR-433 regulates RB cell proliferation and metastasis through suppressing the expression of Notch1 and PAX6. PMID:27470361

  7. Effects of PPARγ agonistrosiglitazone on human retinoblastoma cell in vitro and in vivo

    PubMed Central

    Cao, Xianyong; He, Lin; Li, Yanhua

    2015-01-01

    The aim of the study was to evaluate the antitumor effects of the PPARγ agonist rosiglitazone on the human retinoblastoma. The cell biological behavior was detected, specifically, the effects of rosiglitazone on cell viability and apoptosis of the human retinoblastoma Y79 cells were investigated by MTT assay and Hochest 33258 staining and the migration assay showed that rosiglitazone blocked the invasion and migration of the carcinoma cells through the reconstituted extracellular matrix (Matrigel). The effect of rosiglitazone on NF-κB-dependent reporter gene transcription induced by LPS was analyzed by NF-κB-luciferase assay. Then human retinoblastoma Y79 cells were subcutaneously transplanted in BALB/c nude mice, and the animals were treated with rosiglitazone (20 mg/kg, 40 mg/kg, and 80 mg/kg) to verify its anti-tumor effect in vivo. Rosiglitazone suppressed the viability of Y79 cells dose- and time-dependently and induced apoptosis in Y79 cells in vitro. Molecular biology analysis found that rosiglitazone could modulate the proliferative and apoptosis related signal, reduce NF-κB-dependent reporter gene transcription induced by LPS. Rosiglitazone markedly reduced the growth of Y79 cells transplanted into the mice without causing significant side effects. Our results suggested that rosiglitazone demonstrated antitumor activity against the human retinoblastoma Y79 cells by inhibiting cell growth, inducing apoptosis and inhibiting metastasis and invasion in vitro and delaying tumor growth in vivo. PMID:26722443

  8. Predose and Postdose Blood Gene Expression Profiles Identify the Individuals Susceptible to Acetaminophen-Induced Liver Injury in Rats

    PubMed Central

    Lu, Xiaoyan; Hu, Bin; Zheng, Jie; Ji, Cai; Fan, Xiaohui; Gao, Yue

    2015-01-01

    The extent of drug-induced liver injury (DILI) can vary greatly between different individuals. Thus, it is crucial to identify susceptible population to DILI. The aim of this study was to determine whether transcriptomics analysis of predose and postdose rat blood would allow prediction of susceptible individuals to DILI using the widely applied analgesic acetaminophen (APAP) as a model drug. Based on ranking in alanine aminotransferase levels, five most susceptible and five most resistant rats were identified as two sub-groups after APAP treatment. Predose and postdose gene expression profiles of blood samples from these rats were determined by microarray analysis. The expression of 158 genes innately differed in the susceptible rats from the resistant rats in predose data. In order to identify more reliable biomarkers related to drug responses for detecting individuals susceptibility to APAP-induced liver injury (AILI), the changes of these genes' expression posterior to APAP treatment were detected. Through the further screening method based on the trends of gene expression between the two sub-groups before and after drug treatment, 10 genes were identified as potential predose biomarkers to distinguish between the susceptible and resistant rats. Among them, four genes, Incenp, Rpgrip1, Sbf1, and Mmp12, were found to be reproducibly in real-time PCR with an independent set of animals. They were all innately higher expressed in resistant rats to AILI, which are closely related to cell proliferation and tissue repair functions. It indicated that rats with higher ability of cell proliferation and tissue repair prior to drug treatment might be more resistant to AILI. In this study, we demonstrated that combination of predose and postdose gene expression profiles in blood might identify the drug related inter-individual variation in DILI, which is a novel and important methodology for identifying susceptible population to DILI. PMID:26512990

  9. Differential susceptibility to maternal expressed emotion in children with ADHD and their siblings? Investigating plasticity genes, prosocial and antisocial behaviour.

    PubMed

    Richards, Jennifer S; Hartman, Catharina A; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Arias Vásquez, Alejandro; Buitelaar, Jan K

    2015-02-01

    The differential susceptibility theory states that children differ in their susceptibility towards environmental experiences, partially due to plasticity genes. Individuals carrying specific variants in such genes will be more disadvantaged in negative but, conversely, more advantaged in positive environments. Understanding gene-environment interactions may help unravel the causal mechanisms involved in multifactorial psychiatric disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD). The differential susceptibility theory was examined by investigating the presence of interaction effects between maternal expressed emotion (EE; warmth and criticism) and the solitary and combined effects of plasticity genes (DAT1, DRD4, 5-HTT) on prosocial and antisocial behaviour (measured with parent- and self-reports) in children with ADHD and their siblings (N = 366, M = 17.11 years, 74.9% male). Maternal warmth was positively associated with prosocial behaviour and negatively with antisocial behaviour, while maternal criticism was positively associated with antisocial behaviour and negatively with prosocial behaviour. No evidence of differential susceptibility was found. The current study found no evidence for differential susceptibility based on the selected plasticity genes, in spite of strong EE-behaviour associations. It is likely that additional factors play a role in the complex relationship between genes, environment and behaviour. PMID:24929324

  10. Toxoplasmosis and Polygenic Disease Susceptibility Genes: Extensive Toxoplasma gondii Host/Pathogen Interactome Enrichment in Nine Psychiatric or Neurological Disorders

    PubMed Central

    Carter, C. J.

    2013-01-01

    Toxoplasma gondii is not only implicated in schizophrenia and related disorders, but also in Alzheimer's or Parkinson's disease, cancer, cardiac myopathies, and autoimmune disorders. During its life cycle, the pathogen interacts with ~3000 host genes or proteins. Susceptibility genes for multiple sclerosis, Alzheimer's disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson's disease, attention deficit hyperactivity disorder (P  from  8.01E − 05  (ADHD)  to  1.22E − 71) (multiple sclerosis), and autism (P = 0.013), but not anorexia or chronic fatigue are highly enriched in the human arm of this interactome and 18 (ADHD) to 33% (MS) of the susceptibility genes relate to it. The signalling pathways involved in the susceptibility gene/interactome overlaps are relatively specific and relevant to each disease suggesting a means whereby susceptibility genes could orient the attentions of a single pathogen towards disruption of the specific pathways that together contribute (positively or negatively) to the endophenotypes of different diseases. Conditional protein knockdown, orchestrated by T. gondii proteins or antibodies binding to those of the host (pathogen derived autoimmunity) and metabolite exchange, may contribute to this disruption. Susceptibility genes may thus be related to the causes and influencers of disease, rather than (and as well as) to the disease itself. PMID:23533776

  11. A Rapid Molecular Test for Determining Yersinia pestis Susceptibility to Ciprofloxacin by the Quantification of Differentially Expressed Marker Genes

    PubMed Central

    Steinberger-Levy, Ida; Shifman, Ohad; Zvi, Anat; Ariel, Naomi; Beth-Din, Adi; Israeli, Ofir; Gur, David; Aftalion, Moshe; Maoz, Sharon; Ber, Raphael

    2016-01-01

    Standard antimicrobial susceptibility tests used to determine bacterial susceptibility to antibiotics are growth dependent and time consuming. The long incubation time required for standard tests may render susceptibility results irrelevant, particularly for patients infected with lethal bacteria that are slow growing on agar but progress rapidly in vivo, such as Yersinia pestis. Here, we present an alternative approach for the rapid determination of antimicrobial susceptibility, based on the quantification of the changes in the expression levels of specific marker genes following exposure to growth-inhibiting concentrations of the antibiotic, using Y. pestis and ciprofloxacin as a model. The marker genes were identified by transcriptomic DNA microarray analysis of the virulent Y. pestis Kimberley53 strain after exposure to specific concentrations of ciprofloxacin for various time periods. We identified several marker genes that were induced following exposure to growth-inhibitory concentrations of ciprofloxacin, and we confirmed the marker expression profiles at additional ciprofloxacin concentrations using quantitative RT-PCR. Eleven candidate marker transcripts were identified, of which four mRNA markers were selected for a rapid quantitative RT-PCR susceptibility test that correctly determined the Minimal Inhibitory Concentration (MIC) values and the categories of susceptibility of several Y. pestis strains and isolates harboring various ciprofloxacin MIC values. The novel molecular susceptibility test requires just 2 h of antibiotic exposure in a 7-h overall test time, in contrast to the 24 h of antibiotic exposure required for a standard microdilution test. PMID:27242774

  12. A Rapid Molecular Test for Determining Yersinia pestis Susceptibility to Ciprofloxacin by the Quantification of Differentially Expressed Marker Genes.

    PubMed

    Steinberger-Levy, Ida; Shifman, Ohad; Zvi, Anat; Ariel, Naomi; Beth-Din, Adi; Israeli, Ofir; Gur, David; Aftalion, Moshe; Maoz, Sharon; Ber, Raphael

    2016-01-01

    Standard antimicrobial susceptibility tests used to determine bacterial susceptibility to antibiotics are growth dependent and time consuming. The long incubation time required for standard tests may render susceptibility results irrelevant, particularly for patients infected with lethal bacteria that are slow growing on agar but progress rapidly in vivo, such as Yersinia pestis. Here, we present an alternative approach for the rapid determination of antimicrobial susceptibility, based on the quantification of the changes in the expression levels of specific marker genes following exposure to growth-inhibiting concentrations of the antibiotic, using Y. pestis and ciprofloxacin as a model. The marker genes were identified by transcriptomic DNA microarray analysis of the virulent Y. pestis Kimberley53 strain after exposure to specific concentrations of ciprofloxacin for various time periods. We identified several marker genes that were induced following exposure to growth-inhibitory concentrations of ciprofloxacin, and we confirmed the marker expression profiles at additional ciprofloxacin concentrations using quantitative RT-PCR. Eleven candidate marker transcripts were identified, of which four mRNA markers were selected for a rapid quantitative RT-PCR susceptibility test that correctly determined the Minimal Inhibitory Concentration (MIC) values and the categories of susceptibility of several Y. pestis strains and isolates harboring various ciprofloxacin MIC values. The novel molecular susceptibility test requires just 2 h of antibiotic exposure in a 7-h overall test time, in contrast to the 24 h of antibiotic exposure required for a standard microdilution test. PMID:27242774

  13. Association between vitamin D receptor gene Cdx2 polymorphism and breast cancer susceptibility.

    PubMed

    Zhou, Zhu-Chao; Wang, Jie; Cai, Zi-Hao; Zhang, Qun-hua; Cai, Zhen-Xin; Wu, Jian-Hua

    2013-12-01

    Vitamin D receptor (VDR) gene polymorphisms have been reported to influence susceptibility to breast cancer. However, published findings on the association between VDR Cdx2 polymorphism and breast cancer susceptibility are conflicting. To get a precise estimation of the association between VDR Cdx2 polymorphism and breast cancer susceptibility, we conducted a meta-analysis of four case-control studies with a total of 8,880 subjects (3,841 cases and 5,039 controls). The results showed that VDR Cdx2 polymorphism was not associated with risk of breast cancer (A versus G: OR = 0.96, 95% CI 0.84-1.09; AA versus GG: OR = 0.97, 95% CI 0.64-1.45; AA/GA versus GG: OR = 0.94, 95% CI 0.80-1.10; AA versus GG/GA: OR = 0.99, 95% CI 0.65-1.51). Subgroup analysis in Caucasians also showed that VDR Cdx2 polymorphism was not associated with risk of breast cancer in Caucasians. However, there was a significant association in Africans (A versus G: OR = 0.75, 95% CI 0.60-0.94; AA versus GG: OR = 0.53, 95% CI 0.29-0.99; AA/GA versus GG: OR = 0.75, 95% CI 0.57-0.97). Therefore, the association between VDR Cdx2 polymorphism and breast cancer susceptibility is only found in Africans. More studies are needed to further assess the association in Asians or Africans. PMID:23821301

  14. Tim-3 polymorphism downregulates gene expression and is involved in the susceptibility to ankylosing spondylitis.

    PubMed

    Wang, Mingfei; Ji, Bin; Wang, Jian; Cheng, Xiangyu; Zhou, Qiang; Zhou, Junjie; Cao, Chengfu; Guo, Qunfeng

    2014-10-01

    Ankylosing spondylitis (AS) is a chronic inflammatory disorder primarily affecting the sacroiliac joints and the spine. T-cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3) has been established as a negative regulatory molecule that plays a critical role in controlling inflammation. Studies have shown that polymorphisms in TIM-3 gene may be associated with inflammatory diseases. The current study investigated the association between polymorphisms in the TIM-3 gene and susceptibility to AS, and it examined the effects of these polymorphisms on gene expression. Two polymorphisms in TIM-3 -574G/T and +4259T/G polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism in 282 AS patients and 298 healthy controls. Results showed that frequency of the TIM-3 -574GT genotype was significantly increased in cases than in controls (Odd ratio [OR]=2.50, 95% confidence interval [CI]: 1.39-4.48, p=0.002). Similarly, TIM-3 -574T allele revealed a positive association with the disease (OR=2.39, p=0.002). The TIM-3 +4259T/G polymorphism did not show any correlation with AS. We further evaluated TIM-3 mRNA and protein levels in CD4(+) T cells, CD8(+) T cells, and monocytes from subjects carrying different TIM-3 genotypes. Results revealed that subjects carrying polymorphic -574GT genotype had significantly lower TIM-3 mRNA and protein levels in CD4(+) T cells, CD8(+) T cells, and monocytes than those with wild-type GG genotype. These data suggest that TIM-3 polymorphism is associated with increased susceptibility to AS possibly by downregulating gene expression. PMID:24905803

  15. Down-regulation of promoter methylation level of CD4 gene after MDV infection in MD-susceptible chicken line

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Marek’s disease virus (MDV) is an oncovirus that induces lymphoid tumors in susceptible chickens, and may affect the epigenetic stability of the CD4 gene. The purpose of this study was to find how the effect of MDV infection on DNA methylation status of the CD4 gene differed between MD-resistant (L6...

  16. Serial analysis of gene expression in Rhipcephalus (Boophilus) microplus following organophoosphate treatment of larvae from organophosphate resistant and susceptible strains.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Organophosphate resistant and susceptible tick larvae from laboratory strains of the southern cattle tick, Rhipicephalus (Boophilus) microplus were exposed to low doses of the organophosphate (OP) acaricide, coumaphos. Serial analysis of gene expression (SAGE) was used to analyze differential gene e...

  17. Impacts of CA9 Gene Polymorphisms on Urothelial Cell Carcinoma Susceptibility and Clinicopathologic Characteristics in Taiwan

    PubMed Central

    Ou, Yen-Chuan; Chen, Chuan-Shu; Li, Jian-Ri; Yang, Shun-Fa

    2013-01-01

    Background Carbonic anhydrase 9 (CA9) is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study explored the effect of CA9 gene polymorphisms on the susceptibility of developing urothelial cell carcinoma (UCC) and the clinicopathological status. Methodology and Principal Findings A total of 442 participants, including 221 healthy people and 221 patients with UCC, were recruited for this study. Four single-nucleotide polymorphisms (SNPs) of the CA9 gene were assessed by a real-time PCR with the TaqMan assay. After adjusting for other co-variants, the individuals carrying at least one A allele at CA9 rs1048638 had a 2.303-fold risk of developing UCC than did wild-type (CC) carriers. Furthermore, UCC patients who carried at least one A allele at rs1048638 had a higher invasive stage risk (p< 0.05) than did patients carrying the wild-type allele. Moreover, among the UCC patients with smoker, people with at least one A allele of CA9 polymorphisms (rs1048638) had a 4.75-fold (95% CI = 1.204–18.746) increased risk of invasive cancer. Conclusion The rs1048638 polymorphic genotypes of CA9 might contribute to the prediction of susceptibility to and pathological development of UCC. This is the first study to provide insight into risk factors associated with CA9 variants in carcinogenesis of UCC in Taiwan. PMID:24349364

  18. The relationship between polymorphisms in the glutamate cysteine ligase gene and asthma susceptibility.

    PubMed

    Polonikov, A V; Ivanov, V P; Solodilova, M A; Khoroshaya, I V; Kozhuhov, M A; Panfilov, V I

    2007-11-01

    The present study was designed to investigate an association of common -588C/T and -23G/T polymorphisms within glutamate cysteine ligase modifier subunit gene with susceptibility to bronchial asthma. A total of 435 ethnically Russian subjects were recruited in this study, including 221 patients with asthma and 214 sex and age matched healthy subjects. As previously reported, the -588C/T and -23G/T polymorphisms were completely linked. The -588TT/-23TT genotype was found to be associated with decreased risk of allergic asthma after adjustment for age, gender and smoking status using multivariate logistic regression analysis (OR=0.33 95% CI 0.15-0.70, p=0.036). However, the -588CT/-23GT genotype was associated with increased risk of non-allergic asthma (OR=2.03 95% CI 1.05-3.90, p=0.06). This is a first study reporting the association between genetic variations in the glutamate cysteine ligase gene and susceptibility to bronchial asthma. PMID:17643973

  19. Case-parental control method in the search for disease-susceptibility genes

    SciTech Connect

    Khoury, M.J. )

    1994-08-01

    Historically, the search for disease-susceptibility genes has taken on two approaches, the linkage approach, traditionally the domain of the geneticist, and the association approach, traditionally the domain of the epidemiologist. The problem with association studies has been the choice of an appropriate control group with which cases can be compared with respect to the allelic distribution. The choice of appropriate controls has been extensively discussed in the epidemiology literature. To deal with confounding due to population stratification, sibling controls have been used as one group to adjust for genetic background. In the approach discussed by Knapp et al and Schaid and Sommer, the control group is a fictitious group formed by the parental alleles (at the locus of interest) that have not been transmitted to the proband. Cases and controls can then be compared with respect to the distribution of marker alleles at this locus, and measures of relative risk (haplotype or genotype relative risks) can be derived. The use of parental controls can provide a valuable method to search for disease-susceptibility genes for common diseases and to look for evidence of genotype-environment interaction. It is hoped that this methodology will be increasingly used in genetic-epidemiologic studies of disease.

  20. Impact of VEGF-C Gene Polymorphisms and Environmental Factors on Oral Cancer Susceptibility in Taiwan

    PubMed Central

    Chien, Ming-Hsien; Liu, Yu-Fan; Hsin, Chung-Han; Lin, Chien-Huang; Shih, Chun-Han; Yang, Shun-Fa; Cheng, Chao-Wen; Lin, Chiao-Wen

    2013-01-01

    Background Oral cancer, which is the fourth most common male cancer, is associated with environmental carcinogens in Taiwan. Vascular endothelial growth factor (VEGF)-C, an angiogenic/lymphangiogenic factor with high expression levels in tumor tissues, plays important roles in the development of several malignancies. This study was designed to examine associations of five VEGF-C gene polymorphisms with the susceptibility to and clinicopathological characteristics of oral squamous cell carcinoma. Methodology/Principal Findings Five single-nucleotide polymorphisms (SNPs) of VEGF-C were analyzed by a real-time polymerase chain reaction (PCR) in 470 male patients with oral cancer and 426 cancer-free controls. In this study, we found that the VEGF-C rs7664413 and rs2046463 polymorphisms were associated with oral-cancer susceptibility but not with any clinicopathological parameters. The GGACA or GACTG haplotype of five VEGF-C SNPs (rs3775194, rs11947611, rs1485766, rs7664413, and rs2046463) combined was also related to the risk of oral cancer. Among 611 male smokers, VEGF-C polymorphism carriers who also chewed betel quid were found to have a 14.5–24.2-fold risk of having oral cancer compared to the VEGF-C wild-type carrier who did not chew betel quid. Among 461 male betel-quid chewers, VEGF-C polymorphism carriers who also smoked had a 2.7–18.1-fold risk of having oral cancer compared to those who carried the wild type but did not smoke. Conclusions Our results suggest that the two SNPs of VEGF-C (rs7664413 and rs2046463) and either of two haplotypes of five SNPs combined have potential predictive significance in oral carcinogenesis. Gene-environmental interactions among VEGF-C polymorphisms, smoking, and betel-quid chewing might alter one's susceptibility to oral cancer. PMID:23593187

  1. MicroRNA Gene Polymorphisms and Environmental Factors Increase Patient Susceptibility to Hepatocellular Carcinoma

    PubMed Central

    Chu, Yin-Hung; Hsieh, Ming-Ju; Chiou, Hui-Ling; Liou, Yi-Sheng; Yang, Chen-Chieh; Yang, Shun-Fa; Kuo, Wu-Hsien

    2014-01-01

    Background Micro RNAs (miRNAs) are small RNA fragments that naturally exist in the human body. Through various physiological mechanisms, miRNAs can generate different functions for regulating RNA protein levels and balancing abnormalities. Abnormal miRNA expression has been reported to be highly related to several diseases and cancers. Single-nucleotide polymorphisms (SNPs) in miRNAs have been reported to increase patient susceptibility and affect patient prognosis and survival. We adopted a case-control research design to verify the relationship between miRNAs and hepatocellular carcinoma. Methodology/Principal Findings A total of 525 subjects, including 377 controls and 188 hepatocellular carcinoma patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and real-time PCR were used to analyze miRNA146a (rs2910164), miRNA149 (rs2292832), miRNA196 (rs11614913), and miRNA499 (rs3746444) genetic polymorphisms between the control group and the case group. The results indicate that people who carry the rs3746444 CT or CC genotypes may have a significantly increased susceptibility to hepatocellular carcinoma (adjusted odds ratio [AOR] = 2.84, 95% confidence interval [CI] = 1.88–4.30). In addition, when combined with environmental risk factors, such as smoking and alcohol consumption, interaction effects were observed between gene polymorphisms and environmental factors (odds ratio [OR] = 4.69, 95% CI = 2.52–8.70; AOR = 3.38, 95% CI = 1.68–6.80). Conclusions These results suggest that a significant association exists between miRNA499 SNPs and hepatocellular carcinoma. Gene-environment interactions of miRNA499 polymorphisms, smoking, and alcohol consumption might alter hepatocellular carcinoma susceptibility. PMID:24587132

  2. Retinoblastoma major review with updates on Middle East management protocols

    PubMed Central

    Othman, Ihab Saad

    2012-01-01

    Many advances in the field of management of retinoblastoma emerged in the past few years. Patterns of presentation of retinoblastoma in the Middle East region differ from Western community. The use of enucleation as a radical method of eradicating advanced disease is not easily accepted by patient’s family. We still do see stage E, failed or resistant retinoblastoma and advanced extraocular disease ensues as a result of delayed enucleation decision. In this review, we discuss updates in management of retinoblastoma with its implication on patients in our part of the world. Identifying clinical and high risk characteristics is important prognostically and are discussed for further management of retinoblastoma cases. PMID:23960988

  3. Cytochrome P450 CYP2D6 gene polymorphism and lung cancer susceptibility in Caucasians.

    PubMed

    Legrand-Andréoletti, M; Stücker, I; Marez, D; Galais, P; Cosme, J; Sabbagh, N; Spire, C; Cenée, S; Lafitte, J J; Beaune, P; Broly, F

    1998-02-01

    Many studies have been performed in an attempt to establish a link between the polymorphism of the cytochrome P450 CYP2D6 gene and the incidence of lung cancer. Nevertheless, whether or not this genetic polymorphism has a role in the development of the disease remains unclear. Recently, new advances in our knowledge of the CYP2D6 gene and its locus (CYP2D) have been achieved. In particular, CYP2D6 was found to be highly polymorphic and multiple novel mutations and allelic variants of the gene have been identified. In addition, a number of CYP2D rearrangements, including those with amplification of the gene, have been demonstrated. Taking this new information into account, we have reconsidered the potential influence of CYP2D6 polymorphism in lung cancer susceptibility by performing a comparative analysis of the overall mutational spectrum of CYP2D6 and of the rearrangements of CYP2D in 249 patients with lung cancer and in 265 control individuals matched on age, sex, hospital and residence area. For this purpose, a strategy based on SSCP analysis of the entire coding sequence of CYP2D6 and on RFLP analysis of the gene locus was carried out in DNA samples from each individual. Forty mutations occurring in various combinations on 42 alleles of the gene and 82 different genotypes were identified. No significant difference in the distribution of the mutations, alleles or genotypes was observed between the two groups, except a particular genotype (CYP2D6*1A/*2), which was more common in the sub-group of moderate smokers (< 30 pack-years) suffering from small cell carcinoma (Odds Ratio (OR) 3.6, 95% CI 1.1-11.9). When the phenotype was predicted according to genotype, only a trend toward a higher frequency of ultrarapid metabolizers in patients was obtained. In spite of a complete analysis of the CYP2D6 gene and its locus, this case-control study provides elements against an influence of the CYP2D6 polymorphism on lung cancer susceptibility. PMID:9511176

  4. Functional variants of sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility

    PubMed Central

    Sun, Xiaoguang; Ma, Shwu-Fan; Wade, Michael S.; Flores, Carlos; Pino-Yanes, Maria; Moitra, Jaideep; Ober, Carole; Kittles, Rick; Husain, Aliya N.; Ford, Jean G.; Garcia, Joe G. N.

    2012-01-01

    Background The genetic mechanisms underlying asthma remain unclear. Increased permeability of the microvasculature is a feature of asthma and the sphingosine-1-phosphate receptor, S1PR1, is an essential participant regulating lung vascular integrity and responses to lung inflammation. Objective We explored the contribution of polymorphisms in the S1PR1 gene (S1PR1) to asthma susceptibility. Methods A combination of gene re-sequencing for SNP discovery, case-control association, functional evaluation of associated SNPs, and protein immunochemistry studies was utilized. Results Immunohistochemistry studies demonstrated significantly decreased S1PR1 protein expression in pulmonary vessels in asthmatic lungs compared to non-asthmatic individuals (p<0.05). Direct DNA sequencing of 27 multiethnic samples identified 39 S1PR1 variants (18 novel SNPs). Association studies were performed based on genotyping results from cosmopolitan tagging SNPs in three case-control cohorts from Chicago and New York totaling 1061 subjects (502 cases and 559 controls). Promoter SNP rs2038366 (−1557G/T) was found to be associated with asthma (p=0.03) in European Americans. In African Americans, an association was found for both asthma and severe asthma for intronic SNP rs3753194 (c.−164+170A/G) (p=0.006 and p=0.040, respectively) and for promoter SNP rs59317557 (−532C/G) with severe asthma (p=0.028). Consistent with predicted in silico functionality, alleles of promoter SNPs rs2038366 (−1557G/T) and rs59317557 (−532C/G) influenced the activity of a luciferase S1PR1 reporter vector in transfected endothelial cells exposed to growth factors (EGF, PDGF, VEGF) known to be increased in asthmatic airways. Conclusion These data provide strong support for a role for S1PR1 gene variants in asthma susceptibility and severity. Clinical Implications Our results indicate S1PR1 is a novel asthma candidate gene and an attractive target for future therapeutic strategies. Capsule summary This study

  5. Role of the retinoblastoma protein in cell cycle arrest mediated by a novel cell surface proliferation inhibitor

    NASA Technical Reports Server (NTRS)

    Enebo, D. J.; Fattaey, H. K.; Moos, P. J.; Johnson, T. C.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    A novel cell regulatory sialoglycopeptide (CeReS-18), purified from the cell surface of bovine cerebral cortex cells has been shown to be a potent and reversible inhibitor of proliferation of a wide array of fibroblasts as well as epithelial-like cells and nontransformed and transformed cells. To investigate the possible mechanisms by which CeReS-18 exerts its inhibitory action, the effect of the inhibitor on the posttranslational regulation of the retinoblastoma susceptibility gene product (RB), a tumor suppressor gene, has been examined. It is shown that CeReS-18 mediated cell cycle arrest of both human diploid fibroblasts (HSBP) and mouse fibroblasts (Swiss 3T3) results in the maintenance of the RB protein in the hypophosphorylated state, consistent with a late G1 arrest site. Although their normal nontransformed counterparts are sensitive to cell cycle arrest mediated by CeReS-18, cell lines lacking a functional RB protein, through either genetic mutation or DNA tumor virus oncoprotein interaction, are less sensitive. The refractory nature of these cells is shown to be independent of specific surface receptors for the inhibitor, and another tumor suppressor gene (p53) does not appear to be involved in the CeReS-18 inhibition of cell proliferation. The requirement for a functional RB protein product, in order for CeReS-18 to mediate cell cycle arrest, is discussed in light of regulatory events associated with density-dependent growth inhibition.

  6. Antimicrobial susceptibility and analysis of macrolide resistance genes in Streptococcus pneumoniae isolated in Hamadan

    PubMed Central

    Mosleh, Mohammad Najafi; Gharibi, Marzieh; Alikhani, Mohammad Yousef; Saidijam, Massoud; Vakhshiteh, Faezeh

    2014-01-01

    Objective(s): Macrolide resistant Streptococcus pneumoniae pose an emerging problem globally. The aim of this study was to investigate the prevalence of ermB and mefA genes (macrolide resistant genes) by polymerase chain reaction (PCR) method and to detect drug resistance patterns of S. pneumoniae isolated from clinical samples to macrolides and other antibiotic agents by E-test method. Materials and Methods: Fifty five isolates of S. pneumoniae were obtained from clinical samples with microbial tests. The antibiotic susceptibility of isolates for erythromycin, azithromycin, clarithromycin, ceftazidime, ciprofloxacin and vancomycin were determined by E-test method. Genotypic antibiotic resistance pattern was determined by PCR with primer designed for ermB and mefA genes. Results: The number of S. pneumoniae isolates resistance to erythromycin, azithromycin, clarithromycin, ceftazidim, ciprofloxacin were 25.5%, 18.2%, 16.4%, 21.8% and 10.9%, respectively while no resistance to vancomycin was observed. The macrolide resistance genes of ermB and mefA were found in 10.9% and 18.2% of the isolates, respectively. Conclusion: The result of the current study suggests the necessity of evaluation the changes in MIC (minimum inhibitory concentration) values as well as genetic mutations to estimate the prevalence of the resistance antimicrobial agents in S. pneumoniae. PMID:25422753

  7. Genetic susceptibility to heroin addiction; a candidate-gene association study

    PubMed Central

    Levran, O.; Londono, D.; O’Hara, K.; Nielsen, D. A.; Peles, E.; Rotrosen, J.; Casadonte, P.; Linzy, S.; Randesi, M.; Ott, J.; Adelson, M.; Kreek, M. J.

    2010-01-01

    Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify genetic variants that are associated with susceptibility to develop heroin addiction, by analyzing 1350 variants in 130 candidate genes. All subjects had Caucasian ancestry. The sample consisted of 412 former severe heroin addicts in methadone treatment, and 184 healthy controls with no history of drug abuse. Nine variants, in six genes, showed the lowest nominal P values in the association tests (P < 0.01). These variants were in non-coding regions of the genes encoding the mu (OPRM1; rs510769, rs3778151), kappa (OPRK1; rs6473797), and delta opioid receptors, (OPRD1; rs2236861, rs2236857 and rs3766951), the neuropeptide galanin (GAL; rs694066), the serotonin receptor subtype 3B (HTR3B; rs3758987) and the casein kinase 1 isoform epsilon (CSNK1E; rs1534891). Several haplotypes and multi-locus genotype patterns showed nominally significant associations (e.g. OPRM1; P = 0.0006 and CSNK1E; P = 0.0007). Analysis of a combined effect of OPRM1 and OPRD1 showed that rs510769 and rs2236861 increase the risk of heroin addiction (P = 0.0005). None of these associations remained significant after adjustment for multiple testing. This study suggests the involvement of several genes and variants in heroin addiction that is worthy of future study. PMID:18518925

  8. HSD3B and Gene-Gene Interactions in a Pathway-Based Analysis of Genetic Susceptibility to Bladder Cancer

    PubMed Central

    Andrew, Angeline S.; Hu, Ting; Gu, Jian; Gui, Jiang; Ye, Yuanqing; Marsit, Carmen J.; Kelsey, Karl T.; Schned, Alan R.; Tanyos, Sam A.; Pendleton, Eben M.; Mason, Rebecca A.; Morlock, Elaine V.; Zens, Michael S.; Li, Zhongze; Moore, Jason H.; Wu, Xifeng; Karagas, Margaret R.

    2012-01-01

    Bladder cancer is the 4th most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case–control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene–gene interactions using Multifactor Dimensionality Reduction (MDR) and Statistical Epistasis Network analysis. The 3′UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31–2.62). This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06–12.63). The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40–3.25) than females (OR 1.56 95%CI 0.83–2.95), (SNP-gender interaction P = 0.048). We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003). The fact that bladder cancer incidence is 3–4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis. PMID:23284679

  9. [Trilateral retinoblastoma in Burkina Faso: three cases].

    PubMed

    Nikièma, Zakari; Wenceslas Diallo, Jean; Daboué, Arsène; Seydou Traoré, Sa; Zorom, Bintou Traoré; Bamouni, Abel; Sorgho, Claudine Lougué; Cissé, Rabiou

    2009-01-01

    The authors describe three cases of trilateral retinoblastoma, a rare syndrome that occurs most often in young children. Two of these children were 3 years old at diagnosis, and the other 4 years old. The retinoblastoma was unilateral in one child and bilateral in the others. All underwent computed tomography (CT) imaging, which made it possible to locate the intraocular tumor lesions, to specify the extent of the tumor and to look for a possible intracranial neoplasm. Unfortunately, the cost of CT is high, which limits its use in our context. PMID:20199945

  10. Constitutional genomic instability, chromosome aberrations in tumor cells and retinoblastoma.

    PubMed

    Amare Kadam, P S; Ghule, P; Jose, J; Bamne, M; Kurkure, P; Banavali, S; Sarin, R; Advani, S

    2004-04-01

    Although retinoblastoma (Rb) is initiated as a result of biallelic inactivation of the RB1 gene, additional genetic events (M3) in tumor cells are indicative of their role in the full transformation of retinal cells. We investigated the constitutional genetic instability by fragile site (FS) expression studies and checked its relationship with loci of tumor cytogenetics in a series of 36 retinoblastoma patients (34 nonfamilial and 2 familial cases). Tumor cytogenetics revealed -13/+13, del/t(13)(q14) (50%), +1/del/t(1p/q) (65%), +6/i(6p) (60%), and del(16)(q13)/(q22 approximately q23) (60%). Conventional cytogenetics in leukocytes revealed constitutional del(13q14) in five unilateral Rb (URB) and one trilateral Rb (TRB). Constitutional del(16)(q22) and t(6;12) were also identified in two cases. Constitutional FS analysis showed a significant increase in the cellular fragility, with high prevalence at 13q14, 3p14, 6p23, 16q22 approximately q23, and 13q22 loci in retinoblastoma patients (P<0.05). Patients with constitutional del(13)(q14) demonstrated higher fragility than those with normal constitution. A strong correlation between loci of constitutional FSs and loci of recurrent chromosomal abnormalities in tumors strengthen and support the proposal that FS loci present as inherent genomic instability in retinoblastoma. The chromosomal changes and resultant genetic mutations, along with RB1 mutation events, probably contribute synergistically to the development and progression of Rb malignancy. Implementation of fluorescence in situ hybridization to nonfamilial Rb on a large scale (113 cases) could detect constitutional RB1 deletion in 12.3% of cases, with equally higher incidence in URB (14.7%) and bilateral Rb (13.6%), demonstrating that the true prevalence of patients with predisposition to RB1 mutation in sporadic URB is definitely higher in our populations. Also, higher incidence of constitutional RB1 deletion mosaicism in unilateral than in bilateral Rb

  11. Identification of KCNJ15 as a susceptibility gene in Asian patients with type 2 diabetes mellitus.

    PubMed

    Okamoto, Koji; Iwasaki, Naoko; Nishimura, Chisa; Doi, Kent; Noiri, Eisei; Nakamura, Shinko; Takizawa, Miho; Ogata, Makiko; Fujimaki, Risa; Grarup, Niels; Pisinger, Charlotta; Borch-Johnsen, Knut; Lauritzen, Torsten; Sandbaek, Annelli; Hansen, Torben; Yasuda, Kazuki; Osawa, Haruhiko; Nanjo, Kishio; Kadowaki, Takashi; Kasuga, Masato; Pedersen, Oluf; Fujita, Toshiro; Kamatani, Naoyuki; Iwamoto, Yasuhiko; Tokunaga, Katsushi

    2010-01-01

    Recent advances in genome research have enabled the identification of new genomic variations that are associated with type 2 diabetes mellitus (T2DM). Via fine mapping of SNPs in a candidate region of chromosome 21q, the current study identifies potassium inwardly-rectifying channel, subfamily J, member 15 (KCNJ15) as a new T2DM susceptibility gene. KCNJ15 is expressed in the beta cell of the pancreas, and a synonymous SNP, rs3746876, in exon 4 (C566T) of this gene, with T allele frequency among control subjects of 3.1%, showed a significant association with T2DM affecting lean individuals in three independent Japanese sample sets (p = 2.5 x 10(-7), odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.76-3.67) and with unstratified T2DM (p = 6.7 x 10(-6), OR = 1.76, 95% CI = 1.37-2.25). The diabetes risk allele frequency was, however, very low among Europeans in whom no association between this variant and T2DM could be shown. Functional analysis in human embryonic kidney 293 cells demonstrated that the risk allele of the synonymous SNP in exon 4 increased KCNJ15 expression via increased mRNA stability, which resulted in the higher expression of protein as compared to that of the nonrisk allele. We also showed that KCNJ15 is expressed in human pancreatic beta cells. In conclusion, we demonstrated a significant association between a synonymous variant in KCNJ15 and T2DM in lean Japanese patients with T2DM, suggesting that KCNJ15 is a previously unreported susceptibility gene for T2DM among Asians. PMID:20085713

  12. A locus on mouse Ch10 influences susceptibility to limbic seizure severity: fine mapping and in silico candidate gene analysis

    PubMed Central

    Winawer, Melodie R.; Klassen, Tara L.; Teed, Sarah; Shipman, Marissa; Leung, Emily H.; Palmer, Abraham A.

    2014-01-01

    Identification of genes contributing to mouse seizure susceptibility can reveal novel genes or pathways that provide insight into human epilepsy. Using mouse chromosome substitution strains and interval-specific congenic strains (ISCS), we previously identified an interval conferring pilocarpine-induced limbic seizure susceptibility on distal mouse Chromosome 10 (Ch10). We narrowed the region by generating subcongenics with smaller A/J Ch10 segments on a C57BL/6J (B6) background and tested them with pilocarpine. We also tested pilocarpine susceptible congenics for 6Hz ECT, another model of limbic seizure susceptibility, to determine whether the susceptibility locus might have a broad effect on neuronal hyperexcitability across more than one mode of limbic seizure induction. ISCS Line 1, which contained the distal 2.7 Mb segment from A/J (starting at rs29382217), was more susceptible to both pilocarpine and ECT. Line 2, which was a subcongenic of Line1 (starting at rs13480828), was not susceptible; thus defining a 1.0 Mb critical region that was unique to Line1. Bioinformatic approaches identified 52 human orthologues within the unique Line 1 susceptibility region, the majority syntenic to human Ch12. Applying an epilepsy network analysis of known and suspected excitability genes and examination of interstrain genomic and brain expression differences revealed novel candidates within the region. These include Stat2, which plays a role in hippocampal GABA receptor expression after status epilepticus, and novel candidates Pan2, Cdk2, Gls2, and Cs, which are involved in neural cell differentiation, cellular remodeling, and embryonic development. Our strategy may facilitate discovery of novel human epilepsy genes. PMID:24373497

  13. The retinoblastoma protein induces apoptosis directly at the mitochondria

    PubMed Central

    Hilgendorf, Keren I.; Leshchiner, Elizaveta S.; Nedelcu, Simona; Maynard, Mindy A.; Calo, Eliezer; Ianari, Alessandra; Walensky, Loren D.; Lees, Jacqueline A.

    2013-01-01

    The retinoblastoma protein gene RB-1 is mutated in one-third of human tumors. Its protein product, pRB (retinoblastoma protein), functions as a transcriptional coregulator in many fundamental cellular processes. Here, we report a nonnuclear role for pRB in apoptosis induction via pRB's direct participation in mitochondrial apoptosis. We uncovered this activity by finding that pRB potentiated TNFα-induced apoptosis even when translation was blocked. This proapoptotic function was highly BAX-dependent, suggesting a role in mitochondrial apoptosis, and accordingly, a fraction of endogenous pRB constitutively associated with mitochondria. Remarkably, we found that recombinant pRB was sufficient to trigger the BAX-dependent permeabilization of mitochondria or liposomes in vitro. Moreover, pRB interacted with BAX in vivo and could directly bind and conformationally activate BAX in vitro. Finally, by targeting pRB specifically to mitochondria, we generated a mutant that lacked pRB's classic nuclear roles. This mito-tagged pRB retained the ability to promote apoptosis in response to TNFα and also additional apoptotic stimuli. Most importantly, induced expression of mito-tagged pRB in Rb−/−;p53−/− tumors was sufficient to block further tumor development. Together, these data establish a nontranscriptional role for pRB in direct activation of BAX and mitochondrial apoptosis in response to diverse stimuli, which is profoundly tumor-suppressive. PMID:23618872

  14. Epstein-Barr virus-induced gene 3 (EBI3) polymorphisms and expression are associated with susceptibility to pulmonary tuberculosis.

    PubMed

    Zheng, Ruijuan; Liu, Haipeng; Song, Peng; Feng, Yonghong; Qin, Lianhua; Huang, Xiaochen; Chen, Jianxia; Yang, Hua; Liu, Zhonghua; Cui, Zhenglin; Hu, Zhongyi; Ge, Baoxue

    2015-07-01

    Tuberculosis (TB) remains a major global health problem and host genetic factors play a critical role in susceptibility and resistance to TB. The aim of this study was to identify novel candidate genes associated with TB susceptibility. We performed a population-based case-control study to genotype 13 tag SNPs spanning Epstein-Barr virus-induced gene 3 (EBI3), colony stimulating factor 2 (CSF2), IL-4, interferon beta 1 (IFNB1), chemokine (C-X-C motif) ligand 14 (CXCL14) and myeloid differentiation primary response gene 88 (Myd88) genes in 435 pulmonary TB patients and 375 health donors from China. We observed that EBI3 gene rs4740 polymorphism was associated with susceptibility to pulmonary tuberculosis (PTB) and the allele G was associated with a protective effect against PTB. Furthermore, EBI3 deficiency led to reduced bacterial burden and histopathological impairment in the lung of mice infected with Mycobacterium bovis BCG. Meanwhile, higher abundance of EBI3 was observed in the granuloma of PTB patients and in the lung tissue of BCG-infected mice. Of note, the expression of EBI3 in macrophages was remarkably induced by mycobacteria infection at both mRNA and protein level. In conclusion, EBI3 gene rs4740 polymorphism is closely associated with susceptibility to PTB and the elevation and enrichment of EBI3 in the lung which at least partially derived from macrophages may contribute to the exacerbation of mycobacterial infection. PMID:25937126

  15. Differential Expression of Apoptosis Related Genes in Selected Strains of Aedes aegypti with Different Susceptibilities to Dengue Virus

    PubMed Central

    Ocampo, Clara B.; Caicedo, Paola A.; Jaramillo, Gloria; Ursic Bedoya, Raul; Baron, Olga; Serrato, Idalba M.; Cooper, Dawn M.; Lowenberger, Carl

    2013-01-01

    Aedes aegypti is the principal vector of Dengue viruses worldwide. We identified field collected insects with differential susceptibility to Dengue-2 virus (DENv-2) and used isofemale selection to establish susceptible and refractory strains based on midgut infection barriers. Previous experiments had identified higher expression of apoptosis-related genes in the refractory strain. To identify potential molecular mechanisms associated with DENv susceptibility, we evaluated the differential expression of Caspase-16, Aedronc, Aedredd, Inhibitor of apoptosis (AeIAP1) and one member of the RNAi pathway, Argonaute-2 in the midguts and fat body tissues of the selected strains at specific times post blood feeding or infection with DENv-2. In the refractory strain there was significantly increased expression of caspases in midgut and fatbody tissues in the presence of DENv-2, compared to exposure to blood alone, and significantly higher caspase expression in the refractory strain compared with the susceptible strain at timepoints when DENv was establishing in these tissues. We used RNAi to knockdown gene expression; knockdown of AeIAP1 was lethal to the insects. In the refractory strain, knockdown of the pro-apoptotic gene Aedronc increased the susceptibility of refractory insects to DENv-2 from 53% to 78% suggesting a contributing role of this gene in the innate immune response of the refractory strain. PMID:23593426

  16. Analysis of HLA and disease susceptibility: Chromosome 6 genes and sex influence long-QT phenotype

    SciTech Connect

    Weitkamp, L.R.; Moss, A.J.; Hall, W.J.; Robinson, J.L.; Guttormsen, S.A.; Lewis, R.A.; MacCluer, J.W.; Schwartz, P.J.; Locati, E.H.; Tzivoni, D.

    1994-12-01

    The long-QT (LQT) syndrome is a genetically complex disorder that is characterized by syncope and fatal ventricular arrhythmias. LQT syndrome, as defined by a prolonged electrocardiographic QT interval, has a higher incidence in females than in males and does not exhibit Mendelian transmission patterns in all families. Among those families that are nearly consistent with Mendelian transmission, linkage between a locus for LQT syndrome and the H-ras-1 locus on the short arm of chromosome 11 has been reported in some families but not in others. Earlier analyses suggesting that LQT syndrome might be caused by a gene in the HLA region of chromosome 6 were not confirmed by standard linkage analyses. Here, we present an analysis of HLA haplotype sharing among affected pedigree members, showing an excess of haplotype sharing in a previously published Japanese pedigree and possibly also in 15 families of European descent. The haplotypes shared by affected individuals derive from both affected and unaffected parents. In an analysis of independent (unrelated) HLA haplotypes, we also found a nonrandom distribution of HLA-DR genes in LQT syndrome patients compared with controls, suggesting an association between the LQT phenotype and specific HLA-DR genes. Our data indicate that DR2 has a protective effect and, particularly in males, that DR7 may increase susceptibility to the LQT syndrome. Thus, LQT syndrome may be influenced by genes on chromosomes 11 and 6, possibly with a sex-specific effect. These results provide a model for an effect of HLA-region genes inherited from either parent on the expression of an illness that may be determined principally by alleles at loci not linked to HLA.

  17. Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility

    PubMed Central

    Hosgood, H Dean; Cawthon, Richard; He, Xingzhou; Chanock, Stephen; Lan, Qing

    2009-01-01

    Telomeres are responsible for the protection of the chromosome ends and shortened telomere length has been associated with risk of multiple cancers. Genetic variation in telomere related genes may alter cancer risk associated with telomere length. Using lung cancer cases (n = 120) and population-based controls (n = 110) from Xuanwei, China, we analyzed telomere length separately and in conjunction with single nucleotide polymorphisms in the telomere maintenance genes POT1, TERT, and TERF2, which we have previously reported were associated with risk of lung cancer in this study. POT1 rs10244817, TERT rs2075786, and TERF2 rs251796 were significantly associated with lung cancer (ptrend ≤ 0.05). The shortest tertile of telomere length was not significantly associated with risk of lung cancer (OR = 1.58; 95% CI = 0.79 – 3.18) when compared to the longest tertile of telomere length. When stratified by genotype, there was a suggestion of a dose-response relationship between tertiles of telomere length and risk of lung cancer among the POT1 rs10244817 common variant carriers (OR (95%CI) = 1.33 (0.47 – 3.75), 3.30 (1.14 – 9.56), respectively) but not among variant genotype carriers (pinteraction = 0.05). Our findings provide evidence that telomere length and genetic variation in telomere maintenance genes may be associated with risk of lung cancer susceptibility and warrant replication in larger studies. PMID:19285750

  18. Effect of RECK Gene Polymorphisms on Hepatocellular Carcinoma Susceptibility and Clinicopathologic Features

    PubMed Central

    Li, Yi-Ching; Su, Shih-Chi; Chien, Ming-Hsien; Yang, Shun-Fa; Hsieh, Yi-Hsien

    2012-01-01

    Background The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) down-regulation has been confirmed in numerous human cancers and is clinically associated with metastasis. This study investigates the potential associations of RECK single-nucleotide polymorphisms (SNPs) with hepatocellular carcinoma (HCC) susceptibility and its clinicopathologic characteristics. Methodology/Principal Findings A total of 135 HCC cancer patients and 501 cancer-free controls were analyzed for four RECK SNPs (rs10814325, rs16932912, rs11788747, and rs10972727) using real-time PCR and PCR-RFLP genotyping analysis. After adjusting for other co-variants, the individuals carrying RECK promoter rs10814325 inheriting at least one C allele had a 1.85-fold [95% confidence interval (CI), 1.03–3.36] risk of developing HCC compared to TT wild type carriers. The HCC patients, who carried rs11788747 with at least one G allele, had a higher distant metastasis risk than wild type probands. Conclusions RECK gene polymorphisms might be a risk factor increasing HCC susceptibility and distant metastasis in Taiwan. PMID:22428065

  19. Search of type 2 diabetes susceptibility gene on chromosome 20q

    SciTech Connect

    Takeuchi, F.; Yanai, K.; Inomata, H.; Kuzuya, N.; Kajio, H.; Honjo, S.; Takeda, N.; Kaburagi, Y.; Yasuda, K.; Shirasawa, S.; Sasazuki, T.; Kato, N. . E-mail: nokato@ri.imcj.go.jp

    2007-06-15

    Significant evidence of linkage to type 2 diabetes (T2D) has been shown in a relatively broad region on chromosome 20q, where the hepatocyte nuclear factor-4{alpha} (HNF4A) has been noted as a positional candidate. To systematically evaluate genetic susceptibility to T2D in the relevant region, we examined the disease association by using 1145 SNPs in two-step screening in the Japanese population. The marker screening enabled us to identify significant disease association in the lipopolysaccharide binding protein (LBP) but not in the HNF4A locus. In a 17.7-Mb interval screened, the strongest association was identified for a SNP, rs2232592, located in the intron of LBP, with an estimated odds ratio of 1.73 (95% CI 1.30-2.31) (P 0.0002) in the whole study panel involving 675 case and 474 control subjects. Our data suggest that the LBP gene may confer genetic susceptibility to T2D and this warrants further replication study.

  20. Localization of a Susceptibility Gene for Common Forms of Stroke to 5q12

    PubMed Central

    Gretarsdottir, Solveig; Sveinbjörnsdottir, Sigurlaug; Jonsson, Hjörtur H.; Jakobsson, Finnbogi; Einarsdottir, Elisabet; Agnarsson, Uggi; Shkolny, Dana; Einarsson, Gisli; Gudjonsdottir, Herdis M.; Valdimarsson, Einar M.; Einarsson, Olafur B.; Thorgeirsson, Gudmundur; Hadzic, Radinka; Jonsdottir, Sif; Reynisdottir, Sigridur Th.; Bjarnadottir, Sigrun M.; Gudmundsdottir, Thorunn; Gudlaugsdottir, Gudrun J.; Gill, Ramanjit; Lindpaintner, Klaus; Sainz, Jesus; Hannesson, Helgi H.; Sigurdsson, Gunnar Th.; Frigge, Michael L.; Kong, Augustine; Gudnason, Vilmundur; Stefansson, Kari; Gulcher, Jeffrey R.

    2002-01-01

    Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40, P=3.9×10-6). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as “STRK1,” does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke. PMID:11833004

  1. Converging findings from linkage and association analyses on susceptibility genes for smoking and other addictions.

    PubMed

    Yang, J; Li, M D

    2016-08-01

    Experimental approaches to genetic studies of complex traits evolve with technological advances. How do discoveries using different approaches advance our knowledge of the genetic architecture underlying complex diseases/traits? Do most of the findings of newer techniques, such as genome-wide association study (GWAS), provide more information than older ones, for example, genome-wide linkage study? In this review, we address these issues by developing a nicotine dependence (ND) genetic susceptibility map based on the results obtained by the approaches commonly used in recent years, namely, genome-wide linkage, candidate gene association, GWAS and targeted sequencing. Converging and diverging results from these empirical approaches have elucidated a preliminary genetic architecture of this intractable psychiatric disorder and yielded new hypotheses on ND etiology. The insights we obtained by putting together results from diverse approaches can be applied to other complex diseases/traits. In sum, developing a genetic susceptibility map and keeping it updated are effective ways to keep track of what we know about a disease/trait and what the next steps may be with new approaches. PMID:27166759

  2. Correlations between the COMT gene rs4680 polymorphism and susceptibility to ovarian cancer.

    PubMed

    Pan, W; Liao, H

    2015-01-01

    The objective of this study was to perform a systematic review of the correlations between the single nucleotide polymorphism rs4680 in the catechol-O-methyltransferase (COMT) gene and susceptibility to ovarian cancer. A computer search was carried out for relevant case-control studies published between January 2000 to January 2014 in databases such as Ovid, EBSCO, PubMed, CNKI, CBMDISC, VIP, and WanFang Data. The literature was screened based on inclusion and exclusion criteria. A meta-analysis was performed by calculating the combined odds ratios (OR) and 95% confidence intervals (CI) using the RevMan 5.0. A total of 7 case-control studies were selected, which included 1439 cases and 2927 control subjects. Meta-analysis showed that the rs4680 polymorphism was not associated with ovarian cancer [GG vs (GA+AA): OR = 1.02, 95%CI = 0.88-1.19; G vs A allele: OR = 1.0, 95%CI = 0.90-1.11]. We, therefore, conclude that the COMT rs4680 polymorphism is not associated with susceptibility to ovarian cancer. PMID:26681027

  3. Identification of candidate MLO powdery mildew susceptibility genes in cultivated Solanaceae and functional characterization of tobacco NtMLO1.

    PubMed

    Appiano, Michela; Pavan, Stefano; Catalano, Domenico; Zheng, Zheng; Bracuto, Valentina; Lotti, Concetta; Visser, Richard G F; Ricciardi, Luigi; Bai, Yuling

    2015-10-01

    Specific homologs of the plant Mildew Locus O (MLO) gene family act as susceptibility factors towards the powdery mildew (PM) fungal disease, causing significant economic losses in agricultural settings. Thus, in order to obtain PM resistant phenotypes, a general breeding strategy has been proposed, based on the selective inactivation of MLO susceptibility genes across cultivated species. In this study, PCR-based methodologies were used in order to isolate MLO genes from cultivated solanaceous crops that are hosts for PM fungi, namely eggplant, potato and tobacco, which were named SmMLO1, StMLO1 and NtMLO1, respectively. Based on phylogenetic analysis and sequence alignment, these genes were predicted to be orthologs of tomato SlMLO1 and pepper CaMLO2, previously shown to be required for PM pathogenesis. Full-length sequence of the tobacco homolog NtMLO1 was used for a heterologous transgenic complementation assay, resulting in its characterization as a PM susceptibility gene. The same assay showed that a single nucleotide change in a mutated NtMLO1 allele leads to complete gene loss-of-function. Results here presented, also including a complete overview of the tobacco and potato MLO gene families, are valuable to study MLO gene evolution in Solanaceae and for molecular breeding approaches aimed at introducing PM resistance using strategies of reverse genetics. PMID:25947088

  4. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes

    PubMed Central

    Hu, Ying; Shukla, Anjali; Ha, Ngoc-Han; Doran, Anthony; Faraji, Farhoud; Goldberger, Natalie; Lee, Maxwell P.; Keane, Thomas

    2016-01-01

    Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease. PMID:27074153

  5. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes.

    PubMed

    Bai, Ling; Yang, Howard H; Hu, Ying; Shukla, Anjali; Ha, Ngoc-Han; Doran, Anthony; Faraji, Farhoud; Goldberger, Natalie; Lee, Maxwell P; Keane, Thomas; Hunter, Kent W

    2016-04-01

    Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease. PMID:27074153

  6. Multiple type 2 diabetes susceptibility genes following genome-wide association scan in UK samples

    PubMed Central

    Zeggini, Eleftheria; Weedon, Michael N.; Lindgren, Cecilia M.; Frayling, Timothy M.; Elliott, Katherine S.; Lango, Hana; Timpson, Nicholas J.; Perry, John R.B.; Rayner, Nigel W.; Freathy, Rachel M.; Barrett, Jeffrey C.; Shields, Beverley; Morris, Andrew P.; Ellard, Sian; Groves, Christopher J.; Harries, Lorna W.; Marchini, Jonathan L.; Owen, Katharine R.; Knight, Beatrice; Cardon, Lon R.; Walker, Mark; Hitman, Graham A.; Morris, Andrew D.; Doney, Alex S.F.; McCarthy, Mark I.; Hattersley, Andrew T.

    2013-01-01

    The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1,924 diabetic cases and 2,938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3,757 additional cases and 5,346 controls, and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insights into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes. PMID:17463249

  7. A breast-ovarian cancer susceptibility gene maps to chromosome 17q21

    SciTech Connect

    Feunteun, J. ); Narod, S.A.; Parboosingh, J. ); Lynch, H.T.; Watson, P.; Conway, T.; Lynch, J. ); O'Connell, P.; White, R. ); Lenoir, G.M. )

    1993-04-01

    Nineteen North American Caucasian families that contain a minimum of four confirmed cases of breast or ovarian cancer have been studied. Four polymorphisms (cLB17.1, D17S579, D17S588, and D17S74), which span a region of approximately 15 cM on chromosome 17q12, were typed. The data confirm the location of a dominant gene conferring susceptibility to breast and ovarian cancer (maximum lod = 9.78) and suggest that the breast-ovarian cancer syndrome is genetically heterogeneous. Two recombinants in one large family suggest that the breast-ovarian cancer locus lies between D17S588 and D17S579. 14 refs., 3 figs., 3 tabs.

  8. Rubeosis iridis in retinoblastoma and pseudoglioma.

    PubMed Central

    Spaulding, G

    1978-01-01

    The high incidence of rubeosis iridis accompanying retinoblastoma has been reaffired. Factor common to ocular tumors in general and retinoblastoma, as well as reactions to retioblastoma that have some contributory effect upon vascularization of the iris have been studied and complied. No single causative factor emerged, although tumor necrosis obviously played an important role. To a lesser extent, the site, location, and intraocular extension bore some relationship to neovascularization. That iris neovascularization carries a more grave prognosis, until now only a clinical impression, was definitely confirmed. Clinicians, therefore, studying patients with retinoblastoma would be well advised to pay more attention to the iris and anterior segment since recognition of changes leads to more timely and knowledgeable management. It was hoped that increased recognition of rubeosis would differentiate between eyes with retinoblastoma and those with pseudoglioma; however, an equally high incidence of neovascularization accompanied certain pseudogliomas. In both studies, as is often the case, numerous interesting observations were made; several with clinical implications. Finally, a frequently associated glaucoma, suggested by the anterior segment histologic features, went urecognized and unrecorded in these patients. Images FIGURE 1 FIGURE 2 FIGURE 3 A FIGURE 3 B FIGURE 3 C FIGURE 4 FIGURE 5 A FIGURE 5 B and C FIGURE 6 A FIGURE 6 B FIGURE 6 C PMID:754383

  9. Retinoblastoma and Superior Verbal IQ Scores?

    ERIC Educational Resources Information Center

    Tobin, Michael; Hill, Eileen; Hill, John

    2010-01-01

    Experienced teachers have long asserted that children blind from retinoblastoma (Rb), a rare cancer of the eye, are of above average intelligence. To test this hypothesis, standardized verbal intelligence tests were administered to a sample of 85 children and adults, all diagnosed with the early infancy form of this condition. For 42 of the Rb…

  10. HLA non-class II genes may confer type I diabetes susceptibility in a Mapuche (Amerindian) affected family.

    PubMed

    Pérez-Bravo, Francisco; Martinez-Laso, Jorge; Martin-Villa, Jose M; Moscoso, Juan; Moreno, Almudena; Serrano-Vela, Juan I; Zamora, Jorge; Asenjo, Silvia; Gleisner, Andrea; Arnaiz-Villena, Antonio

    2006-01-01

    A rare case of type I diabetes is studied in an Amerindian (Mapuche) family from Chile, analyzing glutamic acid decarboxylase, islet-cell autoantibodies and human leukocyte antigen (HLA) genes. The affected sib is the only one that has one specific HLA haplotype combination that differs from the other sibs only in the HLA class I genes. It is concluded that HLA diabetes susceptibility factors may be placed outside the class II region or even that susceptibility factors do not exist in the HLA region in this Amerindian family. PMID:16473308

  11. Evaluation of voltage-dependent calcium channel γ gene families identified several novel potential susceptible genes to schizophrenia.

    PubMed

    Guan, Fanglin; Zhang, Tianxiao; Liu, Xinshe; Han, Wei; Lin, Huali; Li, Lu; Chen, Gang; Li, Tao

    2016-01-01

    Voltage-gated L-type calcium channels (VLCC) are distributed widely throughout the brain. Among the genes involved in schizophrenia (SCZ), genes encoding VLCC subunits have attracted widespread attention. Among the four subunits comprising the VLCC (α - 1, α -2/δ, β, and γ), the γ subunit that comprises an eight-member protein family is the least well understood. In our study, to further investigate the risk susceptibility by the γ subunit gene family to SCZ, we conducted a large-scale association study in Han Chinese individuals. The SNP rs17645023 located in the intergenic region of CACNG4 and CACNG5 was identified to be significantly associated with SCZ (OR = 0.856, P = 5.43 × 10(-5)). Similar results were obtained in the meta-analysis with the current SCZ PGC data (OR = 0.8853). We also identified a two-SNP haplotype (rs10420331-rs11084307, P = 1.4 × 10(-6)) covering the intronic region of CACNG8 to be significantly associated with SCZ. Epistasis analyses were conducted, and significant statistical interaction (OR = 0.622, P = 2.93 × 10(-6), Pperm < 0.001) was observed between rs192808 (CACNG6) and rs2048137 (CACNG5). Our results indicate that CACNG4, CACNG5, CACNG6 and CACNG8 may contribute to the risk of SCZ. The statistical epistasis identified between CACNG5 and CACNG6 suggests that there may be an underlying biological interaction between the two genes. PMID:27102562

  12. Evaluation of voltage-dependent calcium channel γ gene families identified several novel potential susceptible genes to schizophrenia

    PubMed Central

    Guan, Fanglin; Zhang, Tianxiao; Liu, Xinshe; Han, Wei; Lin, Huali; Li, Lu; Chen, Gang; Li, Tao

    2016-01-01

    Voltage-gated L-type calcium channels (VLCC) are distributed widely throughout the brain. Among the genes involved in schizophrenia (SCZ), genes encoding VLCC subunits have attracted widespread attention. Among the four subunits comprising the VLCC (α − 1, α −2/δ, β, and γ), the γ subunit that comprises an eight-member protein family is the least well understood. In our study, to further investigate the risk susceptibility by the γ subunit gene family to SCZ, we conducted a large-scale association study in Han Chinese individuals. The SNP rs17645023 located in the intergenic region of CACNG4 and CACNG5 was identified to be significantly associated with SCZ (OR = 0.856, P = 5.43 × 10−5). Similar results were obtained in the meta-analysis with the current SCZ PGC data (OR = 0.8853). We also identified a two-SNP haplotype (rs10420331-rs11084307, P = 1.4 × 10−6) covering the intronic region of CACNG8 to be significantly associated with SCZ. Epistasis analyses were conducted, and significant statistical interaction (OR = 0.622, P = 2.93 × 10−6, Pperm < 0.001) was observed between rs192808 (CACNG6) and rs2048137 (CACNG5). Our results indicate that CACNG4, CACNG5, CACNG6 and CACNG8 may contribute to the risk of SCZ. The statistical epistasis identified between CACNG5 and CACNG6 suggests that there may be an underlying biological interaction between the two genes. PMID:27102562

  13. No Significant Effect of ASAP1 Gene Variants on the Susceptibility to Tuberculosis in Chinese Population

    PubMed Central

    Hu, Xuejiao; Peng, Wu; Chen, Xuerong; Zhao, Zhenzhen; Zhang, Jingya; Zhou, Juan; Cai, Bei; Chen, Jie; Zhou, Yanhong; Lu, Xiaojun; Ying, Binwu

    2016-01-01

    Abstract Recent studies have proposed that the ASAP1 gene participates in regulating the adaptive immune response to Mycobacterium tuberculosis infection. A GWAS study has reported that ASAP1 polymorphisms (rs4733781 and rs10956514) were associated with the risk of tuberculosis (TB) in Russians. But due to population heterogeneity, different races would have different causative polymorphisms, and the aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) of the ASAP1 gene and TB risk in Chinese population. A total of 7 SNPs in the ASAP1 gene were genotyped in 1115 Western Chinese Han and 914 Tibetan population using an improved multiplex ligation detection reaction (iMLDR) method. The associations of SNPs with TB risk and clinical phenotypes were determined based on the distributions of allelic frequencies and different genetic models. A meta-analysis was carried out to further assess the relationship between ASAP1 polymorphism and TB risk. Statistical comparisons of cases and controls after correction for multiple testing did not yield any significant associations with the risk of TB via analyses of a single locus, haplotype, and subgroup differences. Meta-analysis showed no evidence supporting association between rs10956514 and overall risk for TB. Subsequent analysis referring to the genotypes of SNPs in relationship to clinical phenotypes identified that rs4236749 was associated with different serum C-reactive protein levels, suggesting a role of this locus in influencing the inflammatory state of Western Chinese Han patients with TB. Our present data revealed that ASAP1 polymorphisms are unlikely to confer susceptibility to TB in the Western Chinese Han and Tibetan populations, which challenges the promising roles of the ASAP1 gene in the development of TB and highlights the importance of validating the association findings across ethnicities. PMID:27227929

  14. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility.

    PubMed

    Barton, Anne; Thomson, Wendy; Ke, Xiayi; Eyre, Steve; Hinks, Anne; Bowes, John; Gibbons, Laura; Plant, Darren; Wilson, Anthony G; Marinou, Ioanna; Morgan, Ann; Emery, Paul; Steer, Sophia; Hocking, Lynne; Reid, David M; Wordsworth, Paul; Harrison, Pille; Worthington, Jane

    2008-08-01

    Rheumatoid arthritis (RA) is an archetypal, common, complex autoimmune disease with both genetic and environmental contributions to disease aetiology. Two novel RA susceptibility loci have been reported from recent genome-wide and candidate gene association studies. We, therefore, investigated the evidence for association of the STAT4 and TRAF1/C5 loci with RA using imputed data from the Wellcome Trust Case Control Consortium (WTCCC). No evidence for association of variants mapping to the TRAF1/C5 gene was detected in the 1860 RA cases and 2930 control samples tested in that study. Variants mapping to the STAT4 gene did show evidence for association (rs7574865, P = 0.04). Given the association of the TRAF1/C5 locus in two previous large case-control series from populations of European descent and the evidence for association of the STAT4 locus in the WTCCC study, single nucleotide polymorphisms mapping to these loci were tested for association with RA in an independent UK series comprising DNA from >3000 cases with disease and >3000 controls and a combined analysis including the WTCCC data was undertaken. We confirm association of the STAT4 and the TRAF1/C5 loci with RA bringing to 5 the number of confirmed susceptibility loci. The effect sizes are less than those reported previously but are likely to be a more accurate reflection of the true effect size given the larger size of the cohort investigated in the current study. PMID:18434327

  15. Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders.

    PubMed

    Xing, Jingrui; Kimura, Hiroki; Wang, Chenyao; Ishizuka, Kanako; Kushima, Itaru; Arioka, Yuko; Yoshimi, Akira; Nakamura, Yukako; Shiino, Tomoko; Oya-Ito, Tomoko; Takasaki, Yuto; Uno, Yota; Okada, Takashi; Iidaka, Tetsuya; Aleksic, Branko; Mori, Daisuke; Ozaki, Norio

    2016-01-01

    PSD-95 associated PSD proteins play a critical role in regulating the density and activity of glutamate receptors. Numerous previous studies have shown an association between the genes that encode these proteins and schizophrenia (SZ) and autism spectrum disorders (ASD), which share a substantial portion of genetic risks. We sequenced the protein-encoding regions of DLG1, DLG2, DLG4, DLGAP1, DLGAP2, and SynGAP in 562 cases (370 SZ and 192 ASD patients) on the Ion PGM platform. We detected 26 rare (minor allele frequency <1%), non-synonymous mutations, and conducted silico functional analysis and pedigree analysis when possible. Three variants, G344R in DLG1, G241S in DLG4, and R604C in DLGAP2, were selected for association analysis in an independent sample set of 1315 SZ patients, 382 ASD patients, and 1793 healthy controls. Neither DLG4-G241S nor DLGAP2-R604C was detected in any samples in case or control sets, whereas one additional SZ patient was found that carried DLG1-G344R. Our results suggest that rare missense mutations in the candidate PSD genes may increase susceptibility to SZ and/or ASD. These findings may strengthen the theory that rare, non-synonymous variants confer substantial genetic risks for these disorders. PMID:27271353

  16. Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders

    PubMed Central

    Xing, Jingrui; Kimura, Hiroki; Wang, Chenyao; Ishizuka, Kanako; Kushima, Itaru; Arioka, Yuko; Yoshimi, Akira; Nakamura, Yukako; Shiino, Tomoko; Oya-Ito, Tomoko; Takasaki, Yuto; Uno, Yota; Okada, Takashi; Iidaka, Tetsuya; Aleksic, Branko; Mori, Daisuke; Ozaki, Norio

    2016-01-01

    PSD-95 associated PSD proteins play a critical role in regulating the density and activity of glutamate receptors. Numerous previous studies have shown an association between the genes that encode these proteins and schizophrenia (SZ) and autism spectrum disorders (ASD), which share a substantial portion of genetic risks. We sequenced the protein-encoding regions of DLG1, DLG2, DLG4, DLGAP1, DLGAP2, and SynGAP in 562 cases (370 SZ and 192 ASD patients) on the Ion PGM platform. We detected 26 rare (minor allele frequency <1%), non-synonymous mutations, and conducted silico functional analysis and pedigree analysis when possible. Three variants, G344R in DLG1, G241S in DLG4, and R604C in DLGAP2, were selected for association analysis in an independent sample set of 1315 SZ patients, 382 ASD patients, and 1793 healthy controls. Neither DLG4-G241S nor DLGAP2-R604C was detected in any samples in case or control sets, whereas one additional SZ patient was found that carried DLG1-G344R. Our results suggest that rare missense mutations in the candidate PSD genes may increase susceptibility to SZ and/or ASD. These findings may strengthen the theory that rare, non-synonymous variants confer substantial genetic risks for these disorders. PMID:27271353

  17. The multiple sclerosis susceptibility genes TAGAP and IL2RA are regulated by vitamin D in CD4+ T cells.

    PubMed

    Berge, T; Leikfoss, I S; Brorson, I S; Bos, S D; Page, C M; Gustavsen, M W; Bjølgerud, A; Holmøy, T; Celius, E G; Damoiseaux, J; Smolders, J; Harbo, H F; Spurkland, A

    2016-03-01

    Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals. The majority of the MS-associated gene variants are located in genetic regions with importance for T-cell differentiation. Vitamin D is a potent immunomodulator, and vitamin D deficiency has been suggested to be associated with increased MS disease susceptibility and activity. In CD4+ T cells, we have analyzed in vitro vitamin D responsiveness of genes that contain an MS-associated single-nucleotide polymorphism (SNP) and with one or more vitamin D response elements in their regulatory regions. We identify IL2RA and TAGAP as novel vitamin D target genes. The vitamin D response is observed in samples from both MS patients and controls, and is not dependent on the genotype of MS-associated SNPs in the respective genes. PMID:26765264

  18. The multiple sclerosis susceptibility genes TAGAP and IL2RA are regulated by vitamin D in CD4+ T cells

    PubMed Central

    Berge, T; Leikfoss, I S; Brorson, I S; Bos, S D; Page, C M; Gustavsen, M W; Bjølgerud, A; Holmøy, T; Celius, E G; Damoiseaux, J; Smolders, J; Harbo, H F; Spurkland, A

    2016-01-01

    Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals. The majority of the MS-associated gene variants are located in genetic regions with importance for T-cell differentiation. Vitamin D is a potent immunomodulator, and vitamin D deficiency has been suggested to be associated with increased MS disease susceptibility and activity. In CD4+ T cells, we have analyzed in vitro vitamin D responsiveness of genes that contain an MS-associated single-nucleotide polymorphism (SNP) and with one or more vitamin D response elements in their regulatory regions. We identify IL2RA and TAGAP as novel vitamin D target genes. The vitamin D response is observed in samples from both MS patients and controls, and is not dependent on the genotype of MS-associated SNPs in the respective genes. PMID:26765264

  19. Phenotypic antimicrobial susceptibility and occurrence of selected resistance genes in gram-positive mastitis pathogens isolated from Wisconsin dairy cows.

    PubMed

    Ruegg, P L; Oliveira, L; Jin, W; Okwumabua, O

    2015-07-01

    In the United States, few intramammary antimicrobials exist that are approved for treatment of bovine mastitis; thus, ensuring judicious use of these products is a priority. The objectives of this study were to determine phenotypic susceptibility and presence of selected antimicrobial resistance genes from staphylococci, streptococci, and streptococcal-like organisms recovered from cases of clinical mastitis occurring in cows on large Wisconsin farms. Staphylococcus aureus (n=35 from 19 herds), coagulase-negative staphylococci (n=51 from 30 herds), Streptococcus spp. (n=78 from 36 herds), and streptococcal-like organisms (n=31 from 19 herds) were used in this study. All Staphylococcus spp. were susceptible to ceftiofur, cephalothin, and the combination of penicillin and novobiocin. Of all staphylococci, only a single Staphylococcus epidermidis exhibited phenotypic resistance to oxacillin. Phenotypic susceptibility to erythromycin was observed in only 8.6 and 15.7% of Staphylococcus aureus and coagulase-negative staphylococci, respectively. Approximately 20% of staphylococci and 13 to 22% of streptococci and streptococcal-like organisms exhibited phenotypic resistance to pirlimycin. All Streptococcus spp. exhibited phenotypic susceptibility to ceftiofur, cephalothin, and oxacillin. The proportion of isolates exhibiting phenotypic susceptibility to pirlimycin and sulfadimethoxine differed among Streptococcus dysgalactiae and Streptococcus uberis. All streptococcal-like organisms exhibited phenotypic susceptibility to ceftiofur, cephalothin, oxacillin, penicillin, and the combination of penicillin and novobiocin. Of all organisms tested, 36.9% did not carry any of the resistance genes (ermC, blaZ, tetK, or tetM), 35.4% carried 1 gene, and 27.7% carried multiple genes (usually blaZ in combination with a tet gene). Eighteen (51.4%) Staph. aureus and 12 (48.0%) Staphylococcus chromogenes carried multiple resistance genes. Six (12.2%) Strep. dysgalactiae and no Strep

  20. FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

    PubMed Central

    Agarwal, D; Pineda, S; Michailidou, K; Herranz, J; Pita, G; Moreno, L T; Alonso, M R; Dennis, J; Wang, Q; Bolla, M K; Meyer, K B; Menéndez-Rodríguez, P; Hardisson, D; Mendiola, M; González-Neira, A; Lindblom, A; Margolin, S; Swerdlow, A; Ashworth, A; Orr, N; Jones, M; Matsuo, K; Ito, H; Iwata, H; Kondo, N; Hartman, M; Hui, M; Lim, W Y; T-C Iau, P; Sawyer, E; Tomlinson, I; Kerin, M; Miller, N; Kang, D; Choi, J-Y; Park, S K; Noh, D-Y; Hopper, J L; Schmidt, D F; Makalic, E; Southey, M C; Teo, S H; Yip, C H; Sivanandan, K; Tay, W-T; Brauch, H; Brüning, T; Hamann, U; Dunning, A M; Shah, M; Andrulis, I L; Knight, J A; Glendon, G; Tchatchou, S; Schmidt, M K; Broeks, A; Rosenberg, E H; van't Veer, L J; Fasching, P A; Renner, S P; Ekici, A B; Beckmann, M W; Shen, C-Y; Hsiung, C-N; Yu, J-C; Hou, M-F; Blot, W; Cai, Q; Wu, A H; Tseng, C-C; Van Den Berg, D; Stram, D O; Cox, A; Brock, I W; Reed, M W R; Muir, K; Lophatananon, A; Stewart-Brown, S; Siriwanarangsan, P; Zheng, W; Deming-Halverson, S; Shrubsole, M J; Long, J; Shu, X-O; Lu, W; Gao, Y-T; Zhang, B; Radice, P; Peterlongo, P; Manoukian, S; Mariette, F; Sangrajrang, S; McKay, J; Couch, F J; Toland, A E; Yannoukakos, D; Fletcher, O; Johnson, N; Silva, I dos Santos; Peto, J; Marme, F; Burwinkel, B; Guénel, P; Truong, T; Sanchez, M; Mulot, C; Bojesen, S E; Nordestgaard, B G; Flyer, H; Brenner, H; Dieffenbach, A K; Arndt, V; Stegmaier, C; Mannermaa, A; Kataja, V; Kosma, V-M; Hartikainen, J M; Lambrechts, D; Yesilyurt, B T; Floris, G; Leunen, K; Chang-Claude, J; Rudolph, A; Seibold, P; Flesch-Janys, D; Wang, X; Olson, J E; Vachon, C; Purrington, K; Giles, G G; Severi, G; Baglietto, L; Haiman, C A; Henderson, B E; Schumacher, F; Le Marchand, L; Simard, J; Dumont, M; Goldberg, M S; Labrèche, F; Winqvist, R; Pylkäs, K; Jukkola-Vuorinen, A; Grip, M; Devilee, P; Tollenaar, R A E M; Seynaeve, C; García-Closas, M; Chanock, S J; Lissowska, J; Figueroa, J D; Czene, K; Eriksson, M; Humphreys, K; Darabi, H; Hooning, M J; Kriege, M; Collée, J M; Tilanus-Linthorst, M; Li, J; Jakubowska, A; Lubinski, J; Jaworska-Bieniek, K; Durda, K; Nevanlinna, H; Muranen, T A; Aittomäki, K; Blomqvist, C; Bogdanova, N; Dörk, T; Hall, P; Chenevix-Trench, G; Easton, D F; Pharoah, P D P; Arias-Perez, J I; Zamora, P; Benítez, J; Milne, R L

    2014-01-01

    Background: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02–1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. PMID:24548884

  1. A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene

    PubMed Central

    Ding, Yonghe; Long, Pamela A.; Bos, J. Martijn; Shih, Yu-Huan; Ma, Xiao; Sundsbak, Rhianna S.; Chen, Jianhua; Jiang, Yiwen; Zhao, Liqun; Hu, Xinyang; Wang, Jianan; Shi, Yongyong; Ackerman, Michael J.; Lin, Xueying; Ekker, Stephen C.; Redfield, Margaret M.; Olson, Timothy M.; Xu, Xiaolei

    2016-01-01

    Mutagenesis screening is a powerful forward genetic approach that has been successfully applied in lower-model organisms to discover genetic factors for biological processes. This phenotype-based approach has yet to be established in vertebrates for probing major human diseases, largely because of the complexity of colony management. Herein, we report a rapid strategy for identifying genetic modifiers of cardiomyopathy (CM). Based on the application of doxorubicin stress to zebrafish insertional cardiac (ZIC) mutants, we identified 4 candidate CM-modifying genes, of which 3 have been linked previously to CM. The long isoform of DnaJ (Hsp40) homolog, subfamily B, member 6b (dnajb6b(L)) was identified as a CM susceptibility gene, supported by identification of rare variants in its human ortholog DNAJB6 from CM patients. Mechanistic studies indicated that the deleterious, loss-of-function modifying effects of dnajb6b(L) can be ameliorated by inhibition of ER stress. In contrast, overexpression of dnajb6(L) exerts cardioprotective effects on both fish and mouse CM models. Together, our findings establish a mutagenesis screening strategy that is scalable for systematic identification of genetic modifiers of CM, feasible to suggest therapeutic targets, and expandable to other major human diseases.

  2. Impact of ESR1 Gene Polymorphisms on Migraine Susceptibility: A Meta-Analysis.

    PubMed

    Li, Li; Liu, Ruozhuo; Dong, Zhao; Wang, Xiaolin; Yu, Shengyuan

    2015-09-01

    An increasing number of studies have explored genetic associations between the functionally important polymorphisms in estrogen receptor 1 (ESR1) gene and migraine susceptibility. The previously reported associations have nevertheless been inconsistent.The present work incorporating the published data derived from 8 publications was performed to assess the impact of these polymorphisms on incident migraine. Strength of the genetic risk was estimated by means of an odds ratio along with the 95% confidence interval (OR and 95% CI).From the results, we found individuals who harbored the 325-GG genotype, compared with those harboring the CC genotype or CG and CC combined genotypes, had almost 50% greater risk of migraine. The same genetic models showed notable associations in subgroups of Caucasians and migraine with aura (MA). For 594G>A, a moderately increased risk of migraine was seen under AG versus GG. The AA + AG versus GG model, however, showed a borderline association with migraine. Subgroup analyses according to ethnicity and subtype of migraine provided statistical evidence of significantly increased risk of migraine in Caucasians and of a marginal association with MA, respectively. Both 325C>G and 594G>A polymorphisms showed no major effects either in males or in females.Based on the statistical data, we conclude some of the ESR1 gene polymorphisms may have major contributions to the pathogenesis of migraine in Caucasian populations. PMID:26334887

  3. Dogs and Humans Share a Common Susceptibility Gene SRBD1 for Glaucoma Risk

    PubMed Central

    Kanemaki, Nobuyuki; Tchedre, Kissaou T.; Imayasu, Masaki; Kawarai, Shinpei; Sakaguchi, Masahiro; Yoshino, Atsushi; Itoh, Norihiko; Meguro, Akira; Mizuki, Nobuhisa

    2013-01-01

    Glaucoma is a degenerative optic neuropathy that is associated with elevated intraocular pressure. Primary open angle glaucoma is the most common type of glaucoma in canines, and its highest incidence among dog breeds has been reported in Shiba-Inus, followed by Shih-Tzus. These breeds are known to have an abnormal iridocorneal angle and dysplastic prectinate ligament. However, the hereditary and genetic backgrounds of these dogs have not yet been clarified. In this study, we investigated the association between polymorphisms of the glaucoma candidate genes, SRBD1, ELOVL5, and ADAMTS10, and glaucoma in Shiba-Inus and Shih-Tzus. We analyzed 11 polymorphisms in these three genes using direct DNA sequencing. Three SRBD1 SNPs, rs8655283, rs22018514 and rs22018513 were significantly associated with glaucoma in Shiba-Inus, while rs22018513, a synonymous SNP in exon 4, showed the strongest association (P = 0.00039, OR = 3.03). Conditional analysis revealed that rs22018513 could account for most of the association of these SNPs with glaucoma in Shiba-Inus. In Shih-Tzus, only rs9172407 in the SRBD1 intron 1 was significantly associated with glaucoma (P = 0.0014, OR = 5.25). There were no significant associations between the ELOVL5 or ADAMTS10 polymorphisms and glaucoma in Shiba-Inus and Shih-Tzus. The results showed that SRBD1 polymorphisms play an important role in glaucoma pathology in both Shiba-Inus and Shih-Tzus. SRBD1 polymorphisms have also been associated with normal- and high-tension glaucomas in humans. Therefore, SRBD1 may be a common susceptibility gene for glaucoma in humans and dogs. We anticipate that the nucleotide sequencing data from this study can be used in genetic testing to determine for the first time, the genetic status and susceptibility of glaucoma in dogs, with high precision. Moreover, canine glaucoma resulting from SRBD1 polymorphisms could be a useful animal model to study human glaucoma. PMID:24040232

  4. Circadian Gene Variants and Susceptibility to Type 2 Diabetes: A Pilot Study

    PubMed Central

    Kelly, M. Ann; Rees, Simon D.; Hydrie, M. Zafar I.; Shera, A. Samad; Bellary, Srikanth; O’Hare, J. Paul; Kumar, Sudhesh; Taheri, Shahrad; Basit, Abdul; Barnett, Anthony H.

    2012-01-01

    Background Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs) in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants. Methodology/Principal Findings The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732) and without (N = 1780) type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium) and white European cohorts (DIAGRAM+) using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66–0.86], p = 3.18×10−5), while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07–1.39], p = 0.003). Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01–1.08], p = 0.008 and OR = 0.95 [0.91–0.99], p = 0.015 respectively). Conclusions/significance None of the selected circadian gene

  5. Simulated microgravity affects ciprofloxacin susceptibility and expression of acrAB-tolC genes in E. coli ATCC25922.

    PubMed

    Xu, Bingxin; Li, Chenglin; Zheng, Yanhua; Si, Shaoyan; Shi, Yuhua; Huang, Yuling; Zhang, Jianzhong; Cui, Yan; Cui, Yimin

    2015-01-01

    As a representative fluoroquinolone antibacterial, ciprofloxacin is frequently used to treat infections caused by bacteria such as E. coli. It is much meaningful to explore ciprofloxacin susceptibility and investigate a possible mechanism of drug susceptibility changes in E. coli ATCC25922 exposed to the environmental stress of simulated microgravity. The subculture of E. coli lasted for 7 days under simulated microgravity conditions (SMG) and normal microgravity (NG) conditions. On the 8th day, the cultures were divided into three groups: (1) NG group (continuous NG cultures); (2) SMG group (continuous SMG cultures); (3) SMCNG group (simulated microgravity change into normal gravity cultures). Ciprofloxacin (a final concentration of 0.125 μg/ml) sensitivity and expression of acrAB-tolC genes were detected in E. coli cells. The count and percentage of viable cells in the SMG cultures bacteria exposed to ciprofloxacin were higher than that in NG cultures and reduced to the levels of NG group when they were subcultivated from SMG to NG. The expressions of efflux pump genes (acrA, acrB and tolC) were upregulated in SMG culture and downregulated to the levels of NG group when they were subcultivated from SMG to NG. Susceptibility to ciprofloxacin and expression of acrAB-tolC genes in E. coli could be reversibly affected by SMG conditions. Over expression of efflux pump genes acrAB-tolC perhaps played an important role in decreased CIP susceptibility under SMG. PMID:26339360

  6. Presence of the KPC carbapenemase gene in Enterobacteriaceae causing bacteremia, and the correlation with in vitro carbapenem susceptibility

    Technology Transfer Automated Retrieval System (TEKTRAN)

    During six months, we obtained Enterobacteriaceae isolates from patients with Gram-negative bacteremia at a 1250-bed teaching hospital in St. Louis, Missouri, and compared carbapenem susceptibility with the presence of blaKPC, a transferable carbapenemase gene. Three (1.2%) out of 243 isolates were ...

  7. cDNA microarray analysis of gene expression in insecticide-susceptible and –resistant Tarnished Plant bug

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insecticide resistance in the tarnished plant bug is most likely associated with increased detoxification gene expression. To better understand the molecular mechanisms of insecticide resistance, an insecticide-susceptible laboratory colony and several resistant field-collected strains of Lygus line...

  8. Simulated microgravity affects ciprofloxacin susceptibility and expression of acrAB-tolC genes in E. coli ATCC25922

    PubMed Central

    Xu, Bingxin; Li, Chenglin; Zheng, Yanhua; Si, Shaoyan; Shi, Yuhua; Huang, Yuling; Zhang, Jianzhong; Cui, Yan; Cui, Yimin

    2015-01-01

    As a representative fluoroquinolone antibacterial, ciprofloxacin is frequently used to treat infections caused by bacteria such as E. coli. It is much meaningful to explore ciprofloxacin susceptibility and investigate a possible mechanism of drug susceptibility changes in E. coli ATCC25922 exposed to the environmental stress of simulated microgravity. The subculture of E. coli lasted for 7 days under simulated microgravity conditions (SMG) and normal microgravity (NG) conditions. On the 8th day, the cultures were divided into three groups: (1) NG group (continuous NG cultures); (2) SMG group (continuous SMG cultures); (3) SMCNG group (simulated microgravity change into normal gravity cultures). Ciprofloxacin (a final concentration of 0.125 μg/ml) sensitivity and expression of acrAB-tolC genes were detected in E. coli cells. The count and percentage of viable cells in the SMG cultures bacteria exposed to ciprofloxacin were higher than that in NG cultures and reduced to the levels of NG group when they were subcultivated from SMG to NG. The expressions of efflux pump genes (acrA, acrB and tolC) were upregulated in SMG culture and downregulated to the levels of NG group when they were subcultivated from SMG to NG. Susceptibility to ciprofloxacin and expression of acrAB-tolC genes in E. coli could be reversibly affected by SMG conditions. Over expression of efflux pump genes acrAB-tolC perhaps played an important role in decreased CIP susceptibility under SMG. PMID:26339360

  9. Identification of susceptibility genes in non-syndromic cleft lip with or without cleft palate using whole-exome sequencing

    PubMed Central

    Liu, Ya-Peng; Xu, Li-Fang; Wang, Qi; Zhou, Xiao-Long; Zhou, Ji-Long; Pan, Chen; Zhang, Jin-Peng; Wu, Qin-Rong; Li, Yi-Qun; Xia, Yu-Juan; Peng, Xiu; Zhang, Mei-Rong; Yu, Hong-Min

    2015-01-01

    Background Non-syndromic cleft lip with or without cleft palate (NSCL/P) is among the most common congenital malformations. The etiology of NSCL/P remains poorly characterized owing to its complex genetic heterogeneity. The objective of this study was to identify genetic variants that increase susceptibility to NSCL/P. Material and Methods Whole-exome sequencing (WES) was performed in 8 fetuses with NSCL/P in China. Bioinformatics analysis was performed using commercially available software. Variants detected by WES were validated by Sanger sequencing. Results By filtering out synonymous variants in exons, we identified average 8575 nonsynonymous single nucleotide variants (SNVs). We subsequently compared the SNVs against public databases including NCBI dbSNP build 135 and 1000 Genomes Project and obtained an average of 203 SNVs. Total 12 reported candidate genes were verified by Sanger sequencing. Sanger sequencing also confirmed 16 novel SNVs shared by two or more samples. Conclusions We have found and confirmed 16 susceptibility genes responsible for NSCL/P, which may play important role in the etiology of NSCL/P. The susceptibility genes identified in this study will not only be useful in revealing the etiology of NSCL/P but also in diagnosis and treatment of the patients with NSCL/P. Key words:Non-syndromic cleft lip with or without cleft palate, whole-exome sequencing, sanger sequencing, susceptibility gene, single nucleotide variants (SNVs). PMID:26449438

  10. Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene.

    PubMed

    Luo, X-J; Li, M; Huang, L; Steinberg, S; Mattheisen, M; Liang, G; Donohoe, G; Shi, Y; Chen, C; Yue, W; Alkelai, A; Lerer, B; Li, Z; Yi, Q; Rietschel, M; Cichon, S; Collier, D A; Tosato, S; Suvisaari, J; Rujescu, Dan; Golimbet, V; Silagadze, T; Durmishi, N; Milovancevic, M P; Stefansson, H; Schulze, T G; Nöthen, M M; Chen, C; Lyne, R; Morris, D W; Gill, M; Corvin, A; Zhang, D; Dong, Q; Moyzis, R K; Stefansson, K; Sigurdsson, E; Hu, F; Su, B; Gan, L

    2014-07-01

    Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility. PMID:23958956

  11. CETP/LPL/LIPC gene polymorphisms and susceptibility to age-related macular degeneration

    PubMed Central

    Wang, Ya-Feng; Han, Yue; Zhang, Rui; Qin, Li; Wang, Ming-Xu; Ma, Le

    2015-01-01

    Three high-density lipoprotein (HDL)-related loci have been reported to be associated with age-related macular degeneration (AMD), but the results were inconsistent. In this study, the cholesteryl ester transfer protein (CETP) rs3764261 variant was significantly associated with an increased risk of AMD (odds ratio [OR] = 1.13, 95% confidence interval [CI]: 1.05–1.21, P < 0.001), and the hepatic lipase (LIPC) rs10468017 variant was associated with a significantly decreased risk of AMD (OR = 0.81, CI: 0.76–0.86, P < 0.001). Individuals carrying the lipoprotein lipase (LPL) rs12678919 polymorphism (A → G) had no significant change in the risk of developing AMD (OR = 1.01, CI: 0.92–1.10, P = 0.17). After adjusting for the complement factor H (CFH) gene, both CETP and LPL conferred a significantly increased AMD risk (ORCETP = 1.17, CI: 1.08–1.26, P < 0.001; ORLPL = 1.11, CI: 1.01–1.22, P = 0.02). Subgroup analysis based on ethnicity revealed a significant association between the CETP variant and AMD in both Americans (OR = 1.12, CI: 1.02–1.23, P = 0.01) and Europeans (OR = 1.10, CI: 1.01–1.19, P = 0.011). This meta-analysis revealed that both CETP rs3764261 and LIPC rs10468017 polymorphisms were significantly associated with AMD risk. After adjustment for the CFH gene, CETP/LPL conferred a significantly increased susceptibility to the disease, indicating potential interactions among genes in the complement system and the lipid metabolism pathway. PMID:26503844

  12. Association of the FCN2 Gene Single Nucleotide Polymorphisms with Susceptibility to Pulmonary Tuberculosis

    PubMed Central

    Jiang, Feng; Wei, Li-Liang; Shi, Li-Ying; Yu, Xiao-Mei; Liu, Chang-Ming; Liu, Xue-Hong; Feng, Xian-Min; Ping, Ze-Peng; Jiang, Ting-Ting; Chen, Zhong-Liang; Li, Zhong-Jie; Li, Ji-Cheng

    2015-01-01

    Ficolin-2 (FCN2) is an innate immune pattern recognition molecule that can activate the complement pathway, opsonophagocytosis, and elimination of the pathogens. The present study aimed to investigate the association of the FCN2 gene single nucleotide polymorphisms (SNPs) with susceptibility to pulmonary tuberculosis (TB). A total of seven SNPs in exon 8 (+6359 C>T and +6424 G>T) and in the promoter region (-986 G>A, -602 G>A, -557 A>G, -64 A>C and -4 A>G) of the FCN2 gene were genotyped using the PCR amplification and DNA sequencing methods in the healthy controls group (n = 254) and the pulmonary TB group (n = 282). The correlation between SNPs and pulmonary TB was analyzed using the logistic regression method. The results showed that there were no significant differences in the distribution of allelic frequencies of seven SNPs between the pulmonary TB group and the healthy controls group. However, the frequency of the variant homozygous genotype (P = 0.037, -557 A>G; P = 0.038, -64 A>C; P = 0.024, +6424 G>T) in the TB group was significantly lower than the control group. After adjustment for age and gender, these variant homozygous genotypes were found to be recessive models in association with pulmonary TB. In addition, -64 A>C (P = 0.047) and +6424 G>T (P = 0.03) were found to be codominant models in association with pulmonary TB. There was strong linkage disequilibrium (r2 > 0.80, P < 0.0001) between 7 SNPs except the -602 G>A site. Therefore, -557 A>G, -64 A>C and +6424 G>T SNPs of the FCN2 gene were correlated with pulmonary TB, and may be protective factors for TB. This study provides a novel idea for the prevention and control of TB transmission from a genetics perspective. PMID:26379154

  13. Association between ERAP1 gene polymorphisms and ankylosing spondylitis susceptibility in Han population

    PubMed Central

    Wang, Jian; Li, Hang; Wang, Jianwei; Gao, Xiang

    2015-01-01

    Purposes: The present study was designed to investigate the relationship between endoplasmic reticulum amino peptidase 1 (ERAP1) gene polymorphisms and ankylosing spondylitis (AS) in Han population of Shaanxi province. Methods: 100 AS patients and 100 healthy people were enrolled in present study as case and control groups respectively, and the control group was matched with the case group by age and gender. ERAP1 gene rs27434 and rs7711564 polymorphisms were test by TaqMan probe genotyping method. SHEsis software was used to operate linkage disequilibrium (LD) and haplotype analysis between the two single nucleotide polymorphisms (SNPs). χ2 test was employed to compare the differences of the genotype, allele and haplotype frequencies between the case and control groups. Relative risk of AS was represented by odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: In ERAP1 rs27434 and rs7711564 polymorphisms, the frequencies of AA and CC genotypes in case group were significantly higher compared to those in control group (P=0.036; P=0.039), and so were the frequencies of A and C alleles (OR=1.589, 95% CI=1.070-2.359, P=0.028; OR=1.535, 95% CI=1.021-2.308, P=0.050). Linkage disequilibrium test and haplotype analysis of the alleles of the two SNPs showed that the frequency of A-C haplotype was higher in case group than that in control group (P=0.005), which indicated that A-C might be the susceptible haplotype to AS. Conclusions: ERAP1 gene rs27434 and rs7711564 polymorphisms may increase the risk of AS. PMID:26617903

  14. Association of Environmental Arsenic Exposure, Genetic Polymorphisms of Susceptible Genes, and Skin Cancers in Taiwan

    PubMed Central

    Hsu, Ling-I; Wu, Meei-Maan; Wang, Yuan-Hung; Lee, Cheng-Yeh; Yang, Tse-Yen; Hsiao, Bo-Yu; Chen, Chien-Jen

    2015-01-01

    Deficiency in the capability of xenobiotic detoxification and arsenic methylation may be correlated with individual susceptibility to arsenic-related skin cancers. We hypothesized that glutathione S-transferase (GST M1, T1, and P1), reactive oxygen species (ROS) related metabolic genes (NQO1, EPHX1, and HO-1), and DNA repair genes (XRCC1, XPD, hOGG1, and ATM) together may play a role in arsenic-induced skin carcinogenesis. We conducted a case-control study consisting of 70 pathologically confirmed skin cancer patients and 210 age and gender matched participants with genotyping of 12 selected polymorphisms. The skin cancer risks were estimated by odds ratio (OR) and 95% confidence interval (CI) using logistic regression. EPHX1 Tyr113His, XPD C156A, and GSTT1 null genotypes were associated with skin cancer risk (OR = 2.99, 95% CI = 1.01–8.83; OR = 2.04, 95% CI = 0.99–4.27; OR = 1.74, 95% CI = 1.00–3.02, resp.). However, none of these polymorphisms showed significant association after considering arsenic exposure status. Individuals carrying three risk polymorphisms of EPHX1 Tyr113His, XPD C156A, and GSTs presented a 400% increased skin cancer risk when compared to those with less than or equal to one polymorphism. In conclusion, GSTs, EPHX1, and XPD are potential genetic factors for arsenic-induced skin cancers. The roles of these genes for arsenic-induced skin carcinogenesis need to be further evaluated. PMID:26295053

  15. Allelic variations in 5, 10-methylenetetrahydrofolate reductase gene and susceptibility to cervical cancer in Indian women.

    PubMed

    Nandan, Naveen Kumar; Wajid, Saima; Biswas, Shilpie; Juneja, Sominder Singh; Rizvi, Moshahid; Prakash, Raminder; Naqvi, Samar Husain

    2008-01-01

    Methylenetetrahydrofolate reductase (MTHFR) gene located on chromosome 1p36.3 catalyses the conversion of 5,10-methylenetetrahydrofolate to 5,methyltetrahydrofolate, the major methyl donor for the conversion of homocysteine to methionine. Two common polymorphisms in the MTHFR gene have been identified, 677C>T in exon 4, leading to substitution of alanine by valine and 1298A>C in exon 7 which leads to the replacement of glutamic acid by alanine resulting into reduced enzyme activity. The potential influence of MTHFR activity on DNA methylation and on the availability of uridylates and thymidylates for DNA synthesis and repair makes MTHFR an attractive candidate for cancer predisposing gene. In order to elucidate the role of MTHFR polymorphism in cervical cancer, both the exons for 677C>T and 1298A>C mutations were analyzed among 219 females, including 77 females with normal cervical cytology, 80 with cervical dysplasia and 62 with squamous cell carcinoma of uterine cervix. Females with mutant allele at 677 position (CT/TT genotypes) were found to be almost three times the risk of cervical dysplasia than females with CC genotype [OR, 2.9; (CI, 1.5-5.7)], but were less likely to develop squamous cell carcinoma [OR, 1.5 (CI, 0.7-3.2)]. Similar findings were observed for mutation at 1298 position, females with AC/CC genotypes were almost four times the risk of cervical dysplasia [OR, 4.3 (CI, 2.1-9.0)], as compared to AA genotype. Our study lends further support to the hypothesis that the MTHFR polymorphism (677C>T or 1298A>C) is involved in susceptibility to cervical dysplasia. PMID:19356065

  16. LMO1 gene polymorphisms contribute to decreased neuroblastoma susceptibility in a Southern Chinese population

    PubMed Central

    Zhu, Jinhong; Zhang, Ruizhong; Wang, Fenghua; Yang, Tianyou; Zou, Yan; Xia, Huimin

    2016-01-01

    Neuroblastoma is one of the most commonly diagnosed extracranial solid tumors in infancy; however, the etiology of neuroblastoma remains largely unknown. Previous genome-wide association study (GWAS) indicated that several common genetic variations (rs110419 A > G, rs4758051 G > A, rs10840002 A > G and rs204938 A > G) in the LIM domain only 1 (LMO1) gene were associated with neuroblastoma susceptibility. The aim of this study was to evaluate the correlation between the four GWAS-identified LMO1 gene polymorphisms and neuroblastoma risk in a Southern Chinese population. We genotyped the four polymorphisms in 256 neuroblastoma cases and 531 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the associations. False-positive report probability was calculated for all significant findings. We found that the rs110419 A > G polymorphism was associated with a significantly decreased neuroblastoma risk (AG vs. AA: adjusted OR = 0.65, 95% CI = 0.47–0.91; GG vs. AA: adjusted OR = 0.58, 95% CI = 0.36–0.91; AG/GG vs. AA: adjusted OR = 0.63, 95% CI = 0.46–0.86), and the protective effect was more predominant in children of age > 18 months, males, subgroups with tumor in adrenal gland and mediastinum, and patients in clinical stages III/IV. These results suggested that LMO1 gene rs110419 A > G polymorphism may contribute to protection against neuroblastoma. Our findings call for further validation studies with larger sample size. PMID:27009839

  17. Examining ERBB2 as a candidate gene for susceptibility to leprosy (Hansen's disease) in Brazil.

    PubMed

    Araújo, Sérgio Ricardo Fernandes; Jamieson, Sarra Elisabeth; Dupnik, Kathryn Margaret; Monteiro, Glória Regina; Nobre, Maurício Lisboa; Dias, Márcia Sousa; Trindade Neto, Pedro Bezerra; Queiroz, Maria do Carmo Palmeira; Gomes, Carlos Eduardo Maia; Blackwell, Jenefer Mary; Jeronimo, Selma Maria Bezerra

    2014-04-01

    Leprosy remains prevalent in Brazil. ErbB2 is a receptor for leprosy bacilli entering Schwann cells, which mediates Mycobacterium leprae-induced demyelination and the ERBB2 gene lies within a leprosy susceptibility locus on chromosome 17q11-q21. To determine whether polymorphisms at the ERBB2 locus contribute to this linkage peak, three haplotype tagging single nucleotide polymorphisms (tag-SNPs) (rs2517956, rs2952156, rs1058808) were genotyped in 72 families (208 cases; 372 individuals) from the state of Pará (PA). All three tag-SNPs were associated with leprosy per se [best SNP rs2517959 odds ratio (OR) = 2.22; 95% confidence interval (CI) 1.37-3.59; p = 0.001]. Lepromatous (LL) (OR = 3.25; 95% CI 1.37-7.70; p = 0.007) and tuberculoid (TT) (OR = 1.79; 95% CI 1.04-3.05; p = 0.034) leprosy both contributed to the association, which is consistent with the previous linkage to chromosome 17q11-q21 in the population from PA and supports the functional role of ErbB2 in disease pathogenesis. To attempt to replicate these findings, six SNPs (rs2517955, rs2517956, rs1810132, rs2952156, rs1801200, rs1058808) were genotyped in a population-based sample of 570 leprosy cases and 370 controls from the state of Rio Grande do Norte (RN) and the results were analysed using logistic regression analysis. However, none of the associations were replicated in the RN sample, whether analysed for leprosy per se, LL leprosy, TT leprosy, erythema nodosum leprosum or reversal reaction conditions. The role of polymorphisms at ERBB2 in controlling susceptibility to leprosy in Brazil therefore remains unclear. PMID:24676663

  18. Relationship between Paraoxonase 1 (PON1) gene polymorphisms and susceptibility of stroke: a meta-analysis.

    PubMed

    Banerjee, Indranil

    2010-07-01

    Genetic variants of paraoxonase 1 (PON1) were implicated in stroke susceptibility in several case-control association studies. However, the studies have reported apparently conflicting results, rendering precise assessment of the disease risk associated with the variants difficult. A meta-analysis was therefore conducted by including the studies that examined the association between two common polymorphisms (L55M and Q192R) in the coding region of PON1 gene and the risk of stroke. Altogether 10 studies on L55M polymorphism and 11 studies on Q192R polymorphism were included in this meta-analysis. The results showed, although there was no significant association of the 55L allele with stroke [random effects OR = 1.09, 95% CI (0.93, 1.27), P = 0.29], the 192R allele conferred significant risk of stroke in the overall study population [random effects OR = 1.25, 95% CI (1.07, 1.46), P = 0.006]. Same pattern of results as both the allele contrasts was obtained for the homozygote contrasts and the dominant, recessive and additive models. Subgroup analyses for stroke type, age of patients and ethnicity revealed no association of the 55L allele with stroke, whereas the association of the 192R allele persisted significantly in the groups comprising ischemic stroke patients, stroke patients with mean age >60 years and Caucasian subjects. But no significant association of this allele with stroke susceptibility was detected in the East Asian population. Therefore, the results of this meta-analysis indicate, the Q192R polymorphism could be an important risk factor for stroke, especially in the Caucasian population. PMID:20532959

  19. Polymorphisms of cystathionine beta-synthase gene are associated with susceptibility to sepsis.

    PubMed

    Sponholz, Christoph; Kramer, Marcel; Schöneweck, Franziska; Menzel, Uwe; Inanloo Rahatloo, Kolsoum; Giamarellos-Bourboulis, Evangelos J; Papavassileiou, Vassileios; Lymberopoulou, Korina; Pavlaki, Maria; Koutelidakis, Ioannis; Perdios, Ioannis; Scherag, André; Bauer, Michael; Platzer, Matthias; Huse, Klaus

    2016-07-01

    Sepsis is the systemic inflammatory host response to infection. Cystathionine beta-synthase (CBS)-dependent homocysteine (Hcy) pathway was demonstrated to affect disease severity and mortality in patients with severe sepsis/septic shock. Independent studies identified a single-nucleotide polymorphism (SNP, rs6586282, hg19 chr21:g.44478497C>T) in intron 14 of the CBS-coding gene (CBS) associated with Hcy plasma levels. We aimed to describe the association of this SNP and variants of a splice donor-affecting variable-number tandem repeat (VNTR, NG_008938.1:g.22763_22793[16_22]) 243 bp downstream of rs6586282 with severe human sepsis. We analyzed the VNTR structure and genotyped variants of rs6586282 and a neighboring SNP (rs34758144, hg19 chr21:g.44478582G>A) in two case-control studies including patients with severe sepsis/septic shock from Germany (n=168) and Greece (n=237). In both studies, we consistently observed an association of CBS VNTR alleles with sepsis susceptibility. Risk linearly increased with number of tandem repeats (per allele odds ratio in the adjusted analysis 1.34; 95% confidence interval (CI)=1.17-1.55; P<0.001). Association had also been shown for rs34758144 whose risk allele is in linkage disequilibrium with one long VNTR allele (19 repeat). In contrast, we observed no evidence for an effect on 28-day survival in patients with severe sepsis/septic shock (per allele hazard ratio in the adjusted analysis for VNTR 1.10; 95% CI=0.95-1.28; P=0.20). In a minigene approach, we demonstrated alternative splicing in distinct VNTR alleles, which, however, was independent of the number of tandem units. In conclusion, there is no ordinary conjunction between human CBS and severe sepsis/septic shock, but CBS genotypes are involved in disease susceptibility. PMID:26508567

  20. Hsp70-2 gene polymorphism: susceptibility implication in Tunisian patients with coronary artery disease

    PubMed Central

    2012-01-01

    Abstract Coronary artery disease (CAD) is a multifactorial disease where genetic and environmental factors interact in complex ways to cause the disease. Heat shock protein genes are involved in the progress of CAD. This implies that genetic variants of Hsp70–2 genes might contribute to the development of the CAD. Aim of study The aim of this study was to characterize statistical correlation of linkage between lipid profiles, polymorphism PstI site of Hsp70–2 gene and CAD. Patients and methods This study was carried out on Tunisian patients with CAD recruited from Hospital of Fattouma Bourguiba of Monastir-Tunisia. Polymerase chain reaction and restriction enzymes were used to determine the genotypic distributions in 252 unrelated patients and 151 healthy control subjects. Further, ApoA-I and ApoB as well as the serum total of cholesterol, HDL, triglyceride, and hs-CRP levels were measured. Results We showed a decreased level of ApoA-I, whereas the levels of each of ApoB and hs-CRP were increased in patients with CAD compared with control group. In addition our studies of a polymorphic PstI site of Hsp70-2 gene at position 1267 of the Hsp70–2 gene have revealed that the allelic frequency of P2 was significantly more frequent in CAD patients than controls group (p=0.007, OR=1.495). The genotypic distribution showed a high incidence of P2/P2 genotype in CAD patients (0.190) compared to healthy control (0.009) with reach significant difference (p=0.006). The P2 carriers showed a significantly increased of Total-Cholesterol (CT) and C-reactive protein (hs-CRP) levels in CAD patients (p=0.008 and p=0.018, respectively). Conclusion The high incidence of P2-Hsp70-2 genotype in CAD patients and the significantly association of P2/P2 genotype with elevated Total Cholesterol and hs-CRP levels, supported that P2–Hsp70–2 genotype has susceptibility implication in CAD and could increased the risk of CAD in Tunisian population. Virtual slides The virtual slide(s) for

  1. [Analysis for susceptibility of breast cancer due to gene SMC4L1 based on a multi-criteria evaluation model].

    PubMed

    Xu, Chao; Jiang, Yan

    2011-06-01

    The recent literature has proposed a multi-criteria evaluation model for breast cancer susceptibility. In this paper we employ the model to analyze the breast cancer susceptibility of several candidate genes having various relations with known breast cancer genes. Based on the model, we employed weight sum and TOPSIS methods to calculate the quantitative relations between candidate genes and breast cancer susceptibility. After the calculation, two ranking evaluation lists of alternatives were resulted from the two methods. The results generated with the two different methods were remarkably similar, while the top 7 were exactly identical. So the top 7 genes were analyzed, and the result from multi-criteria model was consistent with the previous research. A search of the literature using PubMed demonstrates CDC2 gene ranked first is researched frequently. Furthermore, TopBP1 gene ranked second and HMMR gene ranked 6th are identified as susceptibility genes for breast cancer by references in the literature. This multi-objective evaluation model can accurately represent the complex relationship between candidate genes and breast cancer susceptibility. Then this paper focuses on SMC4L1 gene ranked third. The analysis from various aspects indicates that SMC4L1 is potential to be a susceptibility gene for breast cancer. It's worthwhile to research on SMC4L1 and other top genes in result prior to and afterwards. PMID:21774228

  2. Reference Gene Selection and Validation for the Early Responses to Downy Mildew Infection in Susceptible and Resistant Vitis vinifera Cultivars

    PubMed Central

    Monteiro, Filipa; Sebastiana, Mónica; Pais, Maria Salomé; Figueiredo, Andreia

    2013-01-01

    The pivotal role of cultivated grapevine (Vitis vinifera L.) in many countries economy is compromised by its high susceptibility to Plasmopara viticola, the causal agent of downy mildew disease. Recent research has identified a set of genes related to resistance which may be used to track downy mildew infection. Quantification of the expression of these resistance genes requires normalizing qPCR data using reference genes with stable expression in the system studied. In this study, a set of eleven genes (VATP16, 60 S, UQCC, SMD3, EF1α, UBQ, SAND, GAPDH, ACT, PsaB, PTB2) was evaluated to identify reference genes during the first hours of interaction (6, 12, 18 and 24 hpi) between two V. vinifera genotypes and P. viticola. Two analyses were used for the selection of reference genes: direct comparison of susceptible, Trincadeira, and resistant, Regent, V. vinifera cultivars at 0 h, 6, 12, 18 and 24 hours post inoculation with P. viticola (genotype effect); and comparison of each genotype with mock inoculated samples during inoculation time-course (biotic stress effect). Three statistical methods were used, GeNorm, NormFinder, and BestKeeper, allowing to identify UBQ, EF1α and GAPDH as the most stable genes for the genotype effect. For the biotic stress effect, EF1α, SAND and SMD3 were the most constant for the susceptible cultivar Trincadeira and EF1α, GAPDH, UBQ for the resistant cultivar Regent. In addition, the expression of three defense-related transcripts, encoding for subtilisin-like protein, CYP and PR10, was analysed, for both datasets, during inoculation time-course. Taken together, our results provide guidelines for reference gene(s) selection towards a more accurate and widespread use of qPCR to study the first hours of interaction between different grapevine cultivars and P. viticola. PMID:24023800

  3. Reference gene selection and validation for the early responses to downy mildew infection in susceptible and resistant Vitis vinifera cultivars.

    PubMed

    Monteiro, Filipa; Sebastiana, Mónica; Pais, Maria Salomé; Figueiredo, Andreia

    2013-01-01

    The pivotal role of cultivated grapevine (Vitis vinifera L.) in many countries economy is compromised by its high susceptibility to Plasmopara viticola, the causal agent of downy mildew disease. Recent research has identified a set of genes related to resistance which may be used to track downy mildew infection. Quantification of the expression of these resistance genes requires normalizing qPCR data using reference genes with stable expression in the system studied. In this study, a set of eleven genes (VATP16, 60 S, UQCC, SMD3, EF1α, UBQ, SAND, GAPDH, ACT, PsaB, PTB2) was evaluated to identify reference genes during the first hours of interaction (6, 12, 18 and 24 hpi) between two V. vinifera genotypes and P. viticola. Two analyses were used for the selection of reference genes: direct comparison of susceptible, Trincadeira, and resistant, Regent, V. vinifera cultivars at 0 h, 6, 12, 18 and 24 hours post inoculation with P. viticola (genotype effect); and comparison of each genotype with mock inoculated samples during inoculation time-course (biotic stress effect). Three statistical methods were used, GeNorm, NormFinder, and BestKeeper, allowing to identify UBQ, EF1α and GAPDH as the most stable genes for the genotype effect. For the biotic stress effect, EF1α, SAND and SMD3 were the most constant for the susceptible cultivar Trincadeira and EF1α, GAPDH, UBQ for the resistant cultivar Regent. In addition, the expression of three defense-related transcripts, encoding for subtilisin-like protein, CYP and PR10, was analysed, for both datasets, during inoculation time-course. Taken together, our results provide guidelines for reference gene(s) selection towards a more accurate and widespread use of qPCR to study the first hours of interaction between different grapevine cultivars and P. viticola. PMID:24023800

  4. Imaging in the trilateral retinoblastoma syndrome.

    PubMed

    Bagley, L J; Hurst, R W; Zimmerman, R A; Shields, J A; Shields, C L; De Potter, P

    1996-02-01

    The medical records, CT, and MRI of ten children with trilateral retinoblastoma were reviewed. The intracranial pathology consisted of eight pineal neoplasms and two parasellar lesions, at least seven of the which were calcified. Two lesions demonstrated calcification only (no soft tissue mass) at initial presentation. Hydrocephalus was seen in eight cases, and concurrent or subsequent subarachnoid dissemination was documented in seven. Only one patient is known to be alive at the present time. The imaging features of the midline intracranial tumors mirror those of the ocular neoplasm. As calcification may be the only clue to the presence of the intracranial malignancy, close surveillance of high-risk patients with retinoblastoma with initial CT and follow-up MRI is suggested. PMID:8692433

  5. The role of germline alterations in the DNA damage response genes BRIP1 and BRCA2 in melanoma susceptibility.

    PubMed

    Tuominen, Rainer; Engström, Pär G; Helgadottir, Hildur; Eriksson, Hanna; Unneberg, Per; Kjellqvist, Sanela; Yang, Muyi; Lindén, Diana; Edsgärd, Daniel; Hansson, Johan; Höiom, Veronica

    2016-07-01

    We applied a targeted sequencing approach to identify germline mutations conferring a moderately to highly increased risk of cutaneous and uveal melanoma. Ninety-two high-risk melanoma patients were screened for inherited variation in 120 melanoma candidate genes. Observed gene variants were filtered based on frequency in reference populations, cosegregation with melanoma in families and predicted functional effect. Several novel or rare genetic variants in genes involved in DNA damage response, cell-cycle regulation and transcriptional control were identified in melanoma patients. Among identified genetic alterations was an extremely rare variant (minor allele frequency of 0.00008) in the BRIP1 gene that was found to cosegregate with the melanoma phenotype. We also found a rare nonsense variant in the BRCA2 gene (rs11571833), previously associated with cancer susceptibility but not with melanoma, which showed weak association with melanoma susceptibility in the Swedish population. Our results add to the growing knowledge about genetic factors associated with melanoma susceptibility and also emphasize the role of DNA damage response as an important factor in melanoma etiology. © 2016 Wiley Periodicals, Inc. PMID:27074266

  6. Polymorphisms of folate metabolic genes and susceptibility to bladder cancer: a case-control study.

    PubMed

    Lin, Jie; Spitz, Margaret R; Wang, Yunfei; Schabath, Matthew B; Gorlov, Ivan P; Hernandez, Ladia M; Pillow, Patricia C; Grossman, H Barton; Wu, Xifeng

    2004-09-01

    Epidemiological studies have shown an association between low folate intake and an increased cancer risk. Major genes involved in folate metabolism include methylene-tetrahydrofolate reductase (MTHFR) and methionine synthase (MS). We investigated joint effects of polymorphisms of the MTHFR (677 C-->T, 1298A-->C) and MS genes (2756 A-->G), dietary folate intake and cigarette smoking on the risk of bladder cancer in a case-control study. The study population consisted of 457 bladder cancer patients and 457 healthy controls, matched to the cases in terms of age, gender and ethnicity. Genotype data were analyzed in a subset of 410 Caucasian cases and 410 controls. Compared with individuals carrying the MTHFR 677 wild-type (CC) and reporting a high folate intake, those carrying the variant genotype (CT or TT) and reporting a low folate intake were at a significantly 3.51-fold increased risk of bladder cancer (95% CI: 1.59-6.52). In contrast, individuals carrying a variant genotype and reporting a high folate intake were at only a 1.39-fold increased risk (95% CI: 0.71-2.70), and those carrying the wild-type and reporting a low folate intake were at only 1.56-fold increased risk (95% CI: 0.82-2.97). The interaction between genetic polymorphisms and folate intake was significant on the multiplicative scale (P = 0.01). When analyzed in the context of smoking status, compared with never smokers with the MTHFR 677 wild-type, the risk increased to 6.56-fold (95% CI: 3.28-13.12) in current smokers carrying the variant genotype. Analyses of the MTHFR 1298, MS 2756 genes revealed similar results. In addition, age at cancer onset in former smokers increased as the proportion of the heteromorphic haplotype in the individual increased (P = 0.005). Our results strongly suggest that polymorphisms of the MTHFR and MS genes act together with low folate intake and smoking to increase bladder cancer risk. These results have important implications for cancer prevention in susceptible

  7. Antimicrobial susceptibility of Swedish, Norwegian and Danish isolates of Clostridium perfringens from poultry, and distribution of tetracycline resistance genes.

    PubMed

    Johansson, A; Greko, C; Engström, B E; Karlsson, M

    2004-04-19

    This study was undertaken to determine the in vitro susceptibility of Clostridium perfringens, isolated from poultry to antimicrobials used in poultry production. The minimal inhibitory concentration (MIC) of eight antimicrobials, including the ionophoric coccidiostat narasin, was determined for 102 C. perfringens isolates, 58 from Sweden, 24 from Norway and 20 from Denmark. Susceptibility to each antimicrobial compound was determined by broth microdilution. The isolates were obtained from broilers (89), laying hens (9) and turkeys (4), affected by necrotic enteritis (NE) or by C. perfringens associated hepatitis (CPH), and from healthy broilers. All strains, regardless of origin, proved inherently susceptible to ampicillin, narasin, avilamycin, erythromycin and vancomycin. A low frequency of resistance to virginiamycin and bacitracin was also found. Resistance to tetracycline was found in strains isolated in all three countries; Sweden (76%), Denmark (10%) and Norway (29%). In 80% of the tetracycline-resistant isolates, the two resistance genes tetA(P) and tetB(P) were amplified by PCR whereas in 20% only the tetA(P) gene was detected. No tetM gene amplicon was obtained from any of the tetracycline-resistant isolates. The uniform susceptibility to narasin revealed in this study shows that the substance can still be used to control clostridiosis. In this study, C. perfringens also showed a low degree of resistance to most other antimicrobials tested. Despite the small amounts of tetracycline used in poultry, a considerable degree of resistance to tetracycline was found in C. perfringens isolates from Swedish broilers. PMID:15066727

  8. A meta-analysis of xeroderma pigmentosum gene D Ls751Gln polymorphism and susceptibility to hepatocellular carcinoma.

    PubMed

    Wang, Yu; Zhao, Yingren; Zhang, Aiyun; Ma, Juan; Wang, Zhenzhen; Zhang, Xu

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of most common malignant tumors worldwide, but with unclear mechanisms. Xeroderma pigmentosum gene D (XPD) is one important DNA damage repair gene and can be involved in protein mutation. Currently little has been known about XPD polymorphism and HCC susceptibility in Chinese people. This study used a meta-analysis approach to comprehensively investigate the correlation between XPD polymorphism and HCC susceptibility in Chinese population, based on previously published literatures. A computer retrieval system was used to collect all case-control studies about XPD Lys751Gln polymorphism and HCC susceptibility. Data in literatures were extracted for meta-analysis. After the primary screening, four independent studies, which were published in 3 English articles and one Chinese article, were recruited in this study. There were 1,717 samples included in all studies. Using Gln/Gln + Lys/Gln, Lys/Lys + Lys/Gln and Lys allels as the reference, HCC disease alleles including Lys/Lys, Gln/Gln and Gln had OR values (95% CI, I(2)) of 1.007 (0.657~4.672, 91%), 3.516 (0.220~20.661, 48%) and 3.225 (0.278~12.326, 84%), respectively. The polymorphism of XPD751 loci is closely correlated with primary HCC. Lys751Gln polymorphism of XPD gene can be used as one susceptibility factor for HCC. PMID:26722489

  9. A Systems Genetics Approach Identifies CXCL14, ITGAX, and LPCAT2 as Novel Aggressive Prostate Cancer Susceptibility Genes

    PubMed Central

    Andreas, Jonathan; Patel, Shashank J.; Zhang, Suiyuan; Chines, Peter; Elkahloun, Abdel; Chandrasekharappa, Settara; Gutkind, J. Silvio; Molinolo, Alfredo A.; Crawford, Nigel P. S.

    2014-01-01

    Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n = 228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will

  10. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

    PubMed Central

    Nejentsev, Sergey; Howson, Joanna M. M.; Walker, Neil M.; Szeszko, Jeffrey; Field, Sarah F.; Stevens, Helen E.; Reynolds, Pamela; Hardy, Matthew; King, Erna; Masters, Jennifer; Hulme, John; Maier, Lisa M.; Smyth, Deborah; Bailey, Rebecca; Cooper, Jason D.; Ribas, Gloria; Campbell, R. Duncan; Clayton, David G.; Todd, John A.

    2009-01-01

    The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4-11. Owing to the region’s extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression—to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios>1.5; Pcombined=2.01×10-19 and 2.35×10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies4-8,10-16, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. PMID:18004301

  11. Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma.

    PubMed

    Dai, Wei; Zheng, Hong; Cheung, Arthur Kwok Leung; Tang, Clara Sze-Man; Ko, Josephine Mun Yee; Wong, Bonnie Wing Yan; Leong, Merrin Man Long; Sham, Pak Chung; Cheung, Florence; Kwong, Dora Lai-Wan; Ngan, Roger Kai Cheong; Ng, Wai Tong; Yau, Chun Chung; Pan, Jianji; Peng, Xun; Tung, Stewart; Zhang, Zengfeng; Ji, Mingfang; Chiang, Alan Kwok-Shing; Lee, Anne Wing-Mui; Lee, Victor Ho-Fun; Lam, Ka-On; Au, Kwok Hung; Cheng, Hoi Ching; Yiu, Harry Ho-Yin; Lung, Maria Li

    2016-03-22

    Multiple factors, including host genetics, environmental factors, and Epstein-Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying theMST1Rpathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating thatMST1Rgerm-line variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, fiveMST1Rmissense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%,P= 7.94 × 10(-12)). The validation study, including 2,160 cases and 2,433 controls, showed that theMST1Rvariant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0).MST1Ris predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation ofMST1Rwas identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation atMST1Rwere often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways. PMID:26951679

  12. Neuropsychological deficits in mice depleted of the schizophrenia susceptibility gene CSMD1.

    PubMed

    Steen, Vidar M; Nepal, Chirag; Ersland, Kari M; Holdhus, Rita; Nævdal, Marianne; Ratvik, Siri M; Skrede, Silje; Håvik, Bjarte

    2013-01-01

    Recent meta-analyses of schizophrenia genome-wide association studies (GWASs) have identified the CUB and SUSHI multiple domains 1 (CSMD1) gene as a statistically strong risk factor. CSMD1 is a complement control-related protein suggested to inhibit the classical complement pathway, being expressed in developing neurons. However, expression of CSMD1 is largely uncharacterized and relevance for behavioral phenotypes is not previously demonstrated. Here, we assess neuropsychological behaviors of a Csmd1 knockout (KO) mouse in a selection of standard behavioral tests. Deregulation of neuropsychological responses were observed in both the open field and the elevated plus maze tests, in which KO mice spent 55% and 33% less time than WT littermate mice in open areas, respectively. Altered behaviors were also observed in tail suspension and to higher acoustic stimuli, for which Csmd1 KO mice showed helplessness and moderate increase in startle amplitude, respectively. Furthermore, Csmd1 KO mice also displayed increased weight-gain and glucose tolerance, similar to a major phenotype of the metabolic syndrome that also has been associated to the human CSMD1 locus. Consistent with a role in the control of behaviors, Csmd1 was found highly expressed in the central nervous system (CNS), and with some expression in visceral fat and ovary, under tissue-specific control by a novel promoter-associated lncRNA. In summary, disruption of Csmd1 induces behaviors reminiscent of blunted emotional responses, anxiety and depression. These observations suggest an influence of the CSMD1 schizophrenia susceptibility gene on psychopathology and endophenotypes of the negative symptom spectra. PMID:24244513

  13. Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene-Environment Interactions

    PubMed Central

    Schoeps, Anja; Rudolph, Anja; Seibold, Petra; Dunning, Alison M.; Milne, Roger L.; Bojesen, Stig E.; Swerdlow, Anthony; Andrulis, Irene; Brenner, Hermann; Behrens, Sabine; Orr, Nicholas; Jones, Michael; Ashworth, Alan; Li, Jingmei; Cramp, Helen; Connley, Dan; Czene, Kamila; Darabi, Hatef; Chanock, Stephen J.; Lissowska, Jolanta; Figueroa, Jonine D.; Knight, Julia; Glendon, Gord; Mulligan, Anna M.; Dumont, Martine; Severi, Gianluca; Baglietto, Laura; Olson, Janet; Vachon, Celine; Purrington, Kristen; Moisse, Matthieu; Neven, Patrick; Wildiers, Hans; Spurdle, Amanda; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana M.; Hamann, Ute; Ko, Yon-Dschun; Dieffenbach, Aida K.; Arndt, Volker; Stegmaier, Christa; Malats, Núria; Arias Perez, JoséI.; Benítez, Javier; Flyger, Henrik; Nordestgaard, Børge G.; Truong, Théresè; Cordina-Duverger, Emilie; Menegaux, Florence; Silva, Isabel dos Santos; Fletcher, Olivia; Johnson, Nichola; Häberle, Lothar; Beckmann, Matthias W.; Ekici, Arif B.; Braaf, Linde; Atsma, Femke; van den Broek, Alexandra J.; Makalic, Enes; Schmidt, Daniel F.; Southey, Melissa C.; Cox, Angela; Simard, Jacques; Giles, Graham G.; Lambrechts, Diether; Mannermaa, Arto; Brauch, Hiltrud; Guénel, Pascal; Peto, Julian; Fasching, Peter A.; Hopper, John; Flesch-Janys, Dieter; Couch, Fergus; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Garcia-Closas, Montserrat; Schmidt, Marjanka K.; Hall, Per; Easton, Douglas F.; Chang-Claude, Jenny

    2014-01-01

    Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci. PMID:24248812

  14. Polymorphisms in DNA Repair Gene XRCC3 and Susceptibility to Breast Cancer in Saudi Females

    PubMed Central

    Ali, Alaa Mohammed; AbdulKareem, Huda; Al Anazi, Mohammad; Reddy Parine, Narasimha; Shaik, Jilani Purusottapatnam; Alamri, Abdullah; Ali Khan Pathan, Akbar

    2016-01-01

    We investigated three common polymorphisms (SNPs) in the XRCC3 gene (rs861539, rs1799794, and rs1799796) in 143 Saudi females suffering from breast cancer (median age = 51.4 years) and 145 age matched normal healthy controls. DNA was extracted from whole blood and genotyping was conducted using PCR-RFLP. rs1799794 showed significant association, where AA and AA+AG occurred at a significantly higher frequency in the cancer patients compared to the control group (OR: 28.1; 95% CI: 3.76–21.12; χ2: 22.82; p < 0.0001). The G allele was protective and presented with a dominant model. The genotype and allele frequencies of rs861539 C>T and rs1799796 A>G did not show a significant difference when the results in the patients and controls were compared. However, the frequency of rs1799796 differed significantly in patients with different age of diagnosis, tumor grade, and ER and HER2 status. The wild type A allele occurred at a higher frequency in the ER− and HER2− group. Our results among Saudis suggest that some variations in XRCC3 may contribute to breast cancer susceptibility. In conclusion, the results obtained during this study suggest that rs1799794 in XRCC3 shows strong association with breast cancer development in Saudi females. PMID:26881229

  15. Analysis of mutations in the pbp genes of penicillin-non-susceptible pneumococci from Turkey.

    PubMed

    Biçmen, M; Gülay, Z; Ramaswamy, S V; Musher, D M; Gür, D

    2006-02-01

    Sequence analysis of the pbp genes from 20 Streptococcus pneumoniae isolates from Turkey (eight with high-level penicillin-resistance, nine with low-level penicillin-resistance, and three that were penicillin-susceptible) was performed and phylogenetic trees were constructed. Most isolates clustered together within a single branch that was distinct from sequences deposited previously in GenBank, which suggests that these isolates have probably evolved following new recombination events. The most prominent active-site mutations, which have also been associated previously with resistance, were T371A in PBP1a, E481G followed by T451A in PBP2b, and T338A in PBP2x. All isolates also possessed a (570)SVES/TK(574) block in the PBP2b sequence, instead of the QLQPT sequence of R6, which is fairly uncommon in GenBank sequences. This is the first study to analyse alterations in the pbp sequences of pneumococci isolated in Turkey. PMID:16441453

  16. Association of leptin receptor gene Gln223Arg polymorphism with susceptibility to colorectal cancer

    PubMed Central

    Arkani, Maral; Safaei, Akram; Pourhoseingholi, Mohamad Amin; Mohebbi, Seyed Reza; Fatemi, Seyed Reza; Vafaei, Mohammad

    2011-01-01

    Aim Leptin is a 16 kDa polypeptide hormone which secreted by adipose tissue and has an important role in energy balance, insulin pathway and inflammation, because of that it may play an important role in colorectal cancer (CRC). Leptin exerts its effect through the leptin receptor (LEPR) a member of the class I cytokine receptor family. Background We have investigated whether glutamine to arginine substitution (Gln223Arg) in exon 6 of the leptin receptor gene, has implications for susceptibility to CRC. Patients and methods Polymerase chain reaction (PCR) and restriction enzyme digestion (RFLP) was performed to evaluate the association between the Gln223Arg polymorphism of the LEPR and CRC risk in a case-control study in 346 subjects involving 173 cases with CRC and 173 controls. Results There was no statistically evidence of significant difference in genotype and allele frequencies between the cases with CRC and controls for the Gln223Arg polymorphism of LEPR, before or after adjusting for confounders (age, BMI, sex, and smoking status). Furthermore, no significant difference was observed between the CRC cases and controls by BMI, sex and smoking status. Conclusion Our findings suggest that the LEPR Gln223Arg polymorphism is not associated with the risk of CRC in Iranian population. PMID:24834182

  17. A single gene of a commensal microbe affects host susceptibility to enteric infection.

    PubMed

    Yoon, Mi Young; Min, Kyung Bae; Lee, Kang-Mu; Yoon, Yujin; Kim, Yaeseul; Oh, Young Taek; Lee, Keehoon; Chun, Jongsik; Kim, Byung-Yong; Yoon, Seok-Hwan; Lee, Insuk; Kim, Chan Yeong; Yoon, Sang Sun

    2016-01-01

    Indigenous microbes inside the host intestine maintain a complex self-regulating community. The mechanisms by which gut microbes interact with intestinal pathogens remain largely unknown. Here we identify a commensal Escherichia coli strain whose expansion predisposes mice to infection by Vibrio cholerae, a human pathogen. We refer to this strain as 'atypical' E. coli (atEc) because of its inability to ferment lactose. The atEc strain is resistant to reactive oxygen species (ROS) and proliferates extensively in antibiotic-treated adult mice. V. cholerae infection is more severe in neonatal mice transplanted with atEc compared with those transplanted with a typical E. coli strain. Intestinal ROS levels are decreased in atEc-transplanted mice, favouring proliferation of ROS-sensitive V. cholerae. An atEc mutant defective in ROS degradation fails to facilitate V. cholerae infection when transplanted, suggesting that host infection susceptibility can be regulated by a single gene product of one particular commensal species. PMID:27173141

  18. Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours.

    PubMed

    Rapley, E A; Crockford, G P; Teare, D; Biggs, P; Seal, S; Barfoot, R; Edwards, S; Hamoudi, R; Heimdal, K; Fossâ, S D; Tucker, K; Donald, J; Collins, F; Friedlander, M; Hogg, D; Goss, P; Heidenreich, A; Ormiston, W; Daly, P A; Forman, D; Oliver, T D; Leahy, M; Huddart, R; Cooper, C S; Bodmer, J G; Easton, D F; Stratton, M R; Bishop, D T

    2000-02-01

    Testicular germ-cell tumours (TGCT) affect 1 in 500 men and are the most common cancer in males aged 15-40 in Western European populations. The incidence of TGCT has risen dramatically over the last century. Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility, previously diagnosed TGCT (ref. 7) and a family history of the disease. Brothers of men with TGCT have an 8-10-fold risk of developing TGCT (refs 8,9), whereas the relative risk to fathers and sons is fourfold (ref. 9). This familial relative risk is much higher than that for most other types of cancer. We have collected samples from 134 families with two or more cases of TGCT, 87 of which are affected sibpairs. A genome-wide linkage search yielded a heterogeneity lod (hlod) score of 2.01 on chromosome Xq27 using all families compatible with X inheritance. We obtained a hlod score of 4.7 from families with at least one bilateral case, corresponding to a genome-wide significance level of P=0.034. The proportion of families with UDT linked to this locus was 73% compared with 26% of families without UDT (P=0.03). Our results provide evidence for a TGCT susceptibility gene on chromosome Xq27 that may also predispose to UDT. PMID:10655070

  19. Revisiting the Thrifty Gene Hypothesis via 65 Loci Associated with Susceptibility to Type 2 Diabetes

    PubMed Central

    Ayub, Qasim; Moutsianas, Loukas; Chen, Yuan; Panoutsopoulou, Kalliope; Colonna, Vincenza; Pagani, Luca; Prokopenko, Inga; Ritchie, Graham R.S.; Tyler-Smith, Chris; McCarthy, Mark I.; Zeggini, Eleftheria; Xue, Yali

    2014-01-01

    We have investigated the evidence for positive selection in samples of African, European, and East Asian ancestry at 65 loci associated with susceptibility to type 2 diabetes (T2D) previously identified through genome-wide association studies. Selection early in human evolutionary history is predicted to lead to ancestral risk alleles shared between populations, whereas late selection would result in population-specific signals at derived risk alleles. By using a wide variety of tests based on the site frequency spectrum, haplotype structure, and population differentiation, we found no global signal of enrichment for positive selection when we considered all T2D risk loci collectively. However, in a locus-by-locus analysis, we found nominal evidence for positive selection at 14 of the loci. Selection favored the protective and risk alleles in similar proportions, rather than the risk alleles specifically as predicted by the thrifty gene hypothesis, and may not be related to influence on diabetes. Overall, we conclude that past positive selection has not been a powerful influence driving the prevalence of T2D risk alleles. PMID:24412096

  20. A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility

    PubMed Central

    Keller, Mark P.; Choi, YounJeong; Wang, Ping; Belt Davis, Dawn; Rabaglia, Mary E.; Oler, Angie T.; Stapleton, Donald S.; Argmann, Carmen; Schueler, Kathy L.; Edwards, Steve; Steinberg, H. Adam; Chaibub Neto, Elias; Kleinhanz, Robert; Turner, Scott; Hellerstein, Marc K.; Schadt, Eric E.; Yandell, Brian S.; Kendziorski, Christina; Attie, Alan D.

    2008-01-01

    Insulin resistance is necessary but not sufficient for the development of type 2 diabetes. Diabetes results when pancreatic beta-cells fail to compensate for insulin resistance by increasing insulin production through an expansion of beta-cell mass or increased insulin secretion. Communication between insulin target tissues and beta-cells may initiate this compensatory response. Correlated changes in gene expression between tissues can provide evidence for such intercellular communication. We profiled gene expression in six tissues of mice from an obesity-induced diabetes-resistant and a diabetes-susceptible strain before and after the onset of diabetes. We studied the correlation structure of mRNA abundance and identified 105 co-expression gene modules. We provide an interactive gene network model showing the correlation structure between the expression modules within and among the six tissues. This resource also provides a searchable database of gene expression profiles for all genes in six tissues in lean and obese diabetes-resistant and diabetes-susceptible mice, at 4 and 10 wk of age. A cell cycle regulatory module in islets predicts diabetes susceptibility. The module predicts islet replication; we found a strong correlation between 2H2O incorporation into islet DNA in vivo and the expression pattern of the cell cycle module. This pattern is highly correlated with that of several individual genes in insulin target tissues, including Igf2, which has been shown to promote beta-cell proliferation, suggesting that these genes may provide a link between insulin resistance and beta-cell proliferation. PMID:18347327

  1. Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes.

    PubMed

    Izumi, Kenichi; Mine, Keiichiro; Inoue, Yoshitaka; Teshima, Miho; Ogawa, Shuichiro; Kai, Yuji; Kurafuji, Toshinobu; Hirakawa, Kanako; Miyakawa, Daiki; Ikeda, Haruka; Inada, Akari; Hara, Manami; Yamada, Hisakata; Akashi, Koichi; Niho, Yoshiyuki; Ina, Keisuke; Kobayashi, Takashi; Yoshikai, Yasunobu; Anzai, Keizo; Yamashita, Teruo; Minagawa, Hiroko; Fujimoto, Shuji; Kurisaki, Hironori; Shimoda, Kazuya; Katsuta, Hitoshi; Nagafuchi, Seiho

    2015-01-01

    Accumulating evidence suggests that viruses play an important role in the development of diabetes. Although the diabetogenic encephalomyocarditis strain D virus induces diabetes in restricted lines of inbred mice, the susceptibility genes to virus-induced diabetes have not been identified. We report here that novel Tyrosine kinase 2 (Tyk2) gene mutations are present in virus-induced diabetes-sensitive SJL and SWR mice. Mice carrying the mutant Tyk2 gene on the virus-resistant C57BL/6 background are highly sensitive to virus-induced diabetes. Tyk2 gene expression is strongly reduced in Tyk2-mutant mice, associated with low Tyk2 promoter activity, and leads to decreased expression of interferon-inducible genes, resulting in significantly compromised antiviral response. Tyk2-mutant pancreatic β-cells are unresponsive even to high dose of Type I interferon. Reversal of virus-induced diabetes could be achieved by β-cell-specific Tyk2 gene expression. Thus, reduced Tyk2 gene expression in pancreatic β-cells due to natural mutation is responsible for susceptibility to virus-induced diabetes. PMID:25849081

  2. Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes

    PubMed Central

    Izumi, Kenichi; Mine, Keiichiro; Inoue, Yoshitaka; Teshima, Miho; Ogawa, Shuichiro; Kai, Yuji; Kurafuji, Toshinobu; Hirakawa, Kanako; Miyakawa, Daiki; Ikeda, Haruka; Inada, Akari; Hara, Manami; Yamada, Hisakata; Akashi, Koichi; Niho, Yoshiyuki; Ina, Keisuke; Kobayashi, Takashi; Yoshikai, Yasunobu; Anzai, Keizo; Yamashita, Teruo; Minagawa, Hiroko; Fujimoto, Shuji; Kurisaki, Hironori; Shimoda, Kazuya; Katsuta, Hitoshi; Nagafuchi, Seiho

    2015-01-01

    Accumulating evidence suggests that viruses play an important role in the development of diabetes. Although the diabetogenic encephalomyocarditis strain D virus induces diabetes in restricted lines of inbred mice, the susceptibility genes to virus-induced diabetes have not been identified. We report here that novel Tyrosine kinase 2 (Tyk2) gene mutations are present in virus-induced diabetes-sensitive SJL and SWR mice. Mice carrying the mutant Tyk2 gene on the virus-resistant C57BL/6 background are highly sensitive to virus-induced diabetes. Tyk2 gene expression is strongly reduced in Tyk2-mutant mice, associated with low Tyk2 promoter activity, and leads to decreased expression of interferon-inducible genes, resulting in significantly compromised antiviral response. Tyk2-mutant pancreatic β-cells are unresponsive even to high dose of Type I interferon. Reversal of virus-induced diabetes could be achieved by β-cell-specific Tyk2 gene expression. Thus, reduced Tyk2 gene expression in pancreatic β-cells due to natural mutation is responsible for susceptibility to virus-induced diabetes. PMID:25849081

  3. Factors affecting susceptibility to RNA interference in Haemonchus contortus and in vivo silencing of an H11 aminopeptidase gene.

    PubMed

    Samarasinghe, Buddhini; Knox, David P; Britton, Collette

    2011-01-01

    Gene silencing by RNA interference (RNAi) has been applied very successfully to Caenorhabditis elegans to study gene function but has proven less effective in parasitic nematodes. In the sheep gastrointestinal nematode Haemonchus contortus, previous studies demonstrated reproducible silencing of β-tubulin but not of other genes targeted. Here we aimed to examine whether the level of target transcript or site of gene expression influence susceptibility to RNAi by soaking. Target genes represented by a high number of expressed sequence tags (ESTs) in the H. contortus L3 stage were not reproducibly silenced. In contrast, four out of six genes putatively expressed in the intestine, excretory cell or amphids were consistently silenced by RNAi. This suggests that genes expressed in sites accessible to the environment are more likely to be susceptible to RNAi by soaking. Silenced genes included those encoding the highly protective gut aminopeptidase H11, secretory protein Hc-ASP-1, β-tubulin and homologues of aquaporin and RNA helicase. To determine whether RNAi silencing of H11 could mimic H11 vaccination in reducing worm and egg counts, we examined the in vivo effects of H11 RNAi. This is the first, to our knowledge, in vivo study of RNAi in an animal parasitic nematode. RNAi of the H11 gene in infective larvae prior to infection resulted in a 57% reduction in faecal egg count (FEC), 40% reduction in worm burden and 64% decrease in aminopeptidase activity compared with pre-soaking in control dsRNA. Thus, in this study we have established that RNAi is a valid and feasible approach to identify essential gene function. However, using current methods, this may be limited to genes expressed in accessible sites. PMID:20699100

  4. Polymorphisms of metabolic enzyme genes, living habits and prostate cancer susceptibility.

    PubMed

    Yang, Jie; Wu, Hong-fei; Zhang, Wei; Gu, Min; Hua, Li-xin; Sui, Yuan-geng; Zhang, Zheng-dong; Zhou, Jian-wei; Wang, Xin-Ru; Zou, Changping; Qian, Li-xin

    2006-01-01

    In this report, genetic polymorphism of phase I and II metabolic enzyme (CYP2E1, CYP17, GSTM1 and GSTT1) genes, living habits, and risk of prostate cancer (PCa) was studied in 163 patients with prostate carcinoma of Han nationality in Southern China and 202 age-matched controls. The genotypic polymorphism of CYP2E1, CYP17, GSTM1 and GSTT1 genes was analyzed by PCR-RFLP assay using genomic DNA isolated from peripheral blood lymphocytes. The significant risk factors for PCa included long-term exposure to toxicant (OR=2.27, 95%CI: 1.26-4.09), the tumor history of lineal consanguinity (OR=2.19, 95%CI: 1.30-3.67), sexual history before age 30 of no more than 8 times per month (OR=1.85, 95%CI: 1.22-2.81), deep inhalation of cigarette smoke (OR=2.01, 95%CI: 1.20-3.37) or heavy smoking (OR=1.67,95%CI: 1.01-2.76). Among individuals with long-term heavy smoking without tea-drinking habit, the risk increased significantly (OR=4.27, 95%CI: 1.62-11.24 and OR), 2.76, 95%CI: 1.20-6.32). CYP2E1 C1/C1 genotype significantly increased the risk for PCa (OR=1.61, 95%CI: 1.04-2.49) with an apparent interaction with alcohol (OR=2.07, 95%CI: 1.07-4.00). However, stratification by the amount of accumulative smoking revealed that among people with a heavy smoking history, the individuals with the CYP2E1 C1/C1 genotype (OR=2.55, 95%CI: 1.20-5.43) and the individuals with GSTT1 null genotype (OR=2.23, 95%CI: 1.09-4.57) showed a significantly increased risk. Any other significant results with GSTM1 or CYP17 genes were not observed in this research. Individuals with more sensitive genotypes (from one to four) were at an increased risk. The data show that, in the development of PCa, there are many interactions among predisposing genotypes and genetic polymorphisms and unhealthy living habits. Individuals with more susceptible genotypes and unhealthy habits such as prolonged exposure to smoking are at an increased risk. PMID:16720291

  5. Fine mapping of the gene for susceptibility to black spot disease in Japanese pear (Pyrus pyrifolia Nakai).

    PubMed

    Terakami, Shingo; Moriya, Shigeki; Adachi, Yoshihiko; Kunihisa, Miyuki; Nishitani, Chikako; Saito, Toshihiro; Abe, Kazuyuki; Yamamoto, Toshiya

    2016-03-01

    Black spot disease, which is caused by the Japanese pear pathotype of the filamentous fungus Alternaria alternata (Fries) Keissler, is one of the most harmful diseases in Japanese pear cultivation. We mapped a gene for susceptibility to black spot disease in the Japanese pear (Pyrus pyrifolia Nakai) cultivar 'Kinchaku' (Aki gene) at the top of linkage group 11, similar to the positions of the susceptibility genes Ani in 'Osa Nijisseiki' and Ana in 'Nansui'. Using synteny-based marker enrichment, we developed novel apple SSR markers in the target region. We constructed a fine map of linkage group 11 of 'Kinchaku' and localized the Aki locus within a 1.5-cM genome region between SSR markers Mdo.chr11.28 and Mdo.chr11.34. Marker Mdo.chr11.30 co-segregated with Aki in all 621 F1 plantlets of a 'Housui' × 'Kinchaku' cross. The physical size of the Aki region, which includes three markers (Mdo.chr11.28, Mdo.chr11.30, and Mdo.chr11.34), was estimated to be 250 Kb in the 'Golden Delicious' apple genome and 107 Kb in the 'Dangshansuli' Chinese pear genome. Our results will help to identify the candidate gene for susceptibility to black spot disease in Japanese pear. PMID:27162498

  6. Intronic deletions of tva receptor gene decrease the susceptibility to infection by avian sarcoma and leukosis virus subgroup A

    PubMed Central

    Chen, Weiguo; Liu, Yang; Li, Hongxing; Chang, Shuang; Shu, Dingming; Zhang, Huanmin; Chen, Feng; Xie, Qingmei

    2015-01-01

    The group of avian sarcoma and leukosis virus (ASLV) in chickens contains six highly related subgroups, A to E and J. Four genetic loci, tva, tvb, tvc and tvj, encode for corresponding receptors that determine the susceptibility to the ASLV subgroups. The prevalence of ASLV in hosts may have imposed strong selection pressure toward resistance to ASLV infection, and the resistant alleles in all four receptor genes have been identified. In this study, two new alleles of the tva receptor gene, tvar5 and tvar6, with similar intronic deletions were identified in Chinese commercial broilers. These natural mutations delete the deduced branch point signal within the first intron, disrupting mRNA splicing of the tva receptor gene and leading to the retention of intron 1 and introduction of premature TGA stop codons in both the longer and shorter tva isoforms. As a result, decreased susceptibility to subgroup A ASLV in vitro and in vivo was observed in the subsequent analysis. In addition, we identified two groups of heterozygous allele pairs which exhibited quantitative differences in host susceptibility to ASLV-A. This study demonstrated that defective splicing of the tva receptor gene can confer genetic resistance to ASLV subgroup A in the host. PMID:25873518

  7. Fine mapping of the gene for susceptibility to black spot disease in Japanese pear (Pyrus pyrifolia Nakai)

    PubMed Central

    Terakami, Shingo; Moriya, Shigeki; Adachi, Yoshihiko; Kunihisa, Miyuki; Nishitani, Chikako; Saito, Toshihiro; Abe, Kazuyuki; Yamamoto, Toshiya

    2016-01-01

    Black spot disease, which is caused by the Japanese pear pathotype of the filamentous fungus Alternaria alternata (Fries) Keissler, is one of the most harmful diseases in Japanese pear cultivation. We mapped a gene for susceptibility to black spot disease in the Japanese pear (Pyrus pyrifolia Nakai) cultivar ‘Kinchaku’ (Aki gene) at the top of linkage group 11, similar to the positions of the susceptibility genes Ani in ‘Osa Nijisseiki’ and Ana in ‘Nansui’. Using synteny-based marker enrichment, we developed novel apple SSR markers in the target region. We constructed a fine map of linkage group 11 of ‘Kinchaku’ and localized the Aki locus within a 1.5-cM genome region between SSR markers Mdo.chr11.28 and Mdo.chr11.34. Marker Mdo.chr11.30 co-segregated with Aki in all 621 F1 plantlets of a ‘Housui’ × ‘Kinchaku’ cross. The physical size of the Aki region, which includes three markers (Mdo.chr11.28, Mdo.chr11.30, and Mdo.chr11.34), was estimated to be 250 Kb in the ‘Golden Delicious’ apple genome and 107 Kb in the ‘Dangshansuli’ Chinese pear genome. Our results will help to identify the candidate gene for susceptibility to black spot disease in Japanese pear. PMID:27162498

  8. No significant impact of IFN-γ pathway gene variants on tuberculosis susceptibility in a West African population.

    PubMed

    Meyer, Christian G; Intemann, Christopher D; Förster, Birgit; Owusu-Dabo, Ellis; Franke, Andre; Horstmann, Rolf D; Thye, Thorsten

    2016-05-01

    The concept of interferon-γ (IFN-γ) having a central role in cell-mediated immune defence to Mycobacterium tuberculosis has long been proposed. Observations made through early candidate gene studies of constituents of the IFN-γ pathway have identified moderately associated variants associated with resistance or susceptibility to tuberculosis (TB). By analysing 20 major genes whose proteins contribute to IFN-γ signalling we have assessed a large fraction of the variability in genes that might contribute to susceptibility to TB. Genetic variants were identified by sequencing the promoter regions and all exons of IFNG, IFNGR1, IFNGR2, IRF1, IL12A, IL12B, IL12RB1, IL12RB2, IL23A, IL23R, IL27, EBI3, IL27RA, IL6ST, SOCS1, STAT1, STAT4, JAK2, TYK2 and TBX21 in 69 DNA samples from Ghana. In addition, we screened all exons of IFNGR1 in a Ghanaian study group comprising 1999 TB cases and 2589 controls by high-resolution melting point analysis. The fine-mapping approach allows for a detailed screening of all variants, common and rare. Statistical comparisons of cases and controls, however, did not yield significant results after correction for multiple testing with any of the 246 variants selected for genotyping in this investigation. Gene-wise haplotype tests and analysis of rare variants did not reveal any significant association with susceptibility to TB in our investigation as well. Although this analysis was applied on a plausible set of IFN-γ pathway genes in the largest African TB cohort available so far, the lack of significant results challenges the view that genetic marker of the IFN-γ pathway have an important impact on susceptibility to TB. PMID:26242990

  9. Genome-Wide Local Ancestry Approach Identifies Genes and Variants Associated with Chemotherapeutic Susceptibility in African Americans

    PubMed Central

    Wheeler, Heather E.; Gorsic, Lidija K.; Welsh, Marleen; Stark, Amy L.; Gamazon, Eric R.; Cox, Nancy J.; Dolan, M. Eileen

    2011-01-01

    Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5′-deoxyfluorouridine (5′-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−4). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5′-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−3). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information. PMID:21755009

  10. Impact of Maspin Polymorphism rs2289520 G/C and Its Interaction with Gene to Gene, Alcohol Consumption Increase Susceptibility to Oral Cancer Occurrence

    PubMed Central

    Yang, Po-Yu; Miao, Nae-Fang; Lin, Chiao-Wen; Chou, Ying-Erh; Yang, Shun-Fa; Huang, Hui-Chuan; Chang, Hsiu-Ju; Tsai, Hsiu-Ting

    2016-01-01

    Background The purpose of this study was to identify gene polymorphisms of mammary serine protease inhibitor (Maspin) specific to patients with oral cancer susceptibility and clinicopathological status. Methodology/Principal Findings Three single-nucleotide polymorphisms (SNPs) of the Maspin gene from 741 patients with oral cancer and 601 non-cancer controls were analyzed by real-time PCR. The participants with G/G homozygotes or with G/C heterozygotes of Maspin rs2289520 polymorphism had a 2.07-fold (p = 0.01) and a 2.01-fold (p = 0.02) risk of developing oral cancer compared to those with C/C homozygotes. Moreover, gene-gene interaction increased the risk of oral cancer susceptibility among subjects expose to oral cancer related risk factors, including areca, alcohol, and tobacco consumption. Conclusion G allele of Maspin rs2289520 polymorphism may be a factor that increases the susceptibility to oral cancer. The interactions of gene to oral cancer-related environmental risk factors have a synergetic effect that can further enhance oral cancer development. PMID:27525723

  11. Emergency department bedside ultrasound diagnosis of retinoblastoma in a child.

    PubMed

    Presley, Bradley C; Flannigan, Matthew J

    2013-10-01

    A 30-month-old boy presented to a Haitian emergency department with proptosis, periorbital edema, and progressive blindness. Bedside ultrasound examination revealed bilateral ocular masses with dense calcifications pathognomonic for retinoblastoma. This case illustrates the diagnostic utility of bedside ultrasound for an advanced case of retinoblastoma in a resource-poor setting. Ocular ultrasound technique is also reviewed. PMID:24084617

  12. Nucleotide substitutions in the Candida albicans ERG11 gene of azole-susceptible and azole-resistant clinical isolates.

    PubMed

    Strzelczyk, Joanna Katarzyna; Slemp-Migiel, Anna; Rother, Magdalena; Gołąbek, Karolina; Wiczkowski, Andrzej

    2013-01-01

    One of the mechanisms of Candida albicans resistance to azole drugs used in antifungal therapy relies on increased expression and presence of point mutations in the ERG11 gene that encodes sterol 14α demethylase (14DM), an enzyme which is the primary target for the azole class of antifungals. The aim of the study was to analyze nucleotide substitutions in the Candida albicans ERG11 gene of azole-susceptible and azole-resistant clinical isolates. The Candida albicans isolates represented a collection of 122 strains selected from 658 strains isolated from different biological materials. Samples were obtained from hospitalized patients. Fluconazole susceptibility was tested in vitro using a microdilution assay. Candida albicans strains used in this study consisted of two groups: 61 of the isolates were susceptible to azoles and the 61 were resistant to azoles. Four overlapping regions of the ERG11 gene of the isolates of Candida albicans strains were amplified and sequenced. The MSSCP (multitemperature single strand conformation polymorphism) method was performed to select Candida albicans samples presenting genetic differences in the ERG11 gene fragments for subsequent sequence analysis. Based on the sequencing results we managed to detect 19 substitutions of nucleotides in the ERG11 gene fragments. Sequencing revealed 4 different alterations: T495A, A530C, G622A and A945C leading to changes in the corresponding amino acid sequence: D116E, K128T, V159I and E266D. The single nucleotide changes in the ERG11 gene did not affect the sensitivity of Candida albicans strains, whereas multiple nucleotide substitutions in the ERG11 gene fragments indicated a possible relation with the increase in resistance to azole drugs. PMID:24340302

  13. Illumina next generation sequencing data and expression microarrays data from retinoblastoma and medulloblastoma tissues.

    PubMed

    García-Chequer, A J; Méndez-Tenorio, A; Olguín-López, G; Sánchez-Vallejo, C; Isa, P; Arias, C F; Torres, J; Hernández-Angeles, A; Ramírez-Ortiz, M A; Lara, C; Cabrera-Muñoz, Ma de L; Sadowinski-Pine, S; Bravo-Ortiz, J C; Ramón-García, G; Diegopérez-Ramírez, J; Ramírez-Reyes, G; Casarrubias-Islas, R; Ramírez, J; Orjuela, M; Ponce-Castañeda, M V

    2016-03-01

    Retinoblastoma (Rb) is a pediatric intraocular malignancy and probably the most robust clinical model on which genetic predisposition to develop cancer has been demonstrated. Since deletions in chromosome 13 have been described in this tumor, we performed next generation sequencing to test whether recurrent losses could be detected in low coverage data. We used Illumina platform for 13 tumor tissue samples: two pools of 4 retinoblastoma cases each and one pool of 5 medulloblastoma cases (raw data can be found at http://www.ebi.ac.uk/ena/data/view/PRJEB6630). We first created an in silico reference profile generated from a human sequenced genome (GRCh37p5). From this data we calculated an integrity score to get an overview of gains and losses in all chromosomes; we next analyzed each chromosome in windows of 40 kb length, calculating for each window the log2 ratio between reads from tumor pool and in silico reference. Finally we generated panoramic maps with all the windows whether lost or gained along each chromosome associated to its cytogenetic bands to facilitate interpretation. Expression microarrays was done for the same samples and a list of over and under expressed genes is presented here. For this detection a significance analysis was done and a log2 fold change was chosen as significant (raw data can be found at http://www.ncbi.nlm.nih.gov/geo/accession number GSE11488). The complete research article can be found at Cancer Genetics journal (Garcia-Chequer et al., in press) [1]. In summary here we provide an overview with visual graphics of gains and losses chromosome by chromosome in retinoblastoma and medulloblastoma, also the integrity score analysis and a list of genes with relevant expression associated. This material can be useful to researchers that may want to explore gains and losses in other malignant tumors with this approach or compare their data with retinoblastoma. PMID:26937470

  14. Illumina next generation sequencing data and expression microarrays data from retinoblastoma and medulloblastoma tissues

    PubMed Central

    García-Chequer, A.J.; Méndez-Tenorio, A.; Olguín-López, G.; Sánchez-Vallejo, C.; Isa, P.; Arias, C.F.; Torres, J.; Hernández-Angeles, A.; Ramírez-Ortiz, M.A.; Lara, C.; Cabrera-Muñoz, Ma.de.L.; Sadowinski-Pine, S.; Bravo-Ortiz, J.C.; Ramón-García, G.; Diegopérez-Ramírez, J.; Ramírez-Reyes, G.; Casarrubias-Islas, R.; Ramírez, J.; Orjuela, M.; Ponce-Castañeda, M.V.

    2016-01-01

    Retinoblastoma (Rb) is a pediatric intraocular malignancy and probably the most robust clinical model on which genetic predisposition to develop cancer has been demonstrated. Since deletions in chromosome 13 have been described in this tumor, we performed next generation sequencing to test whether recurrent losses could be detected in low coverage data. We used Illumina platform for 13 tumor tissue samples: two pools of 4 retinoblastoma cases each and one pool of 5 medulloblastoma cases (raw data can be found at http://www.ebi.ac.uk/ena/data/view/PRJEB6630). We first created an in silico reference profile generated from a human sequenced genome (GRCh37p5). From this data we calculated an integrity score to get an overview of gains and losses in all chromosomes; we next analyzed each chromosome in windows of 40 kb length, calculating for each window the log2 ratio between reads from tumor pool and in silico reference. Finally we generated panoramic maps with all the windows whether lost or gained along each chromosome associated to its cytogenetic bands to facilitate interpretation. Expression microarrays was done for the same samples and a list of over and under expressed genes is presented here. For this detection a significance analysis was done and a log2 fold change was chosen as significant (raw data can be found at http://www.ncbi.nlm.nih.gov/geo/accession number GSE11488). The complete research article can be found at Cancer Genetics journal (Garcia-Chequer et al., in press) [1]. In summary here we provide an overview with visual graphics of gains and losses chromosome by chromosome in retinoblastoma and medulloblastoma, also the integrity score analysis and a list of genes with relevant expression associated. This material can be useful to researchers that may want to explore gains and losses in other malignant tumors with this approach or compare their data with retinoblastoma. PMID:26937470

  15. Differentially regulated genes in the salivary glands of brown planthopper after feeding in resistant versus susceptible rice varieties.

    PubMed

    Wang, Xiaolan; Zhang, Mei; Feng, Fei; He, Ruifeng

    2015-06-01

    Brown planthopper (BPH) is a damaging insect pest of rice. We used suppression subtractive hybridization (SSH) and mirror orientation selection to identify differentially regulated genes in salivary glands of BPH after feeding on resistant and susceptible varieties. The forward SSH library included 768 clones with insertions ranging from 250 to 1000 bp. After differential screening, a total of 112 transcripts were identified, which included 27 upregulated genes and seven downregulated genes. Several of these transcripts showed sequence homology to known proteins such as trehalase, mucin-like protein, vitellogenin, calcium ion binding protein, and eukaryotic initiation factor-like protein. About half of the transcripts, however, did not match to any sequences in the protein databases currently available. Functional annotation of the transcripts showed gene ontology association with metabolism, signal transduction, and regulatory responses. Notably, many known functional genes were predicted to be secreted proteins. Also, gene expression profiles of the salivary glands of BPH feeding on resistant rice (B5) and susceptible rice (TN1) varieties were compared. Our data provide a molecular resource for future functional studies on salivary glands and will be useful for elucidating the molecular mechanisms between BPH feeding and rice varieties with BPH resistance differences. PMID:25611813

  16. Differential Distribution of Plasmid-Mediated Quinolone Resistance Genes in Clinical Enterobacteria with Unusual Phenotypes of Quinolone Susceptibility from Argentina

    PubMed Central

    Andres, Patricia; Lucero, Celeste; Soler-Bistué, Alfonso; Guerriero, Leonor; Albornoz, Ezequiel; Tran, Tung; Zorreguieta, Angeles; Galas, Marcelo; Corso, Alejandra; Tolmasky, Marcelo E.

    2013-01-01

    We studied a collection of 105 clinical enterobacteria with unusual phenotypes of quinolone susceptibility to analyze the occurrence of plasmid-mediated quinolone resistance (PMQR) and oqx genes and their implications for quinolone susceptibility. The oqxA and oqxB genes were found in 31/34 (91%) Klebsiella pneumoniae and 1/3 Klebsiella oxytoca isolates. However, the oqxA- and oqxB-harboring isolates lacking other known quinolone resistance determinants showed wide ranges of susceptibility to nalidixic acid and ciprofloxacin. Sixty of the 105 isolates (57%) harbored at least one PMQR gene [qnrB19, qnrB10, qnrB2, qnrB1, qnrS1, or aac(6′)-Ib-cr)], belong to 8 enterobacterial species, and were disseminated throughout the country, and most of them were categorized as susceptible by the current clinical quinolone susceptibility breakpoints. We developed a disk diffusion-based method to improve the phenotypic detection of aac(6′)-Ib-cr. The most common PMQR genes in our collection [qnrB19, qnrB10, and aac(6′)-Ib-cr] were differentially distributed among enterobacterial species, and two different epidemiological settings were evident. First, the species associated with community-acquired infections (Salmonella spp. and Escherichia coli) mainly harbored qnrB19 (a unique PMQR gene) located in small ColE1-type plasmids that might constitute its natural reservoirs. qnrB19 was not associated with an extended-spectrum β-lactamase phenotype. Second, the species associated with hospital-acquired infections (Enterobacter spp., Klebsiella spp., and Serratia marcescens) mainly harbored qnrB10 in ISCR1-containing class 1 integrons that may also have aac(6′)-Ib-cr as a cassette within the variable region. These two PMQR genes were strongly associated with an extended-spectrum β-lactamase phenotype. Therefore, this differential distribution of PMQR genes is strongly influenced by their linkage or lack of linkage to integrons. PMID:23478955

  17. Variation analysis of transcriptome changes reveals cochlear genes and their associated functions in cochlear susceptibility to acoustic overstimulation.

    PubMed

    Yang, Shuzhi; Cai, Qunfeng; Bard, Jonathan; Jamison, Jennifer; Wang, Jianmin; Yang, Weiping; Hu, Bo Hua

    2015-12-01

    Individual variation in the susceptibility of the auditory system to acoustic overstimulation has been well-documented at both the functional and structural levels. However, the molecular mechanism responsible for this variation is unclear. The current investigation was designed to examine the variation patterns of cochlear gene expression using RNA-seq data and to identify the genes with expression variation that increased following acoustic trauma. This study revealed that the constitutive expressions of cochlear genes displayed diverse levels of gene-specific variation. These variation patterns were altered by acoustic trauma; approximately one-third of the examined genes displayed marked increases in their expression variation. Bioinformatics analyses revealed that the genes that exhibited increased variation were functionally related to cell death, biomolecule metabolism, and membrane function. In contrast, the stable genes were primarily related to basic cellular processes, including protein and macromolecular syntheses and transport. There was no functional overlap between the stable and variable genes. Importantly, we demonstrated that glutamate metabolism is related to the variation in the functional response of the cochlea to acoustic overstimulation. Taken together, the results indicate that our analyses of the individual variations in transcriptome changes of cochlear genes provide important information for the identification of genes that potentially contribute to the generation of individual variation in cochlear responses to acoustic overstimulation. PMID:26024952

  18. Wild rodents as a model to discover genes and pathways underlying natural variation in infectious disease susceptibility.

    PubMed

    Turner, Andrew K; Paterson, Steve

    2013-04-01

    Individuals vary in their susceptibility to infectious disease and it is now well established that host genetic factors form a major component of this variation. The discovery of genes underlying susceptibility has the potential to lead to improved disease control, through the identification and management of vulnerable individuals and the discovery of novel therapeutic targets. Laboratory rodents have proved invaluable for ascertaining the function of genes involved in immunity to infection. However, these captive animals experience conditions very different to the natural environment, lacking the genetic diversity and environmental pressures characteristic of natural populations, including those of humans. It has therefore often proved difficult to translate basic laboratory research to the real world. In order to further our understanding of the genetic basis of infectious disease resistance, and the evolutionary forces that drive variation in susceptibility, we propose that genetic research traditionally conducted on laboratory animals is expanded to the more ecologically valid arena of natural populations. In this article we highlight the potential of using wild rodents as a new resource for biomedical research, to link the functional genetic knowledge gained from laboratory rodents with the variation in infectious disease susceptibility observed in humans and other natural populations. © 2013 Blackwell Publishing Ltd. PMID:23550923

  19. Relevance of perceived childhood neglect, 5-HTT gene variants and hypothalamus-pituitary-adrenal axis dysregulation to substance abuse susceptibility.

    PubMed

    Gerra, G; Zaimovic, A; Castaldini, L; Garofano, L; Manfredini, M; Somaini, L; Leonardi, C; Gerra, M L; Donnini, C

    2010-04-01

    The hypotheses of (1) gene x environment interaction in the susceptibility to experiment with drugs and (2) hypothalamus-pituitary-adrenal (HPA) axis involvement in mediating the effects of early adverse experiences and gene variants affecting serotonin function on substance abuse vulnerability were tested by investigating in 187 healthy adolescents the possible relevance of 5-HTT "S" polymorphism, childhood parental neglect reported retrospectively and HPA axis function to the susceptibility to experiment with illicit drugs. Higher frequency of the 5-HTT SS genotype seems to be associated with an increased susceptibility to use illegal psychotropic drugs among the adolescents. At the same time, reduced maternal care perception was found to represent a key intermediate factor of the association between SS polymorphism and drug use, suggesting that genetic factors and parental behavior concur to drug use susceptibility. Our results also confirm the relationship between basal plasma levels of cortisol and adrenocorticotropic hormone (ACTH) on the one hand, and retrospective measures of neglect during childhood: the higher the mother and father neglect CECA-Q scores, the higher the plasma levels of the two HPA hormones. Such positive relationship has been proved to be particularly effective and important when associated to the S-allele, both in homozygote and heterozygote individuals. However, when tested together with genotype and parental neglect, the effect of HPA hormones such as cortisol and ACTH was not found to improve significantly the explanatory power of the risk model. PMID:19824018

  20. A Rapid and Sensitive Next-Generation Sequencing Method to Detect RB1 Mutations Improves Care for Retinoblastoma Patients and Their Families.

    PubMed

    Li, Wenhui L; Buckley, Jonathan; Sanchez-Lara, Pedro A; Maglinte, Dennis T; Viduetsky, Lucy; Tatarinova, Tatiana V; Aparicio, Jennifer G; Kim, Jonathan W; Au, Margaret; Ostrow, Dejerianne; Lee, Thomas C; O'Gorman, Maurice; Judkins, Alexander; Cobrinik, David; Triche, Timothy J

    2016-07-01

    Retinoblastoma is a childhood eye malignancy that can lead to the loss of vision, eye(s), and sometimes life. The tumors are initiated by inactivating mutations in both alleles of the tumor-suppressor gene, RB1, or, rarely, by MYCN amplification. Timely identification of a germline RB1 mutation in blood samples or either somatic RB1 mutation or MYCN amplification in tumors is important for effective care and management of retinoblastoma patients and their families. However, current procedures to thoroughly test RB1 mutations are complicated and lengthy. Herein, we report a next-generation sequencing-based method capable of detecting point mutations, small indels, and large deletions or duplications across the entire RB1 gene and amplification of MYCN gene on a single platform. From DNA extraction to clinical interpretation requires only 3 days, enabling early molecular diagnosis of retinoblastoma and optimal treatment outcomes. This method can also detect low-level mosaic mutations in blood samples that can be missed by routine Sanger sequencing. In addition, it can differentiate between RB1 mutation- and MYCN amplification-driven retinoblastomas. This rapid, comprehensive, and sensitive method for detecting RB1 mutations and MYCN amplification can readily identify RB1 mutation carriers and thus improve the management and genetic counseling for retinoblastoma patients and their families. PMID:27155049

  1. Risk definition and management strategies in retinoblastoma: current perspectives

    PubMed Central

    Ghassemi, Fariba; Khodabande, Alireza

    2015-01-01

    This manuscript focuses on high-risk factors of metastatic disease in retinoblastoma and evaluation of the current treatments of retinoblastoma. Presence of histopathologic high-risk factors is associated with a higher risk of local recurrence and systemic metastasis. Currently, globe-sparing therapies, including systemic chemotherapy, intra-arterial chemoreduction, intravitreal chemotherapy, focal consolidation, and combination therapies, are being used and investigated actively. Major advances are being made in the diagnosis and management of retinoblastoma that will lead to improved morbidity and mortality rates in patients with retinoblastoma. By saving the globes, fronting with some high-risk factors for metastasis would be inevitable. International multi-institutional prospective studies could resolve current uncertainties regarding the main tumor treatment regimens for each patient and indications for chemoprophylaxis for high-risk-factor-bearing retinoblastoma cases. PMID:26089630

  2. Schizophrenia susceptibility gene product dysbindin-1 regulates the homeostasis of cyclin D1.

    PubMed

    Ito, Hidenori; Morishita, Rika; Nagata, Koh-Ichi

    2016-08-01

    Dysbindin-1 (dystrobrevin binding protein-1, DTNBP1) is now widely accepted as a potential schizophrenia susceptibility gene and accumulating evidence indicates its functions in the neural development. In this study, we tried to identify new binding partners for dysbindin-1 to clarify the novel function of this molecule. When consulted with BioGRID protein interaction database, cyclin D3 was found to be a possible binding partner for dysbindin-1. We then examined the interaction between various dysbindin-1 isoforms (dysbindin-1A, -1B and -1C) and all three D-type cyclins (cyclin D1, D2, and D3) by immunoprecipitation with the COS7 cell expression system, and found that dysbindin-1A preferentially interacts with cyclin D1. The mode of interaction between these molecules was considered as direct binding since recombinant dysbindin-1A and cyclin D1 formed a complex in vitro. Mapping analyses revealed that the C-terminal region of dysbindin-1A binds to the C-terminal of cyclin D1. Consistent with the results of the biochemical analyses, endogenous dysbindin-1was partially colocalized with cyclin D1 in NIH3T3 fibroblast cells and in neuronal stem and/or progenitor cells in embryonic mouse brain. While co-expression of dysbindin-1A with cyclin D1 changed the localization of the latter from the nucleus to cytosol, cyclin D1-binding partner CDK4 inhibited the dysbindin-cyclin D1 interaction. Meanwhile, depletion of endogenous dysbindin-1A increased cyclin D1 expression. These results indicate that dysbindin-1A may control the cyclin D1 function spatiotemporally and might contribute to better understanding of the pathophysiology of dysbindin-1-associated disorders. PMID:27130439

  3. CD24 gene polymorphism is associated with the disease progression and susceptibility to multiple sclerosis in the Iranian population.

    PubMed

    Ronaghi, Mohammad; Vallian, Sadeq; Etemadifar, Masoud

    2009-12-30

    The impact of a single nucleotide polymorphism (SNP) in the CD24 gene on the risk and progression of multiple sclerosis (MS) was investigated in the Iranian population. Our data revealed that the susceptibility and the progression of MS in individuals with the CD24V/V genotype were greater than in those with the CD24A/V and CD24A/A genotypes. PMID:19896210

  4. STK39 and WNK1 Are Potential Hypertension Susceptibility Genes in the BELHYPGEN Cohort

    PubMed Central

    Persu, Alexandre; Evenepoel, Lucie; Jin, Yu; Mendola, Antonella; Ngueta, Gérard; Yang, Wen-Yi; Gruson, Damien; Horman, Sandrine; Staessen, Jan A.; Vikkula, Miikka

    2016-01-01

    Abstract The serine/threonine kinase With-No-Lysine (K) Kinase 1 (WNK1) activates the thiazide-sensitive Na+/Cl− cotransporter through phosphorylation of STE20/SPS1-related proline/alanine-rich kinase, another serine/threonine kinase encoded by STK39. The aim of this study was to look for association between WNK1 and STK39 gene variants, and blood pressure (BP) and hypertension. Seven hundred seventy-nine Caucasian hypertensive patients (HYP) recruited in 6 academic centers from Belgium, and 906 normotensive (NT) controls were genotyped for 5 single nucleotide polymorphisms—rs3754777, rs6749447, rs35929607 (STK39), rs1468326, and rs765250 (WNK1)—using the Snapshot method. The rare TT genotype at the rs3754777 locus (STK39) was overrepresented in HYP versus NT (7.3% vs 3.0%, P = 0.0002). In the whole study population, the multivariable-adjusted odds ratio (OR) for having hypertension associated with the TT genotype was 5.9 (95% confidence interval: 2.2–15.6), and systolic BP was 10 mm Hg higher in TT compared with wild-type subjects (140.1 vs 130.4 mm Hg, P = 0.002). Similarly, the AA genotype at the rs1468326 locus (WNK1) was twice as frequent in HYP versus NT (5.5% vs 2.3%, P < 0.0001), and associated with an increased adjusted OR of hypertension (4.1; 1.5–11.7) and a higher systolic BP (139.8 vs 130.1 mm Hg, P = 0.003). In the whole cohort, a dose-dependent increase in systolic BP was observed according to the number of at-risk genotypes (0: 129.8 mm Hg; 1: 133.0 mm Hg; 2: 149.3 mm Hg, P = 0.02). Single nucleotide polymorphisms rs3754777 (STK39) and rs1468326 (WNK1) were associated with hypertension and BP in our multicenter Belgian case-control study, which supports the role of STK39 and WNK1 as potential hypertension susceptibility genes. Replication in different clinical settings and study of other candidate loci belonging to the same molecular pathway is warranted. PMID:27082544

  5. The Correlation Between Interferon Lambda 3 Gene Polymorphisms and Susceptibility to Hepatitis B Virus Infection

    PubMed Central

    Heidari, Zahra; Moudi, Bita; Mahmoudzadeh-Sagheb, Hamidreza; Hashemi, Mohammad

    2016-01-01

    Background Cytokines are proteins that mediate innate and adaptive immunity responses. It is hypothesized that interferon lambda 3 (IFNL3) levels can influence the outcome of chronic hepatitis B virus (HBV) infection. Polymorphisms in IFN genes have been associated with response to infection. Objectives This study was carried-out to investigate the association of IFNL3 gene polymorphisms (rs12979860 and rs8099917) with HBV susceptibility, in chronic HBV-infected patients. Patients and Methods In this case-control study, we determined IFNL3 single nucleotide polymorphisms (SNPs) (rs12979860 and rs8099917) in 221 individuals, with chronic HBV infection, and 200 healthy individuals, who were voluntary blood donors, with negative test for HBV. Alleles and genotypes analyses were performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results The frequencies of the rs12979860 and rs8099917 genotypes were not significantly different between the HBV-infected and the control groups (CC:CT:TT of 30.3%:48.0%:21.7% vs. 33.0%:49.0%:18.0%, P > 0.05, and GG:GT:TT of 5.8%:39.4%:54.8% vs. 5.0%:41.0%:54.0%, P > 0.05, respectively). Also, the frequencies of the alleles were not significantly different between both groups (C:T of 54.3%:45.7% vs. 57.5%:42.5%, P > 0.05, and G:T of 25.6%:74.4% vs. 25.5%:74.5%, P > 0.05, respectively) and the chronic HBV infection. There were no significant differences between patients, with at least one rs12979860C and or rs8099917T alleles compared to the healthy controls (rs12979860: CT + CC:TT, OR = 1.26, 95%CI = 0.78 - 2.04, P = 0.341 and rs8099917: GT + TT:GG, OR = 1.03, 95%CI = 0.70 - 1.51, P = 0.877, respectively). Conclusions Our study showed no correlation between rs12979860 and rs8099917 SNPs and chronic HBV infection. Further studies, with larger sample sizes and different ethnicities, are necessary to validate our

  6. STK39 and WNK1 Are Potential Hypertension Susceptibility Genes in the BELHYPGEN Cohort.

    PubMed

    Persu, Alexandre; Evenepoel, Lucie; Jin, Yu; Mendola, Antonella; Ngueta, Gérard; Yang, Wen-Yi; Gruson, Damien; Horman, Sandrine; Staessen, Jan A; Vikkula, Miikka

    2016-04-01

    The serine/threonine kinase With-No-Lysine (K) Kinase 1 (WNK1) activates the thiazide-sensitive Na(+)/Cl(-) cotransporter through phosphorylation of STE20/SPS1-related proline/alanine-rich kinase, another serine/threonine kinase encoded by STK39. The aim of this study was to look for association between WNK1 and STK39 gene variants, and blood pressure (BP) and hypertension. Seven hundred seventy-nine Caucasian hypertensive patients (HYP) recruited in 6 academic centers from Belgium, and 906 normotensive (NT) controls were genotyped for 5 single nucleotide polymorphisms-rs3754777, rs6749447, rs35929607 (STK39), rs1468326, and rs765250 (WNK1)-using the Snapshot method. The rare TT genotype at the rs3754777 locus (STK39) was overrepresented in HYP versus NT (7.3% vs 3.0%, P = 0.0002). In the whole study population, the multivariable-adjusted odds ratio (OR) for having hypertension associated with the TT genotype was 5.9 (95% confidence interval: 2.2-15.6), and systolic BP was 10 mm Hg higher in TT compared with wild-type subjects (140.1 vs 130.4 mm Hg, P = 0.002). Similarly, the AA genotype at the rs1468326 locus (WNK1) was twice as frequent in HYP versus NT (5.5% vs 2.3%, P < 0.0001), and associated with an increased adjusted OR of hypertension (4.1; 1.5-11.7) and a higher systolic BP (139.8 vs 130.1 mm Hg, P = 0.003). In the whole cohort, a dose-dependent increase in systolic BP was observed according to the number of at-risk genotypes (0: 129.8 mm Hg; 1: 133.0 mm Hg; 2: 149.3 mm Hg, P = 0.02). Single nucleotide polymorphisms rs3754777 (STK39) and rs1468326 (WNK1) were associated with hypertension and BP in our multicenter Belgian case-control study, which supports the role of STK39 and WNK1 as potential hypertension susceptibility genes. Replication in different clinical settings and study of other candidate loci belonging to the same molecular pathway is warranted. PMID:27082544

  7. Characterization of gene-environment interactions for colorectal cancer susceptibility loci

    PubMed Central

    Hutter, Carolyn M.; Chang-Claude, Jenny; Slattery, Martha L.; Pflugeisen, Bethann M.; Lin, Yi; Duggan, David; Nan, Hongmei; Lemire, Mathieu; Rangrej, Jagadish; Figueiredo, Jane C.; Jiao, Shuo; Harrison, Tabitha A.; Liu, Yan; Chen, Lin S.; Stelling, Deanna L.; Warnick, Greg S.; Hoffmeister, Michael; Küry, Sébastien; Fuchs, Charles S.; Giovannucci, Edward; Hazra, Aditi; Kraft, Peter; Hunter, David J.; Gallinger, Steven; Zanke, Brent W.; Brenner, Hermann; Frank, Bernd; Ma, Jing; Ulrich, Cornelia M.; White, Emily; Newcomb, Polly A.; Kooperberg, Charles; LaCroix, Andrea Z.; Prentice, Ross L.; Jackson, Rebecca D.; Schoen, Robert E.; Chanock, Stephen J.; Berndt, Sonja I.; Hayes, Richard B.; Caan, Bette J.; Potter, John D.; Hsu, Li; Bézieau, Stéphane; Chan, Andrew T.; Hudson, Thomas J.; Peters, Ulrike

    2012-01-01

    Genome-wide association studies (GWAS) have identified over a dozen loci associated with colorectal cancer (CRC) risk. Here we examined potential effect-modification between single nucleotide polymorphisms (SNPs) at 10 of these loci and probable or established environmental risk factors for CRC in 7,016 CRC cases and 9,723 controls from nine cohort and case-control studies. We used meta-analysis of an efficient empirical-Bayes estimator to detect potential multiplicative interactions between each of the SNPs [rs16892766 at 8q23.3 (EIF3H/UTP23); rs6983267 at 8q24 (MYC); rs10795668 at 10p14 (FLJ3802842); rs3802842 at11q23 (LOC120376); rs4444235 at 14q22.2 (BMP4); rs4779584 at15q13 (GREM1); rs9929218 at16q22.1 (CDH1); rs4939827 at18q21 (SMAD7); rs10411210 at19q13.1 (RHPN2); and rs961253 at 20p12.3 (BMP2)] and select major CRC risk factors (sex, body mass index, height, smoking status, aspirin/non-steroidal anti-inflammatory drug use, alcohol use, and dietary intake of calcium, folate, red meat, processed meat, vegetables, fruit, and fiber). The strongest statistical evidence for a gene-environment interaction across studies was for vegetable consumption and rs16892766, located on chromosome 8q23.3, near the EIF3H and UTP23 genes (nominal p-interaction =1.3×10–4; adjusted p-value 0.02). The magnitude of the main effect of the SNP increased with increasing levels of vegetable consumption. No other interactions were statistically significant after adjusting for multiple comparisons. Overall, the association of most CRC susceptibility loci identified in initial GWAS appears to be invariant to the other risk factors considered; however, our results suggest potential modification of the rs16892766 effect by vegetable consumption. PMID:22367214

  8. TNF-α gene polymorphisms: association with disease susceptibility and response to anti-TNF-α treatment in psoriatic arthritis.

    PubMed

    Murdaca, Giuseppe; Gulli, Rossella; Spanò, Francesca; Lantieri, Francesca; Burlando, Martina; Parodi, Aurora; Mandich, Paola; Puppo, Francesco

    2014-10-01

    The tumor necrosis factor-α (TNF-α) gene has been proposed as a major candidate gene in psoriatic arthritis (PsA). TNF-α is a therapeutic target for patients responding poorly to conventional treatments. We investigated the role of single-nucleotide polymorphisms (SNPs) at positions -238, -308, and +489 of the TNF-α gene in the genetic susceptibility to PsA, in the severity of the disease, and, finally, in the response to TNF-α inhibitors (adalimumab, etanercept, or infliximab). Fifty-seven Caucasian PsA patients and 155 healthy matched controls were studied. The SNP +489 variant allele A was significantly associated with PsA susceptibility (P=0.0136) and severity of clinical (Psoriasis Area and Severity Index score, American College of Rheumatology criteria, Disease Activity Score 28, and Disability Index Health Assessment Questionnaire) and laboratory (C-reactive protein and erythrocyte sedimentation rate) parameters (P-values ranging from 0.016 to 2.908 × 10(-12)). The difference in severity was accounted for by the differences between the AA and GA genotypes with respect to the GG genotype. The SNP +489A allele shows a trend of association with the response to PsA treatment with etanercept. These findings suggest a role of the SNP +489A allele in the susceptibility and severity of PsA. PMID:24594669

  9. Characteristics of carboxylesterase genes and their expression-level between acaricide-susceptible and resistant Tetranychus cinnabarinus (Boisduval).

    PubMed

    Wei, Peng; Shi, Li; Shen, Guangmao; Xu, Zhifeng; Liu, Jialu; Pan, Yu; He, Lin

    2016-07-01

    Carboxylesterases (CarEs) play important roles in metabolism and detoxification of dietary and environmental xenobiotics in insects and mites. On the basis of the Tetranychuscinnabarinus transcriptome dataset, 23 CarE genes (6 genes are full sequence and 17 genes are partial sequence) were identified. Synergist bioassay showed that CarEs were involved in acaricide detoxification and resistance in fenpropathrin- (FeR) and cyflumetofen-resistant (CyR) strains. In order to further reveal the relationship between CarE gene's expression and acaricide-resistance in T. cinnabarinus, we profiled their expression in susceptible (SS) and resistant strains (FeR, and CyR). There were 8 and 4 over-expressed carboxylesterase genes in FeR and CyR, respectively, from which the over-expressions were detected at mRNA level, but not DNA level. Pesticide induction experiment elucidated that 4 of 8 and 2 of 4 up-regulated genes were inducible with significance in FeR and CyR strains, respectively, but they could not be induced in SS strain, which indicated that these genes became more enhanced and effective to withstand the pesticides' stress in resistant T. cinnabarinus. Most expression-changed and all inducible genes possess the Abhydrolase_3 motif, which is a catalytic domain for hydrolyzing. As a whole, these findings in current study provide clues for further elucidating the function and regulation mechanism of these carboxylesterase genes in T. cinnabarinus' resistance formation. PMID:27265830

  10. Association of IFN-γ and P2X7 Receptor Gene Polymorphisms in Susceptibility to Tuberculosis Among Iranian Patients.

    PubMed

    Shamsi, Mahdi; Zolfaghari, Mohammad Reza; Farnia, Parissa

    2016-03-01

    Interferon-gamma (IFN-γ) and P2X7 receptor are crucial for host defence against mycobacterial infections. Recent studies have indicated that IFN-γ, IFN-γ receptor 1 (IFN-γR1) andP2X7 gene polymorphisms are associated with susceptibility to pulmonary tuberculosis (TB). However, the relationship between IFN-γ and P2X7 polymorphism and TB susceptibility remains inconclusive in Iranian population. For this reason, single nucleotide polymorphisms (SNPs) in IFN-γ (G+2109A), IFN-γR1 (G-611A) and P2X7 genes (at -762, 1513 position) in patients (n = 100) were assessed using PCR-RFLP. Data were analysed with SPSS version 18. For the 2109 loci of IFN-γ gene, the frequency of mutant alleles between patients and controls were not statistically significant. However, there was a significant difference between the TB patient and controls for -611 alleles of IFN-γR1 (P = 0.01). Additionally, the frequency of P2X7 gene polymorphisms (SNP-762 and 1513) between patients and controls was statistically significant. In conclusions, our study revealed a significant association of IFN-γR1 and P2X7 genes polymorphisms with risk of developing TB in Iranian population. PMID:27020872

  11. Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors.

    PubMed

    Koster, Roelof; Mitra, Nandita; D'Andrea, Kurt; Vardhanabhuti, Saran; Chung, Charles C; Wang, Zhaoming; Loren Erickson, R; Vaughn, David J; Litchfield, Kevin; Rahman, Nazneen; Greene, Mark H; McGlynn, Katherine A; Turnbull, Clare; Chanock, Stephen J; Nathanson, Katherine L; Kanetsky, Peter A

    2014-11-15

    Genome-wide association (GWA) studies of testicular germ cell tumor (TGCT) have identified 18 susceptibility loci, some containing genes encoding proteins important in male germ cell development. Deletions of one of these genes, DMRT1, lead to male-to-female sex reversal and are associated with development of gonadoblastoma. To further explore genetic association with TGCT, we undertook a pathway-based analysis of SNP marker associations in the Penn GWAs (349 TGCT cases and 919 controls). We analyzed a custom-built sex determination gene set consisting of 32 genes using three different methods of pathway-based analysis. The sex determination gene set ranked highly compared with canonical gene sets, and it was associated with TGCT (FDRG = 2.28 × 10(-5), FDRM = 0.014 and FDRI = 0.008 for Gene Set Analysis-SNP (GSA-SNP), Meta-Analysis Gene Set Enrichment of Variant Associations (MAGENTA) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS) analysis, respectively). The association remained after removal of DMRT1 from the gene set (FDRG = 0.0002, FDRM = 0.055 and FDRI = 0.009). Using data from the NCI GWA scan (582 TGCT cases and 1056 controls) and UK scan (986 TGCT cases and 4946 controls), we replicated these findings (NCI: FDRG = 0.006, FDRM = 0.014, FDRI = 0.033, and UK: FDRG = 1.04 × 10(-6), FDRM = 0.016, FDRI = 0.025). After removal of DMRT1 from the gene set, the sex determination gene set remains associated with TGCT in the NCI (FDRG = 0.039, FDRM = 0.050 and FDRI = 0.055) and UK scans (FDRG = 3.00 × 10(-5), FDRM = 0.056 and FDRI = 0.044). With the exception of DMRT1, genes in the sex determination gene set have not previously been identified as TGCT susceptibility loci in these GWA scans, demonstrating the complementary nature of a pathway-based approach for genome-wide analysis of TGCT. PMID:24943593

  12. The Association between GWAS-identified BARD1 Gene SNPs and Neuroblastoma Susceptibility in a Southern Chinese Population.

    PubMed

    Zhang, Ruizhong; Zou, Yan; Zhu, Jinhong; Zeng, Xinhao; Yang, Tianyou; Wang, Fenghua; He, Jing; Xia, Huimin

    2016-01-01

    A previous genome-wide association study (GWAS) has found that some common variations in the BARD1 gene were associated with neuroblastoma susceptibility especially for high-risk subjects, and the associations have been validated in Caucasians and African-Americans. However, the associations between BARD1 gene polymorphisms and neuroblastoma susceptibility have not been studied among Asians, not to mention Chinese subjects. In the present study, we investigated the association of three BARD1 polymorphisms (rs7585356 G>A, rs6435862 T>G and rs3768716 A>G) with neuroblastoma susceptibility in 201 neuroblastoma patients and 531 controls using TaqMan methodology. Overall, none of these polymorphisms was significantly associated with neuroblastoma susceptibility. However, stratified analysis showed a more profound association between neuroblastoma risk and rs6435862 TG/GG variant genotypes among older children (adjusted OR=1.55, 95% CI=1.04-2.31), and children with adrenal gland-originated disease (adjusted OR=2.94, 95% CI=1.40-6.18), or with ISSN clinical stages III+IV disease (adjusted OR=1.75, 95% CI=1.09-2.84). Similar results were observed for the variant genotypes of rs3768716 A>G polymorphism among these three subgroups. Our results suggest that the BARD1 rs6435862 T>G and rs3768716 A>G polymorphisms may contribute to increased susceptibility to neuroblastoma, especially for the subjects at age ≥12 months, with adrenal gland-originated or with late clinical stage neuroblastoma. These findings need further validation by prospective studies with larger sample size with subjects enrolled from multicenter, involving different ethnicities. PMID:26941572

  13. The Association between GWAS-identified BARD1 Gene SNPs and Neuroblastoma Susceptibility in a Southern Chinese Population

    PubMed Central

    Zhang, Ruizhong; Zou, Yan; Zhu, Jinhong; Zeng, Xinhao; Yang, Tianyou; Wang, Fenghua; He, Jing; Xia, Huimin

    2016-01-01

    A previous genome-wide association study (GWAS) has found that some common variations in the BARD1 gene were associated with neuroblastoma susceptibility especially for high-risk subjects, and the associations have been validated in Caucasians and African-Americans. However, the associations between BARD1 gene polymorphisms and neuroblastoma susceptibility have not been studied among Asians, not to mention Chinese subjects. In the present study, we investigated the association of three BARD1 polymorphisms (rs7585356 G>A, rs6435862 T>G and rs3768716 A>G) with neuroblastoma susceptibility in 201 neuroblastoma patients and 531 controls using TaqMan methodology. Overall, none of these polymorphisms was significantly associated with neuroblastoma susceptibility. However, stratified analysis showed a more profound association between neuroblastoma risk and rs6435862 TG/GG variant genotypes among older children (adjusted OR=1.55, 95% CI=1.04-2.31), and children with adrenal gland-originated disease (adjusted OR=2.94, 95% CI=1.40-6.18), or with ISSN clinical stages III+IV disease (adjusted OR=1.75, 95% CI=1.09-2.84). Similar results were observed for the variant genotypes of rs3768716 A>G polymorphism among these three subgroups. Our results suggest that the BARD1 rs6435862 T>G and rs3768716 A>G polymorphisms may contribute to increased susceptibility to neuroblastoma, especially for the subjects at age ≥12 months, with adrenal gland-originated or with late clinical stage neuroblastoma. These findings need further validation by prospective studies with larger sample size with subjects enrolled from multicenter, involving different ethnicities. PMID:26941572

  14. {sup 106}Ruthenium Brachytherapy for Retinoblastoma

    SciTech Connect

    Abouzeid, Hana; Moeckli, Raphael; Gaillard, Marie-Claire; Beck-Popovic, Maja; Pica, Alessia; Zografos, Leonidas; Balmer, Aubin; Pampallona, Sandro; Munier, Francis L.

    2008-07-01

    Purpose: To evaluate the efficacy of {sup 106}Ru plaque brachytherapy for the treatment of retinoblastoma. Methods and Materials: We reviewed a retrospective, noncomparative case series of 39 children with retinoblastoma treated with {sup 106}Ru plaques at the Jules-Gonin Eye Hospital between October 1992 and July 2006, with 12 months of follow-up. Results: A total of 63 tumors were treated with {sup 106}Ru brachytherapy in 41 eyes. The median patient age was 27 months. {sup 106}Ru brachytherapy was the first-line treatment for 3 tumors (4.8%), second-line treatment for 13 (20.6%), and salvage treatment for 47 tumors (74.6%) resistant to other treatment modalities. Overall tumor control was achieved in 73% at 1 year. Tumor recurrence at 12 months was observed in 2 (12.5%) of 16 tumors for which {sup 106}Ru brachytherapy was used as the first- or second-line treatment and in 15 (31.9%) of 47 tumors for which {sup 106}Ru brachytherapy was used as salvage treatment. Eye retention was achieved in 76% of cases (31 of 41 eyes). Univariate and multivariate analyses revealed no statistically significant risk factors for tumor recurrence. Radiation complications included retinal detachment in 7 (17.1%), proliferative retinopathy in 1 (2.4%), and subcapsular cataract in 4 (9.7%) of 41 eyes. Conclusion: {sup 106}Ru brachytherapy is an effective treatment for retinoblastoma, with few secondary complications. Local vitreous seeding can be successfully treated with {sup 106}Ru brachytherapy.

  15. Differential Gene Expression Profile in the Rat Caudal Vestibular Nucleus is Associated with Individual Differences in Motion Sickness Susceptibility

    PubMed Central

    Zhou, Wei; Tang, Yi-Fan; Pan, Lei-Lei; Cai, Yi-Ling

    2015-01-01

    Objective To identify differentially expressed genes associated with motion sickness (MS) susceptibility in the rat caudal vestibular nucleus. Methods We identified MS susceptible (MSS) and insusceptible (inMSS) rats by quantifying rotation-induced MS symptoms: defecation and spontaneous locomotion activity. Microarray analysis was used to screen differentially expressed genes in the caudal vestibular nucleus (CVN) after rotation. Plasma stress hormones were identified by radioimmunoassay. Candidate genes were selected by bioinformatics analysis and the microarray results were verified by real-time quantitative-PCR (RT-qPCR) methods. By using Elvax implantation, receptor antagonists or recombinant adenovirus targeting the candidate genes were applied to the CVN to evaluate their contribution to MS susceptibility variability. Validity of gene expression manipulation was verified by RT-qPCR and western blot analysis. Results A total of 304 transcripts were differentially expressed in the MSS group compared with the inMSS group. RT-qPCR analysis verified the expression pattern of candidate genes, including nicotinic cholinergic receptor (nAchR) α3 subunit, 5-hydroxytryptamine receptor 4 (5-HT4R), tachykinin neurokinin-1 (NK1R), γ-aminobutyric acid A receptor (GABAAR) α6 subunit, olfactory receptor 81 (Olr81) and homology 2 domain-containing transforming protein 1 (Shc1). In MSS animals, the nAchR antagonist mecamylamine significantly alleviated rotation-induced MS symptoms and the plasma β-endorphin response. The NK1R antagonist CP99994 and Olr81 knock-down were effective for the defecation response, while the 5-HT4R antagonist RS39604 and Shc1 over-expression showed no therapeutic effect. In inMSS animals, rotation-induced changes in spontaneous locomotion activity and the plasma β-endorphin level occurred in the presence of the GABAAR antagonist gabazine. Conclusion Our findings suggested that the variability of the CVN gene expression profile after motion

  16. Microarray analysis of Mycobacterium tuberculosis-infected monocytes reveals IL26 as a new candidate gene for tuberculosis susceptibility

    PubMed Central

    Guerra-Laso, José M; Raposo-García, Sara; García-García, Silvia; Diez-Tascón, Cristina; Rivero-Lezcano, Octavio M

    2015-01-01

    Differences in the activity of monocytes/macrophages, important target cells of Mycobacterium tuberculosis, might influence tuberculosis progression. With the purpose of identifying candidate genes for tuberculosis susceptibility we infected monocytes from both healthy elderly individuals (a tuberculosis susceptibility group) and elderly tuberculosis patients with M. tuberculosis, and performed a microarray experiment. We detected 78 differentially expressed transcripts and confirmed these results by quantitative PCR of selected genes. We found that monocytes from tuberculosis patients showed similar expression patterns for these genes, regardless of whether they were obtained from younger or older patients. Only one of the detected genes corresponded to a cytokine: IL26, a member of the interleukin-10 (IL-10) cytokine family which we found to be down-regulated in infected monocytes from tuberculosis patients. Non-infected monocytes secreted IL-26 constitutively but they reacted strongly to M. tuberculosis infection by decreasing IL-26 production. Furthermore, IL-26 serum concentrations appeared to be lower in the tuberculosis patients. When whole blood was infected, IL-26 inhibited the observed pathogen-killing capability. Although lymphocytes expressed IL26R, the receptor mRNA was not detected in either monocytes or neutrophils, suggesting that the inhibition of anti-mycobacterial activity may be mediated by lymphocytes. Additionally, IL-2 concentrations in infected blood were lower in the presence of IL-26. The negative influence of IL-26 on the anti-mycobacterial activity and its constitutive presence in both serum and monocyte supernatants prompt us to propose IL26 as a candidate gene for tuberculosis susceptibility. PMID:25157980

  17. Trilateral retinoblastoma with unilateral eye involvement.

    PubMed

    Andrade, Gabriel Costa de; Pinto, Neviçolino Pereira de Carvalho; Motono, Márcia; Chojniak, Martha Motono; Chojniak, Rubens; Bezerra, Stephania Martins

    2015-08-01

    Retinoblastomas (RB) are the main forms of intraocular tumor in childhood, with a worldwide incidence of 1 case per 15,000 to 20,000 live births. Trilateral RB (RBT) is a rare combination of unilateral or bilateral RB with a midline intracranial neoplasm of neuroblastic origin, usually found in the pineal region or the suprasellar region, presenting variable incidence of 0.5% up to 6% among patients with RB. The article reports a case of unilateral RBT in a patient treated at Hospital A.C.Camargo. PMID:26466209

  18. Association between two interleukin-2 gene polymorphisms and cancer susceptibility: a meta-analysis

    PubMed Central

    Zhang, Meng; Tan, Xiuxiu; Huang, Junjie; Xie, Lijuan; Wang, Hao; Shi, Jizhou; Lu, Wei; Lv, Zhaojie; Mei, Hongbing; Liang, Chaozhao

    2016-01-01

    Background Several epidemiological studies have illustrated that polymorphisms in interleukin-2 (IL-2) were associated with diverse cancer types. However, recently published statistics were inconsistent and inconclusive. Therefore, the current meta-analysis was performed to elaborate the effects of IL-2 polymorphisms (rs2069762 and rs2069763) on cancer susceptibility. Material and methods A total of 5,601 cancer cases and 7,809 controls from 21 published case–control studies were enrolled in our meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between IL-2 polymorphisms and cancer susceptibility. Results Our study demonstrated an increased susceptibility to cancer in rs2069762 (G vs T: OR =1.268, 95% CI =1.113–1.445; GG vs TT: OR =1.801, 95% CI =1.289–2.516; GT vs TT: OR =1.250, 95% CI =1.061–1.473; GG + GT vs TT: OR =1.329, 95% CI =1.118–1.579; GG vs GT + TT: OR =1.536, 95% CI =1.162–2.030). In the subgroup analysis, increased susceptibility to cancer was identified in the hospital-based group and PHWE<0.05 (P-value of the Hardy–Weinberg equilibrium [HWE]) group. In addition, a positive association with cancer susceptibility was observed among both Chinese and non-Chinese. However, no relationship was detected between the rs2069763 polymorphism of IL-2 and cancer susceptibility. Conclusion To conclude, rs2069762 polymorphism of IL-2 contributed to an increased susceptibility to cancer, whereas no association was identified between rs2069763 polymorphism and cancer susceptibility. Further detailed studies are warranted to confirm our findings. PMID:27143914

  19. Combined analysis of DNA methylome and transcriptome reveal novel candidate genes with susceptibility to bovine Staphylococcus aureus subclinical mastitis

    PubMed Central

    Song, Minyan; He, Yanghua; Zhou, Huangkai; Zhang, Yi; Li, Xizhi; Yu, Ying

    2016-01-01

    Subclinical mastitis is a widely spread disease of lactating cows. Its major pathogen is Staphylococcus aureus (S. aureus). In this study, we performed genome-wide integrative analysis of DNA methylation and transcriptional expression to identify candidate genes and pathways relevant to bovine S. aureus subclinical mastitis. The genome-scale DNA methylation profiles of peripheral blood lymphocytes in cows with S. aureus subclinical mastitis (SA group) and healthy controls (CK) were generated by methylated DNA immunoprecipitation combined with microarrays. We identified 1078 differentially methylated genes in SA cows compared with the controls. By integrating DNA methylation and transcriptome data, 58 differentially methylated genes were shared with differently expressed genes, in which 20.7% distinctly hypermethylated genes showed down-regulated expression in SA versus CK, whereas 14.3% dramatically hypomethylated genes showed up-regulated expression. Integrated pathway analysis suggested that these genes were related to inflammation, ErbB signalling pathway and mismatch repair. Further functional analysis revealed that three genes, NRG1, MST1 and NAT9, were strongly correlated with the progression of S. aureus subclinical mastitis and could be used as powerful biomarkers for the improvement of bovine mastitis resistance. Our studies lay the groundwork for epigenetic modification and mechanistic studies on susceptibility of bovine mastitis. PMID:27411928

  20. Impacts of CA9 Gene Polymorphisms and Environmental Factors on Oral-Cancer Susceptibility and Clinicopathologic Characteristics in Taiwan

    PubMed Central

    Chien, Ming-Hsien; Yang, Jia-Sin; Chu, Yin-Hung; Lin, Chien-Huang; Wei, Lin-Hung; Yang, Shun-Fa; Lin, Chiao-Wen

    2012-01-01

    Background In Taiwan, oral cancer has causally been associated with environmental carcinogens. Carbonic anhydrase 9 (CA9) is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study explored the combined effect of CA9 gene polymorphisms and exposure to environmental carcinogens on the susceptibility of developing oral squamous cell carcinoma (OSCC) and the clinicopathological characteristics of the tumors. Methodology and Principal Findings Four single-nucleotide polymorphisms (SNPs) of the CA9 gene from 462 patients with oral cancer and 519 non-cancer controls were analyzed by a real-time polymerase chain reaction (PCR). While the studied SNPs (CA9 rs2071676, rs3829078, rs1048638 and +376 Del) were not associated with susceptibility to oral cancer, the GAA haplotype of 3 CA9 SNPs (rs2071676, rs3829078, and rs1048638) was related to a higher risk of oral cancer. Moreover, the four CA9 SNPs combined with betel quid chewing and/or tobacco consumption could robustly elevate susceptibility to oral cancer. Finally, patients with oral cancer who had at least one G allele of CA9 rs2071676 were at higher risk for developing lymph-node metastasis (p = 0.022), compared to those patients homozygous for AA. Conclusions Our results suggest that the haplotype of rs2071676, rs3829078, and rs1048638 combined has potential predictive significance in oral carcinogenesis. Gene-environment interactions of CA9 polymorphisms, smoking, and betel-quid chewing might alter oral cancer susceptibility and metastasis. PMID:23226559

  1. Association Between Polymorphisms of DRD2, COMT, DBH, and MAO-A Genes and Migraine Susceptibility: A Meta-Analysis.

    PubMed

    Chen, Hu; Ji, Chun-Xue; Zhao, Lian-Li; Kong, Xiang-Jun; Zeng, Xian-Tao

    2015-11-01

    Some epidemiological studies have investigated the relationship between genetic polymorphisms of DRD2, COMT, DBH, and MAO-A and migraine susceptibility, but the results are still inconsistent. Thus, our aim was to further assess the association through a meta-analysis.We examined 5 single nucleotide polymorphisms (SNPs) in 4 genes, including DRD2 rs1799732 and rs6275, DBH rs7239728, MAI-A-VNTR, and COMT rs4680, and performed a meta-analysis of 11 published case-control studies including 3138 cases and 4126 controls. Odd ratios (ORs) with 95% confidence intervals (95% CIs) were used to evaluate the association between the 5 genetic polymorphisms and migraine susceptibility.There was no significant relationship between migraine susceptibility and 4 genetic polymorphisms of DRD2 rs1799732 and rs6275, DBH rs7239728, and MAO-A-VNTR. Nevertheless, decreased risk of migraine was observed to be in association with COMT rs4680 polymorphism in overall analysis (AA vs. GG + GA: OR = 0.76, 95% CI = 0.60-0.97, PHet > 0.642, I = 0), and in Caucasian group after subgroup analysis (AA vs. GG + GA: OR = 0.75, 95% CI = 0.58-0.96, PHet > 0.433, I = 0).Studied polymorphisms of DRD2, DBH, and MAO-A genes may not be associated with migraine susceptibility. However, COMT rs4680 polymorphism may decrease the risk of migraine, especially in Caucasians. The failure to evaluate environmental influence and provide adjusted effect size estimates highlights the need for additional studies in a large number to take these factors into consideration, thus better elucidating the role of the genes tested in migraine. PMID:26632697

  2. Contribution of Target Gene Mutations and Efflux to Decreased Susceptibility of Salmonella enterica Serovar Typhimurium to Fluoroquinolones and Other Antimicrobials▿

    PubMed Central

    Chen, Sheng; Cui, Shenghui; McDermott, Patrick F.; Zhao, Shaohua; White, David G.; Paulsen, Ian; Meng, Jianghong

    2007-01-01

    The mechanisms involved in fluoroquinolone resistance in Salmonella enterica include target alterations and overexpression of efflux pumps. The present study evaluated the role of known and putative multidrug resistance efflux pumps and mutations in topoisomerase genes among laboratory-selected and naturally occurring fluoroquinolone-resistant Salmonella enterica serovar Typhimurium strains. Strains with ciprofloxacin MICs of 0.25, 4, 32, and 256 μg/ml were derived in vitro using serovar Typhimurium S21. These mutants also showed decreased susceptibility or resistance to many nonfluoroquinolone antimicrobials, including tetracycline, chloramphenicol, and several β-lactams. The expression of efflux pump genes acrA, acrB, acrE, acrF, emrB, emrD, and mdlB were substantially increased (≥2-fold) among the fluoroquinolone-resistant mutants. Increased expression was also observed, but to a lesser extent, with three other putative efflux pumps: mdtB (yegN), mdtC (yegO), and emrA among mutants with ciprofloxacin MICs of ≥32 μg/ml. Deletion of acrAB or tolC in S21 and its fluoroquinolone-resistant mutants resulted in increased susceptibility to fluoroquinolones and other tested antimicrobials. In naturally occurring fluoroquinolone-resistant serovar Typhimurium strains, deletion of acrAB or tolC increased fluoroquinolone susceptibility 4-fold, whereas replacement of gyrA double mutations (S83F D87N) with wild-type gyrA increased susceptibility >500-fold. These results indicate that a combination of topoisomerase gene mutations, as well as enhanced antimicrobial efflux, plays a critical role in the development of fluoroquinolone resistance in both laboratory-derived and naturally occurring quinolone-resistant serovar Typhimurium strains. PMID:17043131

  3. Genetic evaluation of BRCA1-A complex genes with triple-negative breast cancer susceptibility in Chinese women

    PubMed Central

    Zheng, Yi-Zi; Qiao, Feng; Yao, Ling; Cao, Zhi-Gang; Ye, Fu-Gui; Wu, Jiong; Hu, Xin; Wang, Bin; Shao, Zhi-Ming

    2016-01-01

    Background The tumor suppressor BRCA1 plays a pivotal role in maintaining genomic stability and tumor suppression. The BRCA1-A complex is required for recruitment of BRCA1 to DNA damage sites, DNA repair and cell cycle checkpoint control. Since germline mutations of BRCA1 often lead to breast tumors that are triple-negative breast cancer (TNBC) type, we aimed to investigate whether genetic deficiency in genes of the BRCA1-A complex is associated with risk to TNBC development. Results We found that rs7250266 in the promoter region of NBA1 confers a decreased risk to TNBC development, but not to non-TNBC susceptibility. In addition, the haplotypes containing two polymorphisms rs7250266 and rs2278256 are associated with a lower chance of TNBC development specifically. Our studies also showed that the protective alleles of rs7250266 (C > G) and rs2278256 (T > C) down-regulate promoter activity of NBA1 in mammary epithelial cells. Methods We investigated associations between the BRCA1-A complex genes and TNBC developing risk in first case-control study of Chinese Han Women population including 414 patients with TNBC and 354 cancer-free controls. We detected 37 common variants in ABRAXAS, RAP80, BRE, BRCC36 and NBA1/MERIT40 genes encoding the BRCA1-A complex and evaluated their genetic susceptibility to the risk of TNBC. An additional cohort with 652 other types of breast cancer (non-TNBC) cases and 890 controls was used to investigate the associations between TNBC-specific SNPs genotype and non-TNBCs susceptibility. Conclusions Genetic variants in NBA1 may be an important genetic determinant of TNBC susceptibility. Further investigation and validation of these SNPs in larger cohorts may facilitate in predication and prevention of TNBC and in counseling individuals for risk of TNBC development. PMID:26848770

  4. Expression of developmentally defined retinal phenotypes in the histogenesis of retinoblastoma.

    PubMed Central

    Gonzalez-Fernandez, F.; Lopes, M. B.; Garcia-Fernandez, J. M.; Foster, R. G.; De Grip, W. J.; Rosemberg, S.; Newman, S. A.; VandenBerg, S. R.

    1992-01-01

    Retinoblastoma, the most common intraocular tumor of childhood, is a malignant neoplasm that arises during retinal development. The embryonal cell target for neoplastic transformation is not yet clearly defined. To better understand the histogenetic potential of this tumor, the expression of photoreceptor and glial cell-associated proteins were examined in 22 primary retinoblastomas. Interphotoreceptor retinol-binding protein (IRBP), cone and rod opsins were selected as the photoreceptor specific proteins due to their different temporal patterns of expression during normal retinal development. Neoplastic Müller cell differentiation, and non-neoplastic reactive astrocytes were identified using cellular retinaldehyde binding-protein (CRAlBP), and glial fibrillary acidic protein (GFAP), respectively. Photoreceptor proteins were present in 16 cases and showed different cellular patterns of expression. IRBP and cone opsin were usually abundant. Although rod opsin was clearly identified in eight tumors, its expression was more restricted than either IRBP or cone opsin. This differential pattern of expression, opposite to the normal pattern of photoreceptor gene expression in the adult retina, corresponded to a marked decrease in mRNA for rod opsin. Cone opsin and IRBP colocalized in fleurettes demonstrating that neoplastic human cone cells are capable of IRBP synthesis. Müller cell differentiation was present in 12 of the 16 cases in which photoreceptor proteins were detected. In contrast, GFAP was only present in reactive, stromal astrocytes associated with blood vessels. Our data suggest that the retinoblastoma has the histogenetic potential of the immature neural retinal epithelium which can give rise to both photoreceptor and Müller cell lineages. The differential expression of cone and rod phenotypes in retinoblastoma is consistent with the "default" mechanism of cone cell differentiation. Images Figure 7 Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID

  5. Common Variants in the ATP2B1 Gene Are Associated With Susceptibility to Hypertension

    PubMed Central

    Tabara, Yasuharu; Kohara, Katsuhiko; Kita, Yoshikuni; Hirawa, Nobuhito; Katsuya, Tomohiro; Ohkubo, Takayoshi; Hiura, Yumiko; Tajima, Atsushi; Morisaki, Takayuki; Miyata, Toshiyuki; Nakayama, Tomohiro; Takashima, Naoyuki; Nakura, Jun; Kawamoto, Ryuichi; Takahashi, Norio; Hata, Akira; Soma, Masayoshi; Imai, Yutaka; Kokubo, Yoshihiro; Okamura, Tomonori; Tomoike, Hitonobu; Iwai, Naoharu; Ogihara, Toshio; Inoue, Itsuro; Tokunaga, Katsushi; Johnson, Toby; Caulfield, Mark; Munroe, Patricia; Umemura, Satoshi; Ueshima, Hirotsugu; Miki, Tetsuro

    2016-01-01

    Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10−5; allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10−11). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10−4). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10−18). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10−7) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension. PMID:20921432

  6. Identification of Genes That Modulate Susceptibility to Formaldehyde and Imatinib by Functional Genomic Screening in Human Haploid KBM7 Cells.

    PubMed

    Shen, Hua; McHale, Cliona M; Haider, Syed I; Jung, Cham; Zhang, Susie; Smith, Martyn T; Zhang, Luoping

    2016-05-01

    Though current functional genomic screening systems are useful for investigating human susceptibility to chemical toxicity, they have limitations. Well-established, high-throughput yeast mutant screens identify only evolutionarily conserved processes. RNA interference can be applied in human cells but is limited by incomplete gene knockout and off-target effects. Human haploid cell screening is advantageous as it requires knockdown of only a single copy of each gene. A human haploid cell mutant library (KBM7-Mu), derived from a chronic myeloid leukemia (CML) patient, was recently developed and has been used to identify genes that modulate sensitivity to infectious agents and pharmaceutical drugs. Here, we sought to improve the KBM7-Mu screening process to enable efficient screening of environmental chemicals. We developed a semi-solid medium based screening approach that cultures individual mutant colonies from chemically resistant cells, faster (by 2-3 weeks) and with less labor than the original liquid medium-based approach. As proof of principle, we identified genetic mutants that confer resistance to the carcinogen formaldehyde (FA, 12 genes, 18 hits) and the CML chemotherapeutic agent imatinib (6 genes, 13 hits). Validation experiments conducted on KBM7 mutants lacking each of the 18 genes confirmed resistance of 6 FA mutants (CTC1, FCRLA, GOT1, LPR5, M1AP, and MAP2K5) and 1 imatinib-resistant mutant (LYRM9). Despite the improvements to the method, it remains technically challenging to limit false positive findings. Nonetheless, our findings demonstrate the broad applicability of this optimized haploid approach to screen toxic chemicals to identify novel susceptibility genes and gain insight into potential mechanisms of toxicity. PMID:27008852

  7. IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations.

    PubMed

    Weber, F; Fontaine, B; Cournu-Rebeix, I; Kroner, A; Knop, M; Lutz, S; Müller-Sarnowski, F; Uhr, M; Bettecken, T; Kohli, M; Ripke, S; Ising, M; Rieckmann, P; Brassat, D; Semana, G; Babron, M-C; Mrejen, S; Gout, C; Lyon-Caen, O; Yaouanq, J; Edan, G; Clanet, M; Holsboer, F; Clerget-Darpoux, F; Müller-Myhsok, B

    2008-04-01

    Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated. PMID:18354419

  8. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

    PubMed Central

    Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J.; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K. H.; Anton-Culver, Hoda; Antonenkova, Natalia; Bowtell, David; Webb, Penelope M.; deFazio, Anna; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A. T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; James, Paul; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kruger Kjaer, Susanne; Kelemen, Linda E.; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F. A. G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; Nevanlinna, Heli; McNeish, Ian; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Phelan, Catherine M.; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Sellers, Thomas A.; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Monteiro, Alvaro; Pharoah, Paul D.; Gayther, Simon A.; Freedman, Matthew L.

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4 × 10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10−10 for risk variants (P<10−4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC. PMID:26391404

  9. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

    PubMed

    Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V; Bean, Yukie; Beckmann, Matthias W; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T; Edwards, Robert P; Eilber, Ursula; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; James, Paul; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kruger Kjaer, Susanne; Kelemen, Linda E; Kellar, Melissa; Kelley, Joseph L; Kiemeney, Lambertus A; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Nevanlinna, Heli; McNeish, Ian; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Narod, Steven A; Nedergaard, Lotte; Ness, Roberta B; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jennifer; Phelan, Catherine M; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schildkraut, Joellen M; Schwaab, Ira; Sellers, Thomas A; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Sucheston, Lara; Tangen, Ingvild L; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S; van Altena, Anne M; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Monteiro, Alvaro; Pharoah, Paul D; Gayther, Simon A; Freedman, Matthew L

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC. PMID:26391404

  10. Confirmation of FWT1 as a Wilms' tumour susceptibility gene and phenotypic characteristics of Wilms' tumour attributable to FWT1.

    PubMed

    Rahman, N; Abidi, F; Ford, D; Arbour, L; Rapley, E; Tonin, P; Barton, D; Batcup, G; Berry, J; Cotter, F; Davison, V; Gerrard, M; Gray, E; Grundy, R; Hanafy, M; King, D; Lewis, I; Ridolfi Luethy, A; Madlensky, L; Mann, J; O'Meara, A; Oakhill, T; Skolnick, M; Strong, L; Stratton, M R

    1998-11-01

    A susceptibility gene for Wilms' tumour (WT), designated FWT1, was previously mapped to chromosome 17q12-q21 by linkage analysis of a single family. We now confirm the existence of this gene by analysis of additional cases in the original family (3-point LOD score=5.69), and by detecting strong evidence of linkage to this region in an unrelated pedigree with seven cases of WT (3-point LOD score=2.56). Analysis of 11 smaller WT families confirms that there is genetic heterogeneity in familial WT, as three families exhibit strong evidence against linkage to FWT1. One of these was subsequently found to have a predisposing WT1 mutation. However, the other two families show evidence against both FWT1 and WT1, suggesting that at least one further familial WT gene exists. Analysis of the phenotype of 16 WT cases from the families linked to FWT1 demonstrates that they present at a significantly older age and a significantly later stage than both sporadic WT and the six cases from two families unlinked to either FWT1 or WT1. The results confirm the role of FWT1 in susceptibility to WT, provide strong evidence for genetic heterogeneity in familial WT and suggest there are phenotypic differences between familial WT due to FWT1, familial WT due to other genes and non-familial WT. PMID:9860296

  11. The Calcitonin Receptor Gene Is a Candidate for Regulation of Susceptibility to Herpes simplex Type 1 Neuronal Infection Leading to Encephalitis in Rat

    PubMed Central

    Abdelmagid, Nada; Bereczky-Veress, Biborka; Guerreiro-Cacais, André Ortlieb; Bergman, Petra; Luhr, Katarina M.; Bergström, Tomas; Sköldenberg, Birgit; Piehl, Fredrik

    2012-01-01

    Herpes simplex encephalitis (HSE) is a fatal infection of the central nervous system (CNS) predominantly caused by Herpes simplex virus type 1. Factors regulating the susceptibility to HSE are still largely unknown. To identify host gene(s) regulating HSE susceptibility we performed a genome-wide linkage scan in an intercross between the susceptible DA and the resistant PVG rat. We found one major quantitative trait locus (QTL), Hse1, on rat chromosome 4 (confidence interval 24.3–31 Mb; LOD score 29.5) governing disease susceptibility. Fine mapping of Hse1 using recombinants, haplotype mapping and sequencing, as well as expression analysis of all genes in the interval identified the calcitonin receptor gene (Calcr) as the main candidate, which also is supported by functional studies. Thus, using unbiased genetic approach variability in Calcr was identified as potentially critical for infection and viral spread to the CNS and subsequent HSE development. PMID:22761571

  12. A novel differential susceptibility gene: CHRNA4 and moderation of the effect of maltreatment on child personality

    PubMed Central

    Grazioplene, Rachael G.; DeYoung, Colin G.; Rogosch, Fred A.; Cicchetti, Dante

    2012-01-01

    Background The differential susceptibility hypothesis states that some genetic variants that confer risk in adverse environments are beneficial in normal or nurturing environments. The cholinergic system is promising as a source of susceptibility genes because of its involvement in learning and neural plasticity. The cholinergic receptor gene CHRNA4 has been linked to characteristics related to the personality traits Neuroticism and Openness/Intellect. Methods The effects of interaction between CHRNA4 genotype and maltreatment status on child personality were examined in a well-matched sample of 339 maltreated and 275 nonmaltreated children (aged 8–13yrs.). Results Variation in CHRNA4 interacted with childhood maltreatment to predict personality in a manner indicating differential susceptibility. The interaction of CHRNA4 and maltreatment status predicted Neuroticism and Openness/Intellect. Maltreated children with the rs1044396 T/T genotype scored highest on Neuroticism and showed no effect of genotype on Openness/Intellect. Nonmaltreated children with this genotype scored lowest on Neuroticism and highest on Openness/Intellect. Conclusion Variation in CHRNA4 appears to contribute to personality by affecting degree of developmental sensitivity to both normal and adverse environments. PMID:23240931

  13. Indocyanine Green-Enhanced Thermotherapy for Retinoblastoma

    PubMed Central

    Al-Haddad, Christiane E.; Abdulaal, Marwan; Saab, Raya H.; Bashshur, Ziad F.

    2015-01-01

    Purpose To report the outcome of pediatric patients with retinoblastoma refractory to traditional local therapy who were treated with indocyanine green (ICG)-enhanced thermotherapy. Materials and Methods This is a retrospective review of a case series of 3 patients with bilateral retinoblastoma who were treated with ICG-enhanced thermotherapy after showing no response to conventional chemothermotherapy or transpupillary thermotherapy (TTT) alone noted on two consecutive examinations under anesthesia. Results The 3 patients had had one eye enucleated previously due to advanced disease, and the remaining eye was diagnosed with a large tumor, which showed either a marginal or no response to systemic chemotherapy and TTT. Addition of ICG enhancement during the subsequent TTT session shrunk the tumor to a measurable size that could then be followed by TTT alone as a means of treatment. One patient had tumor recurrence, at which time additional TTT without ICG was successfully applied after the tumor size had decreased; ICG enhancement was then added whenever TTT alone provided no response. Conclusions ICG enhancement with TTT led to a measurable tumor regression in lesions that had previously not been responsive to traditional chemothermotherapy or isolated TTT. Message These tumors had shown a minimal to no response to previous TTT treatment. However, adding ICG resulted in a measurable regression even though the same TTT treatment parameters were applied.

  14. Abrp, a new gene, confers reduced susceptibility to tetracycline, glycylcine, chloramphenicol and fosfomycin classes in Acinetobacter baumannii.

    PubMed

    Li, X; Quan, J; Yang, Y; Ji, J; Liu, L; Fu, Y; Hua, X; Chen, Y; Pi, B; Jiang, Y; Yu, Y

    2016-08-01

    Acinetobacter baumannii, a non-fermenting gram-negative coccobacillus, is a major pathogen responsible for a variety of healthcare-associated infections, including pneumonia, urinary tract and bloodstream infections. Moreover, A. baumannii is associated with alarming increases in drug resistance rates to almost all available antibiotics leaving limited treatment options. Here, we characterize the biological functions of a novel gene, abrp, which encodes a peptidase C13 family. We demonstrate that the abrp is associated with decreased susceptibility to tetracycline, minocycline, doxycycline, tigecycline, chloramphenicol and fosfomycin. Deletion of abrp was able to increase cell membrane permeability and display slower cell growth rate. Results from the present study show that abrp plays an important role in conferring reduced susceptibility to different classes of antibiotics and cell growth in A. baumannii. The change of antibiotic sensitivities may result from modifications to the cell membrane permeability of A. baumannii. PMID:27220329

  15. Adenovirus E1A gene induction of susceptibility to lysis by natural killer cells and activated macrophages in infected rodent cells.

    PubMed Central

    Cook, J L; May, D L; Lewis, A M; Walker, T A

    1987-01-01

    Rodent cells immortalized by the E1A gene of nononcogenic adenoviruses are susceptible to lysis by natural killer (NK) cells and activated macrophages. This cytolysis-susceptible phenotype may contribute to the rejection of adenovirus-transformed cells by immunocompetent animals. Such increased cytolytic susceptibility has also been observed with infected rodent cells. This infection model provided a means to study the role of E1A gene products in induction of cytolytic susceptibility without cell selection during transformation. Deletion mutations outside of the E1A gene had no effect on adenovirus type 2 (Ad2) or Ad5 induction of cytolytic susceptibility in infected hamster cells, while E1A-minus mutant viruses could not induce this phenotype. E1A mutant viruses that induced expression of either E1A 12S or 13S mRNA in infected cells were competent to induce cytolytic susceptibility. Furthermore, there was a correlation between the accumulation of E1A gene products in Ad5-infected cells and the level of susceptibility of such target cells to lysis by NK cells. The results of coinfection studies indicated that the E1A gene products of highly oncogenic Ad12 could not complement the lack of induction of cytolytic susceptibility by E1A-minus Ad5 virus in infected cells and also could not block induction of this infected-cell phenotype by Ad5. These data suggest that expression of the E1A gene of nononcogenic adenoviruses may cause the elimination of infected cells by the immunologically nonspecific host inflammatory cell response prior to cellular transformation. The lack of induction of this cytolysis-susceptible phenotype by Ad12 E1A may result in an increased persistence of Ad12-infected cells in vivo and may lead to an increased Ad12-transformed cell burden for the host. Images PMID:2959793

  16. Regulation of the retinoblastoma proteins by the human herpesviruses

    PubMed Central

    Hume, Adam J; Kalejta, Robert F

    2009-01-01

    Viruses are obligate intracellular parasites that alter the environment of infected cells in order to replicate more efficiently. One way viruses achieve this is by modulating cell cycle progression. The main regulators of progression out of G0, through G1, and into S phase are the members of the retinoblastoma (Rb) family of tumor suppressors. Rb proteins repress the transcription of genes controlled by the E2F transcription factors. Because the expression of E2F-responsive genes is required for cell cycle progression into the S phase, Rb arrests the cell cycle in G0/G1. A number of viral proteins directly target Rb family members for inactivation, presumably to create an environment more hospitable for viral replication. Such viral proteins include the extensively studied oncoproteins E7 (from human papillomavirus), E1A (from adenovirus), and the large T (tumor) antigen (from simian virus 40). Elucidating how these three viral proteins target and inactivate Rb has proven to be an invaluable approach to augment our understanding of both normal cell cycle progression and carcinogenesis. In addition to these proteins, a number of other virally-encoded inactivators of the Rb family have subsequently been identified including a surprising number encoded by human herpesviruses. Here we review how the human herpesviruses modulate Rb function during infection, introduce the individual viral proteins that directly or indirectly target Rb, and speculate about what roles Rb modulation by these proteins may play in viral replication, pathogenesis, and oncogenesis. PMID:19146698

  17. Susceptibility towards Enterotoxigenic Escherichia coli F4ac Diarrhea Is Governed by the MUC13 Gene in Pigs

    PubMed Central

    Ren, Jun; Yan, Xueming; Ai, Huashui; Zhang, Zhiyan; Huang, Xiang; Ouyang, Jing; Yang, Ming; Yang, Huaigu; Han, Pengfei; Zeng, Weihong; Chen, Yijie; Guo, Yuanmei; Xiao, Shijun; Ding, Nengshui; Huang, Lusheng

    2012-01-01

    Enterotoxigenic Escherichia coli (ETEC) F4ac is a major determinant of diarrhea and mortality in neonatal and young pigs. Susceptibility to ETEC F4ac is governed by the intestinal receptor specific for the bacterium and is inherited as a monogenic dominant trait. To identify the receptor gene (F4acR), we first mapped the locus to a 7.8-cM region on pig chromosome 13 using a genome scan with 194 microsatellite markers. A further scan with high density markers on chromosome 13 refined the locus to a 5.7-cM interval. Recombination breakpoint analysis defined the locus within a 2.3-Mb region. Further genome-wide mapping using 39,720 informative SNPs revealed that the most significant markers were proximal to the MUC13 gene in the 2.3-Mb region. Association studies in a collection of diverse outbred populations strongly supported that MUC13 is the most likely responsible gene. We characterized the porcine MUC13 gene that encodes two transcripts: MUC13A and MUC13B. Both transcripts have the characteristic PTS regions of mucins that are enriched in distinct tandem repeats. MUC13B is predicated to be heavily O-glycosylated, forming the binding site of the bacterium; while MUC13A does not have the O-glycosylation binding site. Concordantly, 127 independent pigs homozygous for MUC13A across diverse breeds are all resistant to ETEC F4ac, and all 718 susceptible animals from the broad breed panel carry at least one MUC13B allele. Altogether, we conclude that susceptibility towards ETEC F4ac is governed by the MUC13 gene in pigs. The finding has an immediate translation into breeding practice, as it allows us to establish an efficient and accurate diagnostic test for selecting against susceptible animals. Moreover, the finding improves our understanding of mucins that play crucial roles in defense against enteric pathogens. It revealed, for the first time, the direct interaction between MUC13 and enteric bacteria, which is poorly understood in mammals. PMID:22984528

  18. Tumor necrosis factor alpha gene polymorphism contributes to pulmonary tuberculosis susceptibility: evidence from a meta-analysis

    PubMed Central

    Yi, Yong-Xiang; Han, Jian-Bo; Zhao, Liang; Fang, Yuan; Zhang, Yu-Feng; Zhou, Guang-Yao

    2015-01-01

    This study is to estimate the association between polymorphisms in the tumor necrosis factor alpha (TNF-α) gene and pulmonary tuberculosis susceptibility (pTB). Studies were identified by searching PubMed and ISI web of Knowledge. The strength of association between the TNF-α gene and pTB susceptibility was assessed by odds ratios. Totals of 18 studies including 2, 735 cases and 3, 177 controls were identified referring to four single-nucleotide polymorphisms: -308G>A, -863C>A, -857C>T and -238G>A. The significantly associations were found between -308G>A (Dominant model: OR 0.53, 95% CI 0.35-0.81, P=0.004; Homozygote model: OR 0.51, 95% CI 0.33-0.78, P=0.002), -238G>A (Dominant model: OR 0.33, 95% CI 0.18-0.57, P<0.001) and pTB susceptibility. The results showed that the variant genotype of TNF-α -308G>A was protective in pooled groups of patients with pTB in the dominant genetic model (OR 0.16, 95% CI 0.06-0.39, P<0.001), the homozygote comparison (OR 0.14, 95% CI 0.06-0.36, P<0.001) in African, while that was with -238G>A in the dominant genetic model (OR 0.31, 95% CI 0.18-0.56, P<0.001) in Asian. Our meta-analysis suggest TNF-α -308G>A and -238G>A polymorphisms increases the risk of pTB susceptibility regardless of ethnicity and HIV statue. In Asian population, the significantly association with pTB is TNF-α -238G>A, while TNF-α -308G>A is in African population. PMID:26884992

  19. Genetic Predictions of Prion Disease Susceptibility in Carnivore Species Based on Variability of the Prion Gene Coding Region

    PubMed Central

    Stewart, Paula; Campbell, Lauren; Skogtvedt, Susan; Griffin, Karen A.; Arnemo, Jon M.; Tryland, Morten; Girling, Simon; Miller, Michael W.; Tranulis, Michael A.; Goldmann, Wilfred

    2012-01-01

    Mammalian species vary widely in their apparent susceptibility to prion diseases. For example, several felid species developed prion disease (feline spongiform encephalopathy or FSE) during the bovine spongiform encephalopathy (BSE) epidemic in the United Kingdom, whereas no canine BSE cases were detected. Whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or CWD) remains an open question. Variation in the host-encoded prion protein (PrPC) largely explains observed disease susceptibility patterns within ruminant species, and may explain interspecies differences in susceptibility as well. We sequenced and compared the open reading frame of the PRNP gene encoding PrPC protein from 609 animal samples comprising 29 species from 22 genera of the Order Carnivora; amongst these samples were 15 FSE cases. Our analysis revealed that FSE cases did not encode an identifiable disease-associated PrP polymorphism. However, all canid PrPs contained aspartic acid or glutamic acid at codon 163 which we propose provides a genetic basis for observed susceptibility differences between canids and felids. Among other carnivores studied, wolverine (Gulo gulo) and pine marten (Martes martes) were the only non-canid species to also express PrP-Asp163, which may impact on their prion diseases susceptibility. Populations of black bear (Ursus americanus) and mountain lion (Puma concolor) from Colorado showed little genetic variation in the PrP protein and no variants likely to be highly resistant to prions in general, suggesting that strain differences between BSE and CWD prions also may contribute to the limited apparent host range of the latter. PMID:23236380

  20. MicroRNA-21 Down-regulates Rb1 Expression by Targeting PDCD4 in Retinoblastoma

    PubMed Central

    Shen, Fengmei; Mo, Meng-Hsuan; Chen, Liang; An, Shejuan; Tan, Xiaohui; Fu, Yebo; Rezaei, Katayoon; Wang, Zuoren; Zhang, Lin; Fu, Sidney W.

    2014-01-01

    Retinoblastoma (RB) is a children's ocular cancer caused by mutated retinoblastoma 1 (Rb1) gene on both alleles. Rb1 and other related genes could be regulated by microRNAs (miRNA) via complementarily pairing with their target sites. MicroRNA-21 (miR-21) possesses the oncogenic potential to target several tumor suppressor genes, including PDCD4, and regulates tumor progression and metastasis. However, the mechanism of how miR-21 regulates PDCD4 is poorly understood in RB. We investigated the expression of miRNAs in RB cell lines and identified that miR-21 is one of the most deregulated miRNAs in RB. Using qRT-PCR, we verified the expression level of several miRNAs identified by independent microarray assays, and analyzed miRNA expression patterns in three RB cell lines, including Weri-Rb1, Y79 and RB355. We found that miR-19b, -21, -26a, -195 and -222 were highly expressed in all three cell lines, suggesting their potential role in RB tumorigenesis. Using the TargetScan program, we identified a list of potential target genes of these miRNAs, of which PDCD4 is one the targets of miR-21. In this study, we focused on the regulatory mechanism of miR-21 on PDCD4 in RB. We demonstrated an inverse correlation between miR-21 and PDCD4 expression in Weri-Rb1 and Y79 cells. These data suggest that miR-21 down-regulates Rb1 by targeting PDCD4 tumor suppressor. Therefore, miR-21 could serve as a therapeutic target for retinoblastoma. PMID:25520758

  1. Crystal Structure of Human Retinoblastoma Binding Protein 9

    SciTech Connect

    Vorobiev, S.; Su, M; Seetharaman, J; Huang, Y; Chen, C; Maglaqui, M; Janjua, H; Montelione, G; Tong, L; et. al.

    2009-01-01

    As a step towards better integrating protein three-dimensional (3D) structural information in cancer systems biology, the Northeast Structural Genomics Consortium (NESG) (www.nesg.org) has constructed a Human Cancer Pathway Protein Interaction Network (HCPIN) by analysis of several classical cancer-associated signaling pathways and their physical protein-protein interactions. Many well-known cancer-associated proteins play central roles as hubs or bottlenecks in the HCPIN (http://nmr.cabm.rutgers.edu/hcpin). NESG has selected more than 1000 human proteins and protein domains from the HCPIN for sample production and 3D structure determination. The long-range goal of this effort is to provide a comprehensive 3D structure-function database for human cancer-associated proteins and protein complexes, in the context of their interaction networks. Human retinoblastoma binding protein 9 (RBBP9) is one of the HCPIN proteins targeted by NESG. RBBP9 was initially identified as the product of a new gene, Bog (for B5T over-expressed gene), in several transformed rat liver epithelial cell lines resistant to the growth-inhibitory effect of TGF-1 as well as in primary human liver tumors. RBBP9 contains the retinoblastoma (Rb) binding motif LxCxE in its sequence, and was shown to interact with Rb by yeast two-hybrid and coimmunoprecipitation experiments. Mutation of the Leu residue in this motif to Gln blocked the binding to Rb. RBBP9 can displace E2F1 from E2F1-Rb complexes, and over expression of RBBP9 overcomes TGF-1 induced growth arrest and results in transformation of rat liver epithelial cells leading to hepatoblastoma-like tumors in nude mice. RBBP9 may also play a role in cellular responses to chronic low dose radiation. A close homolog of RBBP9, sharing 93% amino acid sequence identity and also known as RBBP10, interacts with a protein with sua5-yciO-yrdC domains.

  2. Identification and expression of caspase-1 gene under heat stress in insecticide-susceptible and -resistant Plutella xylostella (Lepidoptera: Plutellidae).

    PubMed

    Zhuang, Hua Mei; Wang, Kuan Fu; Miyata, Tadashi; Wu, Zu Jian; Wu, Gang; Xie, Lian Hui

    2011-04-01

    A caspase gene in Plutella xylostella (DBM) was identified firstly and named Px-caspase-1. It had a full-length of 1172 bp and contained 900 bp open reading frame that encoded 300 amino acids with 33.6 kDa. The deduced amino acid of Px-caspase-1 had two domain profile including caspase_p20 (position 61-184) and caspase_p10 (position 203-298) (i.e. the big and small catalytic domains), and the highly conserved pentapeptide QACQG in caspase_p20 domain (the recognized catalytic site of caspases). Being highly homologous to effector caspase genes in other insect and mammalian species, Px-caspase-1 was thought to be an effector caspase gene. Heat stress could result in significant mortality increase on adult DBM. Px-caspase-1 mRNA expression and caspase-3 enzyme activity (a effector caspase) were elevated with age and heat treatment. And, heat stress facilitated the procession of Px-caspase-1 expression. Significantly higher mRNA transcription levels were found in a chlorpyrifos-resistant DBM strain, as compared to those in insecticide-susceptible DBM. The results indicated that high temperature could significantly promote apoptosis process resulting in an the increased DBM mortality rate, and that insecticide-susceptible DBM had a significantly higher physiological fitness at high temperatures than insecticide-resistant DBM. PMID:21086181

  3. Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway

    PubMed Central

    Hosgood, H.Dean; Menashe, Idan; Shen, Min; Yeager, Meredith; Yuenger, Jeff; Rajaraman, Preetha; He, Xingzhou; Chatterjee, Nilanjan; Caporaso, Neil E.; Zhu, Yong; Chanock, Stephen J.; Zheng, Tongzhang; Lan, Qing

    2008-01-01

    Common genetic variation may play an important role in altering lung cancer risk. We conducted a pathway-based candidate gene evaluation to identify genetic variations that may be associated with lung cancer in a population-based case–control study in Xuan Wei, China (122 cases and 111 controls). A total of 1260 single-nucleotide polymorphisms (SNPs) in 380 candidate genes for lung cancer were successfully genotyped and assigned to one of 10 pathways based on gene ontology. Logistic regression was used to assess the marginal effect of each SNP on lung cancer susceptibility. The minP test was used to identify statistically significant associations at the gene level. Important pathways were identified using a test of proportions and the rank truncated product methods. The cell cycle pathway was found as the most important pathway (P = 0.044) with four genes significantly associated with lung cancer (PLA2G6 minP = 0.001, CCNA2 minP = 0.006, GSK3β minP = 0.007 and EGF minP = 0.013), after adjusting for multiple comparisons. Interestingly, most cell cycle genes that were associated with lung cancer in this analysis were concentrated in the AKT signaling pathway, which is essential for regulation of cell cycle progression and cellular survival, and may be important in lung cancer etiology in Xuan Wei. These results should be viewed as exploratory until they are replicated in a larger study. PMID:18676680

  4. Refining the mouse chromosomal location of Cdm, the major gene associated with susceptibility to cadmium-induced testicular necrosis.

    PubMed

    Dalton, T P; Miller, M L; Wu, X; Menon, A; Cianciolo, E; McKinnon, R A; Smith, P W; Robinson, L J; Nebert, D W

    2000-03-01

    Cadmium (Cd++) is a widespread environmental pollutant and classifed as an IARC 'Category I' human carcinogen. Cd++ can also cause severe renal toxicity and may be involved clinically in cardiovascular disease and osteoporosis. Genetic differences in sensitivity to cadmium toxicity have been noted in humans, whereas, among inbred mouse strains, unequivocal genetic data exist. Resistance to cadmium-induced testicular damage was reported in 1973 to be associated with a single major recessive gene, named Cdm, which has now been localized to mouse chromosome (Chr) 3. Using polymorphic microsatellite markers and semiquantitative histological parameters, we have corroborated the original 1973 data concerning mendelian inheritance and have further refined the region containing the Cdm gene from more than 24 cM to 0.64 cM (estimated 40-80 genes). We phenotyped 26 recombinant inbred lines generated from C57BL/6J (B6, resistant) and DBA/2J (D2, sensitive) inbred mice, and determined that the Cdm gene maps between microsatellite markers D3Mit110 and D3Mit255. Although toxicity to numerous heavy metals is well known, virtually no molecular mechanisms have yet been uncovered either in humans or laboratory animals. Identification and characterization of the mouse Cdm gene should enhance our understanding of heavy metal toxicity by identifying and characterizing, for the first time, a major mammalian gene responsible for susceptibility to diseases caused by heavy metal toxicity. PMID:10762002

  5. ENHANCED DISEASE SUSCEPTIBILITY 1 and SALICYLIC ACID act redundantly to regulate resistance gene-mediated signaling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Resistance (R) protein–associated pathways are well known to participate in defense against a variety of microbial pathogens. Salicylic acid (SA) and its associated proteinaceous signaling components, including enhanced disease susceptibility 1 (EDS1), non–race-specific disease resistance 1 (NDR1), ...

  6. Genes Expressed Differentially in Hessian Fly Larvae Feeding in Resistant and Susceptible Plants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Hessian fly, Mayetiola destructor, is a destructive pest of wheat worldwide and mainly controlled by deploying resistant cultivars. Hessian fly larvae manipulate susceptible plants extensively, but are unable to manipulate resistant plants and thus die in them. The mechanisms for Hessian fly l...

  7. Genome-Wide Association Study Identifies Novel Susceptibility Genes Associated with Coronary Artery Aneurysm Formation in Kawasaki Disease

    PubMed Central

    Guo, Mindy Ming-Huey; Huang, Ying-Hsien; Yu, Hong-Ren; Huang, Fu-Chen; Jiao, Fuyong; Kuo, Hsing-Chun; Andrade, Jorge

    2016-01-01

    Kawasaki disease (KD) or Kawasaki syndrome is known as a vasculitis of small to medium-sized vessels, and coronary arteries are predominantly involved in childhood. Generally, 20–25% of untreated with IVIG and 3–5% of treated KD patients have been developed coronary artery lesions (CALs), such as dilatation and aneurysm. Understanding how coronary artery aneurysms (CAAs) are established and maintained in KD patients is therefore of great importance. Upon our previous genotyping data of 157 valid KD subjects, a genome-wide association study (GWAS) has been conducted among 11 (7%) CAA-developed KD patients to reveal five significant genetic variants passed pre-defined thresholds and resulted in two novel susceptibility protein-coding genes, which are NEBL (rs16921209 (P = 7.44 × 10−9; OR = 32.22) and rs7922552 (P = 8.43 × 10−9; OR = 32.0)) and TUBA3C (rs17076896 (P = 8.04 × 10−9; OR = 21.03)). Their known functions have been reported to associate with cardiac muscle and tubulin, respectively. As a result, this might imply their putative roles of establishing CAAs during KD progression. Additionally, various model analyses have been utilized to determine dominant and recessive inheritance patterns of identified susceptibility mutations. Finally, all susceptibility genes hit by significant genetic variants were further investigated and the top three representative gene-ontology (GO) clusters were regulation of cell projection organization, neuron recognition, and peptidyl-threonine phosphorylation. Our results help to depict the potential routes of the pathogenesis of CAAs in KD patients and will facilitate researchers to improve the diagnosis and prognosis of KD in personalized medicine. PMID:27171184

  8. Genome-Wide Association Study Identifies Novel Susceptibility Genes Associated with Coronary Artery Aneurysm Formation in Kawasaki Disease.

    PubMed

    Kuo, Ho-Chang; Li, Sung-Chou; Guo, Mindy Ming-Huey; Huang, Ying-Hsien; Yu, Hong-Ren; Huang, Fu-Chen; Jiao, Fuyong; Kuo, Hsing-Chun; Andrade, Jorge; Chan, Wen-Ching

    2016-01-01

    Kawasaki disease (KD) or Kawasaki syndrome is known as a vasculitis of small to medium-sized vessels, and coronary arteries are predominantly involved in childhood. Generally, 20-25% of untreated with IVIG and 3-5% of treated KD patients have been developed coronary artery lesions (CALs), such as dilatation and aneurysm. Understanding how coronary artery aneurysms (CAAs) are established and maintained in KD patients is therefore of great importance. Upon our previous genotyping data of 157 valid KD subjects, a genome-wide association study (GWAS) has been conducted among 11 (7%) CAA-developed KD patients to reveal five significant genetic variants passed pre-defined thresholds and resulted in two novel susceptibility protein-coding genes, which are NEBL (rs16921209 (P = 7.44 × 10-9; OR = 32.22) and rs7922552 (P = 8.43 × 10-9; OR = 32.0)) and TUBA3C (rs17076896 (P = 8.04 × 10-9; OR = 21.03)). Their known functions have been reported to associate with cardiac muscle and tubulin, respectively. As a result, this might imply their putative roles of establishing CAAs during KD progression. Additionally, various model analyses have been utilized to determine dominant and recessive inheritance patterns of identified susceptibility mutations. Finally, all susceptibility genes hit by significant genetic variants were further investigated and the top three representative gene-ontology (GO) clusters were regulation of cell projection organization, neuron recognition, and peptidyl-threonine phosphorylation. Our results help to depict the potential routes of the pathogenesis of CAAs in KD patients and will facilitate researchers to improve the diagnosis and prognosis of KD in personalized medicine. PMID:27171184

  9. PON1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes

    PubMed Central

    Huen, Karen; Yousefi, Paul; Street, Kelly; Eskenazi, Brenda; Holland, Nina

    2016-01-01

    Recent genome- and epigenome-wide studies demonstrate that the DNA methylation is controlled in part by genetics, highlighting the importance of integrating genetic and epigenetic data. To better understand molecular mechanisms affecting gene expression, we used the candidate susceptibility gene paraoxonase 1 (PON1) as a model to assess associations of PON1 genetic polymorphisms with DNA methylation and arylesterase activity, a marker of PON1 expression. PON1 has been associated with susceptibility to obesity, cardiovascular disease, and pesticide exposure. In this study, we assessed DNA methylation in 18 CpG sites located along PON1 shores, shelves, and its CpG island in blood specimens collected from newborns and 9-year-old children participating (n = 449) in the CHAMACOS birth cohort study. The promoter polymorphism, PON1−108, was strongly associated with methylation, particularly for CpG sites located near the CpG island (P << 0.0005). Among newborns, these relationships were even more pronounced after adjusting for blood cell composition. We also observed significant decreases in arylesterase activity with increased methylation at the same nine CpG sites at both ages. Using causal mediation analysis, we found statistically significant indirect effects of methylation (β(95% confidence interval): 6.9(1.5, 12.4)) providing evidence that DNA methylation mediates the relationship between PON1−108 genotype and PON1 expression. Our findings show that integration of genetic, epigenetic, and expression data can shed light on the functional mechanisms involving genetic and epigenetic regulation of candidate susceptibility genes like PON1. PMID:26913202

  10. Comparative antigen-induced gene expression profiles unveil novel aspects of susceptibility/resistance to adjuvant arthritis in rats.

    PubMed

    Yu, Hua; Lu, Changwan; Tan, Ming T; Moudgil, Kamal D

    2013-12-01

    Lewis (LEW) and Wistar Kyoto (WKY) rats of the same major histocompatibility complex (MHC) haplotype (RT.1(l)) display differential susceptibility to adjuvant-induced arthritis (AIA). LEW are susceptible while WKY are resistant to AIA. To gain insights into the mechanistic basis of these disparate outcomes, we compared the gene expression profiles of the draining lymph node cells (LNC) of these two rat strains early (day 7) following a potentially arthritogenic challenge. LNC were tested both ex vivo and after restimulation with the disease-related antigen, mycobacterial heat-shock protein 65. Biotin-labeled fragment cRNA was generated from RNA of LNC and then hybridized with an oligonucleotide-based DNA microarray chip. The differentially expressed genes (DEG) were compared by limiting the false discovery rate to <5% and fold change ≥2.0, and their association with quantitative trait loci (QTL) was analyzed. This analysis revealed overall a more active immune response in WKY than LEW rats. Important differences were observed in the association of DEG with QTL in LEW vs. WKY rats. Both the number of upregulated DEG associated with rat arthritis-QTL and their level of expression were relatively higher in LEW when compared to WKY rat; however, the number of downregulated DEG-associated with rat arthritis-QTL as well as AIA-QTL were found to be higher in WKY than in LEW rats. In conclusion, distinct gene expression profiles define arthritis-susceptible versus resistant phenotype of MHC-compatible inbred rats. These results would advance our understanding of the pathogenesis of autoimmune arthritis and might also offer potential novel targets for therapeutic purposes. PMID:23911410

  11. Association between SLC2A9 (GLUT9) gene polymorphisms and gout susceptibility: an updated meta-analysis.

    PubMed

    Zhang, Xu; Yang, Xiao; Wang, Mengmeng; Li, Xiaona; Xia, Qing; Xu, Shengqian; Xu, Jianhua; Cai, Guoqi; Wang, Li; Xin, Lihong; Zou, Yanfeng; Pan, Faming

    2016-08-01

    The relationship between the SLC2A9 (solute carrier family 2, member 9) gene polymorphisms and gout was still inconsistent among the individual genetic association studies. Therefore, this present research was aimed to systematically evaluate the association between SLC2A9 gene polymorphisms and gout susceptibility. Relevant studies were enrolled by searching databases systematically. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the associations. The heterogeneity between each of the studies was calculated by using the Q statistic methods, and Begg's funnel plot and Egger's tests were performed to evaluate publication bias. A total of 13 studies investigated four single nucleotide polymorphisms (SNPs) in SLC2A9 were included. In this study, we found that the allele C of rs3733591 was higher in patients than in controls in both all-pooled population [C vs. T: OR (95 % CI) = 1.432 (1.213-1.691)] and Asians-pooled population [C vs. T: OR (95 % CI) = 1.583 (1.365-1.835)]. The allele frequency C of s6449213 was lower in the gout patients than in controls in both all-pooled population and Caucasians-pooled population. Additionally, the allele frequency T of rs16890979 and the allele frequency C of rs1014290 were lower in gout patients than in controls. This study demonstrated that the genetic susceptibility for gout is associated with the SLC2A9 gene polymorphisms. Four of them except for the rs3733591 are protective SNPs in Caucasians, and rs16890979 and rs1014290 are protective SNPs in both Caucasians and Asians, while rs3733591 may be susceptibility SNP in Asians. PMID:27255295

  12. Association of the solute carrier family 11 member 1 gene polymorphisms with susceptibility to leprosy in a Brazilian sample.

    PubMed

    Brochado, Maria José Franco; Gatti, Maria Fernanda Chociay; Zago, Marco Antônio; Roselino, Ana Maria

    2016-02-01

    Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1) is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GT)n, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively), and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GT)n polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR) = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66). Patients carrying the 274T allele (p = 0.04; OR = 1.49) and TT homozygosis (p = 0.02; OR = 2.46), such as the 469+14C allele (p = 0.03; OR = 1.53) of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GT)n polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively. PMID:26814595

  13. SnTox3 Acts in Effector Triggered Susceptibility to Induce Disease on Wheat Carrying the Snn3 Gene

    PubMed Central

    Liu, Zhaohui; Faris, Justin D.; Oliver, Richard P.; Tan, Kar-Chun; Solomon, Peter S.; McDonald, Megan C.; McDonald, Bruce A.; Nunez, Alberto; Lu, Shunwen; Rasmussen, Jack B.; Friesen, Timothy L.

    2009-01-01

    The necrotrophic fungus Stagonospora nodorum produces multiple proteinaceous host-selective toxins (HSTs) which act in effector triggered susceptibility. Here, we report the molecular cloning and functional characterization of the SnTox3-encoding gene, designated SnTox3, as well as the initial characterization of the SnTox3 protein. SnTox3 is a 693 bp intron-free gene with little obvious homology to other known genes. The predicted immature SnTox3 protein is 25.8 kDa in size. A 20 amino acid signal sequence as well as a possible pro sequence are predicted. Six cysteine residues are predicted to form disulfide bonds and are shown to be important for SnTox3 activity. Using heterologous expression in Pichia pastoris and transformation into an avirulent S. nodorum isolate, we show that SnTox3 encodes the SnTox3 protein and that SnTox3 interacts with the wheat susceptibility gene Snn3. In addition, the avirulent S. nodorum isolate transformed with SnTox3 was virulent on host lines expressing the Snn3 gene. SnTox3-disrupted mutants were deficient in the production of SnTox3 and avirulent on the Snn3 differential wheat line BG220. An analysis of genetic diversity revealed that SnTox3 is present in 60.1% of a worldwide collection of 923 isolates and occurs as eleven nucleotide haplotypes resulting in four amino acid haplotypes. The cloning of SnTox3 provides a fundamental tool for the investigation of the S. nodorum–wheat interaction, as well as vital information for the general characterization of necrotroph–plant interactions. PMID:19806176

  14. SnTox3 acts in effector triggered susceptibility to induce disease on wheat carrying the Snn3 gene.

    PubMed

    Liu, Zhaohui; Faris, Justin D; Oliver, Richard P; Tan, Kar-Chun; Solomon, Peter S; McDonald, Megan C; McDonald, Bruce A; Nunez, Alberto; Lu, Shunwen; Rasmussen, Jack B; Friesen, Timothy L

    2009-09-01

    The necrotrophic fungus Stagonospora nodorum produces multiple proteinaceous host-selective toxins (HSTs) which act in effector triggered susceptibility. Here, we report the molecular cloning and functional characterization of the SnTox3-encoding gene, designated SnTox3, as well as the initial characterization of the SnTox3 protein. SnTox3 is a 693 bp intron-free gene with little obvious homology to other known genes. The predicted immature SnTox3 protein is 25.8 kDa in size. A 20 amino acid signal sequence as well as a possible pro sequence are predicted. Six cysteine residues are predicted to form disulfide bonds and are shown to be important for SnTox3 activity. Using heterologous expression in Pichia pastoris and transformation into an avirulent S. nodorum isolate, we show that SnTox3 encodes the SnTox3 protein and that SnTox3 interacts with the wheat susceptibility gene Snn3. In addition, the avirulent S. nodorum isolate transformed with SnTox3 was virulent on host lines expressing the Snn3 gene. SnTox3-disrupted mutants were deficient in the production of SnTox3 and avirulent on the Snn3 differential wheat line BG220. An analysis of genetic diversity revealed that SnTox3 is present in 60.1% of a worldwide collection of 923 isolates and occurs as eleven nucleotide haplotypes resulting in four amino acid haplotypes. The cloning of SnTox3 provides a fundamental tool for the investigation of the S. nodorum-wheat interaction, as well as vital information for the general characterization of necrotroph-plant interactions. PMID:19806176

  15. Antimicrobial susceptibility and pathogenic genes of Staphylococcus aureus isolated from the oral cavity of patients with periodontitis

    PubMed Central

    2015-01-01

    Purpose The goal of this study was to characterize the patterns of antimicrobial resistance and virulence genes in samples of Staphylococcus aureus (S. aureus) isolated from periodontitis patients. Methods From July 2015 to August 2015, oral saliva was collected from a total of 112 patients diagnosed with periodontitis, including 80 outpatients in dental hospitals and 32 patients in dental clinics located in Seoul and Cheonan. The samples were subjected to a susceptibility test to evaluate the prevalence of antimicrobial resistance, and the pathogenic factors and antimicrobial resistance factors in the DNA of S. aureus were analyzed using polymerase chain reaction. Results A susceptibility test against 15 antimicrobial agents showed that 88% of cultures were resistant to ampicillin, 88% to penicillin, and 2% to oxacillin. Resistance to at least two drugs was observed in 90% of cultures, and the most common pattern of multidrug resistance was to ampicillin and penicillin. Enterotoxins were detected in 65.9% of samples. The cell hemolysin gene hld was detected in 100% of cultures and hla was detected in 97.6% of samples. All strains resistant to penicillin and ampicillin had the blaZ gene. The aph(3′)IIIa gene, which encodes an aminoglycoside modifying enzyme, was detected in 46.3% of samples. Conclusions In the treatment of oral S. aureus infections, it is important to identify the pathogenic genes and the extent of antimicrobial resistance. Furthermore, it is necessary to study patterns of antimicrobial resistance and cross-infection in the context of periodontological specialties in which antimicrobials are frequently used, such as maxillofacial surgery, where the frequency of antimicrobial use for minor procedures such as implant placement is increasing. PMID:26734493

  16. Evaluating the association of interleukin-10 gene promoter -592 A/C polymorphism with lupus nephritis susceptibility

    PubMed Central

    Abdallah, Emad; Waked, Emam; Abdelwahab, Mahmoud A.

    2015-01-01

    Background Interleukin-10 (IL-10) is an important immunoregulatory cytokine. There are few studies evaluating the association between IL-10 and lupus nephritis (LN). The aim of this study was to evaluate the association of IL-10 gene promoter -592 A/C with LN susceptibility. Methods The study was conducted on 84 patients with systemic lupus erythematosus (SLE). Patients were divided into LN group (Group I, 48 patients) and non-LN group (Group II, 36 patients). The -592 A/C polymorphisms in IL-10 promoter gene were determined by polymerase chain reaction and restriction fragment length polymorphism in both groups. IL-10 was determined by enzyme-linked immunosorbent assay. Frequencies of the genotypes were compared between LN and non-LN patients and among LN patients with different pathologic classes. Results There was a significant increase in serum level of IL-10 (P = 0.001) in Group I compared with Group II and significant positive correlation between serum IL-10 and SLE disease activity index (r = 0.466, P = 0.001) in Group I. There were no significant differences in the distribution of the IL-10 gene promoter -592 A/C genotypes or the allele frequencies between Groups I and II. There was no significant difference between AC/CC and AA genotypes with SLE disease activity index, proteinuria, hematuria, anti-double-stranded DNA, and IL-10 in Group I. There was no significant difference in the distribution of AC and CC genotypes among different pathologic LN classes. Conclusion IL-10 suggested to play a role in pathogenesis and development of LN. However, the promoter -592 A/C of IL-10 gene suggested to be not associated with serum IL-10 levels or LN susceptibility. In addition, it appears that promoter -592 A/C of IL-10 gene not associated with LN activity or the pathologic classes of LN. PMID:27069855

  17. Differences in gene expression within a striking phenotypic mosaic Eucalyptus tree that varies in susceptibility to herbivory

    PubMed Central

    2013-01-01

    Background Long-lived trees can accumulate mutations throughout their lifetimes that may influence biotic and abiotic interactions. For example, some Eucalyptus trees display marked variation in herbivore defence within a single canopy. These “mosaic” trees support foliage with distinct chemotypes which are differentially favoured by insect and vertebrate herbivores, resulting in susceptible and resistant branches within a single canopy. These mosaic trees provide a unique opportunity to explore the biosynthesis and genetic regulation of chemical defences in the foliage. The biosynthesis of the principal defence compounds, terpenoid-dominated essential oils, is well understood. However, the regulation of the genes involved and thus the control of phenotypic variation within a single tree canopy remains a mystery. Results We sequenced the transcriptomes of the leaves of the two different chemotypes of a chemically mosaic Eucalyptus melliodora tree using 454 pyrosequencing technology. We used gene set enrichment analysis to identify differentially expressed transcripts and found the proportion of differentially expressed genes in the resistant and susceptible foliage similar to the transcript difference between functionally distinct tissues of the same organism, for example roots and leaves. We also investigated sequence differences in the form of single nucleotide polymorphisms and found 10 nucleotides that were different between the two branches. These are likely true SNPs and several occur in regulatory genes. Conclusion We found three lines of evidence that suggest changes to a ‘master switch’ can result in large scale phenotypic changes: 1. We found differential expression of terpene biosynthetic genes between the two chemotypes that could contribute to chemical variation within this plant. 2. We identified many genes that are differentially expressed between the two chemotypes, including some unique genes in each branch. These genes are involved in a

  18. Scleral buckling for retinal detachment in patients with retinoblastoma

    SciTech Connect

    Buzney, S.M.; Pruett, R.C.; Regan, C.D.; Walton, D.S.; Smith, T.R.

    1984-10-15

    Three children (two girls and one boy) with bilateral retinoblastoma each developed a presumed rhegmatogenous retinal detachment in one eye. All three eyes had previously received radiation and cryotherapy. In each case the retinal detachment responded promptly to conventional surgical methods via scleral buckling in the area of treated retinoblastoma and presumed retinal break. All three eyes have retained useful vision for follow-up periods of 3.5 to 12 years.

  19. Androgen-inducible gene 1 increases the ER Ca(2+) content and cell death susceptibility against oxidative stress.

    PubMed

    Nickel, Nadine; Cleven, Astrid; Enders, Vitalij; Lisak, Dmitrij; Schneider, Lars; Methner, Axel

    2016-07-15

    Androgen-induced gene 1 (AIG1) is a transmembrane protein implicated with survival (its expression level was shown to correlate with the survival of patients suffering from hepatocellular carcinoma) and Ca(2+) signaling (over-expression of AIG1 increased transcription mediated by the Ca(2+)-dependent nuclear factor of activated T cells). We aimed to shed light on this less-studied protein and investigated its tissue expression, genomic organization, intracellular localization and membrane topology as well as its effects on cell death susceptibility and the Ca(2+) content of the endoplasmic reticulum. Immunoblotting of mouse tissues demonstrated highest expression of AIG1 in the liver, lung and heart. AIG1 has a complex genomic organization and expresses several splice variants in a tissue-dependent manner. Analyzing the topology of AIG1 in the ER membrane using a protease-protection assay suggested that AIG has five transmembrane domains with a luminal N- and cytosolic C-terminus and a hydrophobic stretch between the third and fourth membrane domain that does not cross the membrane. AIG1 over-expression slightly increased susceptibility to oxidative stress, which correlated with an increased ER Ca(2+) concentration in two different cell lines. Together, these results indicate that AIG1 plays a role in the control of the intracellular Ca(2+) concentration and cell death susceptibility. PMID:27040980

  20. Differential Susceptibility in Spillover Between Interparental Conflict and Maternal Parenting Practices: Evidence for OXTR and 5-HTT Genes

    PubMed Central

    Sturge-Apple, Melissa L.; Cicchetti, Dante; Davies, Patrick T.; Suor, Jennifer H.

    2012-01-01

    Guided by the affective spillover hypothesis and the differential susceptibility to environmental influence frameworks, the present study examined how associations between interparental conflict and mothers’ parenting practices were moderated by serotonin transporter (5-HTT) and oxytocin receptor (OXTR) genes. A sample of 201 mothers and their two-year old child participated in a laboratory-based research assessment. Results supported differential susceptibility hypotheses within spillover frameworks. With respect to OXTR rs53576, mothers with the GG genotype showed greater differential maternal sensitivity across varying levels of interparental conflict. Mothers with one or two copies of the 5-HTTLPR S allele demonstrated differential susceptibility for both sensitive and harsh/punitive caregiving behaviors. Finally, analyses examined whether maternal depressive symptoms and emotional closeness to their child mediated the moderating effects. Findings suggest that maternal emotional closeness with their child indirectly linked OXTR with maternal sensitivity. The results highlight how molecular genetics may explain heterogeneity in spillover models with differential implications for specific parenting behaviors. Implications for clinicians and therapists working with maritally distressed parents are discussed. PMID:22563705

  1. Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite.

    PubMed

    Grünewald, Thomas G P; Bernard, Virginie; Gilardi-Hebenstreit, Pascale; Raynal, Virginie; Surdez, Didier; Aynaud, Marie-Ming; Mirabeau, Olivier; Cidre-Aranaz, Florencia; Tirode, Franck; Zaidi, Sakina; Perot, Gaëlle; Jonker, Anneliene H; Lucchesi, Carlo; Le Deley, Marie-Cécile; Oberlin, Odile; Marec-Bérard, Perrine; Véron, Amélie S; Reynaud, Stephanie; Lapouble, Eve; Boeva, Valentina; Rio Frio, Thomas; Alonso, Javier; Bhatia, Smita; Pierron, Gaëlle; Cancel-Tassin, Geraldine; Cussenot, Olivier; Cox, David G; Morton, Lindsay M; Machiela, Mitchell J; Chanock, Stephen J; Charnay, Patrick; Delattre, Olivier

    2015-09-01

    Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls identified 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1-dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis. PMID:26214589

  2. An Epistatic Interaction between the PAX8 and STK17B Genes in Papillary Thyroid Cancer Susceptibility

    PubMed Central

    Inglada-Pérez, Lucía; Sastre-Perona, Ana; Pastor, Susana; Velázquez, Antonia; Mancikova, Veronika; Ruiz-Llorente, Sergio; Schiavi, Francesca; Marcos, Ricard; Malats, Nuria; Opocher, Giuseppe; Diaz-Uriarte, Ramon; Santisteban, Pilar; Valencia, Alfonso; Robledo, Mercedes

    2013-01-01

    Papillary Thyroid Cancer (PTC) is a heterogeneous and complex disease; susceptibility to PTC is influenced by the joint effects of multiple common, low-penetrance genes, although relatively few have been identified to date. Here we applied a rigorous combined approach to assess both the individual and epistatic contributions of genetic factors to PTC susceptibility, based on one of the largest series of thyroid cancer cases described to date. In addition to identifying the involvement of TSHR variation in classic PTC, our pioneer study of epistasis revealed a significant interaction between variants in STK17B and PAX8. The interaction was detected by MD-MBR (p = 0.00010) and confirmed by other methods, and then replicated in a second independent series of patients (MD-MBR p = 0.017). Furthermore, we demonstrated an inverse correlation between expression of PAX8 and STK17B in a set of cell lines derived from human thyroid carcinomas. Overall, our work sheds additional light on the genetic basis of thyroid cancer susceptibility, and suggests a new direction for the exploration of the inherited genetic contribution to disease using association studies. PMID:24086368

  3. Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite

    PubMed Central

    Grünewald, Thomas G. P.; Bernard, Virginie; Gilardi-Hebenstreit, Pascale; Raynal, Virginie; Surdez, Didier; Aynaud, Marie-Ming; Mirabeau, Olivier; Cidre-Aranaz, Florencia; Tirode, Franck; Zaidi, Sakina; Perot, Gaëlle; Jonker, Anneliene H.; Lucchesi, Carlo; Le Deley, Marie-Cécile; Oberlin, Odile; Marec-Bérard, Perrine; Véron, Amélie S.; Reynaud, Stephanie; Lapouble, Eve; Boeva, Valentina; Frio, Thomas Rio; Alonso, Javier; Bhatia, Smita; Pierron, Gaëlle; Cancel-Tassin, Geraldine; Cussenot, Olivier; Cox, David G.; Morton, Lindsay M.; Machiela, Mitchell J.; Chanock, Stephen J.; Charnay, Patrick; Delattre, Olivier

    2015-01-01

    Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs1–3. A recent genome-wide association study4 identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls revealed 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1–dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis. PMID:26214589

  4. Systemic chemotherapy as a new conservative treatment for intraocular retinoblastoma.

    PubMed

    Yanagisawa, Takaaki

    2004-02-01

    Retinoblastoma is the most common malignant intraocular tumor in childhood. With advances in the methods for early detection of this disease, the survival rate is over 90% in developed countries. The management of intraocular retinoblastoma has gradually changed over the past few decades. Every effort has been made to save life, with the preservation of the eye and sight, if possible. External beam radiotherapy has been a standard treatment for medium and large, or visually threatening, intraocular retinoblastoma, but it markedly increases the risk of cosmetic deformities and secondary cancer in children with germline RB mutations. For the past decade, primary systemic chemotherapy called "chemoreduction" has been employed to avoid radiotherapy and enucleation. This article gives an overview of the results of current trials of primary chemoreduction for intraocular retinoblastoma, and discusses its role and its limitations in conservative treatment. The article also discusses future directions to expand the indications for this treatment. Many children with advanced intraocular retinoblastoma could be spared external beam radiotherapy and enucleation, mostly as a result of chemoreduction and focal methods. Chemoreduction combined with focal treatments will continue to play an important role in the conservative management of children with intraocular retinoblastoma, possibly even in children with advanced disease, with the combined use of multidrug-resistance modulators. PMID:15162821

  5. Family-based analysis identified CD2 as a susceptibility gene for primary open