Science.gov

Sample records for mthfr gene predisposes

  1. Relationship of MTHFR gene polymorphisms with renal and cardiac disease

    PubMed Central

    Trovato, Francesca M; Catalano, Daniela; Ragusa, Angela; Martines, G Fabio; Pirri, Clara; Buccheri, Maria Antonietta; Di Nora, Concetta; Trovato, Guglielmo M

    2015-01-01

    AIM: To investigate the effects of different methylenetetrahydrofolate reductase (MTHFR) 677C>T gene polymorphism and hyperhomocysteinemia for the development of renal failure and cardiovascular events, which are controversial. METHODS: We challenged the relationship, if any, of MTHFR 677C>T and MTHFR 1298A>C polymorphisms with renal and heart function. The present article is a reappraisal of these concepts, investigating within a larger population, and including a subgroup of dialysis patients, if the two most common MTHFR polymorphisms, C677T and A1298C, as homozygous, heterozygous or with a compound heterozygous state, show different association with chronic renal failure requiring hemodialysis. MTHFR polymorphism could be a favorable evolutionary factor, i.e., a protective factor for many ominous conditions, like cancer and renal failure. A similar finding was reported in fatty liver disease in which it is suggested that MTHFR polymorphisms could have maintained and maintain their persistence by an heterozygosis advantage mechanism. We studied a total of 630 Italian Caucasian subject aged 54.60 ± 16.35 years, addressing to the increased hazard of hemodialysis, if any, according to the studied MTHFR genetic polymorphisms. RESULTS: A favorable association with normal renal function of MTHFR polymorphisms, and notably of MTHFR C677T is present independently of the negative effects of left ventricular hypertrophy, increased Intra-Renal arterial Resistance and hyperparathyroidism. CONCLUSION: MTHFR gene polymorphisms could have a protective role on renal function as suggested by their lower frequency among our dialysis patients in end-stage renal failure; differently, the association with left ventricular hypertrophy and reduced left ventricular relaxation suggest some type of indirect, or concurrent mechanism. PMID:25664255

  2. MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders.

    PubMed

    Sener, Elif Funda; Oztop, Didem Behice; Ozkul, Yusuf

    2014-01-01

    Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism. PMID:25431675

  3. Genetic and epigenetic variants in the MTHFR gene are not associated with non-Hodgkin lymphoma.

    PubMed

    Bradshaw, Gabrielle; Sutherland, Heidi G; Camilleri, Emily T; Lea, Rodney A; Haupt, Larisa M; Griffiths, Lyn R

    2015-12-01

    The methylenetetrahydrofolate reductase (MTHFR) gene codes for the MTHFR enzyme which plays a key role in the pathway of folate and methionine metabolism. Polymorphisms of genes in this pathway affect its regulation and have been linked to lymphoma. In this study we examined whether we could detect an association between two common non-synonymous MTHFR polymorphisms, 677C > T (rs1801133) and 1298A > C (rs1801131), and susceptibility to non-Hodgkin lymphoma (NHL) in an Australian case-control cohort. We found no significant differences between genotype or allele frequencies for either polymorphisms between lymphoma cases and controls. We also explored whether epigenetic modification of MTHFR, specifically DNA methylation of a CpG island in the MTHFR promoter region, is associated with NHL using blood samples from patients. No difference in methylation levels was detected between the case and control samples suggesting that although hypermethylation of MTHFR has been reported in tumour tissues, particularly in the diffuse large B-cell lymphoma subtype of NHL, methylation of this MTHFR promoter CpG island is not a suitable epigenetic biomarker for NHL diagnosis or prognosis in peripheral blood samples. Further studies into epigenetic variants could focus on genes that are robustly associated with NHL susceptibility. PMID:26629414

  4. Genetic and epigenetic variants in the MTHFR gene are not associated with non-Hodgkin lymphoma

    PubMed Central

    Bradshaw, Gabrielle; Sutherland, Heidi G.; Camilleri, Emily T.; Lea, Rodney A.; Haupt, Larisa M.; Griffiths, Lyn R.

    2015-01-01

    The methylenetetrahydrofolate reductase (MTHFR) gene codes for the MTHFR enzyme which plays a key role in the pathway of folate and methionine metabolism. Polymorphisms of genes in this pathway affect its regulation and have been linked to lymphoma. In this study we examined whether we could detect an association between two common non-synonymous MTHFR polymorphisms, 677C > T (rs1801133) and 1298A > C (rs1801131), and susceptibility to non-Hodgkin lymphoma (NHL) in an Australian case–control cohort. We found no significant differences between genotype or allele frequencies for either polymorphisms between lymphoma cases and controls. We also explored whether epigenetic modification of MTHFR, specifically DNA methylation of a CpG island in the MTHFR promoter region, is associated with NHL using blood samples from patients. No difference in methylation levels was detected between the case and control samples suggesting that although hypermethylation of MTHFR has been reported in tumour tissues, particularly in the diffuse large B-cell lymphoma subtype of NHL, methylation of this MTHFR promoter CpG island is not a suitable epigenetic biomarker for NHL diagnosis or prognosis in peripheral blood samples. Further studies into epigenetic variants could focus on genes that are robustly associated with NHL susceptibility. PMID:26629414

  5. Mutations of the MTHFR gene (428C>T and [458G>T+459C>T]) markedly decrease MTHFR enzyme activity.

    PubMed

    Yano, Hidetaka; Nakaso, Kazuhiro; Yasui, Kenichi; Wakutani, Yosuke; Nakayasu, Hiroyuki; Kowa, Hisanori; Adachi, Yoshiki; Nakashima, Kenji

    2004-06-01

    Methylenetetrahydrofolate reductase (MTHFR) is the only route for the synthesis of 5-methyltetrahydrofolate, which is utilized to convert homocysteine to methionine. In this study, we measured the enzyme activity of a mutant MTHFR that was detected in a patient with hyperhomocysteinemia. The 428C>T mutation in exon 2 of the MTHFR gene is a novel mutation, while the [458G>T+459C>T] mutation in exon 2 is a previously reported mutation. The activity of mutant enzymes containing the 428C>T, [458G>T+459C>T] and 677C>T mutations was 12.7+/-4.7%, 48.1+/-18.8%, and 43.6+/-14.4%, respectively, of that of the wild type enzyme. Our results suggest that these two variants each result in a severe MTHFR deficiency, which causes a developmental delay and cerebral vascular disease. PMID:15048559

  6. A COMMON POLYMORPHISM IN THE METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE IS ASSOCIATED WITH QUANTITATIVE ULTRASOUND IN THOSE WITH LOW PLASMA FOLATE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A study of a polymorphism in the MTHFR gene, plasma folate, and bone phenotypes in 1632 individuals revealed that the genotype effect on BMD and quantitative ultrasound was dependent on the level of folate. Our findings support the hypothesis that the association between an MTHFR polymorphism and bo...

  7. Variants in MTHFR gene and neural tube defects susceptibility in China.

    PubMed

    Wang, Yongxin; Liu, Yuan; Ji, Wenyu; Qin, Hu; Wu, Hao; Xu, Danshu; Turtuohut, Tukebai; Wang, Zengliang

    2015-08-01

    Neural tube defect (NTD) is a severe congenital birth abnormalities involving incomplete neural tube closure. 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene plays key role in folate cycle and methylation cycle, which could affect the DNA synthesis, repair and methylation. In this study, we aim to investigate the correlation between MTHFR polymorphisms and NTD-affected pregnancy. There were 444 participants involved in our study. Tag-SNPs were identified in HapMap Databases. Blood samples were collected from all subjects to further extract the genomic DNAs by TaqMan Blood DNA kits. We also carried out a meta-analysis based on previous published studies to further examine the association between MTHFR polymorphisms and NTD. In case-control study analysis, two SNPs were identified to be associated with NTD risk. The 677 C > T genetic variant was correlated with increased risk of NTD-affected pregnancy. However, the 1298 A > C polymorphism was shown to lower the risk of NTD-affected pregnancy. The protective role of 1298 A > C polymorphisms was further supported by the result of meta-analysis. Our study revealed that the SNPs of 677C > T and 1298A > C in MTHFR were associated with NTD-affected pregnancy, in which 677C > T was a risk factor and in contrast 1298A > C was protective factor against NTD. Our results of meta-analysis also revealed the 1298A > C MTHFR polymorphism play protective role in NTD. PMID:25855017

  8. Genomic scan for genes predisposing to schizophrenia

    SciTech Connect

    Coon, H.; Jensen. S.; Holik, J.

    1994-03-15

    We initiated a genome-wide search for genes predisposing to schizophrenia by ascertaining 9 families, each containing three to five cases of schizophrenia. The 9 pedigrees were initially genotyped with 329 polymorphic DNA loci distributed throughout the genome. Assuming either autosomal dominant or recessive inheritance, 254 DNA loci yielded lod scores less than -2.0 at {theta} = 0.0, 101 DNA markers gave lod scores less than -2.0 at {theta} = 0.05, while 5 DNA loci produced maximum lod scores greater than 1: D4S35, D14S17, D15S1, D22S84, and D22S55. Of the DNA markers yielding lod scores greater than 1, D4S35 and D22S55 also were suggestive of linkage when the Affected-Pedigree-Member method was used. The families were then genotyped with four highly polymorphic simple sequence repeat markers; possible linkage diminished with DNA markers mapping nearby D4S35, while suggestive evidence of linkage remained with loci in the region of D22S55. Although follow-up investigation of these chromosomal regions may be warranted, our linkage results should be viewed as preliminary observations, as 35 unaffected persons are not past the age of risk. 90 refs., 3 tabs.

  9. Population- and Family-Based Studies Associate the "MTHFR" Gene with Idiopathic Autism in Simplex Families

    ERIC Educational Resources Information Center

    Liu, Xudong; Solehdin, Fatima; Cohen, Ira L.; Gonzalez, Maripaz G.; Jenkins, Edmund C.; Lewis, M. E. Suzanne; Holden, Jeanette J. A.

    2011-01-01

    Two methylenetetrahydrofolate reductase gene ("MTHFR") functional polymorphisms were studied in 205 North American simplex (SPX) and 307 multiplex (MPX) families having one or more children with an autism spectrum disorder. Case-control comparisons revealed a significantly higher frequency of the low-activity 677T allele, higher prevalence of the…

  10. Analysis of MTHFR and MTRR Gene Polymorphisms in Iranian Ventricular Septal Defect Subjects

    PubMed Central

    Pishva, Seyyed Reza; Vasudevan, Ramachandran; Etemad, Ali; Heidari, Farzad; Komara, Makanko; Ismail, Patimah; Othman, Fauziah; Karimi, Abdollah; Sabri, Mohammad Reza

    2013-01-01

    Ventricular septal defect (VSD) is one of the most common types of congenital heart defects (CHD). There are vivid multifactorial causes for VSD in which both genetic and environmental risk factors are consequential in the development of CHD. Methionine synthase reductase (MTRR) and methylenetetrahydrofolate reductase (MTHFR) are two of the key regulatory enzymes involved in the metabolic pathway of homocysteine. Genes involved in homocysteine/folate metabolism may play an important role in CHDs. In this study; we determined the association of A66G and C524T polymorphisms of the MTRR gene and C677T polymorphism of the MTHFR gene in Iranian VSD subjects. A total of 123 children with VSDs and 125 healthy children were included in this study. Genomic DNA was extracted from the buccal cells of all the subjects. The restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method was carried out to amplify the A66G and C524T polymorphism of MTRR and C677T polymorphism of MTHFR genes digested with Hinf1, Xho1 and Nde1 enzymes, respectively. The genotype frequencies of CC, CT and TT of MTRR gene among the studied cases were 43.1%, 40.7% and 16.3%, respectively, compared to 52.8%, 43.2% and 4.0%, respectively among the controls. For the MTRR A66G gene polymorphism, the genotypes frequencies of AA, AG and GG among the cases were 33.3%, 43.9% and 22.8%, respectively, while the frequencies were 49.6%, 42.4% and 8.0%, respectively, among control subjects. The frequencies for CC and CT genotypes of the MTHFR gene were 51.2% and 48.8%, respectively, in VSD patients compared to 56.8% and 43.2% respectively, in control subjects. Apart from MTHFR C677T polymorphism, significant differences were noticed (p < 0.05) in C524T and A66G polymorphisms of the MTRR gene between cases and control subjects. PMID:23358257

  11. Screening of polymorphisms for MTHFR and DHFR genes in spina bifida children and their mothers

    NASA Astrophysics Data System (ADS)

    Husna, M. Z.; Endom, I.; Ibrahim, S.; Selvi, N. Amaramalar; Fakhrurazi, H.; Htwe, R. Ohnmar; Kanehaswari, Y.; Halim, A. R. Abdul; Wong, S. W.; Subashini, K.; Syahira, O. Nur; Aishah, S.

    2013-11-01

    Mechanism underlying the beneficial effect of folic acid supplementation in reducing the risk of neural tube defect is still not well understood. Current evidences show the involvement of folic acid metabolic gene's polymorphism as contributing factors that regulate this pathway. Therefore, the objective of this research was to determine the presence of C677T polymorphism for methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR-19 bp deletion) genes between mother-children pairs of case and control. With the approval of UKMMC ethic committee, genomic DNA was extracted from one hundred and forty consented bloods. Polymerase chain reaction (PCR), PCR-RFLP (Restriction Fragment Length Polymorphism) and sequencing were employed to verify each nucleotide change. Our result shows that mutant MTHFR and DHFR alleles are present in all Malaysian sub-ethnic groups, case and control. Even though mutant MTHFR are found to be slightly higher in the case groups, 75% of the affected child is a non carrier for this allele and 62.5% of the mothers with an affected child are genotypically normal. For DHFR, almost all (87.5-100%) investigated samples are a carrier or having a double DHFR deletion be it a case or control pairs. However, strong maternal inheritance shown by the deleted allele might be due to a cascade effect of lacks of folate consumption or maternal uniparental disomy. In conclusion, the use of MTHFR and DHFR as markers in determining the risk of having spina bifida baby is uninformative and plays a small indirect role as the genetic causes of spina bifida. Therefore, spina bifida remains etiologically unknown polygenic and quantitative developmental trait whereby the searches for positive genetic marker need to be continued.

  12. The association between MTHFR 677C>T genotype and folate status and genomic and gene-specific DNA methylation in the colon of individuals without colorectal neoplasia1234

    PubMed Central

    Hanks, Joanna; Ayed, Iyeman; Kukreja, Neil; Rogers, Chris; Harris, Jessica; Gheorghiu, Alina; Liu, Chee Ling; Emery, Peter

    2013-01-01

    Background: Decreased genomic and increased gene-specific DNA methylation predispose to colorectal cancer. Dietary folate intake and the methylenetetrahydrofolate reductase polymorphism (MTHFR 677C>T) may influence risk by modifying DNA methylation. Objective: We investigated the associations between MTHFR 677C>T genotype, folate status, and DNA methylation in the colon. Design: We conducted a cross-sectional study of 336 men and women (age 19–92 y) in the United Kingdom without colorectal neoplasia. We obtained blood samples for measurement of serum and red blood cell folate, plasma homocysteine, and MTHFR 677C>T genotype and colonic tissue biopsies for measurement of colonic tissue folate and DNA methylation (genomic- and gene-specific, estrogen receptor 1, ESR1; myoblast determination protein 1, MYOD1; insulin-like growth factor II, IGF2; tumor suppressor candidate 33, N33; adenomatous polyposis coli, APC; mut-L homolog 1, MLH1; and O6-methylguanine-DNA methyltransferase, MGMT) by liquid chromatography/electrospray ionization mass spectrometry and pyrosequencing, respectively. Results: Of the 336 subjects recruited, 185 (55%) carried the CC, 119 (35%) the CT, and 32 (10%) the TT alleles. No significant differences in systemic markers of folate status and colonic tissue folate between genotypes were found. The MTHFR TT genotype was not associated with genomic or gene-specific DNA methylation. Biomarkers of folate status were not associated with genomic DNA methylation. Relations between biomarkers of folate status and gene-specific methylation were inconsistent. However, low serum folate was associated with high MGMT methylation (P = 0.001). Conclusion: MTHFR 677C>T genotype and folate status were generally not associated with DNA methylation in the colon of a folate-replete population without neoplasia. This trial was registered at clinicaltrials.gov as ISRCTN43577261. PMID:24108782

  13. Association of Polymorphisms in BDNF, MTHFR, and Genes Involved in the Dopaminergic Pathway with Memory in a Healthy Chinese Population

    ERIC Educational Resources Information Center

    Yeh, Ting-Kuang; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Pei-Jung; Wu, Chung-Hsin; Lee, Po-Lei; Chang, Chun-Yen

    2012-01-01

    The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single…

  14. Associations of Polymorphisms in MTHFR Gene with the Risk of Age-Related Cataract in Chinese Han Population: A Genotype-Phenotype Analysis

    PubMed Central

    Wei, Li; Han, Ya-di; Cui, Ning-hua; Huang, Zhu-liang; Li, Zu-hua; Zheng, Fang; Yan, Ming

    2015-01-01

    Homocysteine (Hcy) is a potential risk factor for age-related cataract (ARC). Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme for Hcy metabolism, and variants of MTHFR may affect MTHFR enzyme activity. This study mainly evaluated the associations between variants in MTHFR gene, plasma MTHFR enzyme activity, total Hcy (tHcy) levels and ARC risk in Chinese population. Four single nucleotide polymorphisms (SNPs) in MTHFR gene were genotyped using the high-resolution melting (HRM) method in 502 ARC patients (mean age, 70.2 [SD, 9.0], 46.0% male) and 890 healthy controls (mean age, 67.1 [SD, 11.1], 47.6% male). The plasma MTHFR activity, folic acid (FA), vitamins B12 and B6 levels were detected by enzyme-linked immunosorbent assays (ELISA). The plasma tHcy levels were measured by an automated enzymatic assay. After the Bonferroni correction, the minor allele T of SNP rs1801133 showed a significant association with an increased risk of overall ARC (OR = 1.26, P = 0.003). Consistent association was also found between SNP rs1801133 and cortical ARC risk (OR = 1.44, P = 0.003). Haplotype analyses revealed an adverse effect of the haplotype "C-A-T-C" (alleles in order of SNPs rs3737967, rs1801131, rs1801133 and rs9651118) on ARC risk (OR = 1.55, P = 0.003). Moreover, in a joint analysis of SNPs rs9651118 and rs1801133, subjects with two unfavorable genotypes had a 1.76-fold increased risk of ARC compared with the reference group, and a statistically significant dose-response trend (Ptrend = 0.001) was also observed. Further, in healthy controls and patients with cortical ARC, the allele T of SNP rs1801133 and the increasing number of unfavorable genotypes were significantly correlated with decreased MTHFR activity as well as increased tHcy levels. However, there was no significant association between FA, vitamins B12, B6 levels and MTHFR variants. Our data indicated that variants in MTHFR gene might individually and jointly influence susceptibility to ARC by affecting MTHFR enzyme activity and tHcy levels. PMID:26689687

  15. Functional variants in CYP1B1, KRAS and MTHFR genes are associated with shorter telomere length in postmenopausal women.

    PubMed

    Cerne, Jasmina Z; Pohar-Perme, Maja; Cerkovnik, Petra; Gersak, Ksenija; Novakovic, Srdjan

    2015-07-01

    Estrogens and antioxidants indirectly alleviate telomere attrition. However, available clinical data on the association between hormone exposure and telomere length are inconclusive. In the present study, we examined the effects of exogenous estrogen use and of some genetic factors implicated in estrogen metabolism and oxidative stress response on mean leukocyte telomere length. We studied 259 postmenopausal women. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695), MnSOD (rs4880), KRAS (rs61764370), and MTHFR (rs1801133 and rs1801131) polymorphisms. Mean leukocyte telomere length was measured using a quantitative real-time PCR assay. In multivariate analysis we found no association between oral contraceptives or hormone replacement therapy (HRT) and mean leukocyte telomere length. The presence of variant alleles in CYP1B1, KRAS and MTHFR genes was statistically significantly associated with shorter mean leukocyte telomere length. Further, the data provided evidence for the effect modification of the association between HRT and mean leukocyte telomere length by the CYP1B1, KRAS and MTHFR genotypes. Our findings suggest that functionally relevant genetic variants within estrogen and folate metabolic pathways may influence telomere length. We propose these genetic factors should be taken into consideration when interpreting associations between hormone exposure and telomere length. PMID:25987236

  16. Association of Tagging SNPs in the MTHFR Gene with Risk of Type 2 Diabetes Mellitus and Serum Homocysteine Levels in a Chinese Population

    PubMed Central

    Wang, Han; Wan, Bin

    2014-01-01

    Diabetes is a global public health crisis, and the prevalence is increasing rapidly. Folate supplementation is proved to be effective in reducing the risk of diabetes or improving its symptoms. Methylenetetrahydrofolate reductase is an important enzyme involved in folate metabolism. The aim of this study is to examine whether polymorphisms in the MTHFR gene are associated with risk of type 2 diabetes mellitus (T2DM) and fasting total serum homocysteine (tHcy) levels. We genotyped nine tagging SNPs in the MTHFR gene in a case-control study, including 595 T2DM cases and 681 healthy controls in China. We found that C allele of rs9651118 had significant decreased risk of T2DM (adjusted odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.55–0.87, P = 0.002) compared with T allele. Haplotype analysis also showed that MTHFR CTCCGA haplotype (rs12121543-rs13306553-rs9651118-rs1801133-rs2274976-rs1801131) had significant reduced risk of T2DM (adjusted OR = 0.71, 95% CI: 0.58–0.87, P = 0.001) compared with CTTTGA haplotype. Besides, the MTHFR rs1801133 was significantly associated with serum levels of tHcy in healthy controls (P = 0.0002). These associations were still significant after Bonferroni corrections (P < 0.0056). These findings suggest that variants in the MTHFR gene may influence the risk of T2DM and tHcy levels. PMID:25165408

  17. Significance of the use of the ViennaLab “Cardiovascular Disease panel” (CVD) Assay as a reflex test for the “Factor V/II/MTHFR Assay”?

    PubMed Central

    Hoteit, Rouba; Abbas, Fatmeh; Antar, Ahmad; Abdel Khalek, Rabab; Shammaa, Dina; Mahfouz, Rami

    2013-01-01

    Introduction Trends toward identifying risk factors of thrombotic complications had become essential as an attempt to prevent and decrease the incidence of the complications. Thrombosis has been associated with predisposing factors like mutations in FV, PTH, MTHFR and other genes. Aim Evaluate whether the CVD StripAssay has an added value in the screening for more thrombophilia risk factors, which may predispose for the development of cardiovascular diseases and other thrombotic clinical conditions. Methods We compared the results for 94 patients who were previously tested for Factor V, Factor II and MTHFR gene mutations using the ViennaLab FV-PTH-MTHFR StripAssay, and for whom additional testing for the Cardiovascular Disease panel (CVD StripAssay, ViennaLab) was requested. Results Using the CVD StripAssay, 66% of patients who had no mutations when tested using the FV-PTH-MTHFR StripAssay or carried a mutation for MTHFR, were found to have additional genes' SNPs or mutations that are highly associated with a risk of thrombosis as per the available international literature. Conclusion This observation is of extreme importance in clinical practice for the introduction of the extended CVD panel into routine molecular diagnostic test menus and highlights the importance of genetic analysis of the implicated genes in the management of patients with a thrombotic episode presentation. PMID:25606377

  18. One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in children with autism spectrum disorders

    PubMed Central

    Pa?ca, Sergiu P; Dronca, Eleonora; Kaucsár, Tamás; Cr?ciun, Elena C; Endreffy, Emõke; Ferencz, Beatrix K; Iftene, Felicia; Benga, Ileana; Cornean, Rodica; Banerjee, Ruma; Dronca, Maria

    2009-01-01

    Autism spectrum disorders (ASDs), which include the prototypic autistic disorder (AD), Asperger’s syndrome (AS) and pervasive developmental disorders not otherwise specified (PDD-NOS), are complex neurodevelopmental conditions of unknown aetiology. The current study investigated the metabolites in the methionine cycle, the transsulphuration pathway, folate, vitamin B12 and the C677T polymorphism of the MTHFR gene in three groups of children diagnosed with AD (n= 15), AS (n= 5) and PDD-NOS (n= 19) and their age- and sex-matched controls (n= 25). No metabolic disturbances were seen in the AS patients, while in the AD and PDD-NOS groups, lower plasma levels of methionine (P= 0.01 and P= 0.03, respectively) and ?-aminobutyrate were observed (P= 0.01 and P= 0.001, respectively). Only in the AD group, plasma cysteine (P= 0.02) and total blood glutathione (P= 0.02) were found to be reduced. Although there was a trend towards lower levels of serine, glycine, N, N-dimethylglycine in AD patients, the plasma levels of these metabolites as well as the levels of homocysteine and cystathionine were not statistically different in any of the ASDs groups. The serum levels of vitamin B12 and folate were in the normal range. The results of the MTHFR gene analysis showed a normal distribution of the C677T polymorphism in children with ASDs, but the frequency of the 677T allele was slightly more prevalent in AD patients. Our study indicates a possible role for the alterations in one carbon metabolism in the pathophysiology of ASDs and provides, for the first time, preliminary evidence for metabolic and genetic differences between clinical subtypes of ASDs. PMID:19267885

  19. Maternal and offspring MTHFR gene C677T polymorphism as predictors of congenital atrial septal defect and patent ductus arteriosus.

    PubMed

    Zhu, Wenli L; Li, Yong; Yan, Liying; Dao, Jingjing; Li, Shuqin

    2006-01-01

    To observe the association of MTHFR gene C677T locus polymorphism with occurrence of congenital heart defects (CHDs), 21 patients with atrial septal defect (ASD), 35 patients with patent ductus arteriosus (PDA), one patient with both conditions combined, and their biological parents were collected as the case group. Another 104 normal individuals and their biological parents without a family history of birth defects were selected as the control group. MTHFR C677T genotypes of each sample were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed for the occurrence of ASD, the odds ratio (OR) of TT genotype was 4.08 [95% confidence interval (95% CI) = 1.28-13.24] compared with CT genotype. For the occurrence of PDA, the ORs of TT were 3.44 (95% CI = 0.89-16.13) and 2.38 (95% CI = 0.92-6.14) compared with CC and CT genotypes, respectively. Author as meant? Compared with CC + CT genotype combination, the ORs of TT were 3.95 (95% CI = 1.38-11.44) and 2.60 (95% CI = 1.02-6.36) for ASD and PSD respectively. The results also had sex differences and the statistical significance was only observed in male ASD and female PDA. The ORs of T allele carriers were 2.29 (95% CI = 1.08-4.92) and 1.88 (95% CI = 1.02-3.47) compared with C allele for the occurrences of ASD and PDA respectively. The analysis of parents genotype showed that the OR of TT mothers was 2.31 (95% CI = 0.96-5.59, P < 0.05) compared with (CC + CT) for the occurrence of PDA in offspring. So this study could give a clue that MTHFR C677T locus variation was related with occurrence of ASD and PDA, and the carriers of TT genotype and T allele had higher risk of diseases. The mother carrying TT genotype was associated with occurrence of PDA in offspring. PMID:16373366

  20. The Effectiveness of Pemetrexed Monotherapy Depending on Polymorphisms in TS and MTHFR Genes as Well as Clinical Factors in Advanced NSCLC Patients.

    PubMed

    Kucharczyk, Tomasz; Krawczyk, Pawe?; Powrózek, Tomasz; Kowalski, Dariusz M; Ramlau, Rodryg; Kalinka-Warzocha, Ewa; Knetki-Wróblewska, Magdalena; Winiarczyk, Kinga; Krzakowski, Maciej; Milanowski, Janusz

    2016-01-01

    In NSCLC, second-line chemotherapy using pemetrexed or docetaxel has limited efficacy and should be dedicated to selected groups of patients. Pemetrexed is an antifolate compound with the ability to inhibit enzymes (TS, DHFR and GARFT) involved in pyrimidine and purine synthesis. The objective of this study was to evaluate the association between polymorphisms of TS and MHFR genes and clinical outcomes in NSCLC patients treated with pemetrexed monotherapy. DNA was isolated from peripheral blood of 72 non-squamous NSCLC patients treated with pemetrexed. Using PCR and RFLP methods, the variable number of tandem repeats (VNTR), the G > C SNP in these repeats and insertion/deletion polymorphism of TS gene as well as 677C > T SNP in MTHFR gene were analyzed and correlated with disease control rate, progression-free survival and overall survival (OS) of NSCLC patients. Carriers of 2R/3R(G), 3R(C)/3R(G), 3R(G)/3R(G) genotypes showed significantly more frequent early progression than carriers of 2R/2R, 2R/3R(C), 3R(C)/3R(C) genotypes of TS gene (p < 0.05). Among carriers of triple 28 bp tandem repeats (3R) in TS gene and C/C genotype of MTHFR gene a significantly shorter OS was observed (HR = 3.07; p = 0.003). In multivariate analysis, significantly higher risk of death was observed in carriers of both 3R/3R genotype in TS and C/C genotype in 677C > T SNP in MTHFR (HR = 3.85; p < 0.005) as well as in patients with short duration of response to first-line chemotherapy (HR = 2.09; p < 0.005). Results of our study suggested that genetic factors may have a high predictive and prognostic value (even greater than clinical factors) for patients treated with pemetrexed monotherapy. PMID:26277606

  1. Study on Environmental Causes and SNPs of MTHFR, MS and CBS Genes Related to Congenital Heart Disease

    PubMed Central

    Liu, Yan; Huang, Peng; Lin, Ning; Sun, Xiaoru; Yu, Rongbin; Zhang, Yuanyuan; Qin, Yuming; Wang, Lijuan

    2015-01-01

    Purpose Congenital heart diseases (CHD) are among the most common birth defects in China. Environmental causes and folate metabolism changes may alter susceptibility to CHD. The aim of this study is to evaluate the relevant risk-factors of children with CHD and their mothers. Methods 138 children with CHD and 207 normal children for controls were recruited. Their mothers were also enlisted in this study and interviewed following a questionnaire about their pregnant history and early pregnancy situation. Five single nucleotide polymorphisms (SNPs) in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS) and cystathionine ?-synthase (CBS) of mothers and children were genotyped. Results There were significant differences in the gender of children, occupation of mothers, family history with CHD, history of abortion, history of adverse pregnancy, early pregnancy health, fetus during pregnancy, pesticide exposure and drug exposure in CHD group and control group ( P < 0.05). Logistic regression analyses showed that after adjustment for above factors, MTHFR rs1801131 were significantly associated with their offspring CHD risk in mothers. Compared with the mothers whose MTHFR were rs1801131 AA and AC genotypes, the mothers who got a mutation of MTHFR rs1801131 CC genotypes had a 267% increase in risk of given birth of a CHD children (OR=3.67,95%CI=1.12-12.05). Meanwhile, MTHFR rs1801131 were significantly associated with CHD susceptibility in children (OR = 1.42, 95% CI = 1.00-2.44 in additive model). Conclusions Besides mothers’ social and fertility characteristics, our results suggested that the genetic variants in folate metabolism pathway might be one of the most related risk-factors of CHD. MTHFR rs1801131 were identified as loci in Chinese population that were involved in CHD. PMID:26035828

  2. Variation in Telangiectasia Predisposing Genes Is Associated With Overall Radiation Toxicity

    SciTech Connect

    Tanteles, George A.; Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester ; Murray, Robert J.S.; Mills, Jamie; Barwell, Julian; Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester ; Chakraborti, Prabir; Chan, Steve; Cheung, Kwok-Leung; Ennis, Dawn; Khurshid, Nazish; Lambert, Kelly; Machhar, Rohan; Meisuria, Mitul; Osman, Ahmed; Peat, Irene; Sahota, Harjinder; Woodings, Pamela; Talbot, Christopher J.; and others

    2012-11-15

    Purpose: In patients receiving radiotherapy for breast cancer where the heart is within the radiation field, cutaneous telangiectasiae could be a marker of potential radiation-induced heart disease. We hypothesized that single nucleotide polymorphisms (SNPs) in genes known to cause heritable telangiectasia-associated disorders could predispose to such late, normal tissue vascular damage. Methods and Materials: The relationship between cutaneous telangiectasia as a late normal tissue radiation injury phenotype in 633 breast cancer patients treated with radiotherapy was examined. Patients were clinically assessed for the presence of cutaneous telangiectasia and genotyped at nine SNPs in three candidate genes. Candidate SNPs were within the endoglin (ENG) and activin A receptor, type II-like 1 (ACVRL1) genes, mutations in which cause hereditary hemorrhagic telangiectasia and the ataxia-telangiectasia mutated (ATM) gene associated with ataxia-telangiectasia. Results: A total of 121 (19.1%) patients exhibited a degree of cutaneous telangiectasiae on clinical examination. Regression was used to examine the associations between the presence of telangiectasiae in patients who underwent breast-conserving surgery, controlling for the effects of boost and known brassiere size (n=388), and individual geno- or haplotypes. Inheritance of ACVRL1 SNPs marginally contributed to the risk of cutaneous telangiectasiae. Haplotypic analysis revealed a stronger association between inheritance of a ATM haplotype and the presence of cutaneous telangiectasiae, fibrosis and overall toxicity. No significant association was observed between telangiectasiae and the coinheritance of the candidate ENG SNPs. Conclusions: Genetic variation in the ATM gene influences reaction to radiotherapy through both vascular damage and increased fibrosis. The predisposing variation in the ATM gene will need to be better defined to optimize it as a predictive marker for assessing radiotherapy late effects.

  3. MTHFR and ACE Gene Polymorphisms and Risk of Vascular and Degenerative Dementias in the Elderly

    ERIC Educational Resources Information Center

    Pandey, Pratima; Pradhan, Sunil; Modi, Dinesh Raj; Mittal, Balraj

    2009-01-01

    Focal lacunar infarctions due to cerebral small vessel atherosclerosis or single/multiple large cortical infarcts lead to vascular dementia, and different genes and environmental factors have been implicated in causation or aggravation of the disease. Previous reports suggest that some of the risk factors may be common to both vascular as well as…

  4. Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects

    PubMed Central

    Saunders, Sean P.; Goh, Christabelle S.M.; Brown, Sara J.; Palmer, Colin N.A.; Porter, Rebecca M.; Cole, Christian; Campbell, Linda E.; Gierlinski, Marek; Barton, Geoffrey J.; Schneider, Georg; Balmain, Allan; Prescott, Alan R.; Weidinger, Stephan; Baurecht, Hansjörg; Kabesch, Michael; Gieger, Christian; Lee, Young-Ae; Tavendale, Roger; Mukhopadhyay, Somnath; Turner, Stephen W.; Madhok, Vishnu B.; Sullivan, Frank M.; Relton, Caroline; Burn, John; Meggitt, Simon; Smith, Catherine H.; Allen, Michael A.; Barker, Jonathan N.W. N.; Reynolds, Nick J.; Cordell, Heather J.; Irvine, Alan D.; McLean, W.H. Irwin; Sandilands, Aileen; Fallon, Padraic G.

    2013-01-01

    Background Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype. Objective We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD. Methods A mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD. Results The matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Mattft mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6694514, in the human MATT gene has a small but significant association with AD. Conclusion In mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects. PMID:24084074

  5. A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity

    PubMed Central

    Frayling, Timothy M.; Timpson, Nicholas J.; Weedon, Michael N.; Zeggini, Eleftheria; Freathy, Rachel M.; Lindgren, Cecilia M.; Perry, John R. B.; Elliott, Katherine S.; Lango, Hana; Rayner, Nigel W.; Shields, Beverley; Harries, Lorna W.; Barrett, Jeffrey C.; Ellard, Sian; Groves, Christopher J.; Knight, Bridget; Patch, Ann-Marie; Ness, Andrew R.; Ebrahim, Shah; Lawlor, Debbie A.; Ring, Susan M.; Ben-Shlomo, Yoav; Jarvelin, Marjo-Riitta; Sovio, Ulla; Bennett, Amanda J.; Melzer, David; Ferrucci, Luigi; Loos, Ruth J. F.; Barroso, Inês; Wareham, Nicholas J.; Karpe, Fredrik; Owen, Katharine R.; Cardon, Lon R.; Walker, Mark; Hitman, Graham A.; Palmer, Colin N. A.; Doney, Alex S. F.; Morris, Andrew D.; Smith, George Davey; Hattersley, Andrew T.; McCarthy, Mark I.

    2009-01-01

    Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes–susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass. PMID:17434869

  6. Retinal Ganglion Cell Loss and Mild Vasculopathy in Methylene Tetrahydrofolate Reductase (Mthfr)-Deficient Mice: A Model of Mild Hyperhomocysteinemia

    PubMed Central

    Markand, Shanu; Saul, Alan; Roon, Penny; Prasad, Puttur; Martin, Pamela; Rozen, Rima; Ganapathy, Vadivel; Smith, Sylvia B.

    2015-01-01

    Purpose. Methylenetetrahydrofolate reductase (Mthfr) is a key enzyme in homocysteine-methionine metabolism. We investigated Mthfr expression in retina and asked whether mild hyperhomocysteinemia, due to Mthfr deficiency, alters retinal neurovascular structure and function. Methods. Expression of Mthfr was investigated at the gene and protein level using quantitative (q) RT-PCR, in situ hybridization, immunoblotting, and immunohistochemistry (IHC). The Mthfr+/+ and Mthfr+/? mice were subjected to comprehensive evaluation using ERG, funduscopy, fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), HPLC, and morphometric and IHC analysis of glial fibrillary acidic protein (GFAP) at 8 to 24 weeks. Results. Gene and protein analyses disclosed widespread retinal expression of Mthfr. Electroretinography (ERG) revealed a significant decrease in positive scotopic threshold response in retinas of Mthfr+/? mice at 24 weeks. Fundus examination in mice from both groups was normal; FA revealed areas of focal vascular leakage in 20% of Mthfr+/? mice at 12 to 16 weeks and 60% by 24 weeks. The SD-OCT revealed a significant decrease in nerve fiber layer (NFL) thickness at 24 weeks in Mthfr+/? compared to Mthfr+/+ mice. There was a 2-fold elevation in retinal hcy at 24 weeks in Mthfr+/? mice by HPLC and IHC. Morphometric analysis revealed an approximately 20% reduction in cells in the ganglion cell layer of Mthfr+/? mice at 24 weeks. The IHC indicated significantly increased GFAP labeling suggestive of Müller cell activation. Conclusions. Mildly hyperhomocysteinemic Mthfr+/? mice demonstrate reduced ganglion cell function, thinner NFL, and mild vasculopathy by 24 weeks. The retinal phenotype is similar to that of hyperhomocysteinemic mice with deficiency of cystathionine-?-synthase (Cbs) reported earlier. The data support the hypothesis that hyperhomocysteinemia may be causative in certain retinal neurovasculopathies. PMID:25766590

  7. Ethnic variation of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase (MTHFR) gene in southwestern Mexico.

    PubMed

    Antonio-Véjar, V; Del Moral-Hernández, O; Alarcón-Romero, L C; Flores-Alfaro, E; Leyva-Vázquez, M A; Hernández-Sotelo, D; Illades-Aguiar, B

    2014-01-01

    In this study, we examined the distribution of genotype and allele frequencies of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase gene (MTHFR) in two ethnic groups in the State of Guerrero, Mexico, which were compared with those of the Mestizo population of the region. A comparative study was conducted on 455 women from two ethnic groups and a group of Mestizo women of the State of Guerrero, Mexico: 135 Nahuas, 124 Mixtecas, and 196 Mestizas. Genotyping of both polymorphisms were performed by using polymerase chain reaction-restriction fragment length polymorphism methods. We found that the 677TT genotype was more frequent in Nahua and Mixteca women compared to Mestiza women (P = 0.008), and the most prevalent genotype in both ethnic groups was the 1298AA genotype (P < 0.001). We also compared the 677T allele frequency obtained from the groups studied with the frequencies reported in other ethnic groups of Mexico (Huichol, Tarahumara, and Purepecha). There were significant differences between the three ethnic groups compared to Nahuas (Huicholes, P = 0.004; Tarahumaras, P < 0.001; Purepechas, P = 0.042). Our results indicated significant differences in the frequencies of the C677T and A1298C polymorphisms between the two ethnic groups and the Mestizo population of the State of Guerrero. In addition, we found strong differences with other ethnic groups in Mexico. These results could be useful for future studies investigating diseases related to folate metabolism, and could help the government to design specific nutrition programs for different ethnic groups. PMID:25299110

  8. SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth.

    PubMed

    Corradi, Anna; Fadda, Manuela; Piton, Amélie; Patry, Lysanne; Marte, Antonella; Rossi, Pia; Cadieux-Dion, Maxime; Gauthier, Julie; Lapointe, Line; Mottron, Laurent; Valtorta, Flavia; Rouleau, Guy A; Fassio, Anna; Benfenati, Fabio; Cossette, Patrick

    2014-01-01

    An increasing number of genes predisposing to autism spectrum disorders (ASDs) has been identified, many of which are implicated in synaptic function. This 'synaptic autism pathway' notably includes disruption of SYN1 that is associated with epilepsy, autism and abnormal behavior in both human and mice models. Synapsins constitute a multigene family of neuron-specific phosphoproteins (SYN1-3) present in the majority of synapses where they are implicated in the regulation of neurotransmitter release and synaptogenesis. Synapsins I and II, the major Syn isoforms in the adult brain, display partially overlapping functions and defects in both isoforms are associated with epilepsy and autistic-like behavior in mice. In this study, we show that nonsense (A94fs199X) and missense (Y236S and G464R) mutations in SYN2 are associated with ASD in humans. The phenotype is apparent in males. Female carriers of SYN2 mutations are unaffected, suggesting that SYN2 is another example of autosomal sex-limited expression in ASD. When expressed in SYN2 ?knockout neurons, wild-type human Syn II fully rescues the SYN2 knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtually unable to modify the SYN2 knockout phenotype. These results identify for the first time SYN2 ?as a novel predisposing gene for ASD and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies ASD. PMID:23956174

  9. Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X

    PubMed Central

    Schulz, Eduard; Klampfl, Petra; Holzapfel, Stefanie; Janecke, Andreas R.; Ulz, Peter; Renner, Wilfried; Kashofer, Karl; Nojima, Satoshi; Leitner, Anita; Zebisch, Armin; Wölfler, Albert; Hofer, Sybille; Gerger, Armin; Lax, Sigurd; Beham-Schmid, Christine; Steinke, Verena; Heitzer, Ellen; Geigl, Jochen B.; Windpassinger, Christian; Hoefler, Gerald; Speicher, Michael R.; Richard Boland, C.; Kumanogoh, Atsushi; Sill, Heinz

    2014-01-01

    Familial colorectal cancer type X (FCCTX) is characterized by clinical features of hereditary non-polyposis colorectal cancer with a yet undefined genetic background. Here we identify the SEMA4A p.Val78Met germline mutation in an Austrian kindred with FCCTX, using an integrative genomics strategy. Compared with wild-type protein, SEMA4AV78M demonstrates significantly increased MAPK/Erk and PI3K/Akt signalling as well as cell cycle progression of SEMA4A-deficient HCT-116 colorectal cancer cells. In a cohort of 53 patients with FCCTX, we depict two further SEMA4A mutations, p.Gly484Ala and p.Ser326Phe and the single-nucleotide polymorphism (SNP) p.Pro682Ser. This SNP is highly associated with the FCCTX phenotype exhibiting increased risk for colorectal cancer (OR 6.79, 95% CI 2.63 to 17.52). Our study shows previously unidentified germline variants in SEMA4A predisposing to FCCTX, which has implications for surveillance strategies of patients and their families. PMID:25307848

  10. Gene Expression Profiling of Histiocytic Sarcomas in a Canine Model: The Predisposed Flatcoated Retriever Dog

    PubMed Central

    Boerkamp, Kim M.; van Wolferen, Monique E.; Groot Koerkamp, Marian J. A.; van Leenen, Dik; Grinwis, Guy C. M.; Penning, Louis C.; Wiemer, Erik A. C.; Rutteman, Gerard R.

    2013-01-01

    Background The determination of altered expression of genes in specific tumor types and their effect upon cellular processes may create insight in tumorigenesis and help to design better treatments. The Flatcoated retriever is a dog breed with an exceptionally high incidence of histiocytic sarcomas. The breed develops two distinct entities of histiocytic neoplasia, a soft tissue form and a visceral form. Gene expression studies of these tumors have value for comparable human diseases such as histiocytic/dendritic cell sarcoma for which knowledge is difficult to accrue due to their rare occurrence. In addition, such studies may help in the search for genetic aberrations underlying the genetic predisposition in this dog breed. Methods Microarray analysis and pathway analyses were performed on fresh-frozen tissues obtained from Flatcoated retrievers with localized, soft tissue histiocytic sarcomas (STHS) and disseminated, visceral histiocytic sarcomas (VHS) and on normal canine spleens from various breeds. Expression differences of nine genes were validated with quantitative real-time PCR (qPCR) analyses. Results QPCR analyses identified the significantly altered expression of nine genes; PPBP, SpiC, VCAM1, ENPEP, ITGAD (down-regulated), and GTSF1, Col3a1, CD90 and LUM (up-regulated) in the comparison of both the soft tissue and the visceral form with healthy spleen. DAVID pathway analyses revealed 24 pathways that were significantly involved in the development of HS in general, most of which were involved in the DNA repair and replication process. Conclusions This study identified altered expression of nine genes not yet implicated in histiocytic sarcoma manifestations in the dog nor in comparable human histiocytic/dendritic sarcomas. Exploration of the downside effect of canine inbreeding strategies for the study of similar sarcomas in humans might also lead to the identification of genes related to these rare malignancies in the human. PMID:23936488

  11. Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders.

    PubMed

    Sartor, Francesca; Anderson, Jihan; McCaig, Colin; Miedzybrodzka, Zosia; Müller, Berndt

    2015-12-01

    Brain development is a tightly controlled process that depends upon differentiation and function of neurons to allow for the formation of functional neural networks. Mutation of genes encoding structural proteins is well recognized as causal for neurodevelopmental disorders (NDDs). Recent studies have shown that aberrant gene expression can also lead to disorders of neural development. Here we summarize recent evidence implicating in the aetiology of NDDs mutation of factors acting at the level of mRNA splicing, mRNA nuclear export, translation and mRNA degradation. This highlights the importance of these fundamental processes for human health and affords new strategies and targets for therapeutic intervention. PMID:26614670

  12. Knockout of the TauT Gene Predisposes C57BL/6 Mice to Streptozotocin-Induced Diabetic Nephropathy

    PubMed Central

    Han, Xiaobin; Patters, Andrea B.; Ito, Takashi; Schaffer, Stephen W.; Chesney, Russell W.

    2015-01-01

    Diabetic nephropathy is the leading cause of end stage renal disease in the world. Although tremendous efforts have been made, scientists have yet to identify an ideal animal model that can reproduce the characteristics of human diabetic nephropathy. In this study, we hypothesize that taurine insufficiency is a critical risk factor for development of diabetic nephropathy associated with diabetes mellitus. This hypothesis was tested in vivo in TauT heterozygous (TauT+/-) and homozygous (TauT-/-) knockout in C57BL/6 background mice. We have shown that alteration of the TauT gene (also known as SLC6A6) has a substantial effect on the susceptibility to development of extensive diabetic kidney disease in both TauT+/- and TauT-/-mouse models of diabetes. These animals developed histological changes characteristic of human diabetic nephropathy that included glomerulosclerosis, nodular lesions, arteriosclerosis, arteriolar dilation, and tubulointerstitial fibrosis. Immunohistochemical staining of molecular markers of smooth muscle actin, CD34, Ki67 and collagen IV further confirmed these observations. Our results demonstrated that both homozygous and heterozygous TauT gene deletion predispose C57BL/6 mice to develop end-stage diabetic kidney disease, which closely replicates the pathological features of diabetic nephropathy in human diabetic patients. PMID:25629817

  13. Genetic variants in 3?-UTRs of methylenetetrahydrofolate reductase (MTHFR) predict colorectal cancer susceptibility in Koreans

    PubMed Central

    Joo Jeon, Young; Woo Kim, Jong; Mi Park, Hye; Kim, Jung O; Geun Jang, Hyo; Oh, Jisu; Gyu Hwang, Seong; Won Kwon, Sung; Oh, Doyeun; Keun Kim, Nam

    2015-01-01

    Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) play important roles in tumor development, progression, and metastasis. Moreover, recent studies have reported that a number of 3?-UTR polymorphisms potentially bind to specific microRNAs in a variety of cancers. The aim of this study was to investigate the association of four MTHFR polymorphisms, 2572C>A [rs4846049], 4869C>G [rs1537514], 5488C>T [rs3737967], and 6685T>C [rs4846048] with colorectal cancer (CRC) in Koreans. A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of MTHFR 3?-UTR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan allelic discrimination assay. We found that MTHFR 2572C>A, 4869C>G, and 5488C>T genotypes were substantially associated with CRC susceptibility. Of the potentially susceptible polymorphisms, MTHFR 2572C>A was associated with increased homocysteine and decreased folate levels in the plasma based on MTHFR 677CC. Our study provides the evidences for 3?-UTR variants in MTHFR gene as potential biomarkers for use in CRC prevention. PMID:26046315

  14. Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias

    PubMed Central

    Hara, Munetsugu; Takahashi, Tomoyuki; Mitsumasu, Chiaki; Igata, Sachiyo; Takano, Makoto; Minami, Tomoko; Yasukawa, Hideo; Okayama, Satoko; Nakamura, Keiichiro; Okabe, Yasunori; Tanaka, Eiichiro; Takemura, Genzou; Kosai, Ken-ichiro; Yamashita, Yushiro; Matsuishi, Toyojiro

    2015-01-01

    Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure. PMID:26073556

  15. Lipid Status and Predisposing Genes in Patients with Diabetes Mellitus Type 1 from Various Ethnic Groups.

    PubMed

    Kolesnikova, L I; Kolesnikov, S I; Darenskaya, M A; Grebenkina, L A; Semenova, N V; Osipova, E V; Gnusina, S V; Bardymova, T A

    2015-12-01

    The peculiarities of HLA class II profile and lipid metabolism were examined in Buryat and Russian ethnic groups of patients with diabetes mellitus type 1. The incidence of type 1 haplotypes in HLA class II gene family was lower in Buryats than that in Russians. In comparison with Russians, the course of diabetes mellitus type 1 in Buryat patients was characterized with a lower content of total lipids, triacylglycerols, total cholesterol, and LDL, which probably explains a more favorable course of the disease in Buryat population. PMID:26642791

  16. Polymorphism in the Serotonin Receptor 2a (HTR2A) Gene as Possible Predisposal Factor for Aggressive Traits

    PubMed Central

    Banlaki, Zsofia; Elek, Zsuzsanna; Nanasi, Tibor; Szekely, Anna; Nemoda, Zsofia; Sasvari-Szekely, Maria; Ronai, Zsolt

    2015-01-01

    Aggressive manifestations and their consequences are a major issue of mankind, highlighting the need for understanding the contributory factors. Still, aggression-related genetic analyses have so far mainly been conducted on small population subsets such as individuals suffering from a certain psychiatric disorder or a narrow-range age cohort, but no data on the general population is yet available. In the present study, our aim was to identify polymorphisms in genes affecting neurobiological processes that might explain some of the inter-individual variation between aggression levels in the non-clinical Caucasian adult population. 55 single nucleotide polymorphisms (SNP) were simultaneously determined in 887 subjects who also filled out the self-report Buss-Perry Aggression Questionnaire (BPAQ). Single marker association analyses between genotypes and aggression scores indicated a significant role of rs7322347 located in the HTR2A gene encoding serotonin receptor 2a following Bonferroni correction for multiple testing (p = 0.0007) both for males and females. Taking the four BPAQ subscales individually, scores for Hostility, Anger and Physical Aggression showed significant association with rs7322347 T allele in themselves, while no association was found with Verbal Aggression. Of the subscales, relationship with rs7322347 was strongest in the case of Hostility, where statistical significance virtually equaled that observed with the whole BPAQ. In conclusion, this is the first study to our knowledge analyzing SNPs in a wide variety of genes in terms of aggression in a large sample-size non-clinical adult population, also describing a novel candidate polymorphism as predisposal to aggressive traits. PMID:25658328

  17. A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance

    SciTech Connect

    Coon, H.; Jensen, S.; Hoff, M.; Holik, J.; Plaetke, R.; Reimherr, F.; Wender, P.; Leppert, M.; Byerley, W. )

    1993-06-01

    Manic-depressive illness (MDI), also known as [open quotes]bipolar affective disorder[close quotes], is a common and devastating neuropsychiatric illness. Although pivotal biochemical alterations underlying the disease are unknown, results of family, twin, and adoption studies consistently implicate genetic transmission in the pathogenesis of MDI. In order to carry out linkage analysis, the authors ascertained eight moderately sized pedigrees containing multiple cases of the disease. For a four-allele marker mapping at 5 cM from the disease gene, the pedigree sample has >97% power to detect a dominant allele under genetic homogeneity and has >73% power under 20% heterogeneity. To date, the eight pedigrees have been genotyped with 328 polymorphic DNA loci throughout the genome. When autosomal dominant inheritance was assumed, 273 DNA markers gave lod scores <[minus]2.0 at [theta] = .05, and 4 DNA marker loci yielded lod scores >1 (chromosome 5 -- D5S39, D5S43, and D5S62; chromosome 11 -- D11S85). Of the markers giving lod scores >1, only D5S62 continued to show evidence for linkage when the affected-pedigree-member method was used. The D5S62 locus maps to distal 5q, a region containing neurotransmitter-receptor genes for dopamine, norepinephrine, glutamate, and gamma-aminobutyric acid. Although additional work in this region may be warranted, the linkage results should be interpreted as preliminary data, as 68 unaffected individuals are not past the age of risk. 72 refs., 2 tabs.

  18. Association of the MTHFR A1298C Variant with Unexplained Severe Male Infertility

    PubMed Central

    Eloualid, Abdelmajid; Abidi, Omar; Charif, Majida; El houate, Brahim; Benrahma, Houda; Louanjli, Noureddine; Chadli, Elbakkay; Ajjemami, Maria; Barakat, Abdelhamid; Bashamboo, Anu; McElreavey, Ken; Rhaissi, Houria; Rouba, Hassan

    2012-01-01

    The methylenetetrahydrofolate reductase (MTHFR) gene is one of the main regulatory enzymes involved in folate metabolism, DNA synthesis and remethylation reactions. The influence of MTHFR variants on male infertility is not completely understood. The objective of this study was to analyze the distribution of the MTHFR C677T and A1298C variants using PCR-Restriction Fragment Length Polymorphism (RFLP) in a case group consisting of 344 men with unexplained reduced sperm counts compared to 617 ancestry-matched fertile or normozoospermic controls. The Chi square test was used to analyze the genotype distributions of MTHFR polymorphisms. Our data indicated a lack of association of the C677T variant with infertility. However, the homozygous (C/C) A1298C polymorphism of the MTHFR gene was present at a statistically high significance in severe oligozoospermia group compared with controls (OR?=?3.372, 95% confidence interval CI?=?1.27–8.238; p?=?0.01431). The genotype distribution of the A1298C variants showed significant deviation from the expected Hardy-Weinberg equilibrium, suggesting that purifying selection may be acting on the 1298CC genotype. Further studies are necessary to determine the influence of the environment, especially the consumption of diet folate on sperm counts of men with different MTHFR variants. PMID:22457816

  19. Polymorphism of Alcohol Metabolizing Gene ADH3 Predisposes to Development of Alcoholic Pancreatitis in North Indian Population

    PubMed Central

    Singh, Divya; Negi, Tajwar S.; Upadhyay, Ghanshyam; Choudhuri, Gourdas

    2015-01-01

    Background and aim: Genetic factors regulating alcohol metabolism could predispose in developing alcoholic pancreatitis (ACP). Studies revealed that alcohol could be metabolized by both ways, oxidative and non-oxidative. The main oxidative pathway includes alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and cytochrome P450 enzyme. We investigated the association of polymorphisms in these enzymes with the alcoholic pancreatitis in the north Indian population. Method: Patients with alcoholic pancreatitis (ACP; n = 72), tropical calcific pancreatitis (TCP; n = 75), alcoholic controls (AC; n = 40), and healthy controls (HC; n = 100) were included in the study. Blood samples were collected from the subjects in EDTA coated vials. DNA was extracted and genotyping for ADH3, ALDH2, and CYP2E1 was done by PCR-RFLP (polymerase chain reaction—restriction fragment length polymorphism). The products were analyzed by gel electrophoresis. Result: The frequency distribution of ADH3*1/*1 genotype was significantly higher in ACP group (59.7%) compared with TCP (38.7%), HC (42%), and AC (37.5%) and was found to be associated with increased risk of alcoholic pancreatitis. There was no statistically significant difference between the frequency distribution of ADH3*1/*1, ADH3*1/*2, and ADH3*2/*2 genotypes between TCP and HC or healthy alcoholics. ALDH2 gene was monomorphic in our population, and the frequencies for CYP2E1 intron 6 Dra I polymorphism were comparable in all the four groups. Conclusion: This study shows that carriers of ADH3*1/*1 individuals consuming alcohol are at higher risk for alcoholic pancreatitis than those with other genotypes such as ADH3*1/*2 and ADH3*2/*2.

  20. Idiopathic Male Infertility Is Strongly Associated with Aberrant Promoter Methylation of Methylenetetrahydrofolate Reductase (MTHFR)

    PubMed Central

    Qin, Yufeng; Niu, Xiaobing; Lu, Chuncheng; Xia, Yankai; Song, Ling; Wang, Shoulin; Wang, Xinru

    2010-01-01

    Background Abnormal germline DNA methylation in males has been proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. Previous studies have been focused on imprinted genes with DNA methylation in poor quality human sperms. However, recent but limited data have revealed that sperm methylation abnormalities may involve large numbers of genes or shown that genes that are not imprinted are also affected. Methodology/Principal Findings Using the methylation-specific polymerase chain reaction and bisulfite sequencing method, we examined methylation patterns of the promoter of methylenetetrahydrofolate reductase (MTHFR) gene (NG_013351: 1538–1719) in sperm DNA obtained from 94 idiopathic infertile men and 54 normal fertile controls. Subjects with idiopathic infertility were further divided into groups of normozoospermia and oligozoospermia. Overall, 45% (41/94) of idiopathic infertile males had MTHFR hypermethylation (both hemimethylation and full methylation), compared with 15% of fertile controls (P<0.05). Subjects with higher methylation level of MTHFR were more likely to have idiopathic male infertility (P-value for trend ?=?0.0007). Comparing the two groups of idiopathic infertile subjects with different sperm concentrations, a higher methylation pattern was found in the group with oligozoospermia. Conclusions Hypermethylation of the promoter of MTHFR gene in sperms is associated with idiopathic male infertility. The functional relevance of hypermathylation of MTHFR to male fertility warrants further investigation. PMID:21085488

  1. Analysis of Polymorphisms in Genes (AGT, MTHFR, GPIIIa, and GSTP1) Associated with Hypertension, Thrombophilia and Oxidative Stress in Mestizo and Amerindian Populations of México

    PubMed Central

    Juárez-Velázquez, Rocio; Canto, Patricia; Canto-Cetina, Thelma; Rangel-Villalobos, Hector; Rosas-Vargas, Haydee; Rodríguez, Maricela; Canizales-Quinteros, Samuel; Velázquez Wong, Ana Claudia; Ordoñez-Razo, Rosa María; Vilchis-Dorantes, Guadalupe; Coral-Vázquez, Ramón Mauricio

    2010-01-01

    Several polymorphisms related to hypertension, thrombophilia, and oxidative stress has been associated with the development of cardiovascular disease. We analyzed the frequency of M235T angiotensinogen (AGT), A222V 5,10 methylenete-trahydrofolate reductase (MTHFR), L33P glycoprotein IIIa (GPIIIa), and I105V glutathione S-transferase P1 (GSTP1) polymorphisms in 285 individuals belonging to Mexican-Mestizo and five Amerindian population from México, by real time PCR allelic discrimination. Allele and genotype frequencies were compared using ?2 tests. All populations followed the Hardy Weinberg equilibrium for assay markers with the exception of the Triki, whose were in Hardy Weinberg dysequilibrium for the glutathione S-transferase P1 polymorphism. Interestingly, according to all the analyzed single nucleotide polymorphisms (SNPs), the Triki population was the most differentiated and homogeneous group of the six populations analyzed. A comparison of our data with those previously published for some Caucasian, Asian and Black populations showed quite significant differences. These differences were remarkable with all the Mexican populations having a lower frequency of the 105V allele of the glutathione S-transferase P1 and reduced occurrence of the 222A allele of the 5,10 methylenetetrahydrofolate reductase. Our results show the genetic diversity among different Mexican populations and with other racial groups. PMID:20592457

  2. MTHFR genetic polymorphism increases the risk of preterm delivery

    PubMed Central

    Nan, Yanrong; Li, Hongmei

    2015-01-01

    Aims: This study aimed to investigate the association between the methylene tetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and premature delivery susceptibility. Methods: With matched age and gender, 108 premature delivery pregnant women as cases and 108 healthy pregnant women as controls were recruited in this case-control study. The cases and controls had same gestational weeks. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was adopted to analyze C677T and A1298C polymorphisms of the participants. Linkage disequilibrium (LD) and haplotype analysis were conducted by Haploview software. The differences for frequencies of gene type, allele and haplotypes in cases and controls were tested by chi-square test. The relevant risk of premature delivery was represented by odds ratios (ORs) with 95% confidence intervals (95% CIs). Results: TT gene type frequency of C677T polymorphsim was higher in cases than the controls (P=0.004, OR=3.077, 95% CI=1.469-6.447), so was allele T (P=0.002, OR=1.853, 95% CI=1.265-2.716). Whereas, CC gene type of A1298C polymorphism had a lower distribution in cases than the controls (P=0.008, OR=0.095, 95% CI=0.012-0.775), so was allele C (P=0.047, OR=0.610, 95% CI=0.384-0.970). Haplotype analysis and linkage disequilibrium test conducted on the alleles of two polymorphisms in MTHFR gene, we discovered that haplotype T-A had a higher distribution in cases, which indicated that susceptible haplotype T-A was the candidate factor for premature delivery. Conclusions: Gene type TT of MTHFR C677T polymorphism might make premature delivery risk rise while gene type CC of A1298C polymorphism might have protective influence on premature delivery. PMID:26261642

  3. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice12345

    PubMed Central

    Christensen, Karen E; Mikael, Leonie G; Leung, Kit-Yi; Lévesque, Nancy; Deng, Liyuan; Wu, Qing; Malysheva, Olga V; Best, Ana; Caudill, Marie A; Greene, Nicholas DE

    2015-01-01

    Background: Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. Objective: Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Design: Folic acid–supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr+/+ and Mthfr+/? mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. Results: Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr+/? mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr+/? livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr+/? mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. Conclusions: We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot accommodate the lipid disturbances and altered membrane integrity arising from changes in phospholipid/lipid metabolism. These preliminary findings may have clinical implications for individuals consuming high-dose folic acid supplements, particularly those who are MTHFR deficient. PMID:25733650

  4. A case report of two male siblings with autism and duplication of Xq13-q21, a region including three genes predisposing for autism.

    PubMed

    Wentz, Elisabet; Vujic, Mihailo; Kärrstedt, Ewa-Lotta; Erlandsson, Anna; Gillberg, Christopher

    2014-05-01

    Autism spectrum disorder, severe behaviour problems and duplication of the Xq12 to Xq13 region have recently been described in three male relatives. To describe the psychiatric comorbidity and dysmorphic features, including craniosynostosis, of two male siblings with autism and duplication of the Xq13 to Xq21 region, and attempt to narrow down the number of duplicated genes proposed to be leading to global developmental delay and autism. We performed DNA sequencing of certain exons of the TWIST1 gene, the FGFR2 gene and the FGFR3 gene. We also performed microarray analysis of the DNA. In addition to autism, the two male siblings exhibited severe learning disability, self-injurious behaviour, temper tantrums and hyperactivity, and had no communicative language. Chromosomal analyses were normal. Neither of the two siblings showed mutations of the sequenced exons known to produce craniosynostosis. The microarray analysis detected an extra copy of a region on the long arm of chromosome X, chromosome band Xq13.1-q21.1. Comparison of our two cases with previously described patients allowed us to identify three genes predisposing for autism in the duplicated chromosomal region. Sagittal craniosynostosis is also a new finding linked to the duplication. PMID:23974867

  5. Association between methylenetetrahydrofolate reductase (MTHFR) polymorphism and carotid intima medial thickness progression in post ischaemic stroke patient

    PubMed Central

    Faradz, Sultana M.H.; Sari, Stefani; Hadisaputro, Soeharyo

    2015-01-01

    Background Hyperhomocysteinemia is associated with an increased risk of atherosclerosis. The main cause of elevated levels of homocysteine is 677T allele, the gene encoded by methylenetetrahydrofolate reductase (MTHFR). Carotid atherosclerosis progression, which can be measured by examination of carotid intima-media thickness (C-IMT), is a predictor of recurrent ischemic stroke. The objective of this study was to determine a relationship between MTHFR polymorphism, homocysteine ??levels, and increased C-IMT in post- ischemic stroke patients. Methods This was an epidemiological prospective observational cohort study involving 71 patients with post-ischemic stroke subject of the first (onset 1 month) admitted in the Neurology Clinic of Kariadi Hospital during 2012 to 2013. C-IMT was examined using carotid duplex ultrasound at 1st, 6th, and 12th month after stroke onset. MTHFR gene polymorphism was examined using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). Homocysteine level was measured using Axis® Homocysteine EIA. Results We found 3 categories of MTHFR gene variation, i.e., 677T/T, 677T/C, and 677C/C. The most frequent allele was MTHFR 677C (88.9%), while the MTHFR 677T allele frequency was 11.1%. The majority allele of the subject population was 677C/C, however, there were 3 subjects (4.2%) who had 677T/T allele. The 677T/T allele group had normal homocysteine level and the lowest mean C-IMT among others. Conclusions This study supports that the MTHFR 677T allele polymorphism is not associated with hyperhomocysteinemia as well as an increase in C-IMT in post ischemic stroke patients.

  6. No association between MTHFR C677T polymorphism and completed suicide.

    PubMed

    Chojnicka, Izabela; Sobczyk-Kopcio?, Agnieszka; Fudalej, Marcin; Fudalej, Sylwia; Wojnar, Marcin; Wa?kiewicz, Anna; Broda, Gra?yna; Strawa, Katarzyna; Pawlak, Aleksandra; Krajewski, Pawe?; P?oski, Rafa?

    2012-12-10

    MTHFR C677T polymorphism (rs1801133) was associated with numerous psychiatric conditions but no prior study investigated whether it predisposes to completed suicide. We typed rs1801133 in 692 suicide victims and 3257 controls representative of a Polish adult population (the WOBASZ cohort). Although we had a power of 0.8 to detect (at alpha 0.05) an allelic OR=1.19, we did not find significant difference among suicides vs. controls in the prevalence of the MTHFR 677T allele (OR=1.02, p=0.759) or the TT genotype (OR=1.01, p=0.926). Since among controls we found an association between TT and depression defined by Beck Depression Inventory (BDI, OR=1.61, p=0.049) we also compared suicides with controls without signs of depression (BDI ? 11) but found no association (OR=1.0, p=0.976). Analyses within suicides showed trends (not significant after Bonferroni correction) for correlations between the dose of the T allele and age at death among males and blood ethanol concentration among females, who committed suicide under the influence of alcohol. We conclude that MTHFR C677T polymorphism is not a risk factor for completed suicide. The sex-specific trends for correlations between rs1801133 and age at death, and blood ethanol concentration should be studied further. PMID:22982411

  7. Effect of GDNF on depressive-like behavior, spatial learning and key genes of the brain dopamine system in genetically predisposed to behavioral disorders mouse strains.

    PubMed

    Naumenko, Vladimir S; Kondaurova, Elena M; Bazovkina, Daria V; Tsybko, Anton S; Ilchibaeva, Tatyana V; Khotskin, Nikita V; Semenova, Alina A; Popova, Nina K

    2014-11-01

    The effect of glial cell line-derived neurotrophic factor (GDNF) on behavior and brain dopamine system in predisposed to depressive-like behavior ASC (Antidepressant Sensitive Cataleptics) mice in comparison with the parental "nondepressive" CBA mice was studied. In 7days after administration (800ng, i.c.v.) GDNF decreased escape latency time and the path traveled to reach hidden platform in Morris water maze in ASC mice. GDNF enhanced depressive-like behavioral traits in both "nondepressive" CBA and "depressive" ASC mice. In CBA mice, GDNF decreased functional response to agonists of D1 (chloro-APB hydrobromide) and D2 (sumanirole maleate) receptors in tail suspension test, reduced D2 receptor gene expression in the substantia nigra and increased monoamine oxydase A (MAO A) gene expression in the striatum. GDNF increased D1 and D2 receptor genes expression in the nucleus accumbens of ASC mice but failed to alter expression of catechol-O-methyltransferase, dopamine transporter, MAO B and tyrosine hydroxylase genes in both investigated mouse strains. Thus, GDNF produced long-term genotype-dependent effect on behavior and the brain dopamine system. GDNF pretreatment (1) reduced D1 and D2 receptors functional responses and D2 receptor gene expression in s. nigra of CBA mice; (2) increased D1 and D2 receptor genes expression in n. accumbens of ASC mice and (3) improved spatial learning in ASC mice. GDNF enhanced depressive-like behavior both in CBA and ASC mice. The data suggest that genetically defined variance in the cross-talk between GDNF and brain dopamine system contributes to the variability of GDNF-induced responses and might be responsible for controversial GDNF effects. PMID:25101543

  8. Association of RFC1 A80G and MTHFR C677T polymorphisms with Alzheimer's disease.

    PubMed

    Bi, Xiu-Hua; Zhao, Hua-Lu; Zhang, Zhen-Xin; Zhang, Jun-Wu

    2009-10-01

    We examined polymorphisms in reduced folate carrier gene (RFC1) and methylenetetrahydrofolate reductase gene (MTHFR) for association with sporadic AD (SAD) in Chinese population. Significant associations of RFC1 A80G G allele and GG genotype with SAD (p=0.008, OR=1.312, 95%CI=1.072-1.605, and p=0.042, OR=1.383, 95%CI=1.012-1.890) were found. Further stratification of total samples by APOE epsilon4 carrier status, age/age at onset and gender revealed that RFC1 A80G G allele was an APOE epsilon4-independent risk factor for late-onset AD, and it might increase the risk of AD in females. No significant associations of MTHFR C677T allele and genotype with AD were observed in total samples, but significant associations of T allele and TT genotype with AD (p=0.031, OR=1.586, 95%CI=1.042-2.414, and p=0.028, OR=2.250, 95%CI=1.074-4.712) were identified in APOE epsilon4 carrier subgroup, suggesting that MTHFR 677 T allele and APOE epsilon4 allele may synergistically act to increase AD risk. No significant effect of RFC1 G80A and MTHFR C677T polymorphisms on plasma folate and homocysteine levels was detected. PMID:18258338

  9. Prevalence of MTHFR C677T Polymorphism in North Indian Mothers Having Babies with Trisomy 21 Down Syndrome

    ERIC Educational Resources Information Center

    Kohli, Utkarsh; Arora, Sadhna; Kabra, Madhulika; Ramakrishnan, Lakshmy; Gulati, Sheffali; Pandey, Ravindra

    2008-01-01

    Recent studies have evaluated possible links between polymorphisms in maternal folate metabolism genes and Down syndrome. Some of these studies show a significantly increased prevalence of the C677T polymorphism of the 5,10-methylene tetrahydrofolate reductase (NADPH) gene (MTHFR) among mothers who have had babies with Down syndrome. This study…

  10. Identification of Fetal and Maternal Single Nucleotide Polymorphisms in Candidate Genes That Predispose to Spontaneous Preterm Labor with Intact Membranes

    PubMed Central

    Romero, Roberto; Velez, Digna R.; Kusanovic, Juan Pedro; Hassan, Sonia S.; Mazaki-Tovi, Shali; Vaisbuch, Edi; Kim, Chong Jai; Chaiworapongsa, Tinnakorn; Pearce, Brad; Friel, Lara A.; Bartlett, Jacquelaine; Anant, Madan Kumar; Salisbury, Benjamin A.; Vovis, Gerald F.; Lee, Min Seob; Gomez, Ricardo; Behnke, Ernesto; Oyarzun, Enrique; Tromp, Gerard; Williams, Scott M.; Menon, Ramkumar

    2013-01-01

    Objective To determine whether maternal/fetal SNPs in candidate genes are associated with spontaneous preterm labor/delivery. Study Design A genetic association study was conducted in 223 mothers and 179 fetuses [preterm labor with intact membranes who delivered <37 weeks (PTB)], and 599 mothers and 628 fetuses (normal pregnancy): 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; FDR was used to correct for multiple testing (q*=0.15)]. Results 1) The strongest single locus associations with PTB were IL6R (fetus: p=0.000148) and TIMP2 (mother: p=0.000197), remaining significant after correction for multiple comparisons; 2) Global haplotype analysis indicated an association between a fetal DNA variant in IGF2 and maternal COL4A3 (global p=0.004 and 0.007, respectively). Conclusion A SNP involved in controlling fetal inflammation (IL6R) and DNA variants in maternal genes encoding for proteins involved in extracellular matrix biology approximately doubled the risk of PTB. PMID:20452482

  11. A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM)

    PubMed Central

    ROMERO, Roberto; FRIEL, Lara A.; EDWARDS, Digna R. VELEZ; KUSANOVIC, Juan Pedro; HASSAN, Sonia S.; MAZAKI-TOVI, Shali; VAISBUCH, Edi; KIM, Chong Jai; EREZ, Offer; CHAIWORAPONGSA, Tinnakorn; PEARCE, Brad D.; BARTLETT, Jacquelaine; SALISBURY, Benjamin A.; ANANT, Madan Kumar; VOVIS, Gerald F.; LEE, Min Seob; GOMEZ, Ricardo; BEHNKE, Ernesto; OYARZUN, Enrique; TROMP, Gerard; WILLIAMS, Scott M.; MENON, Ramkumar

    2010-01-01

    Objective To determine whether maternal/fetal SNPs in candidate genes are associated with preterm prelabor rupture of membranes (pPROM). Study Design A case-control study was conducted in patients with pPROM (225 mothers and 155 fetuses) and 599 mothers and 628 fetuses with a normal pregnancy; 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; FDR was used to correct for multiple testing (q*=0.15)]. Results 1) A SNP in TIMP2 in mothers was significantly associated with pPROM(OR=2.12 95% CI [1.47-3.07], p = 0.000068), and this association remained significant after correction for multiple comparisons; 2) Haplotypes for COL4A3 in the mother were associated with pPROM (global p = 0.003); 3) Multilocus analysis identified a three locus model, which included maternal SNPs in COL1A2, DEFA5, and EDN1. Conclusion DNA variants in a maternal gene involved in extracellular matrix metabolism doubled the risk of pPROM. PMID:20673868

  12. ApcMin, A Mutation in the Murine Apc Gene, Predisposes to Mammary Carcinomas and Focal Alveolar Hyperplasias

    NASA Astrophysics Data System (ADS)

    Moser, Amy Rapaich; Mattes, Ellen M.; Dove, William F.; Lindstrom, Mary J.; Haag, Jill D.; Gould, Michael N.

    1993-10-01

    ApcMin (Min, multiple intestinal neoplasia) is a point mutation in the murine homolog of the APC gene. Min/+ mice develop multiple intestinal adenomas, as do humans carrying germ-line mutations in APC. Female mice carrying Min are also prone to develop mammary tumors. Min/+ mammary glands are more sensitive to chemical carcinogenesis than are +/+ mammary glands. Transplantation of mammary cells from Min/+ or +/+ donors into +/+ hosts demonstrates that the propensity to develop mammary tumors is intrinsic to the Min/+ mammary cells. Long-term grafts of Min/+ mammary glands also gave rise to focal alveolar hyperplasias, indicating that the presence of the Min mutation also has a role in the development of these lesions.

  13. The Association of the MTHFR c.1625A>C Genetic Variant with the Risk of Congenital Heart Diseases in the Chinese

    PubMed Central

    Wang, Yuting; Sun, Lei; Du, Weina; Song, Shuang; Wang, Shuo; Jiang, Weiju; Huang, Tianchu

    2015-01-01

    The purpose of this study is to investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with the risk of congenital heart diseases (CHD). The genotypes of the MTHFR genetic variant were determined by the polymerase chain reaction–restriction fragment length polymorphism and DNA sequencing methods. Our data suggested that the allelic and genotypic frequencies of CHD patients were significantly different from non-CHD controls. The MTHFR c.1625A>C genetic variant was significantly associated with the increased risk of CHD (CC vs. AA: odds ratio [OR]=2.29, 95% confidence interval [CI] 1.15–4.53, p=0.016; C vs. A: OR=1.47, 95% CI 1.11–1.96, p=0.008). Results from this study indicate that the MTHFR c.1625A>C genetic variant influences the risk of CHD in the studied population. PMID:25494855

  14. The RETN gene rs1862513 polymorphism as a novel predisposing marker for familial Acne vulgaris in a Pakistani population

    PubMed Central

    Hussain, Sabir; Faraz, Ahmad; Iqbal, Tahir

    2015-01-01

    Resistin (RETN), recently found to be relevant to inflammation and inflammatory disorders. We, therefore, aimed to investigate the potential role of RETN gene polymorphism in pathogenesis of acne vulgaris with familial history. We investigated the RETN-420C/G polymorphism in 180 patients with acne vulgaris and 180 healthy individuals in a case-control association analysis. In this study, we also investigated the heritability of the RETN susceptible allele from 140 trio families with acne affected offspring. The genotyping was performed by polymerase chain reaction and direct DNA sequencing. The RETN-420C/G polymorphism was significantly associated with acne in patients compared with healthy controls (P=0.014). The minor allele G at -420 was more prevalent in cases vs. controls (P=0.002). The RETN-420C/G polymorphism was significantly associated with severity of acne vulgaris in patients (P=0.0097). The results of a transmission disequilibrium test revealed a significant association between the RETN-420C/G polymorphism and acne vulgaris (P<0.001). For the first time in the literature, to our knowledge, we demonstrate a significant association of the RETN-420C/G functional polymorphism with familial acne vulgaris. PMID:26124941

  15. A retrospective comparative exploratory study on two Methylentetrahydrofolate Reductase (MTHFR) polymorphisms in esophagogastric cancer: the A1298C MTHFR polymorphism is an independent prognostic factor only in neoadjuvantly treated gastric cancer patients

    PubMed Central

    2014-01-01

    Background Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas. Methods 569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression). Results Only the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p?=?0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p?=?0.001) and 7th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5-5.7, p?=?0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact. Conclusions The MTHFR A1298C polymorphisms was an independent prognostic factor in patients with neoadjuvantly treated gastric adenocarcinomas (according to both UICC 6th or 7th definitions for gastric cancer) but not in AEG I nor in primarily resected patients, which confirms the impact of this enzyme on chemotherapy associated outcome. PMID:24490800

  16. Low-penetrance alleles predisposing to sporadic colorectal cancers: a French case-controlled genetic association study

    PubMed Central

    Küry, Sébastien; Buecher, Bruno; Robiou-du-Pont, Sébastien; Scoul, Catherine; Colman, Hélène; Le Neel, Tanguy; Le Houérou, Claire; Faroux, Roger; Ollivry, Jean; Lafraise, Bernard; Chupin, Louis-Dominique; Sébille, Véronique; Bézieau, Stéphane

    2008-01-01

    Background Sporadic colorectal cancers (CRC) are multifactorial diseases resulting from the combined effects of numerous genetic, environmental and behavioral risk factors. Genetic association studies have suggested low-penetrance alleles of extremely varied genes to be involved in susceptibility to CRC in Caucasian populations. Methods Through a large genetic association study based on 1023 patients with sporadic CRC and 1121 controls, we tested a panel of these low-penetrance alleles to find out whether they could determine "genotypic profiles" at risk for CRC among individuals of the French population. We examined 52 polymorphisms of 35 genes – drawn from inflammation, xenobiotic detoxification, one-carbon, insulin signaling, and DNA repair pathways – for their possible contribution to colorectal carcinogenesis. The risk of cancer associated with these polymorphisms was assessed by calculation of odds ratios (OR) using multivariate analyses and logistic regression. Results Whereas all these polymorphisms had previously been found to be associated with CRC risk, especially in Caucasian populations, we were able to replicate the association for only five of them. Three SNPs were shown to increase CRC risk: PTGS1 c.639C>A (p.Gly213Gly), IL8 c.-352T>A, and MTHFR c.1286A>C (p.Ala429Glu). On the contrary, two other SNPs, PLA2G2A c.435+230C>T and PPARG c.1431C>T (p.His477His), were associated with a decrease in CRC risk. Further analyses highlighted genotypic combinations having a greater predisposing effect on CRC (OR 1.97, 95%CI 1.31–2.97, p = 0.0009) than the allelic variants that were examined separately. Conclusion The identification of CRC-predisposing combinations, composed of alleles PTGS1 c.639A, PLA2G2A c.435+230C, PPARG c.1431C, IL8 c.-352A, and MTHFR c.1286C, highlights the importance of inflammatory processes in susceptibility to sporadic CRC, as well as a possible crosstalk between inflammation and one-carbon pathways. PMID:18992148

  17. MTHFR 677C>T Polymorphism Increases the Male Infertility Risk: A Meta-Analysis Involving 26 Studies

    PubMed Central

    Gong, Mancheng; Dong, Wenjing; He, Tingyu; Shi, Zhirong; Huang, Guiying; Ren, Rui; Huang, Sichong; Qiu, Shaopeng; Yuan, Runqiang

    2015-01-01

    Background and Objectives Methylenetetrahydrofolate reductase (MTHFR) polymorphism may be a risk factor for male infertility. However, the epidemiologic studies showed inconsistent results regarding MTHFR polymorphism and the risk of male infertility. Therefore, we performed a meta-analysis of published case-control studies to re-examine the controversy. Methods Electronic searches of PubMed, EMBASE, Google Scholar and China National Knowledge Infrastructure (CNKI) were conducted to select eligible literatures for this meta-analysis (updated to June 19, 2014). According to our inclusion criteria and the Newcastle-Ottawa Scale (NOS), only high quality studies that observed the association between MTHFR polymorphism and male infertility risk were included. Crude odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of association between the MTHFR polymorphism and male infertility risk. Results Twenty-six studies involving 5,575 cases and 5,447 controls were recruited. Overall, MTHFR 677C>T polymorphism showed significant associations with male infertility risk in both fixed effects (CT+TT vs. CC: OR = 1.34, 95% CI: 1.23–1.46) and random effects models (CT+TT vs. CC: OR = 1.39, 95% CI: 1.19–1.62). Further, when stratified by ethnicity, sperm concentration and control sources, the similar results were observed in Asians, Caucasians, Azoo or OAT subgroup and both in population-based and hospital-based controls. Nevertheless, no significant association was only observed in oligo subgroup. Conclusions Our results indicated that the MTHFR polymorphism is associated with an increased risk of male infertility. Further well-designed analytical studies are necessary to confirm our conclusions and evaluate gene-environment interactions with male infertility risk. PMID:25793386

  18. MTHFR C677T polymorphism and differential methylation status in gastric cancer: an association with Helicobacter pylori infection.

    PubMed

    Neves Filho, Eduardo Henrique Cunha; Alves, Markenia Kelia Santos; Lima, Valeska Portela; Rabenhorst, Silvia Helena Barem

    2010-12-01

    MTHFR C677T and Helicobacter pylori infection are believed to play critical roles in the DNA methylation process, an epigenetic feature frequently found in gastric cancer. The aim of this study was to verify the associations between the MTHFR C677T polymorphism and the methylation status of three gastric cancer-related genes. The influence of H. pylori strains was also assessed. DNA extracted from 71 gastric tumor samples was available for MTHFR C677T genotyping by PCR-RFLP, promoter methylation identification by MS-PCR and H. pylori detection and posterior subtyping (cagA and vacA genes) by PCR. In the distal tumors, a positive correlation was found between the methylation of CDKN2A and the allele T carriers (r=0.357; p=0.009). Considering the eldest patients (age ?60 years old), this correlation was even higher (r=0,417; p=0.014). H. pylori infection by highly pathogenic strains (cagA+/vacAs1m1) was also found correlated to promoter methylation of CDKN2A and the allele T carriers in distal tumors (r=0.484; p=0.026). No significant correlation was verified between MTHFR C677T genotype and promoter methylation status when we analyzed the general sample. DNA methylation in CDKN2A associated to the MTHFR 677T carrier is suggested to be a distal tumor characteristic, especially in those 60 years old or older, and it seems to depend on the infection by H. pylori cagA/vacAs1m1 strains. PMID:20957490

  19. Depression: Predisposing factors.

    PubMed

    Nystr0m, S; Lindegård, B

    1975-02-01

    Factors predisposing to a depressive state had been investigated in a prospective study on a stratified population, accounted for in the preceding article (Nyström & Lindegård (1975a) ). Of the 114 persons seeking psychiatric care during the period of observation, 37 had a depression as the main diagnosis. As compared to their 370 matched controls, these patients showed a significant overrepresentation of psychasthenic traits (subvalidity according to Sjöbring), a tendency to ruminate, shyness in company and lack of endurance, certain asthenic subclinical symptoms such as habitual fatigue and irritability, certain depressive subclinical phenomena, various expressions of anxiousness, all kinds of insomnia, and certain forms of medical care and examinations. The findings can be used for mental hygienic purposes. It can be recommended that the environmental pressure within occupational as well as within private life, should be kept as low as possible, expecially for persons with characteristics shown to indicate mental vulnerability. PMID:1119321

  20. Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response. We screened 224 subjects (52% female, mean age 39 +/- 11 years) with SCID-diagnosed major...

  1. Association of Methylenetetrahydrofolate Reductase (MTHFR-677 and MTHFR-1298) Genetic Polymorphisms with Occlusive Artery Disease and Deep Venous Thrombosis in Macedonians

    PubMed Central

    Spiroski, Igor; Kedev, Sashko; Antov, Slobodan; Arsov, Todor; Krstevska, Marija; Dzhekova-Stojkova, Sloboda; Kostovska, Stojanka; Trajkov, Dejan; Petlichkovski, Aleksandar; Strezova, Ana; Efinska-Mladenovska, Olivija; Spiroski, Mirko

    2008-01-01

    Aim To analyze the association of methylenetetrahydrofolate reductase polymorphisms (MTHFR-677 and MTHFR-1298) with occlusive artery disease and deep venous thrombosis in Macedonians. Methods We examined 83 healthy respondents, 76 patients with occlusive artery disease, and 67 patients with deep venous thrombosis. Blood samples were collected and DNA was isolated from peripheral blood leukocytes. Identification of MTHFR mutations was done with CVD StripAssay (ViennaLab, Labordiagnostika GmbH, Vienna, Austria) and the population genetics analysis package, PyPop, was used for the analysis. Pearson P values, crude odds ratio, and Wald’s 95% confidence intervals were calculated. Results The frequency of C alleles of MTHFR-677 was 0.575 in patients with deep venous thrombosis, 0.612 in patients with occlusive artery disease, and 0.645 in healthy participants. The frequency of T allele of MTHFR-677 was lower in healthy participants (0.355) than in patients with occlusive artery disease (0.388) and deep venous thrombosis (0.425). The frequency of A allele for MTHFR-1298 was 0.729 in healthy participants, 0.770 in patients with occlusive artery disease, and 0.746 in patients with deep venous thrombosis. The frequency of C allele of MTHFR-1298 was 0.271 in healthy participants, 0.230 in patients with occlusive artery disease, and 0.425 in patients with deep venous thrombosis. No association of MTHFR-677 and MTHFR-1289 polymorphisms with occlusive artery disease and deep venous thrombosis was found, except for the protective effect of MTHFR/CA:CC diplotype for occlusive artery disease. Conclusion We could not confirm a significant association of MTHFR-677 and MTHFR-1289 polymorphisms with occlusive artery disease or deep venous thrombosis in Macedonians, except for the protective effect of MTHFR/CA:CC diplotype against occlusive artery disease. PMID:18293456

  2. 32 CFR 644.391 - Predisposal conference.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Predisposal conference. 644.391 Section 644.391... ESTATE HANDBOOK Disposal Predisposal Action § 644.391 Predisposal conference. (a) Where a substantial Army installation, or portion thereof, is involved, the DE will convene a predisposal conference...

  3. Significant association between the MTHFR A1298C polymorphism and hepatocellular carcinoma risk: a meta-analysis.

    PubMed

    Chang, W; Meng, Q; Liu, J H; Wu, L X; Chen, Y; Chen, S D

    2015-01-01

    The A1298C polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene has been reported to be associated with hepatocellular carcinoma (HCC), but there are conflicting results from previous studies. The present study aimed to investigate the association between this polymorphism and the risk of HCC using a meta-analysis of the published studies. Published literature from PubMed and Embase databases was systematically searched to identify relevant studies before October 2014. The Begg test was used to measure publication bias. Sensitivity analyses were performed to ensure the authenticity of the outcome. The meta-analysis results showed significant association between the MTHFR A1298C polymorphism and HCC risk (CC vs AA: OR = 0.52, 95%CI = 0.33-0.81; CC vs AC: OR = 0.50, 95%CI = 0.32-0.79; dominant model: OR = 1.94, 95%CI = 1.24-3.02; recessive model: OR = 1.00, 95%CI = 0.84-1.18). In the subgroup analysis, significant associations between the MTHFR A1298C polymorphism and HCC risk were found in Asians (CC vs AA: OR = 0.46, 95%CI = 0.27-0.78; CC vs AC: OR = 0.41, 95%CI = 0.24-0.71; dominant model: OR = 2.27, 95%CI = 1.33-3.86; recessive model: OR = 1.03, 95%CI = 0.86-1.24). Our results suggest that the MTHFR A1298C polymorphism might be related to increased risk of HCC in Asians. Further large and well-designed studies are needed to confirm these conclusions. PMID:26662389

  4. A common variant in MTHFR influences response to chemoradiotherapy and recurrence of rectal cancer

    PubMed Central

    Nikas, Jason B; Lee, Janet T; Maring, Elizabeth D; Washechek-Aletto, Jill; Felmlee-Devine, Donna; Johnson, Ruth A; Smyrk, Thomas C; Tawadros, Patrick S; Boardman, Lisa A; Steer, Clifford J

    2015-01-01

    An important determinant of the pathogenesis and prognosis of various diseases is inherited genetic variation. Single-nucleotide polymorphisms (SNPs), variations at a single base position, have been identified in both protein-coding and noncoding DNA sequences, but the vast majority of millions of those variants are far from being functionally understood. Here we show that a common variant in the gene MTHFR [rs1801133 (C>T)] not only influences response to neoadjuvant chemoradiotherapy in patients with rectal cancer, but it also influences recurrence of the disease itself. More specifically, patients with the homozygous ancestral (wild type) genotype (C/C) were 2.91 times more likely (291% increased benefit) to respond to neoadjuvant chemoradiotherapy {95% CI: [1.23, 6.89]; P=0.0150} and 3.25 times more likely (325% increased benefit) not to experience recurrence of the disease {95% CI: [1.37, 7.72]; P=0.0079} than patients with either the heterozygous (C/T) or the homozygous mutation (T/T) genotype. These results identify MTHFR as an important genetic marker and open up new, pharmacogenomic strategies in the treatment and management of rectal cancer. PMID:26693073

  5. Genes and Environment as Predisposing Factors in Autoimmunity: Acceleration of Spontaneous Thyroiditis by Dietary Iodide in NOD.H2(h4) Mice.

    PubMed

    Kolypetri, Panayota; King, Justin; Larijani, Mani; Carayanniotis, George

    2015-11-01

    In the field of autoimmune thyroiditis, NOD.H2(h4) mice have attracted significant and increasing attention since they not only develop spontaneous disease but they present thyroiditis with accelerated incidence and severity if they ingest iodide through their drinking water. This animal model highlights the interplay between genetic and dietary factors in the triggering of autoimmune disease and offers new opportunities to study immunoregulatory parameters influenced by both genes and environment. Here, we review experimental findings with this mouse model of thyroiditis. PMID:26287317

  6. Sodium arsenite alters cell cycle and MTHFR, MT1/2, and c-Myc protein levels in MCF-7 cells

    SciTech Connect

    Ruiz-Ramos, Ruben; Lopez-Carrillo, Lizbeth; Albores, Arnulfo; Hernandez-Ramirez, Raul U.; Cebrian, Mariano E.

    2009-12-15

    There is limited available information on the effects of arsenic on enzymes participating in the folate cycle. Therefore, our aim was to evaluate the effects of sodium arsenite on the protein levels of methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR) and its further relationship with the expression MT1/2 and c-myc in MCF-7 cells. Arsenite treatment (0-10 muM) for 4 h decreased MTHFR levels in a concentration-dependent fashion without significant effects on DHFR. The effects on MTHFR were observed at arsenite concentrations not significantly affecting cell viability. We also observed an increase in S-phase recruitment at all concentrations probed. Lower concentrations (< 5 muM) induced cell proliferation, showing a high proportion of BrdU-stained cells, indicating a higher DNA synthesis rate. However, higher concentrations (>= 5 muM) or longer treatment periods induced apoptosis. Arsenite also induced dose-dependent increases in MT1/2 and c-Myc protein levels. The levels of MTHFR were inversely correlated to MT1/2 and c-Myc overexpression and increased S-phase recruitment. Our findings indicate that breast epithelial cells are responsive to arsenite and suggest that exposure may pose a risk for breast cancer. The reductions in MTHFR protein levels contribute to understand the mechanisms underlying the induction of genes influencing growth regulation, such as c-myc and MT1/2. However, further research is needed to ascertain if the effects here reported following short-time and high-dose exposure are relevant for human populations chronically exposed to low arsenic concentrations.

  7. Association between MTHFR C677T polymorphism and diabetic nephropathy in the Chinese population: An updated meta-analysis and review.

    PubMed

    Xiong, Xuan; Lin, Xiao-Kun; Xiao, Xiao; Qin, Dan-Ping; Zhou, Dao-Yuan; Hu, Jian-Guang; Liu, Yan; Zhong, Xiao-Shi

    2016-01-01

    To clarify the effects of MTHFR C677T polymorphism on the risk of diabetic nephropathy (DN) in the Chinese population, an updated meta-analysis was performed. Related studies were identified from PubMed, Springer Link, Ovid and Chinese Databases up to 24 February 2015. A total of 15 studies including 1227 DN cases, 586 healthy controls and 1277 diabetes mellitus (DM) controls were involved in this meta-analysis. Overall, a significantly elevated risk of DN was associated with all variants of MTHFR C677T when compared with the healthy group (T vs C, odds ratio (OR)?=?2.22, 95% confidence interval (CI)?=?1.88-2.61; TT?vs?CC, OR?=?4.22, 95% CI?=?3.02-5.90; TT?+?CT?vs?CC, OR?=?2.62, 95% CI?=?2.07-3.31; TT?vs?CC?+?CT, OR?=?2.81, 95% CI?=?2.08-3.81) or DM (T?vs?C, OR?=?1.78, 95% CI?=?1.59-2.00; TT?vs?CC, OR?=?2.95, 95% CI?=?2.33-3.73; TT?+?CT?vs?CC, OR?=?1.93, 95% CI?=?1.63-2.29; TT?vs?CC?+?CT, OR?=?2.31, 95% CI?=?1.87-2.84). In subgroup analyses stratified by ethnicity and geographic areas, it revealed the significant results in Chinese Han, in North and South China. The risk conferred by MTHFR C677T polymorphism is higher in North China than in South China. This meta-analysis showed that the MTHFR C677T variants may influence DN risk in Chinese, and further studies with gene-gene and gene-environment interactions are required for definite conclusions. PMID:26072975

  8. Association of the MTHFR 1298A>C (rs1801131) polymorphism with speed and strength sports in Russian and Polish athletes.

    PubMed

    Zarebska, Aleksandra; Ahmetov, Ildus I; Sawczyn, Stanislaw; Weiner, Alexandra S; Kaczmarczyk, Mariusz; Ficek, Krzysztof; Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Leonska-Duniec, Agata; Klocek, Tomasz; Voronina, Elena N; Boyarskikh, Uljana A; Filipenko, Maksim L; Cieszczyk, Pawel

    2014-01-01

    It has been suggested that DNA hypomethylation because of poorer effectiveness of the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme induces muscular growth. We hypothesised that the common, functional 1298A>C polymorphism in the MTHFR gene is associated with athletic status. To test this hypothesis, we investigated the distribution of the 1298A>C variant in Polish (n = 302) and Russian (n = 842) athletes divided into four groups: endurance, strength-endurance, sprint-strength and strength-endurance, as well as in 1540 control participants. We found different genotypes (the AC heterozygote advantage) and allele distributions among sprint-strength athletes and strength athletes than the groups of sedentary controls for each nationality. In the combined study, the allelic frequencies for the 1298C variant were 35.6% in sprint-strength athletes (OR 1.18 [1.02-1.36], P = 0.024 vs. controls) and 38.6% in strength athletes (OR 1.34 [1.10-1.64], P = 0.003 vs. controls). The results of the initial and repetition studies as well as the combined analysis suggest that the functional 1298A>C polymorphism in the MTHFR gene is associated with athletic status. The presence of the C allele seems to be beneficial in sprint-strength and strength athletes. It needs to be established whether and to what extent this effect is mediated by alteration in DNA methylation status. PMID:24015812

  9. Low Birthweight (LBW) and Neonatal Hyperbilirubinemia (NNH) in an Indian Cohort: Association of Homocysteine, Its Metabolic Pathway Genes and Micronutrients as Risk Factors

    PubMed Central

    Sukla, Krishna Kishore; Tiwari, Pankaj Kumar; Kumar, Ashok; Raman, Rajiva

    2013-01-01

    Background & Aims Indian subcontinent has the highest child mortality rates along with a very high frequency of low birthweight (LBW). Folate and vitamin B12 (Vit-B12) are necessary during foetal development and their deficiency prevalence in Indians is very high. The objective of the present paper is to assess whether foetal homocysteine (Hcy)/folate metabolic pathway genes, their cofactors and homocysteine level independently (or collectively) predispose children to Low birth weight. Methods Cord blood was collected for the study. Frequency of 5 SNPs in 4-Hcy-pathway genes, and levels of Hcy, Vit-B12 and folate were evaluated. Results Of the 421 newborns recruited for the study, 38% showed low birth weight (<2.5kg) and 16% were preterm babies. 101 neonates developed neonatal hyperbilirubinemia (NNH). High prevalence of Vit-B12 (65%) and folate (27%) deficiency was observed in newborns along with hyperhomocystinemia (hypHcy-25%). Preterm delivery, micronutrient deficiency, hypHcy and MTHFR 677T SNP are associated as risk factor while G allele of TCN2 C776G is protective against LBW. MTHFR 677T allele and folate deficiency are also independent risk factors for NNH. Conclusion We record the highest incidence of Vit-B12, folate deficiency and elevated Hcy levels, of all the studies so far reported on neonates. These together with MTHFR 677T are potential risk factors for LBW. Association of impaired folate/Hcy metabolism with NNH is reported for the first time and the possible way of interaction is discussed. It appears that proper nutritional management during pregnancy would reduce the risk of complex clinical outcomes. PMID:23936521

  10. NOD2 prevents emergence of disease-predisposing microbiota

    PubMed Central

    Secher, Thomas; Normand, Sylvain; Chamaillard, Mathias

    2013-01-01

    The gut flora is composed of a huge number of diverse, well-adapted symbionts that interact with epithelial lining throughout the host's entire life. Not all commensals have the same ability to maintain quiescent, protective inflammation. Importantly, instability in the composition of gut microbial communities (referred to as dysbiosis) has been linked to loss of gut barrier in the context of common human illnesses with increasing socio-economic impacts, such as Crohn disease and colorectal cancer. Our recent findings suggest that disease-predisposing dysbiosis can now be intentionally manipulated by targeting the major Crohn disease-predisposing NOD2 gene. That knowledge will not only add a new dimension to the often overlooked microbiology of Crohn disease and colorectal cancer, but will also have a broad impact on biomedical sciences worldwide. PMID:23778641

  11. 32 CFR 644.391 - Predisposal conference.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...information is required by GSA for disposal purposes. (c) A report on the predisposal conference will be forwarded to DAEN-REM. Any difficulties indicated by GSA will be summarized in the report, along with any other problems encountered or...

  12. 32 CFR 644.391 - Predisposal conference.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...information is required by GSA for disposal purposes. (c) A report on the predisposal conference will be forwarded to DAEN-REM. Any difficulties indicated by GSA will be summarized in the report, along with any other problems encountered or...

  13. POLE mutations in families predisposed to cutaneous melanoma.

    PubMed

    Aoude, Lauren G; Heitzer, Ellen; Johansson, Peter; Gartside, Michael; Wadt, Karin; Pritchard, Antonia L; Palmer, Jane M; Symmons, Judith; Gerdes, Anne-Marie; Montgomery, Grant W; Martin, Nicholas G; Tomlinson, Ian; Kearsey, Stephen; Hayward, Nicholas K

    2015-12-01

    Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol ? mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer. PMID:26251183

  14. MTHFR C677T polymorphism and anatomopathological characteristics with prognostic significance in sporadic colorectal cancer.

    PubMed

    Delgado-Plasencia, Luciano; Álvarez-Argüelles, Hugo; Salido-Ruiz, Eduardo; Castro-Peraza, M Elisa; Bravo-Gutiérrez, Alberto; Fernández-Peralta, Antonia; González-Aguilera, Juan; Alarcó-Hernández, Antonio; Medina-Arana, Vicente

    2015-12-01

    Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism, and folate is implicated in carcinogenesis due to its role in DNA methylation, repair and synthesis. The MTHFR C677T polymorphism is associated with decreased risk of CRC and increased sensitivity to 5-FU treatment. The present study addressed the relationship between this polymorphism and histopathological and immunohistochemical characteristics of prognostic significance in 50 patients from the Canary Islands. No differences were found between the MTHFR C677T genotypes with respect to tumor budding, tumor necrosis, desmoplastic fibrosis and tumoral eosinophilia. No significant differences were found in Ki-67, bcl-2 (cytoplasmic and nuclear), CD31, CD3+ T lymphocytes (both stromal and intraepithelial) and peritumoral CD20+ B lymphocytes. In carriers of the MTHFR CC variant, tumor margins were infiltrative more frequently (68.7%) than in CT+TT carriers (33.3%, p=0.03). In addition, wild-type CC genotype showed stromal CD20+ B lymphocytes (68.8%) more often than CT+TT carriers (33.3%, p=0.03). Both parameters indicate a better tumor prognosis when the MTHFR 677T variant is present. PMID:26564107

  15. Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer risk in three large nested case-control studies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Few prospective studies have examined the associations between blood levels of folate, in conjunction with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and colorectal cancer. We evaluated the associations between plasma folate, MTHFR C677T, and A1298C, and colorectal cancer in three la...

  16. Macrolide antibiotics allosterically predispose the ribosome for translation arrest.

    PubMed

    Sothiselvam, Shanmugapriya; Liu, Bo; Han, Wei; Ramu, Haripriya; Klepacki, Dorota; Atkinson, Gemma Catherine; Brauer, Age; Remm, Maido; Tenson, Tanel; Schulten, Klaus; Vázquez-Laslop, Nora; Mankin, Alexander S

    2014-07-01

    Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome. PMID:24961372

  17. Macrolide antibiotics allosterically predispose the ribosome for translation arrest

    PubMed Central

    Sothiselvam, Shanmugapriya; Liu, Bo; Han, Wei; Ramu, Haripriya; Klepacki, Dorota; Atkinson, Gemma Catherine; Brauer, Age; Remm, Maido; Tenson, Tanel; Schulten, Klaus; Vázquez-Laslop, Nora; Mankin, Alexander S.

    2014-01-01

    Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome. PMID:24961372

  18. MAT2A mutations predispose individuals to thoracic aortic aneurysms.

    PubMed

    Guo, Dong-chuan; Gong, Limin; Regalado, Ellen S; Santos-Cortez, Regie L; Zhao, Ren; Cai, Bo; Veeraraghavan, Sudha; Prakash, Siddharth K; Johnson, Ralph J; Muilenburg, Ann; Willing, Marcia; Jondeau, Guillaume; Boileau, Catherine; Pannu, Hariyadarshi; Moran, Rocio; Debacker, Julie; Bamshad, Michael J; Shendure, Jay; Nickerson, Deborah A; Leal, Suzanne M; Raman, C S; Swindell, Eric C; Milewicz, Dianna M

    2015-01-01

    Up to 20% of individuals who have thoracic aortic aneurysms or acute aortic dissections but who do not have syndromic features have a family history of thoracic aortic disease. Significant genetic heterogeneity is established for this familial condition. Whole-genome linkage analysis and exome sequencing of distant relatives from a large family with autosomal-dominant inheritance of thoracic aortic aneurysms variably associated with the bicuspid aortic valve was used for identification of additional genes predisposing individuals to this condition. A rare variant, c.1031A>C (p.Glu344Ala), was identified in MAT2A, which encodes methionine adenosyltransferase II alpha (MAT II?). This variant segregated with disease in the family, and Sanger sequencing of DNA from affected probands from unrelated families with thoracic aortic disease identified another MAT2A rare variant, c.1067G>A (p.Arg356His). Evidence that these variants predispose individuals to thoracic aortic aneurysms and dissections includes the following: there is a paucity of rare variants in MAT2A in the population; amino acids Glu344 and Arg356 are conserved from humans to zebrafish; and substitutions of these amino acids in MAT I? are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT II? enzyme function. Knockdown of mat2aa in zebrafish via morpholino oligomers disrupted cardiovascular development. Co-transfected wild-type human MAT2A mRNA rescued defects of zebrafish cardiovascular development at significantly higher levels than mRNA edited to express either the Glu344 or Arg356 mutants, providing further evidence that the p.Glu344Ala and p.Arg356His substitutions impair MAT II? function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease. PMID:25557781

  19. Predisposing factors and prevention of frostbite.

    PubMed

    Rintamäki, H

    2000-04-01

    This review focuses on the physiological, behavioural and environmental factors which predispose to frostbite. Also prevention of frostbite is summarised. Predisposing factors may increase heat loss, decrease heat production, decrease the insulation of the clothing, make people especially susceptible to cold or make them to behave inadequately. Marked increase in convective or conductive heat loss is often the immediate reason for frostbite. Wind (as described by wind chill index) increases convective heat loss and touching of metal objects increases conductive cooling. Poor insulation of the clothing is also a common reason of frostbite. The insulation can be insufficient when clothing is wet, tight, permeable to wind or does not cover the cold sensitive body parts. Individual factors predisposing to frostbite are inadequate behaviour, low physical fitness, fatigue, dehydration, earlier cold injuries, sickness or poor circulation in peripheral parts of the body. Frostbite is often associated with the use of alcohol. To prevent frostbite, it is necessary to recognise cold risks, practise tasks in the cold, eat and drink well, have physical exercise, have sufficient clothing (also spare clothing), change into dry clothing if necessary and take care of companions. In the cold it is not advisable to get fatigued until exhaustion, sweat excessively, use tight and/or wet clothing, drink alcohol, smoke and expose oneself unnecessarily to wind, metals or fluids. PMID:10998828

  20. Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

    PubMed Central

    Jakubowska, A; Rozkrut, D; Antoniou, A; Hamann, U; Scott, R J; McGuffog, L; Healy, S; Sinilnikova, O M; Rennert, G; Lejbkowicz, F; Flugelman, A; Andrulis, I L; Glendon, G; Ozcelik, H; Thomassen, M; Paligo, M; Aretini, P; Kantala, J; Aroer, B; von Wachenfeldt, A; Liljegren, A; Loman, N; Herbst, K; Kristoffersson, U; Rosenquist, R; Karlsson, P; Stenmark-Askmalm, M; Melin, B; Nathanson, K L; Domchek, S M; Byrski, T; Huzarski, T; Gronwald, J; Menkiszak, J; Cybulski, C; Serrano, P; Osorio, A; Cajal, T R; Tsitlaidou, M; Benítez, J; Gilbert, M; Rookus, M; Aalfs, C M; Kluijt, I; Boessenkool-Pape, J L; Meijers-Heijboer, H E J; Oosterwijk, J C; van Asperen, C J; Blok, M J; Nelen, M R; van den Ouweland, A M W; Seynaeve, C; van der Luijt, R B; Devilee, P; Easton, D F; Peock, S; Frost, D; Platte, R; Ellis, S D; Fineberg, E; Evans, D G; Lalloo, F; Eeles, R; Jacobs, C; Adlard, J; Davidson, R; Eccles, D; Cole, T; Cook, J; Godwin, A; Bove, B; Stoppa-Lyonnet, D; Caux-Moncoutier, V; Belotti, M; Tirapo, C; Mazoyer, S; Barjhoux, L; Boutry-Kryza, N; Pujol, P; Coupier, I; Peyrat, J-P; Vennin, P; Muller, D; Fricker, J-P; Venat-Bouvet, L; Johannsson, O Th; Isaacs, C; Schmutzler, R; Wappenschmidt, B; Meindl, A; Arnold, N; Varon-Mateeva, R; Niederacher, D; Sutter, C; Deissler, H; Preisler-Adams, S; Simard, J; Soucy, P; Durocher, F; Chenevix-Trench, G; Beesley, J; Chen, X; Rebbeck, T; Couch, F; Wang, X; Lindor, N; Fredericksen, Z; Pankratz, V S; Peterlongo, P; Bonanni, B; Fortuzzi, S; Peissel, B; Szabo, C; Mai, P L; Loud, J T; Lubinski, J

    2012-01-01

    Background: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. Methods: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. Results: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10–2.04 and HR 2.16, 95%CI 1.24–3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. Conclusion: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. PMID:22669161

  1. Methylenetetrahydrofolate Reductase Gene Polymorphisms in Children with Attention Deficit Hyperactivity Disorder

    PubMed Central

    Gokcen, Cem; Kocak, Nadir; Pekgor, Ahmet

    2011-01-01

    Objective: The purpose of this study was to evaluate the relationship between 5,10- methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Attention Deficit Hyperactivity Disorder (ADHD) in a sample of Turkish children. Study Design: MTHFR gene polymorphisms were assessed in 40 patients with ADHD and 30 healty controls. Two mutations in the MTHFR gene were investigated using polymerase chain reactions and restriction fragment length polymorphisms. Results: Although there were no statistically significant differences in genotype distributions of the C677T alleles between the ADHD and the control groups (p=0,678) but the genotypic pattern of the distributions of the A1298C alleles was different between the ADHD patients and the controls (p=0,033). Conclusions: Preliminary data imply a possible relationship between A1298C MTHFR polymorphisms and the ADHD. PMID:21897766

  2. Meta-analysis of associations between MTHFR and GST polymorphisms and susceptibility to multiple sclerosis.

    PubMed

    Lee, Young Ho; Seo, Young Ho; Kim, Jae-Hoon; Choi, Sung Jae; Ji, Jong Dae; Song, Gwan Gyu

    2015-11-01

    We examined whether methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase (GST) polymorphisms are associated with susceptibility to multiple sclerosis (MS). We performed a meta-analysis on the association between MS and the following genotypes: MTHFR C677T, A1298C, and GSTP1 A313G polymorphisms, and GSTM1 and GSTT1 null alleles. Fifteen comparisons involving 2,486 patients and 2,861 controls were considered. Meta-analysis of all study subjects considered together showed no association between MS and the MTHFR 677 T allele (OR = 1.014, 95 % CI 0.803-1.280, p = 0.909). Stratification by ethnicity showed no similar association in Caucasian and Arab populations. Likewise, no link was found between MS and the MTHFR 1298 C allele in the total data (OR = 2.477, 95 % CI 0.507-12.10, p = 0.263), nor when it was stratified by ethnicity. No association with MS was observed in relation to the GSTM1 null genotype in Caucasian populations (OR = 1.229, 95 % CI 0.693-2.181, p = 0.481), nor with the GSTP1 A313G polymorphism (OR for G allele = 1.133, 95 % CI 0.903-1.421, p = 0.281). However, there was an association between MS and the GSTT1 null genotype in data obtained from Caucasian populations (OR = 1.945, 95 % CI 1.452-2.605, p = 8.6 × 10(-7)). GSTT1 null genotype is associated with MS in Caucasian populations; however, no association was found between MS and polymorphisms of MTHFR, GSTM1, and GSTP1. PMID:26150166

  3. Association between dietary intake of folate, vitamin B6, B12 & MTHFR, MTR Genotype and breast cancer risk

    PubMed Central

    Weiwei, Zheng; Liping, Chen; Dequan, Li

    2014-01-01

    Objective: we conducted a case-control study to investigate the association between dietary folate, vitamin B6 and vitamin B12 intake, MTHFR and MTR genotype, and breast cancer risk. Methods: Genotyping for MTHFR C677T and A1298C and MTR A2756G polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) method. The intake of folate, vitamin B6 and vitamin B12 were calculated by each food item from questionnaire. Results: Subjects with breast cancer tended to have more first-degree relatives (?2=30.77, P<0.001) and have high intake of folate (t=2.42, P=0.008) and Vitamin B6 (t=2.94, P=0.002). Compared to the reference group, women with MTHFR 677 TT genotype and T allele had a significantly increased risk of breast cancer, with ORs (95%CI) of 1.8(1.08-2.27) and 1.39(1.02-1.92), respectively. For those who had folate intake?450 ug/day, MTHFR 667TT genotype was associated with a higher risk of breast cancer (OR=2.45, 95% CI=1.09-5.82, P=0.02). Similarly, subjects with Vitamin B6 intake?0.84 mg/day and MTHFR 667T allele genotype was correlated with a marginally increased risk of breast cancer. A significant interaction was observed between MTHFR C667T polymorphism and folate intake on the risk of breast cancer (P for interaction was 0.025). Conclusion: This case-control study found a significant association between MTHFR C667T polymorphism, folate intake and vitamin B6 and breast cancer risk, and a significant interaction was observed between MTHFR C667T polymorphism and folate intake on the risk of breast cancer. PMID:24639841

  4. What aspects of autism predispose to talent?

    PubMed Central

    Happé, Francesca; Vital, Pedro

    2009-01-01

    In this paper, we explore the question, why are striking special skills so much more common in autism spectrum conditions (ASC) than in other groups? Current cognitive accounts of ASC are briefly reviewed in relation to special skills. Difficulties in ‘theory of mind’ may contribute to originality in ASC, since individuals who do not automatically ‘read other minds’ may be better able to think outside prevailing fashions and popular theories. However, originality alone does not confer talent. Executive dysfunction has been suggested as the ‘releasing’ mechanism for special skills in ASC, but other groups with executive difficulties do not show raised incidence of talents. Detail-focused processing bias (‘weak coherence’, ‘enhanced perceptual functioning’) appears to be the most promising predisposing characteristic, or ‘starting engine’, for talent development. In support of this notion, we summarize data from a population-based twin study in which parents reported on their 8-year-olds' talents and their ASC-like traits. Across the whole sample, ASC-like traits, and specifically ‘restricted and repetitive behaviours and interests’ related to detail focus, were more pronounced in children reported to have talents outstripping older children. We suggest that detail-focused cognitive style predisposes to talent in savant domains in, and beyond, autism spectrum disorders. PMID:19528019

  5. Cox4i2, Ifit2, and Prdm11 Mutant Mice: Effective Selection of Genes Predisposing to an Altered Airway Inflammatory Response from a Large Compendium of Mutant Mouse Lines

    PubMed Central

    Bönisch, Clemens; Côme, Christophe; Kolster-Fog, Cathrine; Jensen, Klaus T.; Lund, Anders H.; Lee, Icksoo; Grossman, Lawrence I.; Sinkler, Christopher; Hüttemann, Maik; Bohn, Erwin; Fuchs, Helmut; Ollert, Markus; Gailus-Durner, Valérie; Hrab? de Angelis, Martin; Beckers, Johannes

    2015-01-01

    We established a selection strategy to identify new models for an altered airway inflammatory response from a large compendium of mutant mouse lines that were systemically phenotyped in the German Mouse Clinic (GMC). As selection criteria we included published gene functional data, as well as immunological and transcriptome data from GMC phenotyping screens under standard conditions. Applying these criteria we identified a few from several hundred mutant mouse lines and further characterized the Cox4i2tm1Hutt, Ifit2tm1.1Ebsb, and Prdm11tm1.1ahl lines following ovalbumin (OVA) sensitization and repeated OVA airway challenge. Challenged Prdm11tm1.1ahl mice exhibited changes in B cell counts, CD4+ T cell counts, and in the number of neutrophils in bronchoalveolar lavages, whereas challenged Ifit2tm1.1Ebsb mice displayed alterations in plasma IgE, IgG1, IgG3, and IgM levels compared to the challenged wild type littermates. In contrast, challenged Cox4i2tm1Hutt mutant mice did not show alterations in the humoral or cellular immune response compared to challenged wild type mice. Transcriptome analyses from lungs of the challenged mutant mouse lines showed extensive changes in gene expression in Prdm11tm1.1ahl mice. Functional annotations of regulated genes of all three mutant mouse lines were primarily related to inflammation and airway smooth muscle (ASM) remodeling. We were thus able to define an effective selection strategy to identify new candidate genes for the predisposition to an altered airway inflammatory response under OVA challenge conditions. Similar selection strategies may be used for the analysis of additional genotype – envirotype interactions for other diseases. PMID:26263558

  6. MTHFR C677T polymorphism is associated with hyperlipidemia in women with polycystic ovary syndrome

    PubMed Central

    Jain, Madhu; Pandey, Priyanka; Tiwary, Narendra K; Jain, Shuchi

    2012-01-01

    CONTEXT: Women with polycystic ovary syndrome (PCOS) are prone for coronary artery disease (CAD), and hyperhomocysteinemia is an independent risk factor for CAD. MTHFR deficiency is the most common cause of hyperhomocysteinemia, thereby provoking a possible association between PCOS and MTHFR C677T polymorphism. AIMS: The aim of this study was to investigate an association of MTHFR C677T polymorphism with PCOS. SETTINGS AND DESIGN: 92 women with PCOS (Rotterdam criteria) and 95 age-matched controls were compared with respect to MTHFR C677T polymorphism. The 2 genotypes (CC and CT) obtained were compared with clinical and laboratory parameters in women with PCOS. MATERIALS AND METHODS: In a case-control study, clinical, biochemical, hormonal and genetic analysis (PCR-RFLP of peripheral leucocytes) was carried out on all women with PCOS as well as controls. STATISTICAL ANALYSIS: Student “t” test for quantitative and Chi-square test for nominal variables was used. For estimation of risk, odds ratio and 95% confidence interval were calculated. RESULTS: The odds ratio of bearing a heterozygous genotype (CT) was 1.32 in women with PCOS as compared to controls (P = 0.48). No homozygous mutation (TT) was found in the study population. Serum cholesterol was more in heterozygous (CT) genotype (215.48 ± 25.56 mg/dl) as compared to normal (CC) genotype (203.29 ± 16.35 mg/dl) in women with PCOS (P = 0.01). Similarly, serum triglyceride was more in heterozygous (CT) genotype (95.86 ± 37.34 mg/dl) as compared to normal (CC) genotype (82.36 ± 20.88 mg/dl) in women with PCOS (P = 0.04). CONCLUSIONS: Although not statistically significant, there is a slightly higher prevalence of heterozygous (CT) genotype in women with PCOS. MTHFR C677T polymorphism when present may confer an increased susceptibility to develop hyperlipidemia in women with PCOS. More prospective studies are needed to confirm whether this hyperlipidemia due to MTHFR C677T polymorphism clinically manifests into CAD in long term in women with PCOS. PMID:22870016

  7. Mutations in the transcriptional repressor REST predispose to Wilms tumor.

    PubMed

    Mahamdallie, Shazia S; Hanks, Sandra; Karlin, Kristen L; Zachariou, Anna; R Perdeaux, Elizabeth; Ruark, Elise; Shaw, Chad A; Renwick, Alexander; Ramsay, Emma; Yost, Shawn; Elliott, Anna; Birch, Jillian; Capra, Michael; Gray, Juliet; Hale, Juliet; Kingston, Judith; Levitt, Gill; McLean, Thomas; Sheridan, Eamonn; Renwick, Anthony; Seal, Sheila; Stiller, Charles; Sebire, Neil; Westbrook, Thomas F; Rahman, Nazneen

    2015-12-01

    Wilms tumor is the most common childhood renal cancer. To identify mutations that predispose to Wilms tumor, we are conducting exome sequencing studies. Here we describe 11 different inactivating mutations in the REST gene (encoding RE1-silencing transcription factor) in four familial Wilms tumor pedigrees and nine non-familial cases. Notably, no similar mutations were identified in the ICR1000 control series (13/558 versus 0/993; P < 0.0001) or in the ExAC series (13/558 versus 0/61,312; P < 0.0001). We identified a second mutational event in two tumors, suggesting that REST may act as a tumor-suppressor gene in Wilms tumor pathogenesis. REST is a zinc-finger transcription factor that functions in cellular differentiation and embryonic development. Notably, ten of 11 mutations clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these mutations compromise REST transcriptional repression. These data establish REST as a Wilms tumor predisposition gene accounting for ?2% of Wilms tumor. PMID:26551668

  8. Role of genetic mutations in folate-related enzyme genes on Male Infertility

    PubMed Central

    Liu, Kang; Zhao, Ruizhe; Shen, Min; Ye, Jiaxin; Li, Xiao; Huang, Yuan; Hua, Lixin; Wang, Zengjun; Li, Jie

    2015-01-01

    Several studies showed that the genetic mutations in the folate-related enzyme genes might be associated with male infertility; however, the results were still inconsistent. We performed a meta-analysis with trial sequential analysis to investigate the associations between the MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G mutations and the MTHFR haplotype with the risk of male infertility. Overall, a total of 37 studies were selected. Our meta-analysis showed that the MTHFR C677T mutation was a risk factor for male infertility in both azoospermia and oligoasthenoteratozoospermia patients, especially in Asian population. Men carrying the MTHFR TC haplotype were most liable to suffer infertility while those with CC haplotype had lowest risk. On the other hand, the MTHFR A1298C mutation was not related to male infertility. MTR A2756G and MTRR A66G were potential candidates in the pathogenesis of male infertility, but more case-control studies were required to avoid false-positive outcomes. All of these results were confirmed by the trial sequential analysis. Finally, our meta-analysis with trial sequential analysis proved that the genetic mutations in the folate-related enzyme genes played a significant role in male infertility. PMID:26549413

  9. High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism.

    PubMed

    Aarabi, Mahmoud; San Gabriel, Maria C; Chan, Donovan; Behan, Nathalie A; Caron, Maxime; Pastinen, Tomi; Bourque, Guillaume; MacFarlane, Amanda J; Zini, Armand; Trasler, Jacquetta

    2015-11-15

    Dietary folate is a major source of methyl groups required for DNA methylation, an epigenetic modification that is actively maintained and remodeled during spermatogenesis. While high-dose folic acid supplementation (up to 10 times the daily recommended dose) has been shown to improve sperm parameters in infertile men, the effects of supplementation on the sperm epigenome are unknown. To assess the impact of 6 months of high-dose folic acid supplementation on the sperm epigenome, we studied 30 men with idiopathic infertility. Blood folate concentrations increased significantly after supplementation with no significant improvements in sperm parameters. Methylation levels of the differentially methylated regions of several imprinted loci (H19, DLK1/GTL2, MEST, SNRPN, PLAGL1, KCNQ1OT1) were normal both before and after supplementation. Reduced representation bisulfite sequencing (RRBS) revealed a significant global loss of methylation across different regions of the sperm genome. The most marked loss of DNA methylation was found in sperm from patients homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common polymorphism in a key enzyme required for folate metabolism. RRBS analysis also showed that most of the differentially methylated tiles were located in DNA repeats, low CpG-density and intergenic regions. Ingenuity Pathway Analysis revealed that methylation of promoter regions was altered in several genes involved in cancer and neurobehavioral disorders including CBFA2T3, PTPN6, COL18A1, ALDH2, UBE4B, ERBB2, GABRB3, CNTNAP4 and NIPA1. Our data reveal alterations of the human sperm epigenome associated with high-dose folic acid supplementation, effects that were exacerbated by a common polymorphism in MTHFR. PMID:26307085

  10. The Methylenetetrahydrofolate Reductase Polymorphism (MTHFR c.677C > T) and Elevated Plasma Homocysteine Levels in a U.S. Pediatric Population with Incident Thromboembolism

    PubMed Central

    Joachim, Emily; Goldenberg, Neil A.; Bernard, Timothy J.; Armstrong-Wells, Jennifer; Stabler, Sally; Manco-Johnson, Marilyn J.

    2014-01-01

    Objective Elevated plasma homocysteine (tHcy) and the MTHFR c.677C > T variant have been postulated to increase the risk of venous thromboembolism (VTE), although mechanisms and implications to pediatrics remain incompletely understood. The objectives of this study were to determine the prevalences of elevated tHcy and MTHFR variant in a pediatric population with VTE or arterial ischemic stroke (AIS), and to determine associations with thrombus outcomes. Study Design Subjects were enrolled in an institution-based prospective cohort of children with VTE or AIS. Inclusion criteria consisted of objectively confirmed thrombus, ?21 years at diagnosis, tHcy measured and MTHFR c.677C > T mutation analysis. Clinical and laboratory data were collected. Frequencies for elevated tHcy and MTHFR variant were compared with NHANES values for healthy US children and also between study groups (VTE vs AIS, provoked vs idiopathic) and by age. Results The prevalences of hyperhomocysteinemia or MTHFR variant were not increased in comparison to NHANES. tHcy did not differ between those with wild-type MTHFR versus either c.677C > T heterozygotes or homozygotes. There was no association between tHcy or MTHFR variant and thrombus outcomes. Conclusion In this cohort of US children with VTE or AIS, neither the prevalence of hyperhomocysteinemia nor that of MTHFR variant was increased relative to reference values, and adverse thrombus outcomes were not definitively associated with either. While it is important to consider that milder forms of pyridoxine-responsive classical homocystinuria will be detected only by tHcy, we suggest that routine testing of MTHFR c.677C > T genotype as part of a thrombophilia evaluation in children with incident thromboembolismis not warranted until larger studies have been performed in order to establish or refute a link between MTHFR and adverse outcomes. PMID:23866722

  11. Epistasis effects of COMT and MTHFR on inter-individual differences in mental health: under the inverted U-shaped prefrontal dopamine model.

    PubMed

    Htun, Nay Chi; Miyaki, Koichi; Zhao, Chenxi; Muramatsu, Masaaki; Sato, Noriko

    2014-09-01

    Higher cognitive performance, maintenance of mental health and psychological well-being require adequate prefrontal cortex (PFC) function. "Inverted U-shaped" dopamine model indicates optimal PFC dopamine level is important to attain its function while high or low levels have adverse effects. Catechol-O-methyltransferase (COMT) and methylenetetrahydrofolate reductase (MTHFR) may be involved in this complex non-linear PFC dopamine regulation. We addressed whether genetic variation reflecting COMT and MTHFR activities can explain the inter-individual mental health differences in healthy Japanese men (n=188). The mental health was measured by Mental Health Inventory (MHI)-5 score. The rs4633-rs4818-rs4680 haplotypes were used to represent the multilevel COMT activities, while for MTHFR, the functional single polymorphism, rs1801133 (C677T), was used. We examined the effectiveness of haplotype-based association analysis of COMT on mental health together with studying its interaction with MTHFR-C677T. As a result, the relation between activity-ranked COMT genotype and MHI-5 score showed a tendency to fit into an "inverted U-shaped" quadratic curve (P=0.054). This curvilinear correlation was significant in the subjects with MTHFR-CC (P<0.001), but not with MTHFR T-allele carriers (P=0.793). Our pilot study implies a potential influence of COMT and MTHFR genotypic combination on normal variation of mental health. PMID:25124664

  12. Host genetic factors predisposing to HIV-associated neurocognitive disorder.

    PubMed

    Kallianpur, Asha R; Levine, Andrew J

    2014-09-01

    The success of combination antiretroviral therapy (cART) in transforming the lives of HIV-infected individuals with access to these drugs is tempered by the increasing threat of HIV-associated neurocognitive disorders (HAND) to their overall health and quality of life. Intensive investigations over the past two decades have underscored the role of host immune responses, inflammation, and monocyte-derived macrophages in HAND, but the precise pathogenic mechanisms underlying HAND remain only partially delineated. Complicating research efforts and therapeutic drug development are the sheer complexity of HAND phenotypes, diagnostic imprecision, and the growing intersection of chronic immune activation with aging-related comorbidities. Yet, genetic studies still offer a powerful means of advancing individualized care for HIV-infected individuals at risk. There is an urgent need for 1) longitudinal studies using consistent phenotypic definitions of HAND in HIV-infected subpopulations at very high risk of being adversely impacted, such as children, 2) tissue studies that correlate neuropathological changes in multiple brain regions with genomic markers in affected individuals and with changes at the RNA, epigenomic, and/or protein levels, and 3) genetic association studies using more sensitive subphenotypes of HAND. The NIH Brain Initiative and Human Connectome Project, coupled with rapidly evolving systems biology and machine learning approaches for analyzing high-throughput genetic, transcriptomic and epigenetic data, hold promise for identifying actionable biological processes and gene networks that underlie HAND. This review summarizes the current state of understanding of host genetic factors predisposing to HAND in light of past challenges and suggests some priorities for future research to advance the understanding and clinical management of HAND in the cART era. PMID:24996618

  13. Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.

    PubMed

    Saliba, Joseph; Saint-Martin, Cécile; Di Stefano, Antonio; Lenglet, Gaëlle; Marty, Caroline; Keren, Boris; Pasquier, Florence; Valle, Véronique Della; Secardin, Lise; Leroy, Gwendoline; Mahfoudhi, Emna; Grosjean, Sarah; Droin, Nathalie; Diop, M'boyba; Dessen, Philippe; Charrier, Sabine; Palazzo, Alberta; Merlevede, Jane; Meniane, Jean-Côme; Delaunay-Darivon, Christine; Fuseau, Pascal; Isnard, Françoise; Casadevall, Nicole; Solary, Eric; Debili, Najet; Bernard, Olivier A; Raslova, Hana; Najman, Albert; Vainchenker, William; Bellanné-Chantelot, Christine; Plo, Isabelle

    2015-10-01

    No major predisposition gene for familial myeloproliferative neoplasms (MPN) has been identified. Here we demonstrate that the autosomal dominant transmission of a 700-kb duplication in four genetically related families predisposes to myeloid malignancies, including MPN, frequently progressing to leukemia. Using induced pluripotent stem cells and primary cells, we demonstrate that overexpression of ATG2B and GSKIP enhances hematopoietic progenitor differentiation, including of megakaryocytes, by increasing progenitor sensitivity to thrombopoietin (TPO). ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during MPN development. Thus, the germline duplication may change the fitness of cells harboring signaling pathway mutations and increases the probability of disease development. PMID:26280900

  14. Detecting disease-predisposing variants: The haplotype method

    SciTech Connect

    Valdes, A.M.; Thomson, G.

    1997-03-01

    For many HLA-associated diseases, multiple alleles - and, in some cases, multiple loci - have been suggested as the causative agents. The haplotype method for identifying disease-predisposing amino acids in a genetic region is a stratification analysis. We show that, for each haplotype combination containing all the amino acid sites involved in the disease process, the relative frequencies of amino acid variants at sites not involved in disease but in linkage disequilibrium with the disease-predisposing sites are expected to be the same in patients and controls. The haplotype method is robust to mode of inheritance and penetrance of the disease and can be used to determine unequivocally whether all amino acid sites involved in the disease have not been identified. Using a resampling technique, we developed a statistical test that takes account of the nonindependence of the sites sampled. Further, when multiple sites in the genetic region are involved in disease, the test statistic gives a closer fit to the null expectation when some - compared with none - of the true predisposing factors are included in the haplotype analysis. Although the haplotype method cannot distinguish between very highly correlated sites in one population, ethnic comparisons may help identify the true predisposing factors. The haplotype method was applied to insulin-dependent diabetes mellitus (IDDM) HLA class II DQA1-DQB1 data from Caucasian, African, and Japanese populations. Our results indicate that the combination DQA1 No. 52 (Arg predisposing) DQB1 No. 57 (Asp protective), which has been proposed as an important IDDM agent, does not include all the predisposing elements. With rheumatoid arthritis HLA class H DRB1 data, the results were consistent with the shared-epitope hypothesis. 35 refs., 2 figs., 6 tabs.

  15. Prediction of Methotrexate Clinical Response in Portuguese Rheumatoid Arthritis Patients: Implication of MTHFR rs1801133 and ATIC rs4673993 Polymorphisms

    PubMed Central

    Lima, Aurea; Monteiro, Joaquim; Bernardes, Miguel; Sousa, Hugo; Azevedo, Rita; Seabra, Vitor; Medeiros, Rui

    2014-01-01

    Objective. Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients. Methods. Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables. Results. Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response. Conclusion. Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment. PMID:24967362

  16. Depressive behavior induced by social isolation of predisposed female rats.

    PubMed

    Zanier-Gomes, Patrícia Helena; de Abreu Silva, Tomaz Eugênio; Zanetti, Guilherme Cia; Benati, Évelyn Raquel; Pinheiro, Nanci Mendes; Murta, Beatriz Martins Tavares; Crema, Virgínia Oliveira

    2015-11-01

    Depression is a mood disorder that is more prevalent in women and has been closely associated with chronic stress. Many models of depression have been suggested that consider different forms of stress. In fact, stress is present in the life of every human being, but only a few develop depression. Accordingly, it seems wrong to consider all stressed animals to be depressed, emphasizing the importance of predisposition for this mood disorder. Based on this finding, we evaluated a predisposition to depressive behavior of female rats on the forced swim test (FST), and the more immobile the animal was during the FST, the more predisposed to depression it was considered to be. Then, animals were subjected to the stress of social isolation for 21days and were re-evaluated by the FST. The Predisposed/Isolated rats presented higher immobility times. Once all the rats had prior experience in the FST, we calculated an Index of Increase by Isolation, confirming the previous results. Based on this result, we considered the Predisposed/Isolated group as presenting depressive behavior ('Depressed') and the Nonpredisposed/Nonisolated group as the control group ('Nondepressed'). The animals were distributed into 4 new groups: Nondepressed/Vehicle, Nondepressed/Amitriptyline, Depressed/Vehicle, Depressed/Amitriptyline. After 21days of treatment, only the Depressed/Vehicle group differed from the other 3 groups, demonstrating the efficacy of amitriptyline in treating the depressive behavior of the Depressed animals, validating the model. This study shows that conducting an FST prior to any manipulation can predict predisposition to depressive behavior in female rats and that the social isolation of predisposed animals for 21days is effective in inducing depressive behavior. This behavior can be considered real depressive behavior because it takes into account predisposition, chronic mild stress, and the prevalent gender. PMID:26209499

  17. Celiac Disease in a Predisposed Subject (HLA-DQ2.5) with Coexisting Graves' Disease

    PubMed Central

    Hwang, In Kyoung; Kim, Seon Hye; Lee, Unjoo; Chin, Sang Ouk; Rhee, Sang Youl; Oh, Seungjoon; Woo, Jeong-Taek; Kim, Sung-Woon; Kim, Young Seol

    2015-01-01

    Celiac disease is an intestinal autoimmune disorder, triggered by ingestion of a gluten-containing diet in genetically susceptible individuals. The genetic predisposition is related to human leukocyte antigen (HLA) class II genes, especially HLA-DQ2-positive patients. The prevalence of celiac disease has been estimated to be ~1% in Europe and the USA, but it is rarer and/or underdiagnosed in Asia. We report a case of celiac disease in a predisposed patient, with a HLA-DQ2 heterodimer, and Graves' disease that was treated successfully with a gluten-free diet. A 47-year-old woman complained of persistent chronic diarrhea and weight loss over a 9 month period. Results of all serological tests and stool exams were negative. However, the patient was found to carry the HLA DQ2 heterodimer. Symptoms improved after a gluten-free diet was initiated. The patient has been followed and has suffered no recurrence of symptoms while on the gluten-free diet. An overall diagnosis of celiac disease was made in a genetically predisposed patient (HLA-DQ2 heterodimer) with Graves' disease. PMID:25325278

  18. Celiac Disease in a Predisposed Subject (HLA-DQ2.5) with Coexisting Graves' Disease.

    PubMed

    Hwang, In Kyoung; Kim, Seon Hye; Lee, Unjoo; Chin, Sang Ouk; Rhee, Sang Youl; Oh, Seungjoon; Woo, Jeong Taek; Kim, Sung Woon; Kim, Young Seol; Chon, Suk

    2015-03-27

    Celiac disease is an intestinal autoimmune disorder, triggered by ingestion of a gluten-containing diet in genetically susceptible individuals. The genetic predisposition is related to human leukocyte antigen (HLA) class II genes, especially HLA-DQ2-positive patients. The prevalence of celiac disease has been estimated to be ~1% in Europe and the USA, but it is rarer and/or underdiagnosed in Asia. We report a case of celiac disease in a predisposed patient, with a HLA-DQ2 heterodimer, and Graves' disease that was treated successfully with a gluten-free diet. A 47-year-old woman complained of persistent chronic diarrhea and weight loss over a 9 month period. Results of all serological tests and stool exams were negative. However, the patient was found to carry the HLA DQ2 heterodimer. Symptoms improved after a gluten-free diet was initiated. The patient has been followed and has suffered no recurrence of symptoms while on the gluten-free diet. An overall diagnosis of celiac disease was made in a genetically predisposed patient (HLA-DQ2 heterodimer) with Graves' disease. PMID:25325278

  19. 32 CFR 644.389 - Army military-modified predisposal procedures where E.O. 11954 surveys have been made.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...2012-07-01 2011-07-01 true Army military-modified predisposal procedures...Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE...Disposal Predisposal Action § 644.389 Army military—modified predisposal...

  20. 32 CFR 644.389 - Army military-modified predisposal procedures where E.O. 11954 surveys have been made.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...2013-07-01 2013-07-01 false Army military-modified predisposal procedures...Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE...Disposal Predisposal Action § 644.389 Army military—modified predisposal...

  1. 32 CFR 644.389 - Army military-modified predisposal procedures where E.O. 11954 surveys have been made.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...2014-07-01 2013-07-01 true Army military-modified predisposal procedures...Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE...Disposal Predisposal Action § 644.389 Army military—modified predisposal...

  2. Glutamatergic synapse protein composition of wild-type mice is sensitive to in utero MTHFR genotype and the timing of neonatal vigabatrin exposure.

    PubMed

    Zuckerman, Chava; Blumkin, Elinor; Melamed, Osnat; Golan, Hava M

    2015-10-01

    The enzyme methylenetetrahydrofolate-reductase (MTHFR) is part of the homocysteine and folate metabolic pathways. In utero, Mthfr-deficient environment has been reported as a risk factor for neurodevelopmental disorders such as autism and neural tube defects. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between Mthfr deficiency and neonatal exposure to the GABA-potentiating drug vigabatrin (GVG) in mice alters anxiety, memory, and social behavior in a gender-dependent manner. In addition, a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the cerebral cortex was shown. Here we show that in utero MTHFR deficiency is sufficient to alter the levels of glutamate receptor subunits GluR1, GluR2, and NR2B in the cerebral cortex and hippocampus of adult offspring with a WT genotype. In addition, FMRP1, CAMKII ? and ?, and NLG1 levels in WT offspring were vulnerable to the in utero genotype. These effects depend on brain region and the cellular compartment tested. The effect of in utero MTHFR deficiency varies with the age of neonatal GVG exposure to modify GluR1, NR2A, reelin, CAMKII ?, and NLG1 levels. These changes in molecular composition of the glutamatergic synapse were associated with increased anxiety-like behavior. Complex, multifactorial disorders of the nervous system show significant association with several genetic and environmental factors. Our data exemplify the contribution of an in utero MTHFR-deficient environment and early exposure to an antiepileptic drug to the basal composition of the glutamatergic synapses. The robust effect is expected to alter synapse function and plasticity and the cortico-hippocampal circuitry. PMID:26235956

  3. Association between the MTHFR C677T polymorphism and risk of cancer: evidence from 446 case-control studies.

    PubMed

    Xie, Shu-Zhe; Liu, Zhi-Zhong; Yu, Jun-Hua; Liu, Li; Wang, Wei; Xie, Dao-Lin; Qin, Jiang-Bo

    2015-11-01

    Many molecular epidemiological studies have been performed to explore the association between MTHFR C677T polymorphism and cancer risk in diverse populations. However, the results were inconsistent. Hence, we performed a meta-analysis to investigate the association between cancer risk and MTHFR C677T (150,086 cases and 200,699 controls from 446 studies) polymorphism. Overall, significantly increased cancer risk was found when all eligible studies were pooled into the meta-analysis. In the further stratified and sensitivity analyses, significantly increased breast cancer risk was found in Asians and Indians, significantly decreased colon cancer risk was found, significantly decreased colorectal cancer risk was found in male population, significantly increased gastric cancer risk was found in Caucasians and Asians, significantly increased hepatocellular cancer risk was found in Asians, significantly decreased adult acute lymphoblastic leukemia (AALL) risk was found in Caucasians, significantly decreased childhood acute lymphoblastic leukemia (CALL) risk was found in Asians, and significantly increased multiple myeloma and NHL risk was found in Caucasians. In summary, this meta-analysis suggests that MTHFR C677T polymorphism is associated with increased breast cancer, gastric cancer, and hepatocellular cancer risk in Asians, is associated with increased gastric cancer, multiple myeloma, and NHL risk in Caucasians, is associated with decreased AALL risk in Caucasians, is associated with decreased CALL risk in Asians, is associated with increased breast cancer risk in Asians, is associated with decreased colon cancer risk, and is associated with decreased colorectal cancer risk in male population. Moreover, this meta-analysis also points out the importance of new studies, such as Asians of HNC, Asians of lung cancer, and Indians of breast cancer, because they had high heterogeneity in this meta-analysis (I (2)?>?75 %). PMID:26081619

  4. Atopy does not predispose to RSV bronchiolitis or postbronchiolitic wheezing.

    PubMed Central

    Sims, D G; Gardner, P S; Weightman, D; Turner, M W; Soothill, J F

    1981-01-01

    Twenty-six 8-year-old children who had had respiratory syncytial virus (RSV) bronchiolitis in infancy and their paired controls underwent skin and blood tests to assess the role of immunodeficiency and atopy in the pathogenesis of RSV bronchiolitis and the wheezing that may follow it. There was no difference between patients and controls in prevalence of atopy; positive results of prick tests to common antigens; eosinophil counts; yeast opsonisation defect; C2 deficiency; IgG, IgA, IgM, and IgE concentrations; or IgE antibody to dermatophagoides, timothy-grass pollen, and cat fur. Those of the children who had had RSV bronchiolitis and who continued to wheeze had a slightly higher mean eosinophil count and levels of IgE antibody to dermatophagoides than those who did not wheeze. Exercise-induced bronchial lability, though higher in patients than controls, did not correlate significantly with eosinophil counts or IgE concentrations. The genetic factors predisposing to RSV bronchiolitis and postbronchiolitic wheezing may differ from those predisposing to atopic asthma, though exclusive breast feeding may protect against both. PMID:6788213

  5. Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment

    PubMed Central

    Mischoulon, David; Lamon-Fava, Stefania; Selhub, Jacob; Katz, Judith; Papakostas, George I.; Iosifescu, Dan V.; Yeung, Albert S.; Dording, Christina M.; Farabaugh, Amy H.; Clain, Alisabet J.; Baer, Lee; Alpert, Jonathan E.; Nierenberg, Andrew A.; Fava, Maurizio

    2014-01-01

    Objective To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response. Methods We screened 224 subjects (52% female, mean age 39 ± 11 years) with SCID-diagnosed major depressive disorder (MDD), and obtained 194 genetic samples. 49 subjects (49% female, mean age 36 ± 11 years) participated in a 12-week open clinical trial of fluoxetine 20–60 mg/day. Association between clinical response and C677T and A2756G polymorphisms, folate, B12, and homocysteine was examined. Results Prevalence of the C677T and A2756G polymorphisms was consistent with previous reports (C/C=41%, C/T=47%, T/T=11%, A/A=66%, A/G=29%, G/G=4%). In the fluoxetine-treated subsample (n=49), intent-to-treat (ITT) response rates were 47% for C/C subjects and 46% for pooled C/T and T/T subjects (nonsignificant). ITT response rates were 38% for A/A subjects and 60% for A/G subjects (nonsignificant), with no subjects exhibiting the G/G homozygote. Mean baseline plasma B12 was significantly lower in A/G subjects compared to A/A, but folate and homocysteine levels were not affected by genetic status. Plasma folate was negatively associated with treatment response. Conclusion The C677T and A2756G polymorphisms did not significantly affect antidepressant response. These preliminary findings require replication in larger samples. PMID:22789065

  6. MTHFR deficiency or reduced intake of folate or choline in pregnant mice results in impaired short-term memory and increased apoptosis in the hippocampus of wild-type offspring.

    PubMed

    Jadavji, N M; Deng, L; Malysheva, O; Caudill, M A; Rozen, R

    2015-08-01

    Genetic or nutritional disturbances in one-carbon metabolism, with associated hyperhomocysteinemia, can result in complex disorders including pregnancy complications and neuropsychiatric diseases. In earlier work, we showed that mice with a complete deficiency of methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate and homocysteine metabolism, had cognitive impairment with disturbances in choline metabolism. Maternal demands for folate and choline are increased during pregnancy and deficiencies of these nutrients result in several negative outcomes including increased resorption and delayed development. The goal of this study was to investigate the behavioral and neurobiological impact of a maternal genetic deficiency in MTHFR or maternal nutritional deficiency of folate or choline during pregnancy on 3-week-old Mthfr(+/+) offspring. Mthfr(+/+) and Mthfr(+/-) females were placed on control diets (CD); and Mthfr(+/+) females were placed on folate-deficient diets (FD) or choline-deficient diets (ChDD) throughout pregnancy and lactation until their offspring were 3weeks of age. Short-term memory was assessed in offspring, and hippocampal tissue was evaluated for morphological changes, apoptosis, proliferation and choline metabolism. Maternal MTHFR deficiency resulted in short-term memory impairment in offspring. These dams had elevated levels of plasma homocysteine when compared with wild-type dams. There were no differences in plasma homocysteine in offspring. Increased apoptosis and proliferation was observed in the hippocampus of offspring from Mthfr(+/-) mothers. In the maternal FD and ChDD study, offspring also showed short-term memory impairment with increased apoptosis in the hippocampus; increased neurogenesis was observed in ChDD offspring. Choline acetyltransferase protein was increased in the offspring hippocampus of both dietary groups and betaine was decreased in the hippocampus of FD offspring. Our results reveal short-term memory deficits in the offspring of dams with MTHFR deficiency or dietary deficiencies of critical methyl donors. We suggest that deficiencies in maternal one-carbon metabolism during pregnancy can contribute to hippocampal dysfunction in offspring through apoptosis or altered choline metabolism. PMID:25956258

  7. PAI-1 4G-4G and MTHFR 677TT in non-hepatitis C virus/hepatitis B virus-related liver cirrhosis

    PubMed Central

    Pasta, Linda; Pasta, Francesca

    2015-01-01

    AIM: To evaluate the different roles of thrombophilia in patients with and without viral etiology. The thrombophilic genetic factors (THRGFs), PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q and prothrombin 20210A, were studied as risk factors in 1079 patients with liver cirrhosis (LC), enrolled from January 2000 to January 2014. METHODS: All Caucasian LC patients consecutively observed in a fourteen-year period were included; the presence of portal vein thrombosis (PVT) and Budd Chiari syndrome (BCS) was registered. The differences between the proportions of each THRGF with regard to the presence or absence of viral etiology and the frequencies of the THRGF genotypes with those predicted in a population by the Hardy-Weinberg equilibrium were registered. RESULTS: Four hundred and seventeen/one thousand and seventy-six patients (38.6%) showed thrombophilia: 217 PAI-1 4G-4G, 176 MTHFR C677TT, 71 V Leiden factor and 41 prothrombin G20210 A, 84 with more than 1 THRGF; 350 presented with no viral liver cirrhosis (NVLC) and 729 with, called viral liver cirrhosis (VLC), of whom 56 patients were hepatitis C virus + hepatitis B virus. PAI-1 4G-4G, MTHFR C677TT, the presence of at least one TRHGF and the presence of > 1 THRGF, were statistically more frequent in patients with NVLC vs patients with VLC: All ?2 > 3.85 and P < 0.05. Patients with PVT and/or BCS with at least one TRHGF were 189/352 (53.7%). The Hardy-Weinberg of PAI-1 and MTHFR 677 genotypes deviated from that expected from a population in equilibrium in patients with NVLC (respectively ?2 = 39.3; P < 0.000 and ?2 = 27.94; P < 0.05), whereas the equilibrium was respected in VLC. CONCLUSION: MTHFR 677TT was nearly twofold and PAI-1 4G-4G more than threefold more frequently found in NVLC vs patients with VLC; the Hardy-Weinberg equilibrium of these two polymorphisms confirms this data in NVLC. We suggest that PAI-1 4G-4G and MTHFR 677TT could be considered as factors of fibrosis and thrombosis mechanisms, increasing the inflammation response, and causing the hepatic fibrosis and augmented intrahepatic vascular resistance typical of LC. PAI-1 4G-4G and MTHFR 677TT screening of LC patients could be useful, mainly in those with NVLC, to identify patients in which new drug therapies based on the attenuation of the hepatic stellate cells activation or other mechanisms could be more easily evaluated. PMID:26689658

  8. Subclinical Mastitis in Dairy Animals: Incidence, Economics, and Predisposing Factors

    PubMed Central

    Sinha, Mukesh Kr.; Thombare, N. N.; Mondal, Biswajit

    2014-01-01

    A study was conducted to assess the incidence and economics of subclinical form of bovine mastitis in Central Region of India. Daily milk records of 187 animals during three seasons were collected and subjected to analysis. The economic loss due to reduction in yield, clinical expenses, and additional resources used were quantified and aggregated. The losses due to mastitis in monetary terms were estimated to be INR1390 per lactation, among which around 49% was owing to loss of value from milk and 37% on account of veterinary expenses. Higher losses were observed in crossbred cows due to their high production potential that was affected during mastitis period. The cost of treating an animal was estimated to be INR509 which includes cost of medicine (31.10%) and services (5.47%). Inadequate sanitation, hygiene, and veterinary services were the main predisposing factors for incidence and spread of mastitis as perceived by the respondents. PMID:25093203

  9. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency

    SciTech Connect

    Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen. R.

    1995-05-01

    5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5{prime} splice-site defect that activates a cryptic splice in the coding sequence. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms. 19 refs., 4 figs., 2 tabs.

  10. Association between the MTHFR C677T polymorphism and gastric cancer susceptibility: A meta-analysis of 5,757 cases and 8,501 controls

    PubMed Central

    CHEN, LONG; LU, NING; ZHANG, BAI-HONG; WENG, LI; LU, JUN

    2015-01-01

    Current data regarding the association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of developing gastric cancer are insufficient to draw definite conclusions. Therefore, the present meta-analysis was conducted to achieve a more precise estimation of the association. MEDLINE, EMBASE and Wanfang database searches resulted in the identification of 28 eligible studies describing 5,757 cases and 8,501 controls. The strength of the association between the MTHFR C677T polymorphism and gastric cancer risk were evaluated using crude odds ratios (ORs), with 95% confidence intervals (CIs). The pooled ORs were determined using homozygous (TT vs. CC), heterozygous (CT vs. CC), dominant (TT+CT vs. CC) and recessive (TT vs. CC+CT) models. When all studies were pooled into the meta-analysis, significant associations were identified between the MTHFR C677T polymorphism and the risk of gastric cancer (homozygous model: OR, 1.39; 95% CI, 1.20–1.62; heterozygous model: OR, 1.18; 95% CI, 1.05–1.32; dominant model: OR, 1.23; 95% CI, 1.10–1.38; recessive model: OR, 1.26; 95% CI, 1.12–1.42). Stratification of the data by ethnicity identified a statistically significantly elevated risk of gastric cancer in Asian MTHFR C677T polymorphism populations (homozygous model: OR, 1.64; 95% CI, 1.43–1.90; heterozygous model: OR, 1.30; 95% CI, 1.16–1.45; dominant model: OR, 1.39; 95% CI, 1.25–1.54; recessive model: OR, 1.41; 95% CI, 1.25–1.51), but not in Caucasian populations (homozygous model: OR, 1.15; 95% CI, 0.89–1.48; heterozygous model: OR, 1.03; 95% CI, 0.84–1.25; dominant model: OR, 1.05; 95% CI, 0.86–1.28; recessive model: OR, 1.09; 95% CI, 0.91–1.31). Following adjustment for heterogeneity, the current meta-analysis demonstrated that the MTHFR C677T polymorphism was not associated with the risk of gastric cancer in Caucasian individuals. Furthermore, no evidence of publication bias was observed. Thus, the current meta-analysis indicates that the MTHFR C677T allele may be a low-penetrant risk factor for the development of gastric cancer in Asian populations.

  11. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma

    PubMed Central

    Yokoyama, Satoru; Woods, Susan L.; Boyle, Glen M.; Aoude, Lauren G.; MacGregor, Stuart; Zismann, Victoria; Gartside, Michael; Cust, Anne E.; Haq, Rizwan; Harland, Mark; Taylor, John C.; Duffy, David L.; Holohan, Kelly; Dutton-Regester, Ken; Palmer, Jane M.; Bonazzi, Vanessa; Stark, Mitchell S.; Symmons, Judith; Law, Matthew H.; Schmidt, Christopher; Lanagan, Cathy; O’Connor, Linda; Holland, Elizabeth A.; Schmid, Helen; Maskiell, Judith A.; Jetann, Jodie; Ferguson, Megan; Jenkins, Mark A.; Kefford, Richard F.; Giles, Graham G.; Armstrong, Bruce K.; Aitken, Joanne F.; Hopper, John L.; Whiteman, David C.; Pharoah, Paul D.; Easton, Douglas F.; Dunning, Alison M.; Newton-Bishop, Julia A.; Montgomery, Grant W.; Martin, Nicholas G.; Mann, Graham J.; Bishop, D. Timothy; Tsao, Hensin; Trent, Jeffrey M.; Fisher, David E.; Hayward, Nicholas K.; Brown, Kevin M.

    2012-01-01

    So far, two familial melanoma genes have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases1, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds2. To identify other familial melanoma genes, here we conducted whole-genome sequencing of probands from several melanoma families, identifying one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log odds ratio (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case–control sample. Likewise, it was similarly associated in an independent case–control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility. PMID:22080950

  12. CTCF Haploinsufficiency Predisposes to Cancer by Destabilizing DNA Methylation

    Cancer.gov

    Humans are diploid organisms, meaning they inherit one set of chromosomes from each parent. One copy of the gene that encodes the DNA binding protein, CCCTC-binding factor (CTCF), is commonly deleted or mutated in some human cancers. CTCF alters chromatin structure, and thus gene expression, by regulating a DNA chemical modification process called methylation.

  13. Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.

    PubMed

    He, Huiling; Li, Wei; Wu, Dayong; Nagy, Rebecca; Liyanarachchi, Sandya; Akagi, Keiko; Jendrzejewski, Jaroslaw; Jiao, Hong; Hoag, Kevin; Wen, Bernard; Srinivas, Mukund; Waidyaratne, Gavisha; Wang, Rui; Wojcicka, Anna; Lattimer, Ilene R; Stachlewska, Elzbieta; Czetwertynska, Malgorzata; Dlugosinska, Joanna; Gierlikowski, Wojciech; Ploski, Rafal; Krawczyk, Marek; Jazdzewski, Krystian; Kere, Juha; Symer, David E; Jin, Victor; Wang, Qianben; de la Chapelle, Albert

    2013-01-01

    Thyroid cancer shows high heritability but causative genes remain largely unknown. According to a common hypothesis the genetic predisposition to thyroid cancer is highly heterogeneous; being in part due to many different rare alleles. Here we used linkage analysis and targeted deep sequencing to detect a novel single-nucleotide mutation in chromosome 4q32 (4q32A>C) in a large pedigree displaying non-medullary thyroid carcinoma (NMTC). This mutation is generally ultra-rare; it was not found in 38 NMTC families, in 2676 sporadic NMTC cases or 2470 controls. The mutation is located in a long-range enhancer element whose ability to bind the transcription factors POU2F and YY1 is significantly impaired, with decreased activity in the presence of the C- allele compared with the wild type A-allele. An enhancer RNA (eRNA) is transcribed in thyroid tissue from this region and is greatly downregulated in NMTC tumors. We suggest that this is an example of an ultra-rare mutation predisposing to thyroid cancer with high penetrance. PMID:23690926

  14. MTHFR 677T is a strong determinant of the degree of hearing loss among Polish males with postlingual sensorineural hearing impairment.

    PubMed

    Pollak, Agnieszka; Mueller-Malesinska, Malgorzata; Lechowicz, Urszula; Skorka, Agata; Korniszewski, Lech; Sobczyk-Kopciol, Agnieszka; Waskiewicz, Anna; Broda, Grazyna; Iwanicka-Pronicka, Katarzyna; Oldak, Monika; Skarzynski, Henryk; P?oski, Rafa?

    2012-07-01

    Hearing impairment (HI) is the most common sensory handicap. Congenital HI often has a genetic basis, whereas the etiology of nonsyndromic postlingual HI (npHI) usually remains unidentified. Our purpose was to test whether the MTHFR C677T (rs1801133) polymorphism affecting folate metabolism is associated with the occurrence or severity of npHI. We studied rs1801133 genotypes in 647 npHI patients (age <40, sudden sensorineural loss excluded, HI characterized as mean of better ear hearing thresholds for 0.5-8 kHz) and 3273 adult controls from the background population. Genotype distribution among patients and controls was similar, but among male cases (n = 302) we found a dose-dependent correlation of MTHFR 677T with the degree of HI (mean thresholds in dB: 38.8, 44.9, and 53.3, for CC, CT, and TT genotypes, respectively; p = 0.0013, p(cor.) = 0.017). Among male patients rs1801133 TT significantly increased the risk of severe/profound HI (odds ratio = 4.88, p = 0.001). Among controls the known effect of MTHFR 677T on plasma total homocysteine was more pronounced in men than in women (p<0.00004 for genotype-sex interaction) suggesting that in Poland folate deficiency is more prevalent in males. In conclusion, we report a novel strong effect of MTHFR 677T among males with npHI. The functional significance of rs1801133 suggests that these patients may benefit from folate supplementation-an intervention which is simple, cheap, and devoid of side effects. PMID:22424391

  15. MTHFR 677T Is a Strong Determinant of the Degree of Hearing Loss Among Polish Males with Postlingual Sensorineural Hearing Impairment

    PubMed Central

    Pollak, Agnieszka; Mueller-Malesinska, Malgorzata; Lechowicz, Urszula; Skorka, Agata; Korniszewski, Lech; Sobczyk-Kopciol, Agnieszka; Waskiewicz, Anna; Broda, Grazyna; Iwanicka-Pronicka, Katarzyna; Oldak, Monika; Skarzynski, Henryk

    2012-01-01

    Hearing impairment (HI) is the most common sensory handicap. Congenital HI often has a genetic basis, whereas the etiology of nonsyndromic postlingual HI (npHI) usually remains unidentified. Our purpose was to test whether the MTHFR C677T (rs1801133) polymorphism affecting folate metabolism is associated with the occurrence or severity of npHI. We studied rs1801133 genotypes in 647 npHI patients (age <40, sudden sensorineural loss excluded, HI characterized as mean of better ear hearing thresholds for 0.5–8 kHz) and 3273 adult controls from the background population. Genotype distribution among patients and controls was similar, but among male cases (n=302) we found a dose-dependent correlation of MTHFR 677T with the degree of HI (mean thresholds in dB: 38.8, 44.9, and 53.3, for CC, CT, and TT genotypes, respectively; p=0.0013, pcor.=0.017). Among male patients rs1801133 TT significantly increased the risk of severe/profound HI (odds ratio=4.88, p=0.001). Among controls the known effect of MTHFR 677T on plasma total homocysteine was more pronounced in men than in women (p<0.00004 for genotype-sex interaction) suggesting that in Poland folate deficiency is more prevalent in males. In conclusion, we report a novel strong effect of MTHFR 677T among males with npHI. The functional significance of rs1801133 suggests that these patients may benefit from folate supplementation—an intervention which is simple, cheap, and devoid of side effects. PMID:22424391

  16. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.

    PubMed

    Su, Zhan; Gay, Laura J; Strange, Amy; Palles, Claire; Band, Gavin; Whiteman, David C; Lescai, Francesco; Langford, Cordelia; Nanji, Manoj; Edkins, Sarah; van der Winkel, Anouk; Levine, David; Sasieni, Peter; Bellenguez, Céline; Howarth, Kimberley; Freeman, Colin; Trudgill, Nigel; Tucker, Art T; Pirinen, Matti; Peppelenbosch, Maikel P; van der Laan, Luc J W; Kuipers, Ernst J; Drenth, Joost P H; Peters, Wilbert H; Reynolds, John V; Kelleher, Dermot P; McManus, Ross; Grabsch, Heike; Prenen, Hans; Bisschops, Raf; Krishnadath, Kausila; Siersema, Peter D; van Baal, Jantine W P M; Middleton, Mark; Petty, Russell; Gillies, Richard; Burch, Nicola; Bhandari, Pradeep; Paterson, Stuart; Edwards, Cathryn; Penman, Ian; Vaidya, Kishor; Ang, Yeng; Murray, Iain; Patel, Praful; Ye, Weimin; Mullins, Paul; Wu, Anna H; Bird, Nigel C; Dallal, Helen; Shaheen, Nicholas J; Murray, Liam J; Koss, Konrad; Bernstein, Leslie; Romero, Yvonne; Hardie, Laura J; Zhang, Rui; Winter, Helen; Corley, Douglas A; Panter, Simon; Risch, Harvey A; Reid, Brian J; Sargeant, Ian; Gammon, Marilie D; Smart, Howard; Dhar, Anjan; McMurtry, Hugh; Ali, Haythem; Liu, Geoffrey; Casson, Alan G; Chow, Wong-Ho; Rutter, Matt; Tawil, Ashref; Morris, Danielle; Nwokolo, Chuka; Isaacs, Peter; Rodgers, Colin; Ragunath, Krish; MacDonald, Chris; Haigh, Chris; Monk, David; Davies, Gareth; Wajed, Saj; Johnston, David; Gibbons, Michael; Cullen, Sue; Church, Nicholas; Langley, Ruth; Griffin, Michael; Alderson, Derek; Deloukas, Panos; Hunt, Sarah E; Gray, Emma; Dronov, Serge; Potter, Simon C; Tashakkori-Ghanbaria, Avazeh; Anderson, Mark; Brooks, Claire; Blackwell, Jenefer M; Bramon, Elvira; Brown, Matthew A; Casas, Juan P; Corvin, Aiden; Duncanson, Audrey; Markus, Hugh S; Mathew, Christopher G; Palmer, Colin N A; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J; Trembath, Richard C; Viswanathan, Ananth C; Wood, Nicholas; Trynka, Gosia; Wijmenga, Cisca; Cazier, Jean-Baptiste; Atherfold, Paul; Nicholson, Anna M; Gellatly, Nichola L; Glancy, Deborah; Cooper, Sheldon C; Cunningham, David; Lind, Tore; Hapeshi, Julie; Ferry, David; Rathbone, Barrie; Brown, Julia; Love, Sharon; Attwood, Stephen; MacGregor, Stuart; Watson, Peter; Sanders, Scott; Ek, Weronica; Harrison, Rebecca F; Moayyedi, Paul; de Caestecker, John; Barr, Hugh; Stupka, Elia; Vaughan, Thomas L; Peltonen, Leena; Spencer, Chris C A; Tomlinson, Ian; Donnelly, Peter; Jankowski, Janusz A Z

    2012-10-01

    Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus. PMID:22961001

  17. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett’s esophagus

    PubMed Central

    2012-01-01

    Barrett’s Esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia. Barrett’s Esophagus strongly predisposes to esophageal adenocarcinoma (EAC), a tumour with a very poor prognosis. We have undertaken the first genome-wide association study on Barrett’s Esophagus, comprising 1,852 UK cases and 5,172 UK controls in discovery and 5,986 cases and 12,825 controls in the replication. Two regions were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10?9, OR(95%CI) =1.21(1.13-1.28)) and chromosome 16q24, rs9936833 (Pcombined=2.74×10?10, OR(95%CI) =1.14(1.10-1.19)). The top SNP on chromosome 6p21 is within the major histocompatibility complex, and the closest protein-coding gene to rs9936833 on chromosome 16q24 is FOXF1, which is implicated in esophageal development and structure. We found evidence that the genetic component of Barrett’s Esophagus is mediated by many common variants of small effect and that SNP alleles predisposing to obesity also increase risk for Barrett’s Esophagus. PMID:22961001

  18. Combined choroidal neovascularization and hypopituitarism in a patient with homozygous mutation in methylenetetrahydrofolate reductase gene

    PubMed Central

    Aydogdu, Aydogan; Haymana, Cem; Baskoy, Kamil; Durukan, Ali H.; Ozgur, Gokhan; Azal, Omer

    2014-01-01

    We report a case of choroidal neovascularization (CNV) secondary to methylenetetrahydrofolate reductase (MTHFR) gene mutation in a 20-year-old male patient with hypopituitarism. Treatment with three consecutive injections of intravitreal ranibizumab (anti-vascular endothelial growth factor) resulted in significant improvement of the patient's vision and the appearance of the macula. A search of the literature produced no previously reported case of MTHFR gene mutation associated both CNV and possibly hypopituitarism. With hormone replacement therapy of hypopituitarism, acetyl salicylic acid 100 mg/day also was started. The patient was clinically stable both for CNV and other thromboembolic disorders over a 6-month follow-up and also 1-year follow-up period. PMID:24672570

  19. Use of mental health services among disaster survivors: predisposing factors

    PubMed Central

    den Ouden, Dirk-Jan; van der Velden, Peter G; Grievink, Linda; Morren, Mattijn; Dirkzwager, Anja JE; Yzermans, C Joris

    2007-01-01

    Background Given the high prevalence of mental health problems after disasters it is important to study health services utilization. This study examines predictors for mental health services (MHS) utilization among survivors of a man-made disaster in the Netherlands (May 2000). Methods Electronic records of survivors (n = 339; over 18 years and older) registered in a mental health service (MHS) were linked with general practice based electronic medical records (EMRs) of survivors and data obtained in surveys. EMR data were available from 16 months pre-disaster until 3 years post-disaster. Symptoms and diagnoses in the EMRs were coded according to the International Classification of Primary Care (ICPC). Surveys were carried out 2–3 weeks and 18 months post-disaster, and included validated questionnaires on psychological distress, post-traumatic stress reactions and social functioning. Demographic and disaster-related variables were available. Predisposing factors for MHS utilization 0–18 months and 18–36 months post-disaster were examined using multiple logistic regression models. Results In multiple logistic models, adjusting for demographic and disaster related variables, MHS utilization was predicted by demographic variables (young age, immigrant, public health insurance, unemployment), disaster-related exposure (relocation and injuries), self-reported psychological problems and pre- and post-disaster physician diagnosed health problems (chronic diseases, musculoskeletal problems). After controlling for all health variables, disaster intrusions and avoidance reactions (OR:2.86; CI:1.48–5.53), hostility (OR:2.04; CI:1.28–3.25), pre-disaster chronic diseases (OR:1.82; CI:1.25–2.65), injuries as a result of the disaster (OR:1.80;CI:1.13–2.86), social functioning problems (OR:1.61;CI:1.05–2.44) and younger age (OR:0.98;CI:0.96–0.99) predicted MHS utilization within 18 months post-disaster. Furthermore, disaster intrusions and avoidance reactions (OR:2.29;CI:1.04–5.07) and hostility (OR:3.77;CI:1.51–9.40) predicted MHS utilization following 18 months post-disaster. Conclusion This study showed that several demographic and disaster-related variables and self-reported and physician diagnosed health problems predicted post-disaster MHS-use. The most important factors to predict post-disaster MHS utilization were disaster intrusions and avoidance reactions and symptoms of hostility (which can be identified as symptoms of PTSD) and pre-disaster chronic diseases. PMID:17650339

  20. COMPARATIVE EVALUATION OF RISK FACTORS FOR CARDIOVASCULAR DISEASE (CVD) IN GENETICALLY PREDISPOSED RATS

    EPA Science Inventory

    Rodent CVD models are increasingly used for understanding individual differences in susceptibility to environmental stressors such as air pollution. We characterized pathologies and a number of known human risk factors of CVD in genetically predisposed, male young adult Spontaneo...

  1. Variants of human papillomavirus type 16 predispose toward persistent infection

    PubMed Central

    Zhang, Lei; Liao, Hong; Yang, Binlie; Geffre, Christopher P; Zhang, Ai; Zhou, Aizhi; Cao, Huimin; Wang, Jieru; Zhang, Zhenbo; Zheng, Wenxin

    2015-01-01

    A cohort study of 292 Chinese women was conducted to determine the relationship between human papillomavirus (HPV) type 16 variants and persistent viral infection. Enrolled patients were HPV16 positive and had both normal cytology and histology. Flow-through hybridization and gene chip technology was used to identify the HPV type. A PCR sequencing assay was performed to find HPV16 E2, E6 and E7 gene variants. The associations between these variants and HPV16 persistent infection was analyzed by Fisher’s exact test. It was found that the variants T178G, T350G and A442C in the E6 gene, as well as C3158A and G3248A variants in the E2 gene were associated with persistent HPV16 infection. No link was observed between E7 variants and persistent viral infection. Our findings suggest that detection of specific HPV variants would help identify patients who are at high risk for viral persistence and development of cervical neoplasia. PMID:26339417

  2. Methylenetetrahydrofolate reductase gene A1298C polymorphism and susceptibility to recurrent pregnancy loss: a meta-analysis.

    PubMed

    Rai, V

    2014-01-01

    Environmental and genetic factors are thought to be involved in the pathogenesis of recurrent pregnancy loss (RPL)/spontaneous abortions (SA), which include endocrine, anatomical abnormalities within the genital organs, autoimmune diseases and some gene variants. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of the folate/methionine metabolic pathway and it is well established fact that folate deficiency causes pregnancy complications like recurrent pregnancy loss, preeclempsia and birth defects affected pregnancies. MTHFR A1298C polymorphism reduces the enzymatic activity and mimics as folate deficiency. To date, many studies have investigated the association between MTHFR A1298C polymorphism and RPL risk; however, the result is still controversial and inconclusive. The aim of the present study was to address the association of MTHFR A1298C polymorphism with RPL risk by meta—analysis. By searching electronic databases, total seventeen studies were identified for present meta—analysis. Crude odds ratios (OR) with 95 % confidence intervals (CIs) was used to assess the strength of association between A1298C polymorphism and RPL. The results indicate that the A1298C polymorphism is not associated with RPL (ORCvs A = 1.13 ,95 % CI= 0.87—1.46, P = 0.36 ; ORACvs AA = 1.22 ,95 % CI= 0.94— 1.6, P = 0.13; ORCCvsAA =1.35, 95 % CI= 76—2.36, P = 0.30; ORCC+AC vs AA = 1.15, 95 % CI= 88 —1.49, P = 0.29; ORCCvs AC+AA = 1.29, 95 % CI= 76 —2.12, P = 0.34). Further prospective studies were needed to confirm the precise relationship between the MTHFR A1298C polymorphism and RPL. PMID:24970119

  3. The chosen genes : Jews, genetics, and the future of ethnic medicine

    E-print Network

    Anthes, Emily Kennedy

    2006-01-01

    All humans have certain genes that cause or predispose them to various diseases. In the ideal medical future, scientists will have hyperfast gene analyzers able to sequence anyone's DNA in a matter of minutes. In that ...

  4. Genetic Association Study of Putative Functional Single Nucleotide Polymorphisms of Genes in Folate Metabolism and Spina Bifida

    PubMed Central

    Martinez, Carla A.; Northrup, Hope; Lin, Jone-Ing; Morrison, Alanna C.; Fletcher, Jack M.; Tyerman, Gayle H.; Au, Kit Sing

    2009-01-01

    OBJECTIVE We tested putative functional single nucleotide polymorphisms (SNPs) in genes which regulate the folate/homocysteine metabolism pathway for their contribution to spina bifida (SB) susceptibility. STUDY DESIGN The study consisted of 610 unrelated simplex SB patient families. Genotypes of 46 SNPs located in the coding sequence or promoter region of 11 genes were investigated. Associations between transmission of alleles and SB in the offspring were examined using the reconstruction-combined transmission disequilibrium test. RESULTS Significant association of SNP rs5742905 in cystathionine-?-synthase (CBS), rs1643649 in dihydrofolate reductase (DHFR), rs2853533 in thymidylate synthetase (TYMS), and rs3737965 in methylene-tetrahydrofolate-reductase (MTHFR) was found (p= 0.015, 0.041, 0.021, and 0.007 respectively). CONCLUSION Transmission disequilibrium of SNP alleles in CBS, DHFR, MTHFR and TYMS confers an increased susceptibility to SB. PMID:19683694

  5. Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours

    PubMed Central

    Arendt, Maja L.; Melin, Malin; Tonomura, Noriko; Koltookian, Michele; Courtay-Cahen, Celine; Flindall, Netty; Bass, Joyce; Boerkamp, Kim; Megquir, Katherine; Youell, Lisa; Murphy, Sue; McCarthy, Colleen; London, Cheryl; Rutteman, Gerard R.; Starkey, Mike; Lindblad-Toh, Kerstin

    2015-01-01

    Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10-16), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT. PMID:26588071

  6. Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours.

    PubMed

    Arendt, Maja L; Melin, Malin; Tonomura, Noriko; Koltookian, Michele; Courtay-Cahen, Celine; Flindall, Netty; Bass, Joyce; Boerkamp, Kim; Megquir, Katherine; Youell, Lisa; Murphy, Sue; McCarthy, Colleen; London, Cheryl; Rutteman, Gerard R; Starkey, Mike; Lindblad-Toh, Kerstin

    2015-11-01

    Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10-16), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT. PMID:26588071

  7. 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

  8. CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer

    PubMed Central

    Kemp, Christopher J.; Moore, James M.; Moser, Russell; Bernard, Brady; Teater, Matt; Smith, Leslie E.; Rabaia, Natalia; Gurley, Kay E.; Guinney, Justin; Busch, Stephanie E.; Shaknovich, Rita; Lobanenkov, Victor V.; Liggitt, Denny; Shmulevich, Ilya; Melnick, Ari; Filippova, Galina N.

    2014-01-01

    SUMMARY Epigenetic alterations, particularly in DNA methylation, are ubiquitous in cancer, yet the molecular origins and the consequences of these alterations are poorly understood. The DNA binding protein CTCF regulates a diverse array of epigenetic processes and is frequently altered by hemizygous deletion or mutation in human cancer. To date, a causal role for CTCF in cancer has not been established. Here we show that Ctcf hemizygous knockout mice are markedly susceptible to spontaneous, radiation, and chemically induced cancer in a broad range of tissues. Ctcf+/? tumors are characterized by increased aggressiveness including invasion, metastatic dissemination, and mixed epithelial/mesenchymal differentiation. Molecular analysis of Ctcf+/? tumors indicates that Ctcf is haploinsufficient for tumor suppression. Tissues with hemizygous loss of CTCF exhibit increased variability in CpG methylation genome-wide. These findings establish CTCF as a prominent tumor suppressor gene and point to CTCF mediated epigenetic stability as a major barrier to neoplastic progression. PMID:24794443

  9. CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer.

    PubMed

    Kemp, Christopher J; Moore, James M; Moser, Russell; Bernard, Brady; Teater, Matt; Smith, Leslie E; Rabaia, Natalia A; Gurley, Kay E; Guinney, Justin; Busch, Stephanie E; Shaknovich, Rita; Lobanenkov, Victor V; Liggitt, Denny; Shmulevich, Ilya; Melnick, Ari; Filippova, Galina N

    2014-05-22

    Epigenetic alterations, particularly in DNA methylation, are ubiquitous in cancer, yet the molecular origins and the consequences of these alterations are poorly understood. CTCF, a DNA-binding protein that regulates higher-order chromatin organization, is frequently altered by hemizygous deletion or mutation in human cancer. To date, a causal role for CTCF in cancer has not been established. Here, we show that Ctcf hemizygous knockout mice are markedly susceptible to spontaneous, radiation-, and chemically induced cancer in a broad range of tissues. Ctcf(+/-) tumors are characterized by increased aggressiveness, including invasion, metastatic dissemination, and mixed epithelial/mesenchymal differentiation. Molecular analysis of Ctcf(+/-) tumors indicates that Ctcf is haploinsufficient for tumor suppression. Tissues with hemizygous loss of CTCF exhibit increased variability in CpG methylation genome wide. These findings establish CTCF as a prominent tumor-suppressor gene and point to CTCF-mediated epigenetic stability as a major barrier to neoplastic progression. PMID:24794443

  10. Assessing predictive capacity and conditional independence of landslide predisposing factors for shallow landslides susceptibility models

    NASA Astrophysics Data System (ADS)

    Pereira, S.; Zêzere, J. L.; Bateira, C.

    2012-04-01

    The aim of this study is to identify the landslide predisposing factors combination, using a bivariate statistical model that best predict landslide susceptibility. The best predictive model should have a good performance in terms of suitability and predictive power, and should be based on landslide predisposing factors that are conditionally independent. The study area is the Santa Marta de Penaguião council (70 km2) located in the Northern Portugal. Several destructive landslides occurred in this area in the last decades promoting landscape degradation and other negative human and economic impacts. A landslide inventory was built in 2005-2009 using aerial photo-interpretation (1/5.000 scale) and field work validation. This inventory contains 767 shallow translational slides. The landslide density is 11 events/square kilometre, and each landslide has, on average, 136 m2 and the depth of the slip surface typically ranges from 1 to 1.5 m. The landslide layer was crossed individually with seven landslide predisposing factors (Aspect; Curvature; Slope Angle; Geomorphological Units; Land Use; Inverse Wetness Index; Lithology) and each class within each predisposing theme was weighted using the Information Value Method. In order to identify the best combination of landslide predisposing factors, all possible combinations were tested which resulted in 120 predictive models. The goodness of fit of each landslide susceptibility model was evaluated by constructing the Success Rate Curves and by computing the Area Under the Curve (AUC). The best landslide susceptibility model was selected according to the model degree of fitness and on the basis of a conditional independence criterion. Two tests were performed to the entire dataset to assess conditional independence: the Overall Conditional Independence (OCI) and the Agterberg & Cheng Conditional Independence Test (ACCIT) (Agterberg and Cheng, 2002). The best landslide susceptibility model was constructed with only three landslide predisposing factors (slope angle, inverse wetness index and land use) and was compared with a model developed using the total set of landslide predisposing factors. Finally, the predictive capacity of the selected landslide susceptibility model was evaluated by computing Prediction Rate Curves based on the partitioning of landslide inventory using temporal, spatial and random criteria. The same procedure was applied to the seven-factors model for comparison purposes. Results showed that the model of spatial distribution of landslide susceptibility built with three factors is not significantly different from the one produced with the total set of factors. Therefore, it is shown that it is possible to produce a reliable landslide susceptibility model using only a few landslides predisposing factors and fulfilling the conditional independence hypothesis.

  11. Predisposing factors for individuals' Lyme disease prevention practices: Connecticut, Maine, and Montana.

    PubMed Central

    Herrington, J E; Campbell, G L; Bailey, R E; Cartter, M L; Adams, M; Frazier, E L; Damrow, T A; Gensheimer, K F

    1997-01-01

    OBJECTIVES: This study examined factors that predispose individuals to protect against Lyme disease. METHODS: Knowledge, attitude, and practice questions concerning Lyme disease prevention were included in the Behavioral Risk Factor Surveillance surveys in Connecticut, Maine, and Montana. A total of 4246 persons were interviewed. RESULTS: Perceived risk of acquiring Lyme disease, knowing anyone with Lyme disease, knowledge about Lyme disease, and believing Lyme disease to be a common problem were significantly associated with prevention practices. CONCLUSIONS: Predisposing factors differ substantially between states and appear related to disease incidence. Personal risk, knowing someone with Lyme disease, and cognizance about Lyme disease and acting on this information are consistent with social learning theories. PMID:9431299

  12. Germline BAP1 Mutations Predispose to Renal Cell Carcinomas

    PubMed Central

    Popova, Tatiana; Hebert, Lucie; Jacquemin, Virginie; Gad, Sophie; Caux-Moncoutier, Virginie; Dubois-d’Enghien, Catherine; Richaudeau, Bénédicte; Renaudin, Xavier; Sellers, Jason; Nicolas, André; Sastre-Garau, Xavier; Desjardins, Laurence; Gyapay, Gabor; Raynal, Virginie; Sinilnikova, Olga M.; Andrieu, Nadine; Manié, Elodie; de Pauw, Antoine; Gesta, Paul; Bonadona, Valérie; Maugard, Christine M.; Penet, Clotilde; Avril, Marie-Françoise; Barillot, Emmanuel; Cabaret, Odile; Delattre, Olivier; Richard, Stéphane; Caron, Olivier; Benfodda, Meriem; Hu, Hui-Han; Soufir, Nadem; Bressac-de Paillerets, Brigitte; Stoppa-Lyonnet, Dominique; Stern, Marc-Henri

    2013-01-01

    The genetic cause of some familial nonsyndromic renal cell carcinomas (RCC) defined by at least two affected first-degree relatives is unknown. By combining whole-exome sequencing and tumor profiling in a family prone to cases of RCC, we identified a germline BAP1 mutation c.277A>G (p.Thr93Ala) as the probable genetic basis of RCC predisposition. This mutation segregated with all four RCC-affected relatives. Furthermore, BAP1 was found to be inactivated in RCC-affected individuals from this family. No BAP1 mutations were identified in 32 familial cases presenting with only RCC. We then screened for germline BAP1 deleterious mutations in familial aggregations of cancers within the spectrum of the recently described BAP1-associated tumor predisposition syndrome, including uveal melanoma, malignant pleural mesothelioma, and cutaneous melanoma. Among the 11 families that included individuals identified as carrying germline deleterious BAP1 mutations, 6 families presented with 9 RCC-affected individuals, demonstrating a significantly increased risk for RCC. This strongly argues that RCC belongs to the BAP1 syndrome and that BAP1 is a RCC-predisposition gene. PMID:23684012

  13. Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance.

    PubMed

    Gurden, Mark D; Westwood, Isaac M; Faisal, Amir; Naud, Sébastien; Cheung, Kwai-Ming J; McAndrew, Craig; Wood, Amy; Schmitt, Jessica; Boxall, Kathy; Mak, Grace; Workman, Paul; Burke, Rosemary; Hoelder, Swen; Blagg, Julian; Van Montfort, Rob L M; Linardopoulos, Spiros

    2015-08-15

    Acquired resistance to therapy is perhaps the greatest challenge to effective clinical management of cancer. With several inhibitors of the mitotic checkpoint kinase MPS1 in preclinical development, we sought to investigate how resistance against these inhibitors may arise so that mitigation or bypass strategies could be addressed as early as possible. Toward this end, we modeled acquired resistance to the MPS1 inhibitors AZ3146, NMS-P715, and CCT251455, identifying five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed how the MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. Notably, we show that these mutations occur in nontreated cancer cell lines and primary tumor specimens, and that they also preexist in normal lymphoblast and breast tissues. In a parallel piece of work, we also show that the EGFR p.T790M mutation, the most common mutation conferring resistance to the EGFR inhibitor gefitinib, also preexists in cancer cells and normal tissue. Our results therefore suggest that mutations conferring resistance to targeted therapy occur naturally in normal and malignant cells and these mutations do not arise as a result of the increased mutagenic plasticity of cancer cells. PMID:26202014

  14. Search for a gene predisposing to manic-depression on chromosome 21

    SciTech Connect

    Byerley, W.; Holik, J.; Hoff, M.; Coon, H.

    1995-06-19

    Six kindreds containing multiple cases of manic-depressive illness (MDI) were genotyped with seven highly polymorphic microsatellite loci used in the construction of an index map for chromosome 21. The kindreds were also genotyped with a microsatellite polymorphism for PFKL, a chromosome 21 locus that has shown suggestive linkage to MDI in one pedigree. Evidence of linkage was not found assuming either autosomal dominant or recessive inheritance. The nonparametric affected sib pair test did not yield significant evidence of linkage. 11 refs., 1 fig., 3 tabs.

  15. The Alu-Rich Genomic Architecture of SPAST Predisposes to Diverse and Functionally Distinct Disease-Associated CNV Alleles

    PubMed Central

    Boone, Philip M.; Yuan, Bo; Campbell, Ian M.; Scull, Jennifer C.; Withers, Marjorie A.; Baggett, Brett C.; Beck, Christine R.; Shaw, Christine J.; Stankiewicz, Pawel; Moretti, Paolo; Goodwin, Wendy E.; Hein, Nichole; Fink, John K.; Seong, Moon-Woo; Seo, Soo Hyun; Park, Sung Sup; Karbassi, Izabela D.; Batish, Sat Dev; Ordóñez-Ugalde, Andrés; Quintáns, Beatriz; Sobrido, María-Jesús; Stemmler, Susanne; Lupski, James R.

    2014-01-01

    Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions and duplications in SPAST (mutations in which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins and molecular consequences remain obscure. We mapped breakpoint junctions of 54 SPAST CNVs at nucleotide resolution. Diverse combinations of exons are deleted or duplicated, highlighting the importance of particular exons for spastin function. Of the 54 CNVs, 38 (70%) appear to be mediated by an Alu-based mechanism, suggesting that the Alu-rich genomic architecture of SPAST renders this locus susceptible to various genome rearrangements. Analysis of breakpoint Alus further informs a model of Alu-mediated CNV formation characterized by small CNV size and potential involvement of mechanisms other than homologous recombination. Twelve deletions (22%) overlap part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects’ genomes. cDNA from a subject with a SPAST final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. SLC30A6 has been implicated in Alzheimer disease, so these fusion gene data could explain a report of spastic paraplegia and dementia cosegregating in a family with deletion of the final exon of SPAST. Our findings provide evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional—and possibly phenotypic—consequences. Moreover, we provide further mechanistic insights into Alu-mediated copy-number change that are extendable to other loci. PMID:25065914

  16. The Influence of Predisposing, Enabling and Need Factors on Condom Use in Ivory Coast

    ERIC Educational Resources Information Center

    Ngamini Ngui, Andre

    2010-01-01

    The main objective of this study was to identify key determinants of condom use in Ivory Coast. Data stem from Ivory Coast Demographic Health Survey (DHS) conducted by ORC Macro in 2005 among a representative sample of 9,686 persons aged 15 - 49. Following the behavioral model, we use logistic regression to assess the effect of predisposing,…

  17. Prothrombotic gene variants as risk factors of acute myocardial infarction in young women

    PubMed Central

    2012-01-01

    Background Acute myocardial infarction (AMI) in young women represent an extreme phenotype associated with a higher mortality compared with similarly aged men. Prothrombotic gene variants could play a role as risk factors for AMI at young age. Methods We studied Factor V Leiden, FII G20210A, MTHFR C677T and beta-fibrinogen -455G>A variants by real-time PCR in 955 young AMI (362 females) and in 698 AMI (245 females) patients. The data were compared to those obtained in 909 unrelated subjects (458 females) from the general population of the same geographical area (southern Italy). Results In young AMI females, the allelic frequency of either FV Leiden and of FII G20210A was significantly higher versus the general population (O.R.: 3.67 for FV Leiden and O.R.: 3.84 for FII G20210A; p<0.001). Among AMI patients we showed only in males that the allelic frequency of the MTHFR C677T variant was significantly higher as compared to the general population. Such difference was due to a significantly higher frequency in AMI males of the MTHFR C677T variant homozygous genotype (O.R. 3.05). Discussion and conclusion Our data confirm that young AMI in females is a peculiar phenotype with specific risk factors as the increased plasma procoagulant activity of FV and FII. On the contrary, the homozygous state for the 677T MTHFR variant may cause increased levels of homocysteine and/or an altered folate status and thus an increased risk for AMI, particularly in males. The knowledge of such risk factors (that may be easily identified by molecular analysis) may help to improve prevention strategies for acute coronary diseases in specific risk-group subjects. PMID:23171482

  18. Correlation of Homocysteine Metabolic Enzymes Gene Polymorphism and Mild Cognitive Impairment in the Xinjiang Uygur Population

    PubMed Central

    Luo, Mei; Ji, Huihui; Zhou, Xiaohui; Liang, Jie; Zou, Ting

    2015-01-01

    Background The aim of this study was to investigate the genetic polymorphisms in the homocysteine (HCY) metabolic enzymes in the Xinjiang Uygur population who have mild cognitive impairment (MCI). Material/Methods Based on the epidemiological investigation, 129 cases of diagnosed Uygur MCI patients and a matched control group with 131 cases were enrolled for analyzing the association between the polymorphisms in the HCY metabolism related genes (C677T, A1298C, and G1968A polymorphisms in MTHFR, as well as the A2756G polymorphism in MS) and MCI by using the SNaPshot method. We then determined the homocysteine level in patients. Results In Xinjiang Uygur subjects, the A1298C polymorphisms in MTHFR and the A2756G polymorphisms in the MS gene in the MCI group were different from those in the control group. However, the C677T and G1968A polymorphisms in the MTHFR gene in MCI patients were not different from those in the control group. Multivariate logistic regression showed that, in addition to the well-known risk factors, such as low education level, high cholesterol level, high level of low-density lipoprotein, and high homocysteine levels, the A>G mutation in the MS gene at the rs1805087 locus was another independent risk factor for MCI in the Uyghur MCI population. The risk of MCI in G allele carriers was 2.265 times higher than that in matched control individuals (95% CI: 1.205~4.256, P<0.05). Conclusions The genetic polymorphism of HCY metabolizing enzymes is correlated to the occurrence of MCI in the Xinjiang Uygur population. The A2756G polymorphism in the MS gene could be an independent risk factor for MCI in the Xinjiang Uygur population. PMID:25625218

  19. Levofloxacin-Induced Achilles Tendinitis in a Young Adult in the Absence of Predisposing Conditions

    PubMed Central

    Durey, Areum; Baek, Yong Soo; Park, Jin Seok; Lee, Kwangsoo; Ryu, Jeong-Seon; Cheong, Moon-Hyun

    2010-01-01

    Fluoroquinolones (FQs) represent a major class of antimicrobials that have a high potential as therapeutic agents. Although FQs are generally safe for the use as antimicrobials, they may induce tendinopathic complications such as tendinitis and tendon rupture. A number of factors have been suggested to further predispose a patient to such injuries. Hitherto, a few published cases on tendon disorders have implicated levofloxacin, a more recently introduced FQ. Here, we report a patient with levofloxacin-induced Achilles tendinitis, who exhibited no known predisposing factors. A 20-year-old man without any history of disease or medication presented with community-acquired pneumonia. Levofloxacin was administered and 3 days later, he complained of pain in the left Achilles tendon and revealed redness and swelling in the area. On suspecting Achilles tendinitis, levofloxacin treatment was discontinued, and the tendinitis subsequently improved. To our knowledge, this is the first case report on FQ-induced Achilles tendinitis in Korea. PMID:20376902

  20. PCAP is the major known prostate cancer predisposing locus in families from south and west Europe.

    PubMed

    Cancel-Tassin, G; Latil, A; Valéri, A; Mangin, P; Fournier, G; Berthon, P; Cussenot, O

    2001-02-01

    To date four prostate cancer predisposing loci have been mapped: HPC1 (Hereditary Prostate Cancer 1) on 1q24-25, PCaP (Predisposing for Cancer Prostate) on 1q42.2-43, CAPB (Cancer Prostate and Brain) on 1p36, and HPCX on Xq27-28. We examined evidence for linkage to those loci in 64 families from south and west Europe. Genotyping of three (six for PCaP) markers encompassing the candidate regions were performed on 221 individuals including 159 affected patients. The resulting data were analysed using both parametric and non parametric linkage methods. No significant evidence of linkage to HPC1, CAPB, or HPCX was found either in the whole population or when pedigrees were stratified according to criteria specific to each locus. By contrast, results in favour of linkage to PCaP locus were observed with maximum multipoint NPL and HLOD scores of 2.8 (P = 0.0026) and 2.65 respectively. Homogeneity analysis performed with multipoint LOD scores gave an estimated proportion of families with linkage to this locus up to 50%. Particularly, families with an earlier age at diagnosis (< or = 65-years-old) contributed significantly to the evidence of linkage with a maximum multipoint NPL score of 2.03 (P = 0.024). Those results suggest that PCaP is the most frequent known locus predisposing to hereditary prostate cancer cases from families from south and west Europe. PMID:11313747

  1. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials

    PubMed Central

    Holmes, Michael V; Newcombe, Paul; Hubacek, Jaroslav A; Sofat, Reecha; Ricketts, Sally L; Cooper, Jackie; Breteler, Monique MB; Bautista, Leonelo E; Sharma, Pankaj; Whittaker, John C; Smeeth, Liam; Fowkes, F Gerald R; Algra, Ale; Shmeleva, Veronika; Szolnoki, Zoltan; Roest, Mark; Linnebank, Michael; Zacho, Jeppe; Nalls, Michael A; Singleton, Andrew B; Ferrucci, Luigi; Hardy, John; Worrall, Bradford B; Rich, Stephen S; Matarin, Mar; Norman, Paul E; Flicker, Leon; Almeida, Osvaldo P; van Bockxmeer, Frank M; Shimokata, Hiroshi; Khaw, Kay-Tee; Wareham, Nicholas J; Bobak, Martin; Sterne, Jonathan AC; Smith, George Davey; Talmud, Philippa J; van Duijn, Cornelia; Humphries, Steve E; Price, Jackie F; Ebrahim, Shah; Lawlor, Debbie A; Hankey, Graeme J; Meschia, James F; Sandhu, Manjinder S; Hingorani, Aroon D; Casas, Juan P

    2011-01-01

    Summary Background The MTHFR 677C?T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C?T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. Methods We established a collaboration of genetic studies consisting of 237 datasets including 59?995 individuals with data for homocysteine and 20?885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45?549 individuals, 2314 stroke events, 269 transient ischaemic attacks). Findings The effect of the MTHFR 677C?T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 ?mol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 ?mol/L, ?0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region. Interpretation In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C?T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption. Funding Full funding sources listed at end of paper (see Acknowledgments). PMID:21803414

  2. A Lower Degree of PBMC L1 Methylation in Women with Lower Folate Status May Explain the MTHFR C677T Polymorphism Associated Higher Risk of CIN in the US Post Folic Acid Fortification Era

    PubMed Central

    Badiga, Suguna; Johanning, Gary L.; Macaluso, Maurizio; Azuero, Andres; Chambers, Michelle M.; Siddiqui, Nuzhat R.; Piyathilake, Chandrika J.

    2014-01-01

    Background Studies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk. Methods The study included 457 US women diagnosed with either CIN 2+ (cases) or ? CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN. Results The 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR?=?2.41, P?=?0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR?=?0.28, P?=?0.017). Conclusions This study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation. PMID:25302494

  3. Maternal air pollution exposure induces fetal neuroinflammation and predisposes offspring to obesity in aduthood in a sex-specific manner

    EPA Science Inventory

    Emerging evidence suggests environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal air pollution exposure would predispose the offspring to weight gain in adulthood. Pre...

  4. Antifolates and MTHFR.

    PubMed

    Trachtman, Joseph N; Pagano, Vincent

    2015-12-01

    We describe a patient who developed symptoms of headache, fatigue, and dizziness after administration of terbinafine (Lamisil). Laboratory tests revealed that he is heterozygous for the C677T variation of the methylenetetrahydrofolate reductase genetic mutation. The prescription of Deplin (L-methylfolate) greatly reduced the symptoms. It was later noted that Lamisil's mechanism of action interferes with cells' methylation cycle, which we suspect compromises cellular function in people with the methylenetetrahydrofolate reductase genetic mutation. PMID:25929315

  5. Technical Note: Assessing predictive capacity and conditional independence of landslide predisposing factors for shallow landslide susceptibility models

    NASA Astrophysics Data System (ADS)

    Pereira, S.; Zêzere, J. L.; Bateira, C.

    2012-04-01

    The aim of this study is to identify the landslide predisposing factors' combination using a bivariate statistical model that best predicts landslide susceptibility. The best model is one that has simultaneously good performance in terms of suitability and predictive power and has been developed using variables that are conditionally independent. The study area is the Santa Marta de Penaguião council (70 km2) located in the Northern Portugal. In order to identify the best combination of landslide predisposing factors, all possible combinations using up to seven predisposing factors were performed, which resulted in 120 predictions that were assessed with a landside inventory containing 767 shallow translational slides. The best landslide susceptibility model was selected according to the model degree of fitness and on the basis of a conditional independence criterion. The best model was developed with only three landslide predisposing factors (slope angle, inverse wetness index, and land use) and was compared with a model developed using all seven landslide predisposing factors. Results showed that it is possible to produce a reliable landslide susceptibility model using fewer landslide predisposing factors, which contributes towards higher conditional independence.

  6. Evidence for homosexuality gene

    SciTech Connect

    Pool, R.

    1993-07-16

    A genetic analysis of 40 pairs of homosexual brothers has uncovered a region on the X chromosome that appears to contain a gene or genes for homosexuality. When analyzing the pedigrees of homosexual males, the researcheres found evidence that the trait has a higher likelihood of being passed through maternal genes. This led them to search the X chromosome for genes predisposing to homosexuality. The researchers examined the X chromosomes of pairs of homosexual brothers for regions of DNA that most or all had in common. Of the 40 sets of brothers, 33 shared a set of five markers in the q28 region of the long arm of the X chromosome. The linkage has a LOD score of 4.0, which translates into a 99.5% certainty that there is a gene or genes in this area that predispose males to homosexuality. The chief researcher warns, however, that this one site cannot explain all instances of homosexuality, since there were some cases where the trait seemed to be passed paternally. And even among those brothers where there was no evidence that the trait was passed paternally, seven sets of brothers did not share the Xq28 markers. It seems likely that homosexuality arises from a variety of causes.

  7. Elevated total plasma homocysteine and 667C{r_arrow}T mutation of the 5,10-methylenetetrahydrofolate reductase gene in thrombotic vascular disease

    SciTech Connect

    De Franchis, R.; Sebastio, G.; Andria, G.

    1996-07-01

    Moderate elevation of total plasma homocysteine (tHcy) has been reported as an independent risk factor for thrombotic vascular disease, a well-known multifactorial disorder. Possible genetic causes of elevated tHcy include defects of the sulfur-containing amino acids metabolism due to deficiencies of cystathionine {Beta}-synthase, of 5,10-methylenetetrahydrofolate reductase (MTHFR), and of the enzymes of cobalamin metabolism. An impaired activity of MTHFR due to a thermolabile form of the enzyme has been observed in {le}28% of hyperhomocysteinemic patients with premature vascular disease. More recently, the molecular basis of such enzymatic thermolability has been related to a common mutation of the MTHFR gene, causing a C-to-T substitution at nt 677 (677C{r_arrow}T). This mutation was found in 38% of unselected chromosomes from 57 French Canadian individuals. The homozygous state for the mutation was present in 12% of these subjects and correlated with significantly elevated tHcy. Preliminary evidence indicates that the frequency of homozygotes for the 677C{r_arrow}T mutation may vary significantly in populations from different geographic areas. 5 refs., 2 tabs.

  8. Assessing factors that may predispose Minnesota farms to wolf predation on cattle

    USGS Publications Warehouse

    Mech, L.D.; Harper, E.K.; Meier, T.J.; Paul, W.J.

    2000-01-01

    Wolf (Canis lupus) depredations on livestock cause considerable conflict and expense in Minnesota. Furthermore, claims are made that such depredations are fostered by the type of animal husbandry practiced. Thus, we tried to detect factors that might predispose farms in Minnesota to wolf depredations. We compared results of interviews with 41 cattle farmers experiencing chronic cattle losses to wolves (chronic farms) with results from 41 nearby matched farms with no wolf losses to determine farm characteristics or husbandry practices that differed and that therefore might have affected wolf depredations. We also used a Geographic Information System (GIS) to detect any habitat differences between the 2 types of farms. We found no differences between chronic and matched farms in the 11 farm characteristics and management practices that we surveyed, except that farms with chronic losses were larger, had more cattle, and had herds farther from human dwellings. Habitat types were the same around farms with and without losses. The role of proper carcass disposal as a possible factor predisposing farms to wolf depredations remains unclear

  9. Primary Otomycosis in the Indian Subcontinent: Predisposing Factors, Microbiology, and Classification

    PubMed Central

    Kotigadde, Subbannayya; Shekhar, Manisha; Thada, Nikhil Dinaker; Prabhu, Prashanth; D' Souza, Tina; Prasad, Kishore Chandra

    2014-01-01

    Objective. To define otomycosis and determine the predisposing factors and microbiology in primary otomycosis. Study Design. Prospective study of two years and review of the literature. Setting. Academic Department of Otolaryngology in a coastal city in India. Patients. 150 immunocompetent individuals of whom 100 consecutive patients with a clinical diagnosis of otomycosis are considered as the study group and 50 consecutive patients with no otomycosis are considered as the control group. Results and Observations. Instillation of coconut oil (42%), use of topical antibiotic eardrops (20%), and compulsive cleaning of external ear with hard objects (32%) appeared to be the main predisposing factors in otomycosis. Aspergilli were the most common isolates (80%) followed by Penicillium (8%), Candida albicans (4%), Rhizopus (1%), and Chrysosporium (1%), the last being reported for the first time in otomycosis. Among aspergilli, A. niger complex (38%) was the most common followed by A. fumigatus complex (27%) and A. flavus complex (15%). Bacterial isolates associated with fungi in otomycosis were S. aureus, P. aeruginosa, and Proteus spp. In 42% of healthy external ears fungi were isolated. Conclusion. Aspergillus spp. were the most common fungi isolated, followed by Penicillium. Otomycotic ears are often associated with bacterial isolates when compared to normal ears. Fungi are also present in a significant number of healthy external auditory canals and their profiles match those in cases of otomycosis. The use of terms “primary” and “secondary” otomycosis is important to standardize reporting. PMID:24949016

  10. A new predisposing factor for trigemino-cardiac reflex during subdural empyema drainage: a case report

    PubMed Central

    2010-01-01

    Introduction The trigemino-cardiac reflex is defined as the sudden onset of parasympathetic dysrhythmia, sympathetic hypotension, apnea, or gastric hypermotility during stimulation of any of the sensory branches of the trigeminal nerve. Clinically, trigemino-cardiac reflex has been reported to occur during neurosurgical skull-base surgery. Apart from the few clinical reports, the physiological function of this brainstem reflex has not yet been fully explored. Little is known regarding any predisposing factors related to the intraoperative occurrence of this reflex. Case presentation We report the case of a 70-year-old Caucasian man who demonstrated a clearly expressed form of trigemino-cardiac reflex with severe bradycardia requiring intervention that was recorded during surgical removal of a large subdural empyema. Conclusion To the best of our knowledge, this is the first report of an intracranial infection leading to perioperative trigemino-cardiac reflex. We therefore add a new predisposing factor for trigemino-cardiac reflex to the existing literature. Possible mechanisms are discussed in the light of the relevant literature. PMID:21118536

  11. Factors predisposing to adjacent 2 and 3:1 disjunctions: study of 161 human reciprocal translocations.

    PubMed Central

    Jalbert, P; Sele, B

    1979-01-01

    Reciprocal translocations produce imbalances by three types of disjunction which are, in decreasing frequency, adjacent 1, 3:1, and adjacent 2. Adjacent 1 disjunction produces duplication deficiencies of inverse topography to those of adjacent 2. The imbalanced chromosome segments in one of these types are balanced in the other. The disjunction 3:1 produces pure trisomies and monosomies. The following situations predispose to adjacent 2 disjunction: translocations between the long arms of two acrocentric chromosomes or between one of these and that of a No 9 chromosome; centric segments, either short or carrying a heterochromatic zone (9qh); a balanced translocation in the mother. The factors predisposing to the disjunction adjacent 2 operate by selection, or directly on the meiotic configuration. Some of them (shortness of the interstitial segment, shortness of the short arms of translocation chromosomes) act in both these ways. Their influence is probably responsible for the repetitive and exclusive character of this disjunction. The conditions for the occurrence of the 3:1 disjunctions seem less strict than those for adjacent 2, although they should be of the same nature (involvement of acrocentrics or a chromosome 9 in the translocation, maternal origin). Images PMID:395305

  12. Univariate and multivariate analyses of risk factors predisposing to auditory toxicity in patients receiving aminoglycosides.

    PubMed Central

    Gatell, J M; Ferran, F; Araujo, V; Bonet, M; Soriano, E; Traserra, J; SanMiguel, J G

    1987-01-01

    Risk factors predisposing to auditory toxicity of aminoglycosides were analyzed from records of 187 patients enrolled in three prospective randomized trials comparing the toxicity of netilmicin, tobramycin, and amikacin. Patients were eligible if they received three or more days of therapy and at least two serial audiograms were available. The overall auditory toxicity rate was 9.6% (18 of 187). Auditory toxicity was detected in 4.4, 10.8, and 23.5% of patients given netilmicin, tobramycin, and amikacin, respectively (P = 0.05). In the univariate analysis, patients who developed auditory toxicity were significantly older (P = 0.01) and had a significantly higher (P = 0.04) percentage of trough levels of netilmicin or tobramycin above 2 mg/liter or amikacin above 5 mg/liter. In the final logistic regression model, only age was retained as independently influencing the development of auditory toxicity (P less than 0.00001). Conversely, factors that did not add significantly to the prediction of auditory toxicity were aminoglycoside serum levels, total aminoglycoside dose, duration of therapy, sex, peak temperature, presence of bacteremia, shock, liver cirrhosis, dehydration, previous otic pathology or renal failure, and development of renal toxicity. At least in certain populations, age is the most important predisposing factor for the development of auditory toxicity in patients receiving aminoglycosides. PMID:3674849

  13. Post spinal puncture headache, an old problem and new concepts: review of articles about predisposing factors

    PubMed Central

    Jabbari, Ali; Alijanpour, Ebrahim; Mir, Mehrafza; Bani hashem, Nadia; Rabiea, Seyed Mozaffar; Rupani, Mohammad Ali

    2013-01-01

    Post spinal puncture headache (PSPH) is a well known complication of spinal anesthesia. It occurs after spinal anesthesia induction due to dural and arachnoid puncture and has a significant effect on the patient’s postoperative well being. This manuscript is based on an observational study that runs on Babol University of Medical Sciences and review of literatures about current concepts about the incidence, risk factors and predisposing factors of post spinal puncture headache. The overall incidence of post-dural puncture headache after intentional dural puncture varies form 0.1-36%, while it is about 3.1% by atraumatic spinal needle 25G Whitacre. 25G Quincke needle with a medium bevel cutting is popular with widespread use and the incidence of PSPH is about 25%, but its incidence obtained 17.3% by spinal needle 25G Quincke in our observation. The association of predisposing factors like female, young age, pregnancy, low body mass index, multiple dural puncture, inexpert operators and past medical history of chronic headache, expose the patient to PSPH. The identification of factors that predict the likelihood of PSPH is important so that measures can be taken to minimize this painful complication resulting from spinal anesthesia. PMID:24009943

  14. Emphysematous Cholecystitis in 24-Year-old Male Without Predisposing Factors

    PubMed Central

    Gunbey, Hediye Pinar

    2015-01-01

    Emphysematous cholecystitis (EC) is a life threatening condition characterized by gangrene of the gallbladder due to an infection with gas-forming organisms. It is more common in elderly men and has been associated with systemic disease, especially diabetes and vascular disease. Computed tomography is the most important and accurate imaging modality for the diagnosis of EC. EC should be thought of when the radiographic presence of gas is detected within the gallbladder wall or lumen. Emergency surgical intervention and antibiotic treatment for the gas-forming organism should be initiated after the diagnosis of the EC. Here, we present the imaging and pathologic findings of a 24-year-old male with EC without any predisposing factors, successfully treated with laparoscopic cholecystectomy. PMID:26393182

  15. Emphysematous Cholecystitis in 24-Year-old Male Without Predisposing Factors.

    PubMed

    Sayit, Asli Tanrivermis; Gunbey, Hediye Pinar

    2015-07-01

    Emphysematous cholecystitis (EC) is a life threatening condition characterized by gangrene of the gallbladder due to an infection with gas-forming organisms. It is more common in elderly men and has been associated with systemic disease, especially diabetes and vascular disease. Computed tomography is the most important and accurate imaging modality for the diagnosis of EC. EC should be thought of when the radiographic presence of gas is detected within the gallbladder wall or lumen. Emergency surgical intervention and antibiotic treatment for the gas-forming organism should be initiated after the diagnosis of the EC. Here, we present the imaging and pathologic findings of a 24-year-old male with EC without any predisposing factors, successfully treated with laparoscopic cholecystectomy. PMID:26393182

  16. IL-9– and mast cell–mediated intestinal permeability predisposes to oral antigen hypersensitivity

    PubMed Central

    Forbes, Elizabeth E.; Groschwitz, Katherine; Abonia, J. Pablo; Brandt, Eric B.; Cohen, Elizabeth; Blanchard, Carine; Ahrens, Richard; Seidu, Luqman; McKenzie, Andrew; Strait, Richard; Finkelman, Fred D.; Foster, Paul S.; Matthaei, Klaus I.; Rothenberg, Marc E.; Hogan, Simon P.

    2008-01-01

    Previous mouse and clinical studies demonstrate a link between Th2 intestinal inflammation and induction of the effector phase of food allergy. However, the mechanism by which sensitization and mast cell responses occurs is largely unknown. We demonstrate that interleukin (IL)-9 has an important role in this process. IL-9–deficient mice fail to develop experimental oral antigen–induced intestinal anaphylaxis, and intestinal IL-9 overexpression induces an intestinal anaphylaxis phenotype (intestinal mastocytosis, intestinal permeability, and intravascular leakage). In addition, intestinal IL-9 overexpression predisposes to oral antigen sensitization, which requires mast cells and increased intestinal permeability. These observations demonstrate a central role for IL-9 and mast cells in experimental intestinal permeability in oral antigen sensitization and suggest that IL-9–mediated mast cell responses have an important role in food allergy. PMID:18378796

  17. Black/white differences in prenatal care utilization: an assessment of predisposing and enabling factors.

    PubMed Central

    LaVeist, T A; Keith, V M; Gutierrez, M L

    1995-01-01

    OBJECTIVE. This article reports on analysis of the predisposing and enabling factors that affect black/white differences in utilization of prenatal care services. DATA SOURCES. We use a secondary data source from a survey conducted by the Michigan Department of Public Health. STUDY DESIGN. The study uses multivariate analysis methods to examine black/white differences in (1) total number of prenatal care visits, (2) timing of start of prenatal care, and (3) adequacy of care received. We use the model advanced by Aday, Andersen, and Fleming (1980) to examine the effect of enabling and predisposing factors on black/white differences in prenatal care utilization. DATA COLLECTION. A questionnaire was administered to all women who delivered in Michigan hospitals with an obstetrical unit. PRINCIPAL FINDINGS. Enabling factors fully accounted for black/white differences in timing of start of prenatal care; however, the model could not fully account for black/white differences in the total number or the adequacy of prenatal care received. CONCLUSION. Although there are no black/white differences in the initiation of prenatal care, black women are still less likely to receive adequate care as measured by the Kessner index, or to have as many total prenatal care contacts as white women. It is possible that barriers within the health care system that could not be assessed in this study may account for the differences we observed. Future research should consider the characteristics of the health care system that may account for the unwillingness or inability of black women to continue to receive care once they initiate prenatal care. PMID:7721584

  18. Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer

    PubMed Central

    Forsberg, Lars A.; Rasi, Chiara; Pekar, Gyula; Davies, Hanna; Piotrowski, Arkadiusz; Absher, Devin; Razzaghian, Hamid Reza; Ambicka, Aleksandra; Halaszka, Krzysztof; Przewo?nik, Marcin; Kruczak, Anna; Mandava, Geeta; Pasupulati, Saichand; Hacker, Julia; Prakash, K. Reddy; Dasari, Ravi Chandra; Lau, Joey; Penagos-Tafurt, Nelly; Olofsson, Helena M.; Hallberg, Gunilla; Skotnicki, Piotr; Mitu?, Jerzy; Skokowski, Jaroslaw; Jankowski, Michal; ?rutek, Ewa; Zegarski, Wojciech; Tiensuu Janson, Eva; Ry?, Janusz; Tot, Tibor; Dumanski, Jan P.

    2015-01-01

    Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1–14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer. PMID:26430163

  19. Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer.

    PubMed

    Forsberg, Lars A; Rasi, Chiara; Pekar, Gyula; Davies, Hanna; Piotrowski, Arkadiusz; Absher, Devin; Razzaghian, Hamid Reza; Ambicka, Aleksandra; Halaszka, Krzysztof; Przewo?nik, Marcin; Kruczak, Anna; Mandava, Geeta; Pasupulati, Saichand; Hacker, Julia; Prakash, K Reddy; Dasari, Ravi Chandra; Lau, Joey; Penagos-Tafurt, Nelly; Olofsson, Helena M; Hallberg, Gunilla; Skotnicki, Piotr; Mitu?, Jerzy; Skokowski, Jaroslaw; Jankowski, Michal; ?rutek, Ewa; Zegarski, Wojciech; Tiensuu Janson, Eva; Ry?, Janusz; Tot, Tibor; Dumanski, Jan P

    2015-10-01

    Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer. PMID:26430163

  20. Population Testing for Cancer Predisposing BRCA1/BRCA2 Mutations in the Ashkenazi-Jewish Community: A Randomized Controlled Trial

    PubMed Central

    Manchanda, Ranjit; Loggenberg, Kelly; Sanderson, Saskia; Burnell, Matthew; Wardle, Jane; Gessler, Sue; Side, Lucy; Balogun, Nyala; Desai, Rakshit; Kumar, Ajith; Dorkins, Huw; Wallis, Yvonne; Chapman, Cyril; Taylor, Rohan; Jacobs, Chris; Tomlinson, Ian; McGuire, Alistair; Beller, Uziel; Menon, Usha

    2015-01-01

    Background: Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)–based testing. Methods: In a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the population screening (PS) arm with testing those fulfilling standard FH-based clinical criteria (FH arm). Following a targeted community campaign, AJ participants older than 18 years were recruited by self-referral after pretest genetic counseling. The effects of BRCA1/2 genetic testing on acceptability, psychological impact, and quality-of-life measures were assessed by random effects regression analysis. All statistical tests were two-sided. Results: One thousand, one hundred sixty-eight AJ individuals were counseled, 1042 consented, 1034 were randomly assigned (691 women, 343 men), and 1017 were eligible for analysis. Mean age was 54.3 (SD = 14.66) years. Thirteen BRCA1/2 carriers were identified in the PS arm, nine in the FH arm. Five more carriers were detected among FH-negative FH-arm participants following study completion. There were no statistically significant differences between the FH and PS arms at seven days or three months on measures of anxiety, depression, health anxiety, distress, uncertainty, and quality-of-life. Contrast tests indicated that overall anxiety (P = .0001) and uncertainty (P = .005) associated with genetic testing decreased; positive experience scores increased (P = .0001); quality-of-life and health anxiety did not change with time. Overall, 56% of carriers did not fulfill clinical criteria for genetic testing, and the BRCA1/2 prevalence was 2.45%. Conclusion: Compared with FH-based testing, population-based genetic testing in Ashkenazi Jews doesn’t adversely affect short-term psychological/quality-of-life outcomes and may detect 56% additional BRCA carriers. PMID:25435541

  1. Incisional Hernia in Women: Predisposing Factors and Management Where Mesh is not Readily Available

    PubMed Central

    Agbakwuru, EA; Olabanji, JK; Alatise, OI; Okwerekwu, RO; Esimai, OA

    2009-01-01

    Background / Aim: Incisional hernia is still relatively common in our practice. The aim of the study was to identify risk factors associated with incisional hernia in our region. The setting is the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria during a period when prosthetic mesh was not readily available. Patients and Methods: All the women who presented with incisional hernia between 1996 and 2005 were prospectively studied using a standard form to obtain information on pre-hernia (index) operations and possible predisposing factors. They all had open surgical repair and were followed up for 18–60 months. Results: Forty-four women were treated during study period. The index surgeries leading to the hernias were emergency caesarian section 26/44 (59.1%), emergency exploratory laparotomy 6/44 (13.6%), and elective surgeries 12/44 (27.3%). Major associated risk factors were the use of wrong suture materials for fascia repair, midline incisions, wound sepsis, and overweight. Conclusion: For elective surgeries, reduction of weight should be encouraged when appropriate, and transverse incisions are preferred. Absorbable sutures, especially chromic catgut, should be avoided in fascia closure. Antibiotics should be used for complicated obstetric cases. PMID:21483511

  2. Putting the brakes on mammary tumorigenesis: loss of STAT1 predisposes to intraepithelial neoplasias.

    PubMed

    Schneckenleithner, Christine; Bago-Horvath, Zsuzsanna; Dolznig, Helmut; Neugebauer, Nina; Kollmann, Karoline; Kolbe, Thomas; Decker, Thomas; Kerjaschki, Dontscho; Wagner, Kay-Uwe; Müller, Mathias; Stoiber, Dagmar; Sexl, Veronika

    2011-12-01

    Multiparous Stat1-/- mice spontaneously develop mammary tumors with increased incidence: at an average age of 12 months, 55% of the animals suffer from mammary cancer, although the histopathology is heterogeneous. We consistently observed mosaic expression or down-regulation of STAT1 protein in wild-type mammary cancer evolving in the control group. Transplantation experiments show that tumorigenesis in Stat1-/- mice is partially influenced by impaired CTL mediated tumor surveillance. Additionally, STAT1 exerts an intrinsic tumor suppressing role by controlling and blocking proliferation of the mammary epithelium. Loss of STAT1 in epithelial cells enhances cell growth in both transformed and primary cells. The increased proliferative capacity leads to the loss of structured acini formation in 3D-cultures. Analogous effects were observed when Irf1-/- epithelial cells were used. Accordingly, the rate of mammary intraepithelial neoplasias (MINs) is increased in Stat1-/- animals: MINs represent the first step towards mammary tumors. The experiments characterize STAT1/IRF1 as a key growth inhibitory and tumor suppressive signaling pathway that prevents mammary cancer formation by maintaining growth control. Furthermore, they define the loss of STAT1 as a predisposing event via enhanced MIN formation. PMID:22185785

  3. Putting the brakes on mammary tumorigenesis: Loss of STAT1 predisposes to intraepithelial neoplasias

    PubMed Central

    Schneckenleithner, Christine; Bago-Horvath, Zsuzsanna; Dolznig, Helmut; Neugebauer, Nina; Kollmann, Karoline; Kolbe, Thomas; Decker, Thomas; Kerjaschki, Dontscho; Wagner, Kay-Uwe; Müller, Mathias; Stoiber, Dagmar; Sexl, Veronika

    2011-01-01

    Multiparous Stat1?/? mice spontaneously develop mammary tumors with increased incidence: at an average age of 12 months, 55% of the animals suffer from mammary cancer, although the histopathology is heterogeneous. We consistently observed mosaic expression or down-regulation of STAT1 protein in wild-type mammary cancer evolving in the control group. Transplantation experiments show that tumorigenesis in Stat1?/? mice is partially influenced by impaired CTL mediated tumor surveillance. Additionally, STAT1 exerts an intrinsic tumor suppressing role by controlling and blocking proliferation of the mammary epithelium. Loss of STAT1 in epithelial cells enhances cell growth in both transformed and primary cells. The increased proliferative capacity leads to the loss of structured acini formation in 3D-cultures. Analogous effects were observed when Irf1?/? epithelial cells were used. Accordingly, the rate of mammary intraepithelial neoplasias (MINs) is increased in Stat1?/? animals: MINs represent the first step towards mammary tumors. The experiments characterize STAT1/IRF1 as a key growth inhibitory and tumor suppressive signaling pathway that prevents mammary cancer formation by maintaining growth control. Furthermore, they define the loss of STAT1 as a predisposing event via enhanced MIN formation. PMID:22185785

  4. Helminth infections predispose mice to pneumococcal pneumonia but not to other pneumonic pathogens.

    PubMed

    Apiwattanakul, Nopporn; Thomas, Paul G; Kuhn, Raymond E; Herbert, De'Broski R; McCullers, Jonathan A

    2014-10-01

    Pneumonia is the leading killer of children worldwide. Here, we report that helminth-infected mice develop fatal pneumonia when challenged with Streptococcus pneumoniae. Mice were chronically infected with either the flatworm Taenia crassiceps or the roundworm Heligmosomoides polygyrus. Upon challenge with a pneumonic type 3 strain of S. pneumoniae (A66.1), the worm-infected mice developed pneumonia at a rate and to a degree higher than age-matched control mice as measured by bioluminescent imaging and lung titers. This predisposition to pneumonia appears to be specific to S. pneumoniae, as worm-infected mice did not show evidence of increased morbidity when challenged with a lethal dose of influenza virus or sublethal doses of Staphylococcus aureus or Listeria monocytogenes. The defect was also present when worm-infected mice were challenged with a type 2 sepsis-causing strain (D39); an increased rate of pneumonia, decreased survival, and increased lung and blood titers were found. Pneumococcal colonization and immunity against acute otitis media were unaffected. Anti-helminthic treatment in the H. polygyrus model reversed this susceptibility. We conclude that helminth coinfection predisposes mice to fatal pneumococcal pneumonia by promoting increased outgrowth of bacteria in the lungs and blood. These data have broad implications for the prevention and treatment for pneumonia in the developing world, where helminth infections are endemic and pneumococcal pneumonia is common. PMID:24952091

  5. Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo.

    PubMed

    Caserta, Enrico; Egriboz, Onur; Wang, Hui; Martin, Chelsea; Koivisto, Christopher; Pecót, Thierry; Kladney, Raleigh D; Shen, Changxian; Shim, Kang-Sup; Pham, Thac; Karikomi, Matthew K; Mauntel, Melissa J; Majumder, Sarmila; Cuitino, Maria C; Tang, Xing; Srivastava, Arunima; Yu, Lianbo; Wallace, Julie; Mo, Xiaokui; Park, Morag; Fernandez, Soledad A; Pilarski, Robert; La Perle, Krista M D; Rosol, Thomas J; Coppola, Vincenzo; Castrillon, Diego H; Timmers, Cynthia; Cohn, David E; O'Malley, David M; Backes, Floor; Suarez, Adrian A; Goodfellow, Paul; Chamberlin, Helen M; Macrae, Erin R; Shapiro, Charles L; Ostrowski, Michael C; Leone, Gustavo

    2015-08-15

    Inactivation of phosphatase and tensin homology deleted on chromosome 10 (PTEN) is linked to increased PI3K-AKT signaling, enhanced organismal growth, and cancer development. Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (Pten(FV)), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten(FV/FV) embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous Pten(FV/+) mice develop carcinoma in the thymus, stomach, adrenal medulla, and mammary gland but not in other organs typically sensitive to Pten deficiency, including the thyroid, prostate, and uterus. Progression to carcinoma in sensitive organs ensues in the absence of overt AKT activation. Carcinoma in the uterus, a cancer-resistant organ, requires a second clonal event associated with the spontaneous activation of AKT and downstream signaling. In summary, this PTEN noncatalytic missense mutation exposes a core tumor suppressor function distinct from inhibition of canonical AKT signaling that predisposes to organ-selective cancer development in vivo. PMID:26302789

  6. Assessment of Fatty Liver Syndrome and Its Predisposing Factors in a Dairy Herd from Venezuela

    PubMed Central

    Gonzalez, Clara I.

    2013-01-01

    The present on-farm research evaluated the occurrence of fatty liver syndrome and its predisposing risk factors for multiparous dairy cows from a commercial herd in Venezuela. Liver biopsy samples were collected at 35 days (d) prepartum (Holstein, n = 14; Holstein × Carora crossbred, n = 17) as well as 1 to 7?d (Holstein, n = 8; Holstein × Carora crossbred, n = 11) and 28 to 35?d (Holstein, n = 6; Holstein × Carora crossbred, n = 14) postpartum in order to analyse hepatic triacylglycerols (TAG, % wet basis) and glycogen concentrations. At postpartum, an occurrence of 72.0% for severe fatty liver along with 73.5% of subclinical ketosis (SCK) was found. The multiple regression model that best explained the association between milk production in the previous lactation (MYP) and TAG at first week postpartum was as follows: TAG, % = ?11.2 + 3.16 (prepartum body condition) + 0.0009176 (MYP) (R² = 0.36, P < 0.05). Logistic regression indicated that Holstein × Carora crossbred cows tended to have 27% higher relative risk than Holstein to experience SCK, whereas prepartum liver TAG greater than 3% tended to be associated with a higher relative risk for SCK compared to cows with TAG ?3%. PMID:23738138

  7. Necrotizing ulcerative gingivitis, periodontitis, and stomatitis: clinical staging and predisposing factors.

    PubMed

    Horning, G M; Cohen, M E

    1995-11-01

    Necrotizing ulcerative gingivitis (NUG), necrotizing ulcerative periodontitis (NUP), and necrotizing stomatitis (NS), collectively termed necrotizing gingivostomatitis (NG), represent a dramatic, but rare oral infection associated with diminished systemic resistance, including HIV infection. Over a 5-year period, 68 consecutive NG patients from a population with known HIV status were evaluated and treated. Lesions were staged (modified Pindborg), and clinical findings and predictor variables were compared to 68 random control subjects without NG. Most cases (52%) were stage 1, with necrosis of the tip of the interdental papilla only; 19% were stage 2, with the entire papilla affected; 22% had necrosis of marginal (stage 3) or attached gingiva (stage 4); and 7% were more advanced, with mucosal necrosis or bone exposure. Attachment loss was a feature of stage 2 or greater NG. Beside HIV infection, significant predisposing factors included poor oral hygiene, unusual life stress, inadequate sleep, Caucasian race, age 18 to 21 years, and recent illness. Ten of 68 NG patients were HIV-positive. These patients were older than seronegative patients, less likely to be Caucasian, and maintained better oral hygiene and sleep. HIV-positive NG cases were clinically indistinguishable from HIV-negative cases in this series. PMID:8558402

  8. Induced resistance in tomato by SAR activators during predisposing salinity stress

    PubMed Central

    Pye, Matthew F.; Hakuno, Fumiaki; MacDonald, James D.; Bostock, Richard M.

    2013-01-01

    Plant activators are chemicals that induce disease resistance. The phytohormone salicylic acid (SA) is a crucial signal for systemic acquired resistance (SAR), and SA-mediated resistance is a target of several commercial plant activators, including Actigard (1,2,3-benzothiadiazole-7-thiocarboxylic acid-S-methyl-ester, BTH) and Tiadinil [N-(3-chloro-4-methylphenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, TDL]. BTH and TDL were examined for their impact on abscisic acid (ABA)-mediated, salt-induced disease predisposition in tomato seedlings. A brief episode of salt stress to roots significantly increased the severity of disease caused by Pseudomonas syringae pv. tomato (Pst) and Phytophthora capsici relative to non-stressed plants. Root treatment with TDL induced resistance to Pst in leaves and provided protection in both non-stressed and salt-stressed seedlings in wild-type and highly susceptible NahG plants. Non-stressed and salt-stressed ABA-deficient sitiens mutants were highly resistant to Pst. Neither TDL nor BTH induced resistance to root infection by Phytophthora capsici, nor did they moderate the salt-induced increment in disease severity. Root treatment with these plant activators increased the levels of ABA in roots and shoots similar to levels observed in salt-stressed plants. The results indicate that SAR activators can protect tomato plants from bacterial speck disease under predisposing salt stress, and suggest that some SA-mediated defense responses function sufficiently in plants with elevated levels of ABA. PMID:23653630

  9. Predisposing factors for dural tear in patients undergoing lumbar spine surgery.

    PubMed

    Smorgick, Yossi; Baker, Kevin C; Herkowitz, Harry; Montgomery, David; Badve, Siddharth A; Bachison, Casey; Ericksen, Steven; Fischgrund, Jeffrey S

    2015-05-01

    OBJECT The purpose of this prospective cohort study was to identify risk factors for incidental durotomies in lumbar spine surgery. The authors hypothesized that the incidence of durotomy would be higher in cases involving multiple operations. METHODS The authors prospectively evaluated 523 patients who underwent lumbar and thoracolumbar spine surgery. They compared data on patients in whom a dural tear occurred and those in whom a dural tear did not occur. Data from patients in whom a dural tear occurred were compared with data from patients who did not experience durotomy. The data included basic demographic information, intraoperative data, and clinical information from a medical record review. RESULTS One hundred thirty-one patients underwent discectomy and 392 patients underwent laminectomy. Among the 131 patients who underwent discectomy 6 patients had a dural tear. Among the 392 patients who underwent discectomy 49 patients had dural tear. Patients with incidental durotomy were older (mean 65 ± 13 vs 60 ± 14 years of age; p = 0.044, t-test), and had longer surgery (146 ± 59 vs 110 ± 54 minutes; p = 0.025, t-test), compared with the patients without dural tear. The incidence of dural tear was more common in patients with a history of previous spine surgery (p < 0.001). CONCLUSIONS In patients who underwent lumbar and thoracolumbar spine surgery for degenerative problems, previous surgery and older age were found to be predisposing factors for dural tear. PMID:25700240

  10. CTCF Haploinsufficiency Predisposes to Cancer by Destabilizing DNA Methylation | Office of Cancer Genomics

    Cancer.gov

    Humans are diploid organisms, meaning they inherit one set of chromosomes from each parent. One copy of the gene that encodes the DNA binding protein, CCCTC-binding factor (CTCF), is commonly deleted or mutated in some human cancers. CTCF alters chromatin structure, and thus gene expression, by regulating a DNA chemical modification process called methylation.

  11. Rnd3 haploinsufficient mice are predisposed to hemodynamic stress and develop apoptotic cardiomyopathy with heart failure

    PubMed Central

    Yue, X; Yang, X; Lin, X; Yang, T; Yi, X; Dai, Y; Guo, J; Li, T; Shi, J; Wei, L; Fan, G-C; Chen, C; Chang, J

    2014-01-01

    Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of the small Rho GTPase family, has been suggested to regulate cell actin cytoskeleton dynamics, cell migration, and apoptosis through the Rho kinase-dependent signaling pathway. The biological function of Rnd3 in the heart is unknown. The downregulation of small GTPase Rnd3 transcripts was found in patients with end-stage heart failure. The pathological significance of Rnd3 loss in the transition to heart failure remains unexplored. To investigate the functional consequence of Rnd3 downregulation and the associated molecular mechanism, we generated Rnd3+/? haploinsufficient mice to mimic the downregulation of Rnd3 observed in the failing human heart. Rnd3+/? mice were viable; however, the mice developed heart failure after pressure overload by transverse aortic constriction (TAC). Remarkable apoptosis, increased caspase-3 activity, and elevated Rho kinase activity were detected in the Rnd3+/? haploinsufficient animal hearts. Pharmacological inhibition of Rho kinase by fasudil treatment partially improved Rnd3+/? mouse cardiac functions and attenuated myocardial apoptosis. To determine if Rho-associated coiled-coil kinase 1 (ROCK1) was responsible for Rnd3 deficiency-mediated apoptotic cardiomyopathy, we established a double-knockout mouse line, the Rnd3 haploinsufficient mice with ROCK1-null background (Rnd3+/?/ROCK1?/?). Again, genetic deletion of ROCK1 partially but not completely rescued Rnd3 deficiency-mediated heart failure phenotype. These data suggest that downregulation of Rnd3 correlates with cardiac loss of function as in heart failure patients. Animals with Rnd3 haploinsufficiency are predisposed to hemodynamic stress. Hyperactivation of Rho kinase activity is responsible in part for the apoptotic cardiomyopathy development. Further investigation of ROCK1-independent mechanisms in Rnd3-mediated cardiac remodeling should be the focus for future study. PMID:24901055

  12. Cannabis Use Disorders Predispose to the Development of Sexually Transmitted Diseases among Youth

    PubMed Central

    Cornelius, Jack R.; Kirisci, Levent; Clark, Duncan B.

    2013-01-01

    Background Previous cross-sectional studies involving adults suggest that sexually transmitted diseases (STD) such as cocaine use disorders and opioid use disorders are associated with the development of sexually transmitted diseases (STD). However, it is less clear whether cannabis use disorders (CUD) are associated with the development of STDs, or whether those associations extend to adolescent populations. Longitudinal studies examining those associations are particularly scarce. The current report provides findings from a longitudinal study that examined the relationship between STD and CUD among youth transitioning to young adulthood. Method The subjects in this longitudinal study were initially recruited when the index sons of these fathers were 10-12 years of age, and subsequent assessments were conducted at age 12-14, 16, 19, and 22. Multivariate logistic regression and path analyses were conducted. Results At age 22, of the 345 subjects, 30 subjects were diagnosed with one or more STD, and 105 were diagnosed with a CUD. STDs were almost four times as common among those with a CUD as among those without a CUD, which was a significant difference. Path analyses demonstrated that peer deviance mediated the association between a measure of risk for SUD knows as the TLI and CUD, and that peer deviance mediated the association between TLI and STD. Risky sexual behaviors were common. Conclusions These finding suggest that cannabis use disorders (CUD) predispose to the development of sexually transmitted disorders (STD) among youth. These findings also suggest that peer deviance mediates the development of STD and of CUD among teenagers making the transition to young adulthood. PMID:25328372

  13. Urine Stasis Predisposes to Urinary Tract Infection by an Opportunistic Uropathogen in the Megabladder (Mgb) Mouse

    PubMed Central

    Becknell, Brian; Mohamed, Ahmad Z.; Li, Birong; Wilhide, Michael E.; Ingraham, Susan E.

    2015-01-01

    Purpose Urinary stasis is a risk factor for recurrent urinary tract infection (UTI). Homozygous mutant Megabladder (Mgb-/-) mice exhibit incomplete bladder emptying as a consequence of congenital detrusor aplasia. We hypothesize that this predisposes Mgb-/- mice to spontaneous and experimental UTI. Methods Mgb-/-, Mgb+/-, and wild-type female mice underwent serial ultrasound and urine cultures at 4, 6, and 8 weeks to detect spontaneous UTI. Urine bacterial isolates were analyzed by Gram stain and speciated. Bladder stones were analyzed by x-ray diffractometry. Bladders and kidneys were subject to histologic analysis. The pathogenicity of coagulase-negative Staphylococcus (CONS) isolated from Mgb-/- urine was tested by transurethral administration to culture-negative Mgb-/- or wild-type animals. The contribution of urinary stasis to CONS susceptibility was evaluated by cutaneous vesicostomy in Mgb-/- mice. Results Mgb-/- mice develop spontaneous bacteriuria (42%) and struvite bladder stones (31%) by 8 weeks, findings absent in Mgb+/- and wild-type controls. CONS was cultured as a solitary isolate from Mgb-/- bladder stones. Bladders and kidneys from mice with struvite stones exhibit mucosal injury, inflammation, and fibrosis. These pathologic features of cystitis and pyelonephritis are replicated by transurethral inoculation of CONS in culture-negative Mgb-/- females, whereas wild-type animals are less susceptible to CONS colonization and organ injury. Cutaneous vesicostomy prior to CONS inoculation significantly reduces the quantity of CONS recovered from Mgb-/- urine, bladders, and kidneys. Conclusions CONS is an opportunistic uropathogen in the setting of urinary stasis, leading to enhanced UTI incidence and severity in Mgb-/- mice. PMID:26401845

  14. Astroglia overexpressing heme oxygenase-1 predispose co-cultured PC12 cells to oxidative injury.

    PubMed

    Song, Linyang; Song, Wei; Schipper, Hyman M

    2007-08-01

    The mechanisms responsible for the progressive degeneration of dopaminergic neurons and pathologic iron deposition in the substantia nigra pars compacta of patients with Parkinson's disease (PD) remain unclear. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in the oxidative degradation of heme to ferrous iron, carbon monoxide, and biliverdin, is upregulated in affected PD astroglia and may contribute to abnormal mitochondrial iron sequestration in these cells. To determine whether glial HO-1 hyper-expression is toxic to neuronal compartments, we co-cultured dopaminergic PC12 cells atop monolayers of human (h) HO-1 transfected, sham-transfected, or non-transfected primary rat astroglia. We observed that PC12 cells grown atop hHO-1 transfected astrocytes, but not the astroglia themselves, were significantly more susceptible to dopamine (1 microM) + H(2)O(2) (1 microM)-induced death (assessed by nuclear ethidium monoazide bromide staining and anti-tyrosine hydroxylase immunofluorescence microscopy) relative to control preparations. In the experimental group, PC12 cell death was attenuated significantly by the administration of the HO inhibitor, SnMP (1.5 microM), the antioxidant, ascorbate (200 microM), or the iron chelators, deferoxamine (400 microM), and phenanthroline (100 microM). Exposure to conditioned media derived from HO-1 transfected astrocytes also augmented PC12 cell killing in response to dopamine (1 microM) + H(2)O(2) (1 microM) relative to control media. In PD brain, overexpression of HO-1 in nigral astroglia and accompanying iron liberation may facilitate the bioactivation of dopamine to neurotoxic free radical intermediates and predispose nearby neuronal constituents to oxidative damage. PMID:17526019

  15. Obesity accentuates circadian variability in breathing during sleep in mice but does not predispose to apnea

    PubMed Central

    Locke, Landon W.; McDowell, Angela L.; Strollo, Patrick J.; O'Donnell, Christopher P.

    2013-01-01

    Obesity is a primary risk factor for the development of obstructive sleep apnea in humans, but the impact of obesity on central sleep apnea is less clear. Given the comorbidities associated with obesity in humans, we developed techniques for long-term recording of diaphragmatic EMG activity and polysomnography in obese mice to assess breathing patterns during sleep and to determine the effect of obesity on apnea generation. We hypothesized that genetically obese ob/ob mice would exhibit less variability in breathing across the 24-h circadian cycle, be more prone to central apneas, and be more likely to exhibit patterns of increased diaphragm muscle activity consistent with obstructive apneas compared with lean mice. Unexpectedly, we found that obese mice exhibited a greater circadian impact on respiratory rate and diaphragmatic burst amplitude than lean mice, particularly during rapid eye movement (REM) sleep. Central apneas were more common in REM sleep (42 ± 17 h?1) than non-REM (NREM) sleep (14 ± 5 h?1) in obese mice (P < 0.05), but rates were not different between lean and obese mice in either sleep state. Even after experimentally enhancing central apnea generation by acute withdrawal of hypoxic chemoreceptor activation during sleep, central apnea rates remained comparable between lean and obese mice. Last, we were unable to detect patterns of diaphragmatic burst activity suggestive of obstructive apnea events in obese mice. In summary, obesity does not predispose mice to increased occurrence of central or obstructive apneas during sleep, but does lead to a more pronounced circadian variability in respiration. PMID:23722707

  16. Sexual activity does not predispose to reflux episodes in patients with gastroesophageal reflux disease

    PubMed Central

    Bor, Serhat; Valytova, Elen; Yildirim, Esra; Vardar, Rukiye

    2014-01-01

    Background The role of sexual activity on gastroesophageal reflux disease (GERD) is an under-recognized concern of patients, and one rarely assessed by physicians. Objective The objective of this article is to determine the influence of sexual activity on the intraesophageal acid exposure and acid reflux events in GERD patients. Methods Twenty-one patients with the diagnosis of GERD were prospectively enrolled. Intraesophageal pH monitoring was recorded for 48 hours with a Bravo capsule. All patients were instructed to have sexual intercourse or abstain in a random order two hours after the same refluxogenic dinner within two consecutive nights. Patients were requested to have sex in the standard “missionary position” and women were warned to avoid abdominal compression. The patients completed a diary reporting the time of the sexual intercourse and GERD symptoms. The percentage of reflux time and acid reflux events were compared in two ways: within 30 and 60 minutes prior to and after sexual intercourse on the day of sexual intercourse and in the same time frame of the day without sexual intercourse. Results Fifteen of 21 GERD patients were analyzed. The percentage of reflux time and number of acid reflux events did not show a significant difference within the 30- and 60-minute periods prior to and after sexual intercourse on the day of sexual intercourse and on the day without sexual intercourse, as well. Conclusion Sexual activity does not predispose to increased intraesophageal acid exposure and acid reflux events. Larger studies are needed to confirm our findings in patients who define reflux symptoms during sexual intercourse. PMID:25452843

  17. Prestimulus oscillatory alpha power and connectivity patterns predispose perceptual integration of an audio and a tactile stimulus.

    PubMed

    Leonardelli, Elisa; Braun, Christoph; Weisz, Nathan; Lithari, Chrysa; Occelli, Valeria; Zampini, Massimiliano

    2015-09-01

    To efficiently perceive and respond to the external environment, our brain has to perceptually integrate or segregate stimuli of different modalities. The temporal relationship between the different sensory modalities is therefore essential for the formation of different multisensory percepts. In this magnetoencephalography study, we created a paradigm where an audio and a tactile stimulus were presented by an ambiguous temporal relationship so that perception of physically identical audiotactile stimuli could vary between integrated (emanating from the same source) and segregated. This bistable paradigm allowed us to compare identical bimodal stimuli that elicited different percepts, providing a possibility to directly infer multisensory interaction effects. Local differences in alpha power over bilateral inferior parietal lobules (IPLs) and superior parietal lobules (SPLs) preceded integrated versus segregated percepts of the two stimuli (audio and tactile). Furthermore, differences in long-range cortical functional connectivity seeded in rIPL (region of maximum difference) revealed differential patterns that predisposed integrated or segregated percepts encompassing secondary areas of all different modalities and prefrontal cortex. We showed that the prestimulus brain states predispose the perception of the audiotactile stimulus both in a global and a local manner. Our findings are in line with a recent consistent body of findings on the importance of prestimulus brain states for perception of an upcoming stimulus. This new perspective on how stimuli originating from different modalities are integrated suggests a non-modality specific network predisposing multisensory perception. PMID:26109518

  18. A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs

    PubMed Central

    Olsson, Mia; Mauceli, Evan; Quilez, Javier; Tonomura, Noriko; Zanna, Giordana; Docampo, Maria José; Bassols, Anna; Avery, Anne C.; Karlsson, Elinor K.; Thomas, Anne; Kastner, Daniel L.; Bongcam-Rudloff, Erik; Webster, Matthew T.; Sanchez, Armand; Hedhammar, Åke; Remmers, Elaine F.; Andersson, Leif; Ferrer, Lluis; Tintle, Linda; Lindblad-Toh, Kerstin

    2011-01-01

    Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (praw?=?2.3×10?6, pgenome?=?0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p<0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation. PMID:21437276

  19. Evaluation of White Striping prevalence and predisposing factors in broilers at slaughter.

    PubMed

    Russo, Elisa; Drigo, Michele; Longoni, Corrado; Pezzotti, Raffaele; Fasoli, Paolo; Recordati, Camilla

    2015-08-01

    White striping ( WS: ) is an alteration of breast and thigh muscles of broiler chickens characterized by the presence of white striations parallel to the direction of muscle fibers. This study was performed to evaluate the prevalence and the predisposing factors to WS in commercial broilers of different weight reared in northern Italy. Fifty seven broiler flocks, including animals of medium- and heavy-weight, were grossly evaluated at slaughter for the presence of WS. For each flock, breeding data (mean BW at slaughter, ADG, sex, color of skin and fat, genetic line, age, antibiotic treatment, and prevalence of deep pectoral myopathy) were collected and statistically analyzed to assess their correlation with WS. Histology of breast fillets affected by different grades of WS was performed to evaluate potential differences between medium- and heavy-weight broilers. The overall prevalence of WS in medium- and heavy-weight broilers (mean BW 2.59 ± 0.13 kg and 3.64 ± 0.34 kg, respectively) was 70.2 ± 7.9% and 82.51 ± 8.5%, respectively, while the percentage of severe WS was 13.3 ± 7.1% and 25.7 ± 12.8%, respectively. A strong correlation was found between presence of WS, BW at slaughter, and ADG (Pearson correlation = 0.69, P < 0.01; Pearson correlation = 0.67, P < 0.01). WS also closely correlated with the prevalence of deep pectoral myopathy (Spearman's Rho slaughterhouse 1 = 0.74, Spearman's Rho slaughterhouse 2 = 0.51, P < 0.01). No correlation was found between genetics or sanitary status of the flock and WS. Histology confirmed that breasts with WS lesions were affected by a polyphasic degenerative and necrotizing myopathy, and that the lesions, as expected, were more severe in heavy-weight broilers. In conclusion, WS is a major concern in commercial meat poultry reared in Italy, affecting more severely heavier broilers, and it is mainly related to the BW and ADG of animals. PMID:26112037

  20. AN INITIAL INDICATION OF PREDISPOSING RISK OF SCHISTOSOMA MANSONI INFECTION FOR HEPATOCELLULAR CARCINOMA.

    PubMed

    Sabry, Abd El Hamid A; El-Aal, Amany A Abd; Mahmoud, Naglaa Saad; Nabil, Yossra; Aziz, Inas Z Abdel

    2015-08-01

    Estimated 500,000 - 1 million cases of hepatocellular carcinoma (HCC) are reported to occur yearly worldwide, with a mean annual incidence of around 3 - 4% of global population. HCC is rapidly fatal in most patients; that makes its incidence and mortality rates almost equal. In the last 5-10 years there were many alarming reports of sharply increased incidence of HCC. In Egypt, HCC reported to account for about 4.7% of chronic liver disease (CLD) patients, which has tremendous impact on socio-economic development in the country. Available data suggests indirect evidence of an association between Schistosoma mansoni and hepatocellular carcinoma, possibly through potentiation of hepatitis infections. The present study was conducted case control analysis of 60 HCC patients. Chronic schistosomiasis cases were confirmed by finding Anti-Schistosoma mansoni antibodies IgG by ELISA. Hepatitis C viral infection was proved by detection of viral load by quantitative Real time PCR. Among the study group 56.6% (34/60) were dweller in rural in Al-Fayoum governorate. Within hepatocellular carcinoma cases 26.7% (16/60) and 33.3% (20/60) suffered mono chronic schistosomiasis and mono hepatitis C (HCV) infections respectively, with no statistically significant differences (p=0.37), indicating comparable risk value of both infections in predisposing directly to HCC. Additionally; frequency of HCC patients with assumed potentiated HCV infection by chronic Schistosoma mansoni 6.7% (4/60) were statistically significant (p<0.05) less among total HCC patients included in this study, when compared to HCC patients preceded by either pure chronic schistosomiasis 26.7% (16/60) or pure HCV infection 33.3% (20/60). Our present study is one of few, addressing the possibility of direct relation between S. mansoni & hepatic carcinoma, concluding an initial indication of equal risk value of both human chronic S. mansoni infection and hepatitis C viral infections in precipitating hepatocellular carcinoma among Egyptian patients. PMID:26485842

  1. Germline mutations in fumarate hydratase (FH) do not predispose to prostate cancer.

    PubMed

    Bevan, S; Edwards, S M; Ardern Jones, A; Dowe, A; Southgate, C; Dearnaley, D; Easton, D F; Houlston, R S; Eeles, R A

    2003-01-01

    Inherited susceptibility to prostate cancer has been linked to a number of chromosomal regions, however no genes have been unequivocally shown to underlie reported linkages. The putative gene localised to chromosome 1q42-q43, has been designated PCaP. We have recently shown that germline mutations in the fumarate hydratase (FH) gene located on 1q43 cause smooth muscle tumours and renal cell carcinoma. It is conceivable that germline FH mutations might confer an increased risk of prostate cancer and underlie linkage of prostate cancer to PCaP. To examine this proposition we have analysed the entire coding region of FH in 160 prostate cancer cases in 77 multiple case families. No pathogenic mutations in FH were identified in any of the cases. This data makes it highly unlikely that mutations in FH confer susceptibility to prostate cancer. PMID:12664059

  2. Absence of the predisposing factors and signs and symptoms usually associated with overreaching and overtraining in physical fitness centers

    PubMed Central

    Ackel?D'Elia, Carolina; Vancini, Rodrigo Luiz; Castelo, Adauto; Nouailhetas, Viviane Louise Andrée; da Silva, Antonio Carlos

    2010-01-01

    OBJECTIVE: The aim of this study was to evaluate the occurrence of the well?known predisposing factors and signs and symptoms usually associated with either overreaching or overtraining syndrome in physical fitness centers in São Paulo City, Brazil. METHOD: A questionnaire consisting of 13 question groups pertaining to either predisposing factors (1?7) or signs and symptoms (8?13) was given to 413 subjects. The general training schedule of the volunteers was characterized by workout sessions of 2.18 ± 0.04 h for a total of 11.0 ± 0.3 h/week for 33 ± 2 months independent of the type of exercise performed (walking, running, spinning, bodybuilding and stretching). A mean score was calculated ranging from 1 (completely absent) to 5 (severe) for each question group. A low occurrence was considered to be a question group score lower than 4, which was observed in all 13 question groups. RESULTS: The psychological evaluation by POMS Mood State Questionnaire indicated a normal non?inverted iceberg. The hematological parameters, creatine kinase activity, cortisol, total testosterone and free testosterone concentrations were within the normal ranges for the majority of the volunteers selected for this analysis (n ?=? 60). CONCLUSION: According to the questionnaire score analysis, no predisposing factors or signs and symptoms usually associated with either overreaching or overtraining were detected among the members of physical fitness centers in São Paulo City, Brazil. This observation was corroborated by the absence of any significant hematological or stress hormone level alterations in blood analyses of the majority of the selected volunteers (n ?=? 60). PMID:21243291

  3. Heat acclimation memory: do the kinetics of the deacclimated transcriptome predispose to rapid reacclimation and cytoprotection?

    PubMed

    Tetievsky, Anna; Assayag, Miri; Ben-Hamo, Rotem; Efroni, Sol; Cohen, Gal; Abbas, Atallah; Horowitz, Michal

    2014-12-01

    Faster reinduction of heat acclimation (AC) after its decline indicates "AC memory." Our previous results revealed involvement of epigenetic mechanisms of transcriptional regulation. We hypothesized that the decline of AC (DeAC) is a period of "dormant memory" during which many processes are alerted to enable rapid reacclimation (ReAC). Using a genomewide approach we studied the AC, DeAC, and ReAC transcriptomes, to uncover hallmark pathways linked to "molecular memory" in the cardioacclimatome. Fifty rats subjected to heat acclimation [34°C for 2d (AC2d) or 30d (AC30)], DeAC (24°C, 30 days), ReAC (34°C, 2 days), and untreated controls were used. The GeneChip Rat Gene 1.0 ST Array was employed for left ventricular (cardiac) mRNA hybridization. Three independent bioinformatic analyses showed that 1) during AC2d enrichment of DNA impair/repair-linked genes is seen, and this is the molecular on-switch of acclimation; 2) genes activated in AC30 underlie the qualitative physiological adaptations of cardiac performance; 3) particular molecular programs encompassing constitutive upregulation of p38 MAPK, Jak/Stat, and Akt pathways and targets are specifically activated during DeAC and ReAC; and 4) epigenetic markers such as linker histones (histones H1 cluster), associated with nucleosome spacing, transcriptional chromatin modifiers, poly-(ADP-ribose) polymerase-1 (PARP1) linked to chromatin compaction, and microRNAs are only altered during DeAC/ReAC. The latter are newcomers to the AC/DeAC puzzle. We suggest that these transcriptional responses maintain euchromatin and proteostasis and enable faster physiological recovery upon ReAC by rapidly reestablishing the protected acclimated cardiophenotype. We propose that the cardiac AC model can be applied to acclimation processes in general. PMID:25237184

  4. LQTS gene LOVD database.

    PubMed

    Zhang, Tao; Moss, Arthur; Cong, Peikuan; Pan, Min; Chang, Bingxi; Zheng, Liangrong; Fang, Quan; Zareba, Wojciech; Robinson, Jennifer; Lin, Changsong; Li, Zhongxiang; Wei, Junfang; Zeng, Qiang; Qi, Ming

    2010-11-01

    The Long QT Syndrome (LQTS) is a group of genetically heterogeneous disorders that predisposes young individuals to ventricular arrhythmias and sudden death. LQTS is mainly caused by mutations in genes encoding subunits of cardiac ion channels (KCNQ1, KCNH2,SCN5A, KCNE1, and KCNE2). Many other genes involved in LQTS have been described recently(KCNJ2, AKAP9, ANK2, CACNA1C, SCNA4B, SNTA1, and CAV3). We created an online database(http://www.genomed.org/LOVD/introduction.html) that provides information on variants in LQTS-associated genes. As of February 2010, the database contains 1738 unique variants in 12 genes. A total of 950 variants are considered pathogenic, 265 are possible pathogenic, 131 are unknown/unclassified, and 292 have no known pathogenicity. In addition to these mutations collected from published literature, we also submitted information on gene variants, including one possible novel pathogenic mutation in the KCNH2 splice site found in ten Chinese families with documented arrhythmias. The remote user is able to search the data and is encouraged to submit new mutations into the database. The LQTS database will become a powerful tool for both researchers and clinicians. PMID:20809527

  5. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma

    PubMed Central

    Shi, Jianxin; Yang, Xiaohong R.; Ballew, Bari; Rotunno, Melissa; Calista, Donato; Fargnoli, Maria Concetta; Ghiorzo, Paola; Paillerets, Brigitte Bressac-de; Nagore, Eduardo; Avril, Marie Francoise; Caporaso, Neil E.; McMaster, Mary L.; Cullen, Michael; Wang, Zhaoming; Zhang, Xijun; Bruno, William; Pastorino, Lorenza; Queirolo, Paola; Banuls-Roca, Jose; Garcia-Casado, Zaida; Vaysse, Amaury; Mohamdi, Hamida; Riazalhosseini, Yasser; Foglio, Mario; Jouenne, Fanélie; Hua, Xing; Hyland, Paula L.; Yin, Jinhu; Vallabhaneni, Haritha; Chai, Weihang; Minghetti, Paola; Pellegrini, Cristina; Ravichandran, Sarangan; Eggermont, Alexander; Lathrop, Mark; Peris, Ketty; Scarra, Giovanna Bianchi; Landi, Giorgio; Savage, Sharon A.; Sampson, Joshua N.; He, Ji; Yeager, Meredith; Goldin, Lynn R.; Demenais, Florence; Chanock, Stephen J.; Tucker, Margaret A.; Goldstein, Alisa M.; Liu, Yie; Landi, Maria Teresa

    2014-01-01

    Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin POT1 gene (g.7:124493086 C>T, Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere length and elevated fragile telomeres suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two other Italian families, yielding a frequency of POT1 variants comparable to that of CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in American and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations. PMID:24686846

  6. A Novel Quantitative Hemolytic Assay Coupled with Restriction Fragment Length Polymorphisms Analysis Enabled Early Diagnosis of Atypical Hemolytic Uremic Syndrome and Identified Unique Predisposing Mutations in Japan

    PubMed Central

    Yoshida, Yoko; Miyata, Toshiyuki; Matsumoto, Masanori; Shirotani-Ikejima, Hiroko; Uchida, Yumiko; Ohyama, Yoshifumi; Kokubo, Tetsuro; Fujimura, Yoshihiro

    2015-01-01

    For thrombotic microangiopathies (TMAs), the diagnosis of atypical hemolytic uremic syndrome (aHUS) is made by ruling out Shiga toxin-producing Escherichia coli (STEC)-associated HUS and ADAMTS13 activity-deficient thrombotic thrombocytopenic purpura (TTP), often using the exclusion criteria for secondary TMAs. Nowadays, assays for ADAMTS13 activity and evaluation for STEC infection can be performed within a few hours. However, a confident diagnosis of aHUS often requires comprehensive gene analysis of the alternative complement activation pathway, which usually takes at least several weeks. However, predisposing genetic abnormalities are only identified in approximately 70% of aHUS. To facilitate the diagnosis of complement-mediated aHUS, we describe a quantitative hemolytic assay using sheep red blood cells (RBCs) and human citrated plasma, spiked with or without a novel inhibitory anti-complement factor H (CFH) monoclonal antibody. Among 45 aHUS patients in Japan, 24% (11/45) had moderate-to-severe (?50%) hemolysis, whereas the remaining 76% (34/45) patients had mild or no hemolysis (<50%). The former group is largely attributed to CFH-related abnormalities, and the latter group has C3-p.I1157T mutations (16/34), which were identified by restriction fragment length polymorphism (RFLP) analysis. Thus, a quantitative hemolytic assay coupled with RFLP analysis enabled the early diagnosis of complement-mediated aHUS in 60% (27/45) of patients in Japan within a week of presentation. We hypothesize that this novel quantitative hemolytic assay would be more useful in a Caucasian population, who may have a higher proportion of CFH mutations than Japanese patients. PMID:25951460

  7. An Overview of IAEA Activities to Support Pre-disposal Management of Radioactive Wastes in Member States - 12334

    SciTech Connect

    Kumar Samanta, Susanta; Drace, Zoran; Ojovan, Michael

    2012-07-01

    The International Atomic Energy Agency (IAEA) promotes safe and effective management of radioactive waste and has suitable programmes in place to serve the needs of Member States in this area. These programmes cover the development and use of safety standards, planning, technologies and approaches needed for the management of different types of radioactive waste, resulting both from the nuclear fuel cycle and nuclear applications. In the pre-disposal area, the assistance to Members States covers a wide range of topics, including policy and strategy, inventory assessment, technologies and approaches for waste minimization, selection of technical options for waste processing and storage, improvement in operating practices at nuclear facilities, optimization of waste management capacity, etc. and is delivered through the publication of technical guidance documents, coordinated research projects, networks, technical cooperation projects and organization of training and technical review services. This report presents an overview of recent IAEA accomplishments aiming to support activities in pre-disposal management of radioactive waste with focus on technological aspects. (authors)

  8. Cancer predisposing BARD1 mutations affect exon skipping and are associated with overexpression of specific BARD1 isoforms.

    PubMed

    Ratajska, Magdalena; Matusiak, Magdalena; Kuzniacka, Alina; Wasag, Bartosz; Brozek, Izabela; Biernat, Wojciech; Koczkowska, Magdalena; Debniak, Jaroslaw; Sniadecki, Marcin; Kozlowski, Piotr; Klonowska, Katarzyna; Pilyugin, Maxim; Wydra, Dariusz; Laurent, Geoff; Limon, Janusz; Irminger-Finger, Irmgard

    2015-11-01

    BARD1 is the main binding partner of BRCA1 and is required for its stability and tumor-suppressor functions. In breast cancer and other epithelial cell carcinomas, alternatively spliced isoforms of BARD1 are highly upregulated and correlated with poor outcome. Recent data indicate that germline mutations of BARD1 may predispose to breast and/or ovarian cancer. To evaluate the role of BARD1 germline mutations in predisposition to ovarian cancer we scanned a cohort of 255 patients for the presence of previously reported mutations located in exons 5, 8 and 10 using high-resolution melting analysis. Within this group we identified single-patients carrying mutation in exon 8 (c.1690C>T, p.Gln564Ter), two different variants in exon 10 (c.1972C>T, p.Arg658Tyr; c.1977A>G, p.=) and a carrier of novel missense mutation located in exon 5 (c.1361C>T, p.Pro454Leu). Three out of four identified mutations alter exonic splicing enhancing motives and result in expression of incorrect splicing skipping of exons 5, 8, and 2-9, respectively. Our data indicate that BARD1 variants may predispose to ovarian cancer in limited number of patients although based on actual data it is difficult to estimate its actual penetrance. PMID:26329992

  9. MTHFR POLYMORPHISMS AND COLORECTAL NEOPLASIA

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Folate is essential for the synthesis, repair and methylation of DNA. Aberrations in folate metabolism can modify our risk for cancer. Folate depletion alters DNA methylation patterns and increases DNA uracil-content and the frequency of DNA breaks. These DNA aberrations are involved in the etiology...

  10. Echocardiographic evaluation of pre-diagnostic development in young relatives genetically predisposed to hypertrophic cardiomyopathy.

    PubMed

    Jensen, Morten K; Havndrup, Ole; Christiansen, Michael; Andersen, Paal S; Axelsson, Anna; Køber, Lars; Bundgaard, Henning

    2015-12-01

    Identification of the first echocardiographic manifestations of hypertrophic cardiomyopathy may be important for clinical management and our understanding of the pathogenesis. We studied the development of pre-diagnostic echocardiographic changes in young relatives to HCM patients during long-term years follow-up. HCM-relatives not fulfilling the diagnostic criteria for HCM and age of <18 years were included in this study. We performed echocardiographic evaluations at inclusion and after 12 ± 1 years follow-up. Based on family screening of 11 sarcomere genes, CRYAB, ?-GAL, and titin, we evaluated: (1) non-carriers (known family mutation ruled out-controls), (2) carriers (phenotype negative gene mutation carriers) and (3) phenotype negative relatives with unknown genetic status (relatives from families without identified mutations). At inclusion (age 11 ± 5 years), there were no differences in echocardiographic chamber dimensions, systolic or diastolic function between the three groups. During follow-up (age 23 ± 5 years), carriers (n = 8) developed lower left ventricular end-diastolic dimension (LVEDd) compared to non-carriers (n = 23) (41 ± 4 vs. 46 ± 4 mm; p = 0.04) and a higher ratio of early left ventricular filling velocity and early diastolic velocity of lateral mitral annulus (E/e' 6 ± 1 vs. 5 ± 1; p = 0.003). No significant differences in LVEDd or E/e' were found between relatives with unknown genetic status (n = 24) and non-carriers though Z-scores for these parameters were >2 in a subset of relatives with unknown genetic status. Children carrying pathogenic sarcomere gene mutations develop reduced LVEDd and increased E/e' as first pre-diagnostic echocardiographic manifestations during follow-up into adulthood. PMID:26231341

  11. Methylenetetrahydrofolate Reductase Gene Polymorphism and Risk of Type 2 Diabetes Mellitus

    PubMed Central

    Yang, Na-Na; Li, Le-Qun

    2013-01-01

    Objective This review aimed to comprehensively assess the literature examining a possible link between the rs1801133 polymorphism (677C?T) in the gene encoding the methylenetetrahydrofolate reductase (MTHFR) gene and risk of type 2 diabetes mellitus (DM). Research Design and Methods Several research databases were systematically searched for studies examining the genotype at the rs1801133 polymorphism in healthy control individuals and individuals with type 2 DM. Genotype frequency data were examined across all studies and across subsets of studies according to ethnicity and presence of serious DM-related complications. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results A total of 4855 individuals with type 2 DM and 5242 healthy controls from 15 countries comprising Asian, Caucasian and African ethnicities were found to satisfy the inclusion criteria and included in the review. Genotype at the rs1801133 polymorphism was not consistently associated with either increased or reduced risk of type 2 DM; the OR across all studies was 0.91 (95%CI 0.82 to 1.00) for the C- vs. T-allele, 0.88 (0.75 to 1.03) for CC vs. CT+TT, 0.82 (0.71 to 0.95) for CC vs. TT, and 1.15 (1.03 to 1.29) for TT vs. CC+CT. Similar results were found when the meta-analysis was repeated separately for each ethnic subgroup, and for subgroups with or without serious DM-related complications. Conclusions There does not appear to be compelling evidence of an association between the genotype at the rs1801133 polymorphism of the MTHFR gene and risk of type 2 DM. PMID:24023947

  12. Genes and Gene Therapy

    MedlinePLUS

    ... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  13. Pulmonary Embolism in a Sarcoidosis Patient Double Heterozygous for Methylenetetrahydrofolate Reductase Gene Polymorphisms and Factor V Leiden and Homozygous for the D-Allele of Angiotensin Converting Enzyme Gene

    PubMed Central

    El-Majzoub, Nadim; Mahfouz, Rami; Kanj, Nadim

    2015-01-01

    Sarcoidosis is a multisystem granulomatous disease of unknown etiology and pathogenesis. It presents in patients younger than 40 years of age. The lungs are the most commonly affected organ. Till the present day, there is no single specific test that will accurately diagnose sarcoidosis; as a result, the diagnosis of sarcoidosis relies on a combination of clinical, radiologic, and histologic findings. Patients with sarcoidosis have been found to have an increased risk of pulmonary embolism compared to the normal population. MTHFR and factor V Leiden mutations have been reported to increase the risk of thrombosis in patients. We hereby present a case of a middle aged man with sarcoidosis who developed a right main pulmonary embolism and was found to be double heterozygous for methylenetetrahydrofolate reductase gene polymorphisms and factor V Leiden and homozygous for the D-allele of the angiotensin converting enzyme gene. PMID:26347783

  14. Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer.

    PubMed Central

    Moisio, A. L.; Sistonen, P.; Weissenbach, J.; de la Chapelle, A.; Peltomäki, P.

    1996-01-01

    Two mutations in the DNA mismatch repair gene MLH1, referred to as mutations 1 and 2, are frequent among Finnish kindreds with hereditary nonpolyposis colorectal cancer (HNPCC). In order to assess the ages and origins of these mutations, we constructed a map of 15 microsatellite markers around MLH1 and used this information in haplotype analyses of 19 kindreds with mutation 1 and 6 kindreds with mutation 2. All kindreds with mutation 1 showed a single allele for the intragenic marker D3S1611 that was not observed on any unaffected chromosome. They also shared portions of a haplotype of 4-15 markers encompassing 2.0-19.0 cM around MLH1. All kindreds with mutation 2 shared another allele for D3S1611 and a conserved haplotype of 5-14 markers spanning 2.0-15.0 cM around MLH1. The degree of haplotype conservation was used to estimate the ages of these two mutations. While some recessive disease genes have been estimated to have existed and spread for as long as thousands of generations worldwide and hundreds of generations in the Finnish population, our analyses suggest that the spread of mutation 1 started 16-43 generations (400-1,075 years) ago and that of mutation 2 some 5-21 generations (125-525 years) ago. These datings are compatible with our genealogical results identifying a common ancestor born in the 16th and 18th century, respectively. Overall, our results indicate that all Finnish kindreds studied to date showing either mutation 1 or mutation 2 are due to single ancestral founding mutations relatively recent in origin in the population. Alternatively, the mutations arose elsewhere earlier and were introduced in Finland more recently. PMID:8940269

  15. The Mycotoxin Deoxynivalenol Predisposes for the Development of Clostridium perfringens-Induced Necrotic Enteritis in Broiler Chickens

    PubMed Central

    Antonissen, Gunther; Ducatelle, Richard; Haesebrouck, Freddy; Timbermont, Leen; Verlinden, Marc; Janssens, Geert Paul Jules; Eeckhaut, Venessa; Eeckhout, Mia; De Saeger, Sarah; Hessenberger, Sabine; Martel, An; Croubels, Siska

    2014-01-01

    Both mycotoxin contamination of feed and Clostridium perfringens-induced necrotic enteritis have an increasing global economic impact on poultry production. Especially the Fusarium mycotoxin deoxynivalenol (DON) is a common feed contaminant. This study aimed at examining the predisposing effect of DON on the development of necrotic enteritis in broiler chickens. An experimental Clostridium perfringens infection study revealed that DON, at a contamination level of 3,000 to 4,000 µg/kg feed, increased the percentage of birds with subclinical necrotic enteritis from 20±2.6% to 47±3.0% (P<0.001). DON significantly reduced the transepithelial electrical resistance in duodenal segments (P<0.001) and decreased duodenal villus height (P?=?0.014) indicating intestinal barrier disruption and intestinal epithelial damage, respectively. This may lead to an increased permeability of the intestinal epithelium and decreased absorption of dietary proteins. Protein analysis of duodenal content indeed showed that DON contamination resulted in a significant increase in total protein concentration (P?=?0.023). Furthermore, DON had no effect on in vitro growth, alpha toxin production and netB toxin transcription of Clostridium perfringens. In conclusion, feed contamination with DON at concentrations below the European maximum guidance level of 5,000 µg/kg feed, is a predisposing factor for the development of necrotic enteritis in broilers. These results are associated with a negative effect of DON on the intestinal barrier function and increased intestinal protein availability, which may stimulate growth and toxin production of Clostridium perfringens. PMID:25268498

  16. Replacing sugary drinks with milk is inversely associated with weight gain among young obesity-predisposed children.

    PubMed

    Zheng, Miaobing; Rangan, Anna; Allman-Farinelli, Margaret; Rohde, Jeanett Friis; Olsen, Nanna Julie; Heitmann, Berit Lilienthal

    2015-11-01

    The aim of the present study was to examine the associations of sugary drink consumption and its substitution with alternative beverages with body weight gain among young children predisposed to future weight gain. Secondary analysis of the Healthy Start Study, a 1·5-year randomised controlled trial designed to prevent overweight among Danish children aged 2-6 years (n 366), was carried out. Multivariate linear regression models were used to investigate the associations of beverage consumption with change in body weight (?weight) or BMI(?BMI) z-score. Substitution models were used to extrapolate the influence of replacing sugary drinks with alternative beverages (water, milk and diet drinks) on ?weight or ?BMI z-score. Sugary drink intake at baseline and substitution of sugary drinks with milk were associated with both ?weight and ?BMI z-score. Every 100 g/d increase in sugary drink intake was associated with 0·10 kg and 0·06 unit increases in body weight (P=0·048) and BMI z-score (P=0·04), respectively. Substitution of 100 g/d sugary drinks with 100 g/d milk was inversely associated with ?weight (?=-0·16 kg; P=0·045) and ?BMI z-score (?=-0·07 units; P=0·04). The results of this study suggest that sugary drink consumption was associated with body weight gain among young children with high predisposition for future overweight. In line with the current recommendations, sugary drinks, whether high in added or natural sugar, should be discouraged to help prevent childhood obesity. Milk may be a good alternative to sugary drinks with regard to weight management among young obesity-predisposed children. PMID:26328600

  17. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer.

    PubMed

    Lammi, Laura; Arte, Sirpa; Somer, Mirja; Jarvinen, Heikki; Lahermo, Paivi; Thesleff, Irma; Pirinen, Sinikka; Nieminen, Pekka

    2004-05-01

    Wnt signaling regulates embryonic pattern formation and morphogenesis of most organs. Aberrations of regulation of Wnt signaling may lead to cancer. Here, we have used positional cloning to identify the causative mutation in a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal neoplasia segregate with dominant inheritance. Eleven members of the family lacked at least eight permanent teeth, two of whom developed only three permanent teeth. Colorectal cancer or precancerous lesions of variable types were found in eight of the patients with oligodontia. We show that oligodontia and predisposition to cancer are caused by a nonsense mutation, Arg656Stop, in the Wnt-signaling regulator AXIN2. In addition, we identified a de novo frameshift mutation 1994-1995insG in AXIN2 in an unrelated young patient with severe tooth agenesis. Both mutations are expected to activate Wnt signaling. The results provide the first evidence of the importance of Wnt signaling for the development of dentition in humans and suggest that an intricate control of Wnt-signal activity is necessary for normal tooth development, since both inhibition and stimulation of Wnt signaling may lead to tooth agenesis. Our findings introduce a new gene for hereditary colorectal cancer and suggest that tooth agenesis may be an indicator of cancer susceptibility. PMID:15042511

  18. Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation.

    PubMed

    Papadakis, Konstantinos A; Krempski, James; Svingen, Phyllis; Xiong, Yuning; Sarmento, Olga F; Lomberk, Gwen A; Urrutia, Raul A; Faubion, William A

    2015-12-01

    Krüppel-like factor (KLF)-10 is an important transcriptional regulator of TGF-?1 signaling in both CD8(+) and CD4(+) T lymphocytes. In the present study, we demonstrate a novel role for KLF10 in the regulation of TGF?RII expression with functional relevance in macrophage differentiation and activation. We first show that transfer of KLF10(-/-) bone marrow-derived macrophages into wild-type (WT) mice leads to exacerbation of experimental colitis. At the cell biological level, using two phenotypic strategies, we show that KLF10-deficient mice have an altered colonic macrophage phenotype with higher frequency of proinflammatory LyC6(+)MHCII(+) cells and a reciprocal decrease of the anti-inflammatory LyC6(-)MHCII(+) subset. Additionally, the anti-inflammatory CD11b(+)CX3CR1(hi) subset of colonic macrophages is significantly decreased in KLF10(-/-) compared with WT mice under inflammatory conditions. Molecularly, CD11b(+) colonic macrophages from KLF10(-/-) mice exhibit a proinflammatory cytokine profile with increased production of TNF-? and lower production of IL-10 in response to LPS stimulation. Because KLF10 is a transcription factor, we explored how this protein may regulate macrophage function. Consequently, we analyzed the expression of TGF?RII expression in colonic macrophages and found that, in the absence of KLF10, macrophages express lower levels of TGF?RII and display an attenuated Smad-2 phosphorylation following TGF-?1 stimulation. We further show that KLF10 directly binds to the TGF?RII promoter in macrophages, leading to enhanced gene expression through histone H3 acetylation. Collectively, our data reveal a critical role for KLF10 in the epigenetic regulation of TGF?RII expression in macrophages and the acquisition of a "regulatory" phenotype that contributes to intestinal mucosal homeostasis. PMID:26472224

  19. Decision-Making after Prenatal Diagnosis of a Syndrome Predisposing to Intellectual Disability: What Prospective Parents Need to Know and the Importance of Non-Medical Information

    ERIC Educational Resources Information Center

    Huyard, Caroline

    2012-01-01

    Background: Recently researchers have suggested that non-medical information may impact the decision to continue or terminate a pregnancy after a prenatal diagnosis. This study is an investigation of what type of information prospective parents need for this decision-making in the case of a condition predisposing to intellectual disability.…

  20. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility

    PubMed Central

    Kumar, Pradeep; Yadav, Upendra; Rai, Vandana

    2015-01-01

    There are several evidences supporting the role of 5–10 methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in breast cancer (BC). Case control association studies on breast cancer have been repeatedly performed over the last two decades, but results are inconsistent. We performed a meta-analysis to confirm the association between MTHFR C677T polymorphism and BC risk. The articles were retrieved by searching the PubMed, Google Scholar, and Springer Link databases. Crude odds ratios (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between C677T polymorphism and BC. Publication bias was assessed by Egger's and Begg-Mazumdar tests. Meta-analysis was performed with Open Meta Analyst. Total 75 studies with 31,315 cases and 35, 608 controls were found suitable for the inclusion in the present meta-analysis. The results of meta-analysis suggested that there were moderate significant association between C677T polymorphism and BC risk using overall comparisons in five genetic models (T vs. C: OR = 1.08, 95% CI = 1.03–1.13, p = < 0.001; TT + CT vs. CC: OR = 1.06, 95% CI = 1.02–1.09, p = < 0.001; TT vs. CC: OR = 1.17, 95% CI = 1.06–1.28, p = 0.001; CT vs. CC OR = 1.05, 95% CI = 1.01–1.08, p = 0.005; TT vs. CT + CC: OR = 1.12, 95% CI = 1.03–1.22, p = 0.005). In conclusion, results of present meta-analysis showed modest association between MTHFR C677T polymorphism with breast cancer in total studies. However, sub-group analysis results based on ethnicity showed strong significant association between TT genotype and breast cancer (TT vs. CC; OR°=°1.26; 95% CI: 1.06–1.51; p = 0.009) in Asian population but in Caucasian population such association was not observed (TT vs. CC; OR°=°1.08; 95% CI: 0.99–1.14; p = 0.05). PMID:26629412

  1. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility.

    PubMed

    Kumar, Pradeep; Yadav, Upendra; Rai, Vandana

    2015-12-01

    There are several evidences supporting the role of 5-10 methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in breast cancer (BC). Case control association studies on breast cancer have been repeatedly performed over the last two decades, but results are inconsistent. We performed a meta-analysis to confirm the association between MTHFR C677T polymorphism and BC risk. The articles were retrieved by searching the PubMed, Google Scholar, and Springer Link databases. Crude odds ratios (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between C677T polymorphism and BC. Publication bias was assessed by Egger's and Begg-Mazumdar tests. Meta-analysis was performed with Open Meta Analyst. Total 75 studies with 31,315 cases and 35, 608 controls were found suitable for the inclusion in the present meta-analysis. The results of meta-analysis suggested that there were moderate significant association between C677T polymorphism and BC risk using overall comparisons in five genetic models (T vs. C: OR = 1.08, 95% CI = 1.03-1.13, p = < 0.001; TT + CT vs. CC: OR = 1.06, 95% CI = 1.02-1.09, p = < 0.001; TT vs. CC: OR = 1.17, 95% CI = 1.06-1.28, p = 0.001; CT vs. CC OR = 1.05, 95% CI = 1.01-1.08, p = 0.005; TT vs. CT + CC: OR = 1.12, 95% CI = 1.03-1.22, p = 0.005). In conclusion, results of present meta-analysis showed modest association between MTHFR C677T polymorphism with breast cancer in total studies. However, sub-group analysis results based on ethnicity showed strong significant association between TT genotype and breast cancer (TT vs. CC; OR°=°1.26; 95% CI: 1.06-1.51; p = 0.009) in Asian population but in Caucasian population such association was not observed (TT vs. CC; OR°=°1.08; 95% CI: 0.99-1.14; p = 0.05). PMID:26629412

  2. Identification of differentially expressed genes associated with osteochondrosis in standardbred horses using RNA arbitrarily primed PCR.

    PubMed

    Austbø, Lars; Røed, Knut H; Dolvik, Nils I; Skretting, Grethe

    2010-04-01

    The aim of this study was to investigate genes for differential expression in cartilage of foals predisposed to osteochondrosis (OC). Tissue was sampled from the cranial part of the distal intermediate ridge of the tibia in the tarso-crural joint. Foals were considered predisposed to OC when parents had OC at the distal intermediate ridge of the tibia. RNA was isolated and subjected to arbitrarily primed PCR (RAP-PCR) followed by fingerprinting to screen for differentially expressed genes. By verification of results from the RAP-PCR fingerprint screening using real-time RT-PCR, we identified two genes not previously correlated with OC as differentially expressed. The two genes, which were identical to TLK2 and an equine EST, are good targets for future research on OC. PMID:20379890

  3. Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

    PubMed Central

    Tapper, William; Jones, Amy V.; Kralovics, Robert; Harutyunyan, Ashot S.; Zoi, Katerina; Leung, William; Godfrey, Anna L.; Guglielmelli, Paola; Callaway, Alison; Ward, Daniel; Aranaz, Paula; White, Helen E.; Waghorn, Katherine; Lin, Feng; Chase, Andrew; Joanna Baxter, E.; Maclean, Cathy; Nangalia, Jyoti; Chen, Edwin; Evans, Paul; Short, Michael; Jack, Andrew; Wallis, Louise; Oscier, David; Duncombe, Andrew S.; Schuh, Anna; Mead, Adam J.; Griffiths, Michael; Ewing, Joanne; Gale, Rosemary E.; Schnittger, Susanne; Haferlach, Torsten; Stegelmann, Frank; Döhner, Konstanze; Grallert, Harald; Strauch, Konstantin; Tanaka, Toshiko; Bandinelli, Stefania; Giannopoulos, Andreas; Pieri, Lisa; Mannarelli, Carmela; Gisslinger, Heinz; Barosi, Giovanni; Cazzola, Mario; Reiter, Andreas; Harrison, Claire; Campbell, Peter; Green, Anthony R.; Vannucchi, Alessandro; Cross, Nicholas C.P.

    2015-01-01

    Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2V617F-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10?10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10?9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10?7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic ?2 P=7.3 × 10?7). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype. PMID:25849990

  4. EFFECTS OF DIETARY FOLATE AND AGING ON GENE EXPRESSION IN THE COLONIC MUCOSA OF RATS: IMPLICATIONS FOR CARCINOGENESIS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Folate depletion and aging are risk factors for human & rodent colorectal (CR) cancer. We investigated the effects of folate status and aging on gene expression patterns in the rat colon and hypothesized that folate depletion and advancing age cause deleterious changes in expression that predispose ...

  5. Molecular analysis of a family with three cases of first cousins with free trisomy 21 excludes the existence of a familial predisposing factor for nondisjunction

    SciTech Connect

    Girginoudis, P.; Avramopoulos, D.; Robert, E.

    1994-09-01

    We have studied a French family with three individuals, paternally related first cousins, that presented free and complete trisomy 21. Using short sequence repeat polymorphisms from chromosome 21, we analyzed the DNA of two of the three affected individuals that were available. We determined the parental origin of the supernumerary chromosome in both cases. The trisomy in these cases was found to be due to maternal meiotic errors. Since the individuals were related through their paternal grandparents (their fathers were siblings) we conclude that the recurrence of trisomy 21 in this family is a result of chance and is not due to any possible genetic predisposing factors. This is in accordance with previous results on recurrent trisomy 21 families, where predisposing factors were also often excluded through the same kind of analysis.

  6. Arterial distensibility in patients with ruptured and unruptured intracranial aneurysms: Is it a predisposing factor for rupture risk?

    PubMed Central

    Dusak, Abdurrahim; Kamasak, Kaan; Goya, Cemil; Adin, Mehmet E.; Elbey, Mehmet A.; Bilici, Aslan

    2013-01-01

    Background A risk factor assessment that reliably predicts whether patients are predisposed to intracranial aneurysm (IA) rupture has yet to be formulated. As such, the clinical management of unruptured IA remains unclear. Our aim was to determine whether impaired arterial distensibility and hypertrophic remodeling might be indicators of risk for IA rupture. Material/Methods The study population (n=49) was selected from consecutive admissions for either unruptured IA (n=23) or ruptured IA (n=26) from January to December 2010. Hemodynamic measures were taken from every patient, including systolic and diastolic blood pressure using a sphygmomanometer. Unruptured IA and ruptured IA characteristics, including aneurysmal shape, size, angle, aspect ratio, and bottleneck factor, were measured and calculated from transverse brain CT angiography images. With ultrasound, the right common carotid artery intima-media thickness was measured, as well as the lumen diameter during systole and diastole. Arterial wall strain, distensibility, stiffness index, and elastic modulus were calculated and compared between patients with unruptured IAs and ruptured IAs. A p-value less than 0.05 was considered statistically significant. Results General demographic data did not differ between patients with unruptured IAs and ruptured IAs. Greater mean intima-media thickness (p=0.013), mean stiffness index (p=0.044), and mean elastic modulus (p=0.026) were observed for patients with ruptured IAs. Moreover, mean strain (p=0.013) and mean distensibility (p=0.024) were decreased in patients with ruptured IAs. Conclusions Patients with ruptured IAs demonstrated decreased arterial distensibility and increased intima-media thickness at the level of the carotid arteries. By measuring these parameters via ultrasound, it may be possible to predict whether patients with existing IAs might rupture and hemorrhage into the subarachnoid space. PMID:23974299

  7. 5?-Reductase type 1 deficiency or inhibition predisposes to insulin resistance, hepatic steatosis, and liver fibrosis in rodents.

    PubMed

    Livingstone, Dawn E W; Barat, Pascal; Di Rollo, Emma M; Rees, Georgina A; Weldin, Benjamin A; Rog-Zielinska, Eva A; MacFarlane, David P; Walker, Brian R; Andrew, Ruth

    2015-02-01

    5?-Reductase type 1 (5?R1) catalyses A-ring reduction of androgens and glucocorticoids in liver, potentially influencing hepatic manifestations of the metabolic syndrome. Male mice, homozygous for a disrupted 5?R1 allele (5?R1 knockout [KO] mice), were studied after metabolic (high-fat diet) and fibrotic (carbon tetrachloride [CCl4]) challenge. The effect of the 5?-reductase inhibitor finasteride on metabolism was investigated in male obese Zucker rats. While eating a high-fat diet, male 5?R1-KO mice demonstrated greater mean weight gain (21.6 ± 1.4 vs 16.2 ± 2.4 g), hyperinsulinemia (insulin area under the curve during glucose tolerance test 609 ± 103 vs. 313 ± 66 ng ? mL(-1) ? min), and hepatic steatosis (liver triglycerides 136.1 ± 17.0 vs. 89.3 ± 12.1 ?mol ? g(-1)). mRNA transcript profiles in liver were consistent with decreased fatty acid ?-oxidation and increased triglyceride storage. 5?R1-KO male mice were more susceptible to fibrosis after CCl4 administration (37% increase in collagen staining). The nonselective 5?-reductase inhibitor finasteride induced hyperinsulinemia and hepatic steatosis (10.6 ± 1.2 vs. 7.0 ± 1.0 ?mol ? g(-1)) in obese male Zucker rats, both intact and castrated. 5?R1 deficiency induces insulin resistance and hepatic steatosis, consistent with the intrahepatic accumulation of glucocorticoids, and predisposes to hepatic fibrosis. Hepatic steatosis is independent of androgens in rats. Variations in 5?R1 activity in obesity and with nonselective 5?-reductase inhibition in men with prostate disease may have important consequences for the onset and progression of metabolic liver disease. PMID:25239636

  8. Clinical profile, predisposing factors, and associated co-morbidities of children with cerebral palsy in South India

    PubMed Central

    Gowda, Vykuntaraju K.; Kumar, Anil; Shivappa, Sanjay K.; Srikanteswara, Praveen Kumar; Shivananda; Mahadeviah, M. S.; Govindraj, M.; Ramaswamy, Premalatha

    2015-01-01

    Introduction: Cerebral palsy (CP) is the most common physical disorder of children. Causes like jaundice and birth injury though are decreasing; complications resulting from the survival of low birth weight babies are replacing some of the older etiologies. Hence, this study was planned. Objectives: The objective was to study the clinical patterns, predisposing factors, and co-morbidities in children with CP. Materials and Methods: The present study is a hospital based prospective study conducted from January 2012 to January 2013 in children presenting to neurodevelopmental clinic at a tertiary care teaching hospital in India. Hundred cases with clinical features suggestive of CP were included in the study. Cases were evaluated by history, clinical examination, and necessary investigations. Results: Results of the study showed 81% of spastic, 12% of hypotonic, 5% of dystonic, and 2% of mixed CP cases. The mean age of presentation was 2 year, 2 month, and male to female ratio of 1:2. Pregnancy-induced hypertension (PIH) was the most common antenatal complication observed in 6%. Four percent had neonatal sepsis and 19% were born premature. Associated co-morbidities were mental retardation (55%), seizure disorder (46%), visual problems (26%), hearing problems (19%), and failure to thrive (47%). Discussion: Sex distribution observed in our study was male to female ratio of 1.2, which was comparable with a multicenter study in Europe. PIH was observed in 6% of cases, which was comparable with prior studies. Birth asphyxia was observed in 43% of cases. Eighty-one percent of the cases constituted a spastic variety of CP which was comparable to other studies. Conclusion: Perinatal asphyxia was the important etiological factor. We found preventable intranatal causes (60%) and antenatal causes (20%) forming a significant proportion. Co-morbidities were significantly observed in our study. PMID:26167210

  9. First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm.

    PubMed

    van de Luijtgaarden, Koen M; Heijsman, Daphne; Maugeri, Alessandra; Weiss, Marjan M; Verhagen, Hence J M; IJpma, Arne; Brüggenwirth, Hennie T; Majoor-Krakauer, Danielle

    2015-08-01

    Genetic causes for abdominal aortic aneurysm (AAA) have not been identified and the role of genes associated with familial thoracic aneurysms in AAA has not been explored. We analyzed nine genes associated with familial thoracic aortic aneurysms, the vascular Ehlers-Danlos gene COL3A1 and the MTHFR p.Ala222Val variant in 155 AAA patients. The thoracic aneurysm genes selected for this study were the transforming growth factor-beta pathway genes EFEMP2, FBN1, SMAD3, TGBF2, TGFBR1, TGFBR2, and the smooth muscle cells genes ACTA2, MYH11 and MYLK. Sanger sequencing of all coding exons and exon-intron boundaries of these genes was performed. Patients with at least one first-degree relative with an aortic aneurysm were classified as familial AAA (n = 99), the others as sporadic AAA. We found 47 different rare heterozygous variants in eight genes: two pathogenic, one likely pathogenic, twenty-one variants of unknown significance (VUS) and twenty-three unlikely pathogenic variants. In familial AAA we found one pathogenic and segregating variant (COL3A1 p.Arg491X), one likely pathogenic and segregating (MYH11 p.Arg254Cys), and fifteen VUS. In sporadic patients we found one pathogenic (TGFBR2 p.Ile525Phefs*18) and seven VUS. Thirteen patients had two or more variants. These results show a previously unknown association and overlapping genetic defects between AAA and familial thoracic aneurysms, indicating that genetic testing may help to identify the cause of familial and sporadic AAA. In this view, genetic testing of these genes specifically or in a genome-wide approach may help to identify the cause of familial and sporadic AAA. PMID:26017485

  10. Genes Affecting ?-Cell Function in Type 1 Diabetes.

    PubMed

    Fløyel, Tina; Kaur, Simranjeet; Pociot, Flemming

    2015-11-01

    Type 1 diabetes (T1D) is a multifactorial disease resulting from an immune-mediated destruction of the insulin-producing pancreatic ? cells. Several environmental and genetic risk factors predispose to the disease. Genome-wide association studies (GWAS) have identified around 50 genetic regions that affect the risk of developing T1D, but the disease-causing variants and genes are still largely unknown. In this review, we discuss the current status of T1D susceptibility loci and candidate genes with focus on the ? cell. At least 40 % of the genes in the T1D susceptibility loci are expressed in human islets and ? cells, where they according to recent studies modulate the ?-cell response to the immune system. As most of the risk variants map to noncoding regions of the genome, i.e., promoters, enhancers, intergenic regions, and noncoding genes, their possible involvement in T1D pathogenesis as gene regulators will also be addressed. PMID:26391391

  11. Studying Genes

    MedlinePLUS

    ... Area What are genes? Genes are sections of DNA that contain instructions for making the molecules—many ... material in an organism. This includes genes and DNA elements that control the activity of genes. Does ...

  12. Heme-related gene expression signatures of meat intakes in lung cancer tissues

    PubMed Central

    Lam, Tram Kim; Rotunno, Melissa; Ryan, Brid M.; Pesatori, Angela C.; Bertazzi, Pier Alberto; Spitz, Margaret; Caporaso, Neil E.; Landi, Maria Teresa

    2014-01-01

    Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the Environment and Genetics in Lung cancer Etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression. We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus-low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a False Discovery Rate (FDR) ?0.15. We studied whether the identified genes played a role in heme-iron related processes by means of manually curated literature search and gene ontology-based pathway analysis. We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR=0.12). Sixty-three (~28%) of the 232 identified genes (12 expected by chance, p-value<0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, UCP3) and oxidative stress (e.g., TPO, SGK2, MTHFR) that may be indirectly related to heme-toxicity. The study’s results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer. PMID:23681825

  13. Understanding Idiopathic Interstitial Pneumonia: A Gene-Based Review of Stressed Lungs

    PubMed Central

    van Moorsel, Coline H. M.; Hoffman, Thijs W.; van Batenburg, Aernoud A.; Klay, Dymph; van der Vis, Joanne J.; Grutters, Jan C.

    2015-01-01

    Pulmonary fibrosis is the main cause of severe morbidity and mortality in idiopathic interstitial pneumonias (IIP). In the past years, there has been major progress in the discovery of genetic factors that contribute to disease. Genes with highly penetrant mutations or strongly predisposing common risk alleles have been identified in familial and sporadic IIP. This review summarizes genes harbouring causative rare mutations and replicated common predisposing alleles. To date, rare mutations in nine different genes and five risk alleles fulfil this criterion. Mutated genes represent three genes involved in surfactant homeostasis and six genes involved in telomere maintenance. We summarize gene function, gene expressing cells, and pathological consequences of genetic alterations associated with disease. Consequences of the genetic alteration include dysfunctional surfactant processing, ER stress, immune dysregulation, and maintenance of telomere length. Biological evidence shows that these processes point towards a central role for alveolar epithelial type II cell dysfunction. However, tabulation also shows that function and consequence of most common risk alleles are not known. Most importantly, the predisposition of the MUC5B risk allele to disease is not understood. We propose a mechanism whereby MUC5B decreases surface tension lowering capacity of alveolar surfactant at areas with maximal mechanical stress. PMID:26539479

  14. NIAM-Deficient Mice Are Predisposed to the Development of Proliferative Lesions including B-Cell Lymphomas

    PubMed Central

    Reed, Sara M.; Hagen, Jussara; Muniz, Viviane P.; Rosean, Timothy R.; Borcherding, Nick; Sciegienka, Sebastian; Goeken, J. Adam; Naumann, Paul W.; Zhang, Weizhou; Tompkins, Van S.; Janz, Siegfried; Meyerholz, David K.; Quelle, Dawn E.

    2014-01-01

    Nuclear Interactor of ARF and Mdm2 (NIAM, gene designation Tbrg1) is a largely unstudied inhibitor of cell proliferation that helps maintain chromosomal stability. It is a novel activator of the ARF-Mdm2-Tip60-p53 tumor suppressor pathway as well as other undefined pathways important for genome maintenance. To examine its predicted role as a tumor suppressor, we generated NIAM mutant (NIAMm/m) mice homozygous for a ?-galactosidase expressing gene-trap cassette in the endogenous gene. The mutant mice expressed significantly lower levels of NIAM protein in tissues compared to wild-type animals. Fifty percent of aged NIAM deficient mice (14 to 21 months) developed proliferative lesions, including a uterine hemangioma, pulmonary papillary adenoma, and a Harderian gland adenoma. No age-matched wild-type or NIAM+/m heterozygous animals developed lesions. In the spleen, NIAMm/m mice had prominent white pulp expansion which correlated with enhanced increased reactive lymphoid hyperplasia and evidence of systemic inflammation. Notably, 17% of NIAM mutant mice had splenic white pulp features indicating early B-cell lymphoma. This correlated with selective expansion of marginal zone B cells in the spleens of younger, tumor-free NIAM-deficient mice. Unexpectedly, basal p53 expression and activity was largely unaffected by NIAM loss in isolated splenic B cells. In sum, NIAM down-regulation in vivo results in a significant predisposition to developing benign tumors or early stage cancers. These mice represent an outstanding platform for dissecting NIAM's role in tumorigenesis and various anti-cancer pathways, including p53 signaling. PMID:25393878

  15. Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner.

    PubMed

    Mochizuki-Kashio, Makiko; Aoyama, Kazumasa; Sashida, Goro; Oshima, Motohiko; Tomioka, Takahisa; Muto, Tomoya; Wang, Changshan; Iwama, Atsushi

    2015-09-01

    Recent genome sequencing revealed inactivating mutations in EZH2, which encodes an enzymatic component of polycomb-repressive complex 2 (PRC2), in patients with myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), and MDS/MPN overlap disorders. We herein demonstrated that the hematopoietic-specific deletion of Ezh2 in mice induced heterogeneous hematopoietic malignancies. Myelodysplasia was detected in mice following the deletion of Ezh2, and resulted in the development of MDS and MDS/MPN. Thrombocytosis was induced by Ezh2 loss and sustained in some mice with myelodysplasia. Although less frequent, Ezh2 loss also induced T-cell acute lymphoblastic leukemia and the clonal expansion of B-1a B cells. Gene expression profiling showed that PRC2 target genes were derepressed upon the deletion of Ezh2 in hematopoietic stem and progenitor cells, but were largely repressed during the development of MDS and MDS/MPN. Chromatin immunoprecipitation-sequence analysis of trimethylation of histone H3 at lysine 27 (H3K27me3) revealed a compensatory function of Ezh1, another enzymatic component of PRC2, in this process. The deletion of Ezh1 alone did not cause dysplasia or any hematologic malignancies in mice, but abolished the repopulating capacity of hematopoietic stem cells when combined with Ezh2 loss. These results clearly demonstrated an essential role of Ezh1 in the pathogenesis of hematopoietic malignancies induced by Ezh2 insufficiency, and highlighted the differential functions of Ezh1 and Ezh2 in hematopoiesis. PMID:26219303

  16. WILLIAMS SYNDROME PREDISPOSES TO VASCULAR STIFFNESS MODIFIED BY ANTI-HYPERTENSIVE USE AND COPY NUMBER CHANGES IN NCF1

    PubMed Central

    Kozel, Beth A.; Danback, Joshua; Waxler, Jessica; Knutsen, Russell H.; Fuentes, Lisa de las; Reusz, Gyorgy S.; Kis, Eva; Bhatt, Ami; Pober, Barbara R

    2014-01-01

    Williams syndrome, is caused by the deletion of 26-28 genes, including elastin, on human chromosome 7. Elastin insufficiency leads to the cardiovascular hallmarks of this condition, namely focal stenosis and hypertension. Extrapolation from the Eln+/? mouse suggests that affected persons may also have stiff vasculature, a risk factor for stroke, myocardial infarction and cardiac death. NCF1, one of the variably deleted Williams genes, is a component of the NAD(P)H oxidase complex and is involved in the generation of oxidative stress, making it an interesting candidate modifier for vascular stiffness. Using a case-control design, vascular stiffness was evaluated by pulse wave velocity in 77 Williams cases and matched controls. Cases had stiffer conducting vessels than controls (p<0.001), with increased stiffness observed in even the youngest Williams children. Pulse wave velocity increased with age at comparable rates in cases and controls and, although the degree of vascular stiffness varied, it was seen in both hypertensive and normotensive Williams participants. Use of anti-hypertension medication and extension of the Williams deletion to include NCF1 were associated with protection from vascular stiffness. These findings demonstrate that vascular stiffness is a primary vascular phenotype in Williams syndrome and that treatment with anti-hypertensives and/or agents inhibiting oxidative stress may be important in managing patients with this condition, potentially even those who are not overtly hypertensive. PMID:24126171

  17. DQB1*06:02-Associated Pathogenic Anti-Myelin Autoimmunity in Multiple Sclerosis-Like Disease: Potential Function of DQB1*06:02 as a Disease-Predisposing Allele

    PubMed Central

    Kaushansky, Nathali; Ben-Nun, Avraham

    2014-01-01

    Susceptibility to multiple sclerosis (MS) has been linked mainly to the HLA-DRB1 locus, with the HLA-DR15 haplotype (DRB1*1501-DQA1*0102-DQB1*0602-DRB5*0101) dominating MS risk in Caucasians. Although genes in the HLA-II region, particularly DRB1*1501, DQA1*0102-DQB1*0602, are in tight linkage disequilibrium, genome-wide-association, and gene candidate studies identified the DRB1*15:01 allele as the primary risk factor in MS. Many genetic and immune-functional studies have indicated DRB1*15:01 as a primary risk factor in MS, while only some functional studies suggested a disease-modifying role for the DRB5*01 or DQB1*06 alleles. In this respect, the susceptibility of DRB1*15:01-transgenic (Tg) mice to myelin basic protein- or myelin oligodendrocyte glycoprotein-induced MS-like disease is consistent with primary contribution of DRB1*15:01 to HLA-DR15+ MS. The studies summarized here show that susceptibility to MS-like disease, induced in HLA-“humanized” mice by myelin oligodendrocytic basic protein or by the proteolipid protein, one of the most prominent encephalitogenic target antigens implicated in human MS, is determined by DQB1*06:02, rather than by the DRB1*15:01 allele. These findings not only offer a rationale for a potential role for DQB1*06:02 in predisposing susceptibility to MS, but also suggest a more complex and differential functional role for HLA-DR15 alleles, depending on the primary target myelin antigen. However, the conflict between these findings in HLA-Tg mice and the extensive genome-wide-association studies, which could not detect any significant effect from the DQB1*06:02 allele on MS risk, is rather puzzling. Functional analysis of MS PBLs for DQB1*06:02-associated anti-myelin autoimmunity may indicate whether or not DQB1*06:02 is associated with MS pathogenesis. PMID:25360418

  18. Induced pluripotency with endogenous and inducible genes

    SciTech Connect

    Duinsbergen, Dirk; Eriksson, Malin; Hoen, Peter A.C. 't; Frisen, Jonas; Mikkers, Harald

    2008-10-15

    The recent discovery that two partly overlapping sets of four genes induce nuclear reprogramming of mouse and even human cells has opened up new possibilities for cell replacement therapies. Although the combination of genes that induce pluripotency differs to some extent, Oct4 and Sox2 appear to be a prerequisite. The introduction of four genes, several of which been linked with cancer, using retroviral approaches is however unlikely to be suitable for future clinical applications. Towards developing a safer reprogramming protocol, we investigated whether cell types that express one of the most critical reprogramming genes endogenously are predisposed to reprogramming. We show here that three of the original four pluripotency transcription factors (Oct4, Klf4 and c-Myc or MYCER{sup TAM}) induced reprogramming of mouse neural stem (NS) cells exploiting endogenous SoxB1 protein levels in these cells. The reprogrammed neural stem cells differentiated into cells of each germ layer in vitro and in vivo, and contributed to mouse development in vivo. Thus a combinatorial approach taking advantage of endogenously expressed genes and inducible transgenes may contribute to the development of improved reprogramming protocols.

  19. Ionizing radiation predisposes non-malignant human mammaryepithelial cells to undergo TGF beta-induced epithelial to mesenchymaltransition

    SciTech Connect

    Andarawewa, Kumari L.; Erickson, Anna C.; Chou, William S.; Costes, Sylvain; Gascard, Philippe; Mott, Joni D.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen

    2007-04-06

    Transforming growth factor {beta}1 (TGF{beta}) is a tumor suppressor during the initial stage of tumorigenesis, but it can switch to a tumor promoter during neoplastic progression. Ionizing radiation (IR), both a carcinogen and a therapeutic agent, induces TGF{beta}, activation in vivo. We now show that IR sensitizes human mammary epithelial cells (HMEC) to undergo TGF{beta}-mediated epithelial to mesenchymal transition (EMT). Non-malignant HMEC (MCF10A, HMT3522 S1 and 184v) were irradiated with 2 Gy shortly after attachment in monolayer culture, or treated with a low concentration of TGF{beta} (0.4 ng/ml), or double-treated. All double-treated (IR+TGF{beta}) HMEC underwent a morphological shift from cuboidal to spindle-shaped. This phenotype was accompanied by decreased expression of epithelial markers E-cadherin, {beta}-catenin and ZO-1, remodeling of the actin cytoskeleton, and increased expression of mesenchymal markers N-cadherin, fibronectin and vimentin. Furthermore, double-treatment increased cell motility, promoted invasion and disrupted acinar morphogenesis of cells subsequently plated in Matrigel{trademark}. Neither radiation nor TGF{beta} alone elicited EMT, even though IR increased chronic TGF{beta} signaling and activity. Gene expression profiling revealed that double treated cells exhibit a specific 10-gene signature associated with Erk/MAPK signaling. We hypothesized that IR-induced MAPK activation primes non-malignant HMEC to undergo TGF{beta}-mediated EMT. Consistent with this, Erk phosphorylation were transiently induced by irradiation, persisted in irradiated cells treated with TGF{beta}, and treatment with U0126, a Mek inhibitor, blocked the EMT phenotype. Together, these data demonstrate that the interactions between radiation-induced signaling pathways elicit heritable phenotypes that could contribute to neoplastic progression.

  20. 27-Hydroxycholesterol up-regulates CD14 and predisposes monocytic cells to superproduction of CCL2 in response to lipopolysaccharide.

    PubMed

    Kim, Sun-Mi; Kim, Bo-Young; Eo, Seong-Kug; Kim, Chi-Dae; Kim, Koanhoi

    2015-03-01

    We investigated the possibility that a cholesterol-rich milieu can accelerate response to pathogen-associated molecular patterns in order to elucidate mechanisms underlying aggravation of atherosclerosis after bacterial infection. The consumption of a high-cholesterol diet resulted in enhanced the expression of CD14 in arteries of ApoE(-/-) mice. 27-Hydroxycholesterol (27OHChol), the most abundant cholesterol oxide in atherosclerotic lesions, induced the significant expression of CD14 by THP-1 monocytic cells, but not by vascular smooth muscle cells or Jurkat T cells. Additions of lipopolysaccharide (LPS) to 27OHChol-treated THP-1 monocytic cells resulted in superinduction in terms of the gene transcription of CCL2 and the secretion of its gene product. In contrast, cholesterol did not cause increased the expression of CD14 in the aforementioned cells, and the addition of LPS to cholesterol-treated monocytic cells did not result in enhanced the expression of CCL2. The conditioned medium isolated from THP-1 cells exposed to 27OHChol plus LPS further induced the migration of monocytic cells in comparison with conditioned media obtained from THP-1 cells treated with 27OHChol or LPS alone. Treatment with 27OHChol also resulted in the enhanced secretion of MMP-9 and soluble CD14 (sCD14), and the secretion of sCD14 was blocked by a selective MMP-9 inhibitor. The inhibition of the ERK pathway resulted in significantly attenuated the secretion of sCD14 via mechanisms that were distinct from those by PI3K inhibition. We propose that 27OHChol can prime monocytes/macrophages by up-regulation of CD14 such that LPS-mediated inflammatory reaction is accelerated, thereby contributing to aggravated development of atherosclerotic lesions by enhancing recruitment of monocytic cells after infection with Gram-negative bacteria. PMID:25497142

  1. TP53 p.R337H is a conditional cancer-predisposing mutation: further evidence from a homozygous patient

    PubMed Central

    2013-01-01

    Background Adrenocortical carcinomas (ACCs) are among the most common childhood cancers occurring in infants affected with the Li-Fraumeni and Li- Fraumeni-like (LFS/LFL) syndromes, which are caused by dominant germline mutations in the TP53 gene. In Brazil, a particular mutation, occurring in the tetramerisation domain of the gene, p.R337H, is exceedingly common due to a founder effect and is strongly associated with ACC. In this report, we describe the phenotype and long-term clinical follow-up of a female child diagnosed with ACC and homozygous for the TP53 p.R337H founder mutation. Case presentation At age 11 months, the patient was diagnosed with a virilising anaplastic adrenal cortical tumour, which was completely excised without disturbing the adrenal capsule. Family history was consistent with an LFL tumour pattern, and genotyping identified the TP53 p.R337H mutation in both alleles in genomic DNA from lymphocytes and fibroblasts. Haplotype analysis confirmed the occurrence of the mutation in the same founder haplotype previously described in other Brazilian patients. No other germline or somatic TP53 mutations or rearrangements were identified. At age 9 years, the child was asymptomatic and had no evidence of endocrine derangements. Full body and brain magnetic resonance imaging (MRI) failed to detect any suspicious proliferative lesions, and cardiopulmonary exercise testing results were within the normal reference for the child’s age, ruling out a major exercise capacity deficiency. Conclusion This is the first clinical and aerobic functional capacity documentation of a patient who carries two mutant TP53 alleles and no wild-type allele. Our results support the hypothesis that TP53 p.R337H, the most common TP53 mutation ever described in any population, is a conditional mutant. Furthermore, our observations over a long period of clinical follow-up suggest that TP53 p.R337H homozygotes do not have a more severe disease phenotype than do heterozygote carriers of the same mutation. Patients with the homozygous TP53 p.R337H genotype will require careful surveillance for lifetime cancer risk and for effects on metabolic capacity later in life. PMID:23570263

  2. Constitutional trisomy 8p11.21-q11.21 mosaicism: a germline alteration predisposing to myeloid leukaemia.

    PubMed

    Ripperger, Tim; Tauscher, Marcel; Praulich, Inka; Pabst, Brigitte; Teigler-Schlegel, Andrea; Yeoh, Allen; Göhring, Gudrun; Schlegelberger, Brigitte; Flotho, Christian; Niemeyer, Charlotte M; Steinemann, Doris

    2011-10-01

    Juvenile myelomonocytic leukaemia (JMML) is a unique myeloproliferative disorder of early childhood. Frequently, mutations in NRAS, KRAS, PTPN11, NF1 or CBL are found in these patients. Monosomy 7 is the most common cytogenetic aberration. To identify submicroscopic genomic copy number alterations, 20 JMML samples were analysed by comparative genomic hybridization. Ten out of 20 samples displayed additional submicroscopic alterations. In two patients, an almost identical gain of chromosome 8 was identified. In both patients, fluorescence in situ hybridization confirmed a constitutional partial trisomy 8 mosaic (cT8M). A survey on 27 cT8M patients with neoplasms showed that 21 had myeloid malignancies, and five of these had a JMML. Notably, the region gained in our cases is the smallest gain of chromosome 8 reported in cT8M cases with malignancies so far. Our results dramatically reduce the critical region to 8p11.21q11.21 harbouring 31 protein coding genes and two non-coding RNAs, e.g. MYST3, IKBKB, UBE2V2, GOLGA7, FNTA and MIR486--a finding with potential implications for the role of somatic trisomy 8 in myeloid malignancies. Further investigations are required to more comprehensively determine how constitutional partial trisomy 8 mosaicisms may contribute to leukaemogenesis in different mutational subtypes of JMML and other myeloid malignancies. PMID:21848520

  3. The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

    PubMed

    Sakae, D Y; Marti, F; Lecca, S; Vorspan, F; Martín-García, E; Morel, L J; Henrion, A; Gutiérrez-Cuesta, J; Besnard, A; Heck, N; Herzog, E; Bolte, S; Prado, V F; Prado, M A M; Bellivier, F; Eap, C B; Crettol, S; Vanhoutte, P; Caboche, J; Gratton, A; Moquin, L; Giros, B; Maldonado, R; Daumas, S; Mameli, M; Jamain, S; El Mestikawy, S

    2015-11-01

    Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse. PMID:26239290

  4. [Gene expression and its role on urolithiasis].

    PubMed

    Miyazawa, Katsuhito; Suzuki, Koji

    2011-10-01

    Kidney stone disease is a common condition, affecting up to 10% of the population in Japan as well as in the industrial world. Calcium oxalate is major stone composition, consists of crystal and stone matrix, and arises from a combination of environmental and genetic factors. To date, considerable progress has been made identifying the metabolic risk factors predisposing to this complex disease. The familial association of calcium oxalate stone has been corroborated by numerous studies. The specific genetic and epigenetic factors have remained less clear. However genetic variations have indicated using single nucleotide polymorphism (SNP) , and recent technological advances by way of commercially available SNP array or chips, which capture common human variation across the entire genome, have been revolutionizing the study and identifying a new gene as a risk locus in idiopathic calcium oxalate kidney stone disease. PMID:21960232

  5. Targeted resequencing of candidate genes reveals novel variants associated with severe Behçet's uveitis

    PubMed Central

    Kim, Sang Jin; Lee, Seungbok; Park, Changho; Seo, Jeong-Sun; Kim, Jong-Il; Yu, Hyeong Gon

    2013-01-01

    Behçet's disease (BD) is a chronic systemic inflammatory disorder characterized by four major manifestations: recurrent uveitis, oral and genital ulcers and skin lesions. To identify some pathogenic variants associated with severe Behçet's uveitis, we used targeted and massively parallel sequencing methods to explore the genetic diversity of target regions. A solution-based target enrichment kit was designed to capture whole-exonic regions of 132 candidate genes. Using a multiplexing strategy, 32 samples from patients with a severe type of Behçet's uveitis were sequenced with a Genome Analyzer IIx. We compared the frequency of each variant with that of 59 normal Korean controls, and selected five rare and eight common single-nucleotide variants as the candidates for a replication study. The selected variants were genotyped in 61 cases and 320 controls and, as a result, two rare and seven common variants showed significant associations with severe Behçet's uveitis (P<0.05). Some of these, including rs199955684 in KIR3DL3, rs1801133 in MTHFR, rs1051790 in MICA and rs1051456 in KIR2DL4, were predicted to be damaging by either the PolyPhen-2 or SIFT prediction program. Variants on FCGR3A (rs396991) and ICAM1 (rs5498) have been previously reported as susceptibility loci of this disease, and those on IFNAR1, MTFHR and MICA also replicated the previous reports at the gene level. The KIR3DL3 and KIR2DL4 genes are novel susceptibility genes that have not been reported in association with BD. In conclusion, this study showed that target enrichment and next-generation sequencing technologies can provide valuable information on the genetic predisposition for Behçet's uveitis. PMID:24136464

  6. Mutation Screening of the Neurexin 1 Gene in Thai Patients with Intellectual Disability and Autism Spectrum Disorder

    PubMed Central

    Yangngam, Supaporn; Plong-On, Oradawan; Sripo, Thanya; Roongpraiwan, Rawiwan; Hansakunachai, Tippawan; Wirojanan, Juthamas; Sombuntham, Tasnawat; Ruangdaraganon, Nichara

    2014-01-01

    Aim: Neurexin 1 has two major protein isoforms using alternative promoters, coding for the alpha-neurexin 1 (?-NRXN1) and beta-neurexin 1 (?-NRXN1) genes. This study is to explore the possibility that variants of the NRXN1 gene predispose to intellectual disability (ID) and autism spectrum disorder (ASD). Methods: The coding regions in 24 exons and exon–intron boundaries of the NRXN1 gene were investigated in 115 Thai patients with ID and ASD by direct DNA sequencing. Results: Nine novel variants of the NRXN1 gene were identified. Four novel variants were found in the ?-NRXN1 gene, one variant of six GGC repeats in exon 1, and three variants at the 5?UTR. Five novel variants were identified in the ?-NRXN1 gene, four intronic variants and one missense variant in exon 14 (c.2713T>A or p.F905I). Conclusion: Mutation screening of the NRXN1gene in patients with ID and ASD may be useful to identify potential variants predisposing to ID and ASD. However, further studies utilizing protein functional analysis of the novel variants are required for a more definite conclusion. PMID:24832020

  7. Genes to Diseases (G2D) Computational Method to Identify Asthma Candidate Genes

    PubMed Central

    Tremblay, Karine; Lemire, Mathieu; Potvin, Camille; Tremblay, Alexandre; Hunninghake, Gary M.; Raby, Benjamin A.; Hudson, Thomas J.; Perez-Iratxeta, Carolina; Andrade-Navarro, Miguel A.; Laprise, Catherine

    2008-01-01

    Asthma is a complex trait for which different strategies have been used to identify its environmental and genetic predisposing factors. Here, we describe a novel methodological approach to select candidate genes for asthma genetic association studies. In this regard, the Genes to Diseases (G2D) computational tool has been used in combination with a genome-wide scan performed in a sub-sample of the Saguenay?Lac-St-Jean (SLSJ) asthmatic familial collection (n?=?609) to identify candidate genes located in two suggestive loci shown to be linked with asthma (6q26) and atopy (10q26.3), and presenting differential parent-of-origin effects. This approach combined gene selection based on the G2D data mining analysis of the bibliographic and protein public databases, or according to the genes already known to be associated with the same or a similar phenotype. Ten genes (LPA, NOX3, SNX9, VIL2, VIP, ADAM8, DOCK1, FANK1, GPR123 and PTPRE) were selected for a subsequent association study performed in a large SLSJ sample (n?=?1167) of individuals tested for asthma and atopy related phenotypes. Single nucleotide polymorphisms (n?=?91) within the candidate genes were genotyped and analysed using a family-based association test. The results suggest a protective association to allergic asthma for PTPRE rs7081735 in the SLSJ sample (p?=?0.000463; corrected p?=?0.0478). This association has not been replicated in the Childhood Asthma Management Program (CAMP) cohort. Sequencing of the regions around rs7081735 revealed additional polymorphisms, but additional genotyping did not yield new associations. These results demonstrate that the G2D tool can be useful in the selection of candidate genes located in chromosomal regions linked to a complex trait. PMID:18682798

  8. Medical exposures in youth and the frequency of narcolepsy with cataplexy: a population-based case-control study in genetically predisposed people.

    PubMed

    Koepsell, Thomas D; Longstreth, William T; Ton, Thanh G N

    2010-03-01

    Epidemiological observations suggest that exposures in youth may trigger narcolepsy in genetically predisposed individuals. In this population-based case-control study, we sought to identify all prevalent cases of narcolepsy with cataplexy aged 18-50 years as of 1 July 2001, in King County, Washington. The 45 eligible cases who were DQB1*0602-positive were compared with 95 controls with this allele, identified through random-digit dialing and buccal smears. Cases and controls were interviewed in person about physician-diagnosed infectious and non-infectious illnesses, immunizations, head trauma and parasomnias or psychiatric problems during youth. Narcolepsy with cataplexy was more frequent in African-Americans and in poorer households. Adjusting for these factors, the condition was 5.4-fold more common [95% confidence interval (CI) = 1.5-19.1] among people reporting a physician-diagnosed strep throat before the age of 21 years. No other significant associations with childhood diseases, immunizations or head trauma were found. However, prevalence was increased 16.3-fold (95% CI = 6.1-44.1) in subjects who reported having had 'night terrors'. Strep throat may be related to narcolepsy with cataplexy in genetically susceptible individuals. The association with night terrors could simply reflect early symptoms of narcolepsy, or they could be a prodromal sign of disturbed sleep physiology. PMID:19732319

  9. Modulation of inflammatory genes by natural dietary bioactive compounds.

    PubMed

    Pan, Min-Hsiung; Lai, Ching-Shu; Dushenkov, Slavik; Ho, Chi-Tang

    2009-06-10

    Several epidemiologic studies have shown that chronic inflammation predisposes individuals to various types of cancer. Many cancers arise from sites of infection, chronic irritation, and inflammation. Conversely, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumors. Natural bioactive compounds in dietary plant products including fruits, vegetables, grains, legumes, tea, and wine are claimed to help prevent cancer, degenerative diseases, and chronic and acute inflammation. Modern methods in cell and molecular biology allow us to understand the interactions of different natural bioactive compounds with basic mechanisms of inflammatory response. The molecular pathways of this cancer-related inflammation are now unraveled. Natural bioactive compounds exert anti-inflammatory activity by modulating pro-inflammatory gene expressions have shown promising chemopreventive activity. This review summarizes current knowledge on natural bioactive compounds that act through the signaling pathways and modulate inflammatory gene expressions, thus providing evidence for these substances in cancer chemopreventive action. PMID:19489612

  10. Obstructive heart defects associated with candidate genes, maternal obesity, and folic acid supplementation.

    PubMed

    Tang, Xinyu; Cleves, Mario A; Nick, Todd G; Li, Ming; MacLeod, Stewart L; Erickson, Stephen W; Li, Jingyun; Shaw, Gary M; Mosley, Bridget S; Hobbs, Charlotte A

    2015-06-01

    Right-sided and left-sided obstructive heart defects (OHDs) are subtypes of congenital heart defects, in which the heart valves, arteries, or veins are abnormally narrow or blocked. Previous studies have suggested that the development of OHDs involved a complex interplay between genetic variants and maternal factors. Using the data from 569 OHD case families and 1,644 control families enrolled in the National Birth Defects Prevention Study (NBDPS) between 1997 and 2008, we conducted an analysis to investigate the genetic effects of 877 single nucleotide polymorphisms (SNPs) in 60 candidate genes for association with the risk of OHDs, and their interactions with maternal use of folic acid supplements, and pre-pregnancy obesity. Applying log-linear models based on the hybrid design, we identified a SNP in methylenetetrahydrofolate reductase (MTHFR) gene (C677T polymorphism) with a main genetic effect on the occurrence of OHDs. In addition, multiple SNPs in betaine-homocysteine methyltransferase (BHMT and BHMT2) were also identified to be associated with the occurrence of OHDs through significant main infant genetic effects and interaction effects with maternal use of folic acid supplements. We also identified multiple SNPs in glutamate-cysteine ligase, catalytic subunit (GCLC) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) that were associated with elevated risk of OHDs among obese women. Our findings suggested that the risk of OHDs was closely related to a combined effect of variations in genes in the folate, homocysteine, or glutathione/transsulfuration pathways, maternal use of folic acid supplements and pre-pregnancy obesity. PMID:25846410

  11. Gene Concepts, Gene Talk, and Gene Patents

    E-print Network

    Torrance, Andrew W.

    2010-01-01

    concepts have exerted strong effects on institutions such as medicine, the biotechnology industry, politics, and the law. A particularly rich example of this is the interplay between gene concepts and patent law. Over the last century, biology has...

  12. Altered Circadian Rhythm and Metabolic Gene Profile in Rats Subjected to Advanced Light Phase Shifts

    PubMed Central

    Herrero, Laura; Valcarcel, Lorea; da Silva, Crhistiane Andressa; Albert, Nerea; Diez-Noguera, Antoni; Cambras, Trinitat; Serra, Dolors

    2015-01-01

    The circadian clock regulates metabolic homeostasis and its disruption predisposes to obesity and other metabolic diseases. However, the effect of phase shifts on metabolism is not completely understood. We examined whether alterations in the circadian rhythm caused by phase shifts induce metabolic changes in crucial genes that would predispose to obesity. Three-month-old rats were maintained on a standard diet under lighting conditions with chronic phase shifts consisting of advances, delays or advances plus delays. Serum leptin, insulin and glucose levels decreased only in rats subjected to advances. The expression of the clock gene Bmal 1 increased in the hypothalamus, white adipose tissue (WAT), brown adipose tissue (BAT) and liver of the advanced group compared to control rats. The advanced group showed an increase in hypothalamic AgRP and NPY mRNA, and their lipid metabolism gene profile was altered in liver, WAT and BAT. WAT showed an increase in inflammation and ER stress and brown adipocytes suffered a brown-to-white transformation and decreased UCP-1 expression. Our results indicate that chronic phase advances lead to significant changes in neuropeptides, lipid metabolism, inflammation and ER stress gene profile in metabolically relevant tissues such as the hypothalamus, liver, WAT and BAT. This highlights a link between alteration of the circadian rhythm and metabolism at the transcriptional level. PMID:25837425

  13. Linkage analysis of schizophrenia with five dopamine receptor genes in nine pedigrees

    SciTech Connect

    Coon, H.; Byerley, W.; Holik, J.; Hoff, M.; Myles-Worsley, M.; Plaetke, R. ); Lannfelt, L. ); Sokoloff, P.; Schwartz, J.C. ); Waldo, M.; Freedman, R. )

    1993-02-01

    Alterations in dopamine neurotransmission have been strongly implicated in the pathogenesis of schizophrenia for nearly 2 decades. Recently, the genes for five dopamine receptors have been cloned and characterized, and genetic and physical map information has become available. Using these five loci as candidate genes, the authors have tested for genetic linkage to schizophrenia in nine multigenerational families which include multiple affected individuals. In addition to testing conservative disease models, the have used a neurophysiological indicator variable, the P50 auditory evoked response. Deficits in gating of the P50 response have been shown to segregate with schizophrenia in this sample and may identify carriers of gene(s) predisposing for schizophrenia. Linkage results were consistently negative, indicating that a defect at any of the actual receptor sites is unlikely to be a major contributor to schizophrenia in the nine families studied. 47 refs., 1 fig., 4 tabs.

  14. Gene-Gene Associations with the Susceptibility of Kawasaki Disease and Coronary Artery Lesions

    PubMed Central

    Kuo, Ho-Chang; Chang, Jen-Chieh; Guo, Mindy Ming-Huey; Hsieh, Kai-Sheng; Yeter, Deniz; Li, Sung-Chou; Yang, Kuender D.

    2015-01-01

    Kawasaki disease (KD) is a systemic vasculitis primarily affecting children < 5 years old. Genes significantly associated with KD mostly involve cardiovascular, immune, and inflammatory responses. Recent studies have observed stronger associations for KD risk with multiple genes compared to individual genes. Therefore, we investigated whether gene combinations influenced KD susceptibility or coronary artery lesion (CAL) formation. We examined 384 single-nucleotide polymorphisms (SNPs) for 159 immune-related candidate genes in DNA samples from KD patients with CAL (n = 73), KD patients without CAL (n = 153), and cohort controls (n = 575). Individual SNPs were first assessed by univariate analysis (UVA) and multivariate analysis (MVA). We used multifactor dimensionality reduction (MDR) to examine individual SNPs in one-, two-, and three-locus best fit models. UVA identified 53 individual SNPs that were significantly associated with KD risk or CAL formation (p < 0.10), while 35 individual SNPs were significantly associated using MVA (p ? 0.05). Significant associations in MDR analysis were only observed for the two-locus models after permutation testing (p ? 0.05). In logistic regression, combined possession of PDE2A (rs341058) and CYFIP2 (rs767007) significantly increased KD susceptibility (OR = 3.54; p = 4.14 x 10?7), while combinations of LOC100133214 (rs2517892) and IL2RA (rs3118470) significantly increased the risk of CAL in KD patients (OR = 5.35; p = 7.46 x 10?5). Our results suggest varying gene-gene associations respectively predispose individuals to KD risk or its complications of CAL. PMID:26619243

  15. Identifying Clients Predisposed To Failure

    ERIC Educational Resources Information Center

    Carnes, G. D.

    1973-01-01

    Studies are reviewed that report the prediction of rehabilitation failure from personality measures. Related research is discussed that suggest the dynamics underlying a key concept, the "hypochondriacally organized personality" which is identifiable from the Rorschach anatomy response percentage. (Author)

  16. Prior pathology in the basal forebrain cholinergic system predisposes to inflammation-induced working memory deficits: reconciling inflammatory and cholinergic hypotheses of delirium.

    PubMed

    Field, Robert H; Gossen, Anna; Cunningham, Colm

    2012-05-01

    Delirium is a profound, acute confusional state that leads to long-term cognitive decline. Increased anticholinergic medications and prior dementia, in which basal forebrain cholinergic degeneration is a prominent feature, both predict delirium. Thus, cholinergic hypoactivity is thought to be important in cognitive dysfunction during delirium, and acute systemic inflammation is a major trigger for this dysfunction. Here, we hypothesize that decreased cholinergic function confers increased susceptibility to acute inflammation-induced cognitive deficits. We used the murine-p75-saporin immunotoxin (mu-p75-sap) to induce selective lesions of the basal forebrain cholinergic system in mice, mimicking early dementia-associated cholinergic loss, and superimposed systemic inflammation using low-dose bacterial lipopolysaccharide (LPS). Intracerebroventricular injection of mu-p75-sap produced depletion of cholinergic neurons in the basal forebrain and decreased innervation of the hippocampus, but left performance on hippocampal-dependent reference and working memory tasks relatively intact. However, systemic LPS (100 ?g/kg) induced acute and transient working memory deficits in lesioned animals without effect in unlesioned controls. CNS inflammatory responses were similar in normal and lesioned animals and the acetylcholinesterase inhibitor, donepezil (1 mg/kg), protected against the acute cognitive deficits in this cholinergic-dependent task. Thus, cholinergic depletion predisposes to development of acute cognitive deficits upon subsequent systemic inflammatory insult. These data provide a useful model for examining interactions between acute systemic inflammation and chronic cholinergic hypofunction in delirium and have implications for the recent trial of rivastigmine in sepsis-associated delirium. PMID:22553034

  17. Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease: A Scientific Statement From the American Heart Association.

    PubMed

    Goldstein, Benjamin I; Carnethon, Mercedes R; Matthews, Karen A; McIntyre, Roger S; Miller, Gregory E; Raghuveer, Geetha; Stoney, Catherine M; Wasiak, Hank; McCrindle, Brian W

    2015-09-01

    In the 2011 "Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents," several medical conditions among youth were identified that predispose to accelerated atherosclerosis and early cardiovascular disease (CVD), and risk stratification and management strategies for youth with these conditions were elaborated. Major depressive disorder (MDD) and bipolar disorder (BD) among youth satisfy the criteria set for, and therefore merit inclusion among, Expert Panel tier II moderate-risk conditions. The combined prevalence of MDD and BD among adolescents in the United States is ?10%, at least 10 times greater than the prevalence of the existing moderate-risk conditions combined. The high prevalence of MDD and BD underscores the importance of positioning these diseases alongside other pediatric diseases previously identified as moderate risk for CVD. The overall objective of this statement is to increase awareness and recognition of MDD and BD among youth as moderate-risk conditions for early CVD. To achieve this objective, the primary specific aims of this statement are to (1) summarize evidence that MDD and BD are tier II moderate-risk conditions associated with accelerated atherosclerosis and early CVD and (2) position MDD and BD as tier II moderate-risk conditions that require the application of risk stratification and management strategies in accordance with Expert Panel recommendations. In this scientific statement, there is an integration of the various factors that putatively underlie the association of MDD and BD with CVD, including pathophysiological mechanisms, traditional CVD risk factors, behavioral and environmental factors, and psychiatric medications. PMID:26260736

  18. The cognitive-interpersonal maintenance model of anorexia nervosa revisited: a summary of the evidence for cognitive, socio-emotional and interpersonal predisposing and perpetuating factors

    PubMed Central

    2013-01-01

    Aim To describe the evidence base relating to the Cognitive-Interpersonal Maintenance Model for anorexia nervosa (AN). Background A Cognitive-Interpersonal Maintenance Model maintenance model for anorexia nervosa was described in 2006. This model proposed that cognitive, socio-emotional and interpersonal elements acted together to both cause and maintain eating disorders. Method A review of the empirical literature relating to the key constructs of the model (cognitive, socio-emotional, interpersonal) risk and maintaining factors for anorexia nervosa was conducted. Results Set shifting and weak central coherence (associated with obsessive compulsive traits) have been widely studied. There is some evidence to suggest that a strong eye for detail and weak set shifting are inherited vulnerabilities to AN. Set shifting and global integration are impaired in the ill state and contribute to weak central coherence. In addition, there are wide-ranging impairments in socio-emotional processing including: an automatic bias in attention towards critical and domineering faces and away from compassionate faces; impaired signalling of, interpretation and regulation of emotions. Difficulties in social cognition may in part be a consequence of starvation but inherited vulnerabilities may also contribute to these traits. The shared familial traits may accentuate family members’ tendency to react to the frustrating and frightening symptoms of AN with high expressed emotion (criticism, hostility, overprotection), and inadvertently perpetuate the problem. Conclusion The cognitive interpersonal model is supported by accumulating evidence. The model is complex in that cognitive and socio-emotional factors both predispose to the illness and are exaggerated in the ill state. Furthermore, some of the traits are inherited vulnerabilities and are present in family members. The clinical formulations from the model are described as are new possibilities for targeted treatment. PMID:24999394

  19. Increased Stiffness Is the Major Early Abnormality in a Pig Model of Severe Aortic Stenosis and Predisposes to Congestive Heart Failure in the Absence of Systolic Dysfunction

    PubMed Central

    Ishikawa, Kiyotake; Aguero, Jaume; Oh, Jae Gyun; Hammoudi, Nadjib; A Fish, Lauren; Leonardson, Lauren; Picatoste, Belén; Santos-Gallego, Carlos G; M. Fish, Kenneth; Hajjar, Roger J

    2015-01-01

    Background It remains unclear whether abnormal systolic function and relaxation are essential for developing heart failure in pathophysiology of severe aortic stenosis. Methods and Results Yorkshire pigs underwent surgical banding of the ascending aorta. The animals were followed for up to 5 months after surgery, and cardiac function was assessed comprehensively by invasive pressure–volume measurements, 3-dimensional echocardiography, echocardiographic speckle-tracking strain, and postmortem molecular and histological analyses. Pigs with aortic banding (n=6) exhibited significant left ventricular hypertrophy with increased stiffness compared with the control pigs (n=7) (end-diastolic pressure–volume relationship ?: 0.053±0.017 versus 0.028±0.009 mm Hg/mL, P=0.007); however, all other parameters corresponding to systolic function, including ejection fraction, end-systolic pressure–volume relationship, preload recruitable stroke work, echocardiographic circumferential strain, and longitudinal strain, were not impaired in pigs with aortic banding. Relaxation parameters were also similar between groups. Sarcoplasmic reticulum calcium (Ca2+) ATPase protein levels in the left ventricle were similar. There were significant increases in 3-dimensional echocardiographic left atrial volumes, suggesting the usefulness of these indexes to detect increased stiffness. Right atrial pacing with a heart rate of 120 beats per minute induced increased end-diastolic pressure in pigs with aortic banding in contrast to decreased end-diastolic pressure in the control pigs. Histological evaluation revealed that increased stiffness was accompanied by cardiomyocyte hypertrophy and increased perimysial and perivascular fibrosis. Conclusion Increased stiffness is the major early pathological process that predisposes to congestive heart failure without abnormalities in systolic function and relaxation in a clinically relevant animal model of aortic stenosis. PMID:25994443

  20. Trichoderma genes

    DOEpatents

    Foreman, Pamela (Los Altos, CA); Goedegebuur, Frits (Vlaardingen, NL); Van Solingen, Pieter (Naaldwijk, NL); Ward, Michael (San Francisco, CA)

    2012-06-19

    Described herein are novel gene sequences isolated from Trichoderma reesei. Two genes encoding proteins comprising a cellulose binding domain, one encoding an arabionfuranosidase and one encoding an acetylxylanesterase are described. The sequences, CIP1 and CIP2, contain a cellulose binding domain. These proteins are especially useful in the textile and detergent industry and in pulp and paper industry.

  1. Mapping eQTLs in the Norfolk Island Genetic Isolate Identifies Candidate Genes for CVD Risk Traits

    PubMed Central

    Benton, Miles C.; Lea, Rod A.; Macartney-Coxson, Donia; Carless, Melanie A.; Göring, Harald H.; Bellis, Claire; Hanna, Michelle; Eccles, David; Chambers, Geoffrey K.; Curran, Joanne E.; Harper, Jacquie L.; Blangero, John; Griffiths, Lyn R.

    2013-01-01

    Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10?7) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations. PMID:24314549

  2. Population-Calibrated Gene Characterization: Estimating Age at Onset Distributions Associated With Cancer Genes

    PubMed Central

    Iversen, Edwin S.; Chen, Sining

    2008-01-01

    Phenotypic characterization of rare disease genes poses a significant statistical challenge, but the need to do so is clear. Clinical management of patients carrying a disease gene depends crucially on an accurate characterization of the genetically predisposed disease, including its likelihood of occurrence among mutation carriers, natural history, and response to treatment. We propose a formal yet practical method for controlling for bias due to ignoring ascertainment, defined as the sampling mechanism, when quantifying the association between genotype and disease using data on high-risk families. The approach is more statistically efficient than conditioning on the variables used in sampling. In it, the likelihood is adjusted by a factor that is a function of sampling weights in strata defined by those variables. It requires that these variables and the sampling probabilities in the strata they define either are known or can be estimated. The latter requires a second, population-based dataset. As an example, we derive ascertainment-corrected estimates of penetrance for the breast cancer susceptibility genes BRCA1 and BRCA2. The Bayesian analysis that we use incorporates a modified segregation model and prior data on penetrance derived from the literature. Markov chain Monte Carlo methods are used for inference. PMID:18418465

  3. Loci influencing blood pressure identified using a cardiovascular gene-centric array

    PubMed Central

    Ganesh, Santhi K.; Tragante, Vinicius; Guo, Wei; Guo, Yiran; Lanktree, Matthew B.; Smith, Erin N.; Johnson, Toby; Castillo, Berta Almoguera; Barnard, John; Baumert, Jens; Chang, Yen-Pei Christy; Elbers, Clara C.; Farrall, Martin; Fischer, Mary E.; Franceschini, Nora; Gaunt, Tom R.; Gho, Johannes M.I.H.; Gieger, Christian; Gong, Yan; Isaacs, Aaron; Kleber, Marcus E.; Leach, Irene Mateo; McDonough, Caitrin W.; Meijs, Matthijs F.L.; Mellander, Olle; Molony, Cliona M.; Nolte, Ilja M.; Padmanabhan, Sandosh; Price, Tom S.; Rajagopalan, Ramakrishnan; Shaffer, Jonathan; Shah, Sonia; Shen, Haiqing; Soranzo, Nicole; van der Most, Peter J.; Van Iperen, Erik P.A.; Van Setten, Jessic A.; Vonk, Judith M.; Zhang, Li; Beitelshees, Amber L.; Berenson, Gerald S.; Bhatt, Deepak L.; Boer, Jolanda M.A.; Boerwinkle, Eric; Burkley, Ben; Burt, Amber; Chakravarti, Aravinda; Chen, Wei; Cooper-DeHoff, Rhonda M.; Curtis, Sean P.; Dreisbach, Albert; Duggan, David; Ehret, Georg B.; Fabsitz, Richard R.; Fornage, Myriam; Fox, Ervin; Furlong, Clement E.; Gansevoort, Ron T.; Hofker, Marten H.; Hovingh, G. Kees; Kirkland, Susan A.; Kottke-Marchant, Kandice; Kutlar, Abdullah; LaCroix, Andrea Z.; Langaee, Taimour Y.; Li, Yun R.; Lin, Honghuang; Liu, Kiang; Maiwald, Steffi; Malik, Rainer; Murugesan, Gurunathan; Newton-Cheh, Christopher; O'Connell, Jeffery R.; Onland-Moret, N. Charlotte; Ouwehand, Willem H.; Palmas, Walter; Penninx, Brenda W.; Pepine, Carl J.; Pettinger, Mary; Polak, Joseph F.; Ramachandran, Vasan S.; Ranchalis, Jane; Redline, Susan; Ridker, Paul M.; Rose, Lynda M.; Scharnag, Hubert; Schork, Nicholas J.; Shimbo, Daichi; Shuldiner, Alan R.; Srinivasan, Sathanur R.; Stolk, Ronald P.; Taylor, Herman A.; Thorand, Barbara; Trip, Mieke D.; van Duijn, Cornelia M.; Verschuren, W. Monique; Wijmenga, Cisca; Winkelmann, Bernhard R.; Wyatt, Sharon; Young, J. Hunter; Boehm, Bernhard O.; Caulfield, Mark J.; Chasman, Daniel I.; Davidson, Karina W.; Doevendans, Pieter A.; FitzGerald, Garret A.; Gums, John G.; Hakonarson, Hakon; Hillege, Hans L.; Illig, Thomas; Jarvik, Gail P.; Johnson, Julie A.; Kastelein, John J.P.; Koenig, Wolfgang; März, Winfried; Mitchell, Braxton D.; Murray, Sarah S.; Oldehinkel, Albertine J.; Rader, Daniel J.; Reilly, Muredach P.; Reiner, Alex P.; Schadt, Eric E.; Silverstein, Roy L.; Snieder, Harold; Stanton, Alice V.; Uitterlinden, André G.; van der Harst, Pim; van der Schouw, Yvonne T.; Samani, Nilesh J.; Johnson, Andrew D.; Munroe, Patricia B.; de Bakker, Paul I.W.; Zhu, Xiaofeng; Levy, Daniel; Keating, Brendan J.; Asselbergs, Folkert W.

    2013-01-01

    Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ?50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ?2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10?6). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention. PMID:23303523

  4. Studying Genes

    MedlinePLUS

    ... one generation to the next. What is a genome? A genome is all of the genetic material in an ... activity of genes. Does everybody have the same genome? While the human genome is mostly the same ...

  5. Resilience to orthostasis and haemorrhage: A pilot study of common genetic and conditioning mechanisms

    PubMed Central

    Davydov, Dmitry M.; Zhdanov, Renad I.; Dvoenosov, Vladimir G.; Kravtsova, Olga A.; Voronina, Elena N.; Filipenko, Maxim L.

    2015-01-01

    A major challenge presently is not only to identify the genetic polymorphisms increasing risk to diseases, but to also find out factors and mechanisms, which can counteract a risk genotype by developing a resilient phenotype. The objective of this study was to examine acquired and innate vagal mechanisms that protect against physical challenges and haemorrhages in 19 athletes and 61 non-athletes. These include examining change in heart rate variability (HF-HRV; an indicator of vagus activity) in response to orthostatic challenge, platelet count (PLT), mean platelet volume (MPV), and single-nucleotide polymorphisms in genes that encode several coagulation factors, PAI-1, and MTHFR. Individual differences in PLT and MPV were significant predictors, with opposite effects, of the profiles of the HF-HRV changes in response to orthostasis. Regular physical training of athletes indirectly (through MPV) modifies the genetic predisposing effects of some haemostatic factors (PAI-1 and MTHFR) on vagal tone and reactivity. Individual differences in vagal tone were also associated with relationships between Factor 12 C46T and Factor 11 C22771T genes polymorphisms. This study showed that genetic predispositions for coagulation are modifiable. Its potential significance is promoting advanced protection against haemorrhages in a variety of traumas and injuries, especially in individuals with coagulation deficits. PMID:26024428

  6. Gene Coexpression Networks in Human Brain Developmental Transcriptomes Implicate the Association of Long Noncoding RNAs with Intellectual Disability

    PubMed Central

    Gudenas, Brian L.; Wang, Liangjiang

    2015-01-01

    The advent of next-generation sequencing for genetic diagnoses of complex developmental disorders, such as intellectual disability (ID), has facilitated the identification of hundreds of predisposing genetic variants. However, there still exists a vast gap in our knowledge of causal genetic factors for ID as evidenced by low diagnostic yield of genetic screening, in which identifiable genetic causes are not found for the majority of ID cases. Most methods of genetic screening focus on protein-coding genes; however, noncoding RNAs may outnumber protein-coding genes and play important roles in brain development. Long noncoding RNAs (lncRNAs) specifically have been shown to be enriched in the brain and have diverse roles in gene regulation at the transcriptional and posttranscriptional levels. LncRNAs are a vastly uncharacterized group of noncoding genes, which could function in brain development and harbor ID-predisposing genetic variants. We analyzed lncRNAs for coexpression with known ID genes and affected biological pathways within a weighted gene coexpression network derived from RNA-sequencing data spanning human brain development. Several ID-associated gene modules were found to be enriched for lncRNAs, known ID genes, and affected biological pathways. Utilizing a list of de novo and pathogenic copy number variants detected in ID probands, we identified lncRNAs overlapping these genetic structural variants. By integrating our results, we have made a prioritized list of potential ID-associated lncRNAs based on the developing brain gene coexpression network and genetic structural variants found in ID probands. PMID:26523118

  7. pRb2/p130: a gene target for diagnosis and treatment of cancer.

    PubMed

    Coleman, William B; Rivenbark, Ashley G

    2008-10-01

    This application claims: i) a method for detecting cancer cells based on analysis of gene mutations and/or promoter methylation of the pRb2/p130 gene; ii) a method for diagnosing cancer based on analysis of gene mutations and/or promoter methylation of the pRb2/p130 gene; iii) a method for detection of cells that are predisposed to tumorigenesis based on analysis of gene mutations and/or promoter methylation of the pRb2/p130 gene; iv) a method for treating cancer and/or inhibiting tumorigenesis based on demethylation of the pRb2/p130 gene promoter; and v) a method for treating cancer and/or inhibiting tumorigenesis based on inhibition of other proteins that interact with or regulate pRb2/p130. This application is founded on the recognition that: i) pRb2/p130 is a frequent target of genetic or epigenetic alteration in various human cancers; ii) the resulting loss of regulation of cell cycle progression contributes to the phenotypic characteristics of these neoplasms; iii) pRb2/p130 represents a valuable biomarker for detection/diagnosis of some cancers; and iv) pRb2/p130 may be a useful gene target for development of new cancer therapeutics. PMID:23496428

  8. SERCA2a Gene Transfer Decreases SR Calcium Leak and Reduces Ventricular Arrhythmias in a Model of Chronic Heart Failure

    PubMed Central

    Lyon, Alexander R.; Bannister, Mark L.; Collins, Tom; Pearce, Emma; Sepehripour, Amir H.; Dubb, Sukhpreet S.; Garcia, Edwin; O'Gara, Peter; Liang, Lifan; Kohlbrenner, Erik; Hajjar, Roger J.; Peters, Nicholas S.; Poole-Wilson, Philip A.; Macleod, Ken T.; Harding, Sian E.

    2011-01-01

    Background Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy improves mechanical function in heart failure, and is under evaluation in a clinical trial. A critical question is whether SERCA2a gene therapy predisposes to increased sarcoplasmic reticulum calcium (SR Ca2+) leak, cellular triggered activity and ventricular arrhythmias in the failing heart. Methods and Results We studied the influence of SERCA2a gene therapy upon ventricular arrhythmogenesis in a rat chronic heart failure model. ECG telemetry studies revealed a significant antiarrhythmic effect of SERCA2a gene therapy with reduction of both spontaneous and catecholamine-induced arrhythmias in vivo. SERCA2a gene therapy also reduced susceptibility to reentry arrhythmias in ex vivo programmed electrical stimulation studies. Subcellular Ca2+ homeostasis and spontaneous SR Ca2+ leak characteristics were measured in failing cardiomyocytes transfected in vivo with a novel AAV9.SERCA2a vector. SR Ca2+ leak was reduced following SERCA2a gene therapy, with reversal of the greater spark mass observed in the failing myocytes, despite normalisation of SR Ca2+ load. SERCA2a reduced ryanodine receptor phosphorylation, thereby resetting SR Ca2+ leak threshold, leading to reduced triggered activity in vitro. Both indirect effects of reverse remodelling and direct SERCA2a effects appear to underlie the antiarrhythmic action. Conclusions SERCA2a gene therapy stabilizes SR Ca2+ load, reduces ryanodine receptor phosphorylation and decreases SR Ca2+ leak, reduces cellular triggered activity in vitro and spontaneous and catecholamine-induced ventricular arrhythmias in vivo in failing hearts. SERCA2a gene therapy did not therefore predispose to arrhythmias, and may even represent a novel antiarrhythmic strategy in heart failure. PMID:21406682

  9. NF2 gene in neurofibromatosis type 2 patients.

    PubMed

    Zucman-Rossi, J; Legoix, P; Der Sarkissian, H; Cheret, G; Sor, F; Bernardi, A; Cazes, L; Giraud, S; Ollagnon, E; Lenoir, G; Thomas, G

    1998-12-01

    Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder that predisposes to nervous system tumors. The schwannomin (also termed merlin) protein encoded by the NF2 gene shows a close relationship to the family of cytoskeleton-to-membrane proteins linkers ERM (ezrin-radixin-moesin proteins). Even though penetrance of the disease is >95% and no genetic heterogeneity has been described, point mutations in the NF2 gene have been observed in only 34-66% of the screened NF2 patients, depending on the series. In order to generate tools that would enable an exhaustive alteration screening for the NF2 gene, we have deduced its entire genomic sequence. This knowledge has provided the delineation of a mutation screening strategy which, when applied to a series of 19 NF2 patients, has revealed a high recurrence of large deletions in the gene and has raised the efficiency of mutation detection in NF2 patients to 84% of the cases in this series. The remaining three patients who express two functional NF2 alleles are all sporadic cases, an observation compatible with the presence of mosaicism for NF2 mutation. PMID:9817927

  10. Postnatal cerebellar defects in mice deficient in methylenetetrahydrofolate reductase.

    PubMed

    Chen, Zhoutao; Schwahn, Bernd C; Wu, Qing; He, Xinying; Rozen, Rima

    2005-08-01

    Patients with severe deficiency of methylenetetrahydrofolate reductase (MTHFR) suffer from a wide variety of neurological problems, which can begin in the neonatal period. MTHFR is a critical enzyme in folate metabolism; the product of the MTHFR reaction, 5-methyltetrahydrofolate, is required for homocysteine remethylation to methionine and synthesis of S-adenosylmethionine (SAM). To understand the mechanisms by which MTHFR deficiency leads to significant neuropathology, we examined early postnatal brain development in mice with a homozygous knockout of the Mthfr gene. These mice displayed a dramatically reduced size of the cerebellum and cerebral cortex, with enlarged lateral ventricles. Mthfr deficiency affected granule cell maturation, but not neurogenesis. Depletion of external granule cells and disorganization of Purkinje cells were mainly confined to the anterior lobules of mutant cerebella. Decreased cellular proliferation and increased cell death contributed to the granule cell loss. Reduced expression of Engrailed-2 (En2), Reelin (Reln) and inositol 1,4,5-triphosphate receptor type 1 (Itpr1) genes was observed in the cerebellum. Supplementation of Mthfr(+/-) dams with an alternate methyl donor, betaine, reduced cerebellar abnormalities in the Mthfr(-/-) pups. Our findings suggest that MTHFR plays a role in cerebellar patterning, possibly through effects on proliferation or apoptosis. PMID:15979267

  11. Candidate tumor suppressor genes at FRA7G are coamplified with MET and do not suppress malignancy in a gastric cancer.

    PubMed

    Han, Shuang-Yin; Druck, Teresa; Huebner, Kay

    2003-02-01

    Common fragile sites predispose to specific chromosomal breakage associated with deletion, amplification, and/or translocation in certain forms of cancer. Chromosomal fragile sites not only are susceptible to DNA instability in cancer cells, but may also be associated with genes that contribute to the neoplastic process. FRA7G is a common fragile site containing the candidate tumor suppressor genes CAV1, CAV2, and TESTIN (TES). The human gastric cancer cell line GTL-16 has an amplification of this genomic region and was used to seek evidence for the suppressor candidacy of one of these genes. Our results demonstrate that CAV1, CAV2, and TESTIN are coamplified with the MET oncogene and overexpressed in GTL-16. Somatic mutation was not detected in the coding regions of these genes, although they were each overexpressed. The results show that CAV1, CAV2, and TESTIN are not tumor suppressor genes in this gastric cancer. PMID:12620387

  12. Attention Genes

    ERIC Educational Resources Information Center

    Posner, Michael I.; Rothbart, Mary K.; Sheese, Brad E.

    2007-01-01

    A major problem for developmental science is understanding how the cognitive and emotional networks important in carrying out mental processes can be related to individual differences. The last five years have seen major advances in establishing links between alleles of specific genes and the neural networks underlying aspects of attention. These…

  13. Designer Genes.

    ERIC Educational Resources Information Center

    Miller, Judith; Miller, Mark

    1983-01-01

    Genetic technologies may soon help fill some of the most important needs of humanity from food to energy to health care. The research of major designer genes companies and reasons why the initial mad rush for biotechnology has slowed are reviewed. (SR)

  14. Investigating highly replicated asthma genes as candidate genes for allergic rhinitis

    PubMed Central

    2013-01-01

    Background Asthma genetics has been extensively studied and many genes have been associated with the development or severity of this disease. In contrast, the genetic basis of allergic rhinitis (AR) has not been evaluated as extensively. It is well known that asthma is closely related with AR since a large proportion of individuals with asthma also present symptoms of AR, and patients with AR have a 5–6 fold increased risk of developing asthma. Thus, the relevance of asthma candidate genes as predisposing factors for AR is worth investigating. The present study was designed to investigate if SNPs in highly replicated asthma genes are associated with the occurrence of AR. Methods A total of 192 SNPs from 21 asthma candidate genes reported to be associated with asthma in 6 or more unrelated studies were genotyped in a Swedish population with 246 AR patients and 431 controls. Genotypes for 429 SNPs from the same set of genes were also extracted from a Singapore Chinese genome-wide dataset which consisted of 456 AR cases and 486 controls. All SNPs were subsequently analyzed for association with AR and their influence on allergic sensitization to common allergens. Results A limited number of potential associations were observed and the overall pattern of P-values corresponds well to the expectations in the absence of an effect. However, in the tests of allele effects in the Chinese population the number of significant P-values exceeds the expectations. The strongest signals were found for SNPs in NPSR1 and CTLA4. In these genes, a total of nine SNPs showed P-values <0.001 with corresponding Q-values <0.05. In the NPSR1 gene some P-values were lower than the Bonferroni correction level. Reanalysis after elimination of all patients with asthmatic symptoms excluded asthma as a confounding factor in our results. Weaker indications were found for IL13 and GSTP1 with respect to sensitization to birch pollen in the Swedish population. Conclusions Genetic variation in the majority of the highly replicated asthma genes were not associated to AR in our populations which suggest that asthma and AR could have less in common than previously anticipated. However, NPSR1 and CTLA4 can be genetic links between AR and asthma and associations of polymorphisms in NPSR1 with AR have not been reported previously. PMID:23663310

  15. Analysis of alpha-1 antichymotrypsin, presenilin-1, angiotensin-converting enzyme, and methylenetetrahydrofolate reductase loci as candidates for dementia.

    PubMed

    Tysoe, C; Galinsky, D; Robinson, D; Brayne, C E; Easton, D F; Huppert, F A; Dening, T; Paykel, E S; Rubinsztein, D C

    1997-04-18

    The genetic factors which predispose individuals to dementia in old age have not been fully defined. Although the apolipoprotein E4 allele accounts for a proportion of the genetic risk for late-onset Alzheimer disease (AD), it is neither necessary nor sufficient to cause this disease. Recent suggestions that other loci are involved in dementia risk have been supported by findings of associations of genotypes at the alpha-1 antichymotrypsin (ACT) and presenilin-1 (PS-1) loci with AD. We investigated these loci in two community-based aged Cambridgeshire populations: the rural Ely population (cohort 1) comprised 60 pairs of demented and nondemented elderly individuals, with a mean age of 84.2 years; and the Cambridge city population (cohort 2) comprised 81 pairs all over age 84, with a mean age of 87.3 years. Since vascular risk factors are likely to impact on dementia risk, we also examined the angiotensin-converting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR) genes as candidates. ACE, ACT, PS-1, and MTHFR genotype and allele frequencies were not significantly different in cases and matched controls. These data support the doubts which have been raised about the involvement of the PS-1 and ACT polymorphisms in late-onset dementia. PMID:9129727

  16. What Is a Gene?

    MedlinePLUS

    ... their lungs as healthy as possible. What Is Gene Therapy? Gene therapy is a new kind of medicine — so new ... tested is replacing sick genes with healthy ones. Gene therapy trials — where the research is tested on people — ...

  17. Genes and Psoriasis

    MedlinePLUS

    ... Diet Tips" to find out more! Email * Zipcode Genes and Psoriasis Genes hold the key to understanding ... is responsible for causing psoriatic disease. How do genes work? Genes control everything from height to eye ...

  18. Genes and Hearing Loss

    MedlinePLUS

    ... Meeting Calendar Find an ENT Doctor Near You Genes and Hearing Loss Genes and Hearing Loss Patient ... mutation may only have dystopia canthorum. How Do Genes Work? Genes are a road map for the ...

  19. Effect of brain-derived neurotrophic factor on behavior and key members of the brain serotonin system in genetically predisposed to behavioral disorders mouse strains.

    PubMed

    Naumenko, V S; Kondaurova, E M; Bazovkina, D V; Tsybko, A S; Tikhonova, M A; Kulikov, A V; Popova, N K

    2012-07-12

    The effect of brain-derived neurotrophic factor (BDNF) on depressive-like behavior and serotonin (5-HT) system in the brain of antidepressant sensitive cataleptics (ASC)/Icg mouse strain, characterized by depressive-like behavior, in comparison with the parental nondepressive CBA/Lac mouse strain was examined. Significant decrease of catalepsy and tail suspension test (TST) immobility was shown 17days after acute central BDNF administration (300ng i.c.v.) in ASC mice. In CBA mouse strain, BDNF moderately decreased catalepsy without any effect on TST immobility time. Significant difference between ASC and CBA mice in the effect of BDNF on 5-HT system was revealed. It was shown that central administration of BDNF led to increase of 5-HT(1A) receptor gene expression but not 5-HT(1A) functional activity in ASC mice. Increased tryptophan hydroxylase-2 (Tph-2) and 5-HT(2A) receptor genes expression accompanied by 5-HT(2A) receptor sensitization was shown in BDNF-treated ASC but not in CBA mouse strain, suggesting BDNF-induced increase of the brain 5-HT system functional activity and activation of neurogenesis in "depressive" ASC mice. There were no changes found in the 5-HT transporter mRNA level in BDNF-treated ASC and CBA mice. In conclusion, central administration of BDNF produced prolonged ameliorative effect on depressive-like behavior accompanied by increase of the Tph-2, 5-HT(1A) and 5-HT(2A) genes expression and 5-HT(2A) receptor functional activity in animal model of hereditary behavior disorders. PMID:22531372

  20. Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response

    SciTech Connect

    Sun Yang; Kojima, Chikara; Chignell, Colin; Mason, Ronald; Waalkes, Michael P.

    2011-09-15

    Inorganic arsenic and UV, both human skin carcinogens, may act together as skin co-carcinogens. We find human skin keratinocytes (HaCaT cells) are malignantly transformed by low-level arsenite (100 nM, 30 weeks; termed As-TM cells) and with transformation concurrently undergo full adaptation to arsenic toxicity involving reduced apoptosis and oxidative stress response to high arsenite concentrations. Oxidative DNA damage (ODD) is a possible mechanism in arsenic carcinogenesis and a hallmark of UV-induced skin cancer. In the current work, inorganic arsenite exposure (100 nM) did not induce ODD during the 30 weeks required for malignant transformation. Although acute UV-treatment (UVA, 25 J/cm{sup 2}) increased ODD in passage-matched control cells, once transformed by arsenic to As-TM cells, acute UV actually further increased ODD (> 50%). Despite enhanced ODD, As-TM cells were resistant to UV-induced apoptosis. The response of apoptotic factors and oxidative stress genes was strongly mitigated in As-TM cells after UV exposure including increased Bcl2/Bax ratio and reduced Caspase-3, Nrf2, and Keap1 expression. Several Nrf2-related genes (HO-1, GCLs, SOD) showed diminished responses in As-TM cells after UV exposure consistent with reduced oxidant stress response. UV-exposed As-TM cells showed increased expression of cyclin D1 (proliferation gene) and decreased p16 (tumor suppressor). UV exposure enhanced the malignant phenotype of As-TM cells. Thus, the co-carcinogenicity between UV and arsenic in skin cancer might involve adaptation to chronic arsenic exposure generally mitigating the oxidative stress response, allowing apoptotic by-pass after UV and enhanced cell survival even in the face of increased UV-induced oxidative stress and increased ODD. - Highlights: > Arsenic transformation adapted to UV-induced apoptosis. > Arsenic transformation diminished oxidant response. > Arsenic transformation enhanced UV-induced DNA damage.

  1. Status of vitamin B-12 and B-6 but not of folate, homocysteine and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene differs in frequency in different ethnic groups which have differing prevalence of age-related cognitive impairments. We used a battery of neuropsychological tests to examine association of the MTHFR C677T polymorphism w...

  2. Amino-terminal p53 mutations lead to expression of apoptosis proficient p47 and prognosticate better survival, but predispose to tumorigenesis

    PubMed Central

    Phang, Beng Hooi; Othman, Rashidah; Bougeard, Gaelle; Chia, Ren Hui; Frebourg, Thierry; Tang, Choong Leong; Cheah, Peh Yean; Sabapathy, Kanaga

    2015-01-01

    Whereas most mutations in p53 occur in the DNA-binding domain and lead to its functional inactivation, their relevance in the amino-terminal transactivation domain is unclear. We show here that amino-terminal p53 (ATp53) mutations often result in the abrogation of full-length p53 expression, but concomitantly lead to the expression of the amino-terminally truncated p47 isoform. Using genetically modified cancer cells that only express p47, we demonstrate it to be up-regulated in response to various stimuli, and to contribute to cell death, through its ability to selectively activate a group of apoptotic target genes. Target gene selectivity is influenced by K382 acetylation, which depends on the amino terminus, and is required for recruitment of selective cofactors. Consistently, cancers capable of expressing p47 had a better overall survival. Nonetheless, retention of the apoptotic function appears insufficient for tumor suppression, because these mutations are also found in the germ line and lead to Li–Fraumeni syndrome. These data from ATp53 mutations collectively demonstrate that p53’s apoptosis proficiency is dispensable for tumor suppression, but could prognosticate better survival. PMID:26578795

  3. Amino-terminal p53 mutations lead to expression of apoptosis proficient p47 and prognosticate better survival, but predispose to tumorigenesis.

    PubMed

    Phang, Beng Hooi; Othman, Rashidah; Bougeard, Gaelle; Chia, Ren Hui; Frebourg, Thierry; Tang, Choong Leong; Cheah, Peh Yean; Sabapathy, Kanaga

    2015-11-17

    Whereas most mutations in p53 occur in the DNA-binding domain and lead to its functional inactivation, their relevance in the amino-terminal transactivation domain is unclear. We show here that amino-terminal p53 (ATp53) mutations often result in the abrogation of full-length p53 expression, but concomitantly lead to the expression of the amino-terminally truncated p47 isoform. Using genetically modified cancer cells that only express p47, we demonstrate it to be up-regulated in response to various stimuli, and to contribute to cell death, through its ability to selectively activate a group of apoptotic target genes. Target gene selectivity is influenced by K382 acetylation, which depends on the amino terminus, and is required for recruitment of selective cofactors. Consistently, cancers capable of expressing p47 had a better overall survival. Nonetheless, retention of the apoptotic function appears insufficient for tumor suppression, because these mutations are also found in the germ line and lead to Li-Fraumeni syndrome. These data from ATp53 mutations collectively demonstrate that p53's apoptosis proficiency is dispensable for tumor suppression, but could prognosticate better survival. PMID:26578795

  4. Fine-scaling mapping of the gene responsible for multiple endocrine neoplasia type I (MEN1)

    SciTech Connect

    Fujimori, Minoru; Nakamura, Yusuke ); Wells, S.A. )

    1992-02-01

    The authors have constructed a high-resolution genetic linkage map in the vicinity of the gene responsible for multiple endocrine neoplasia type 1 (MEN1). The mutation causing this disease, inherited as an autosomal dominant, predisposes carriers to development of neoplastic tumors in the parathyroid, the endocrine pancreas, and the anterior lobe of the pituitary. The 12 markers on the genetic linkage map reported here span nearly 20 cM, and linkage analysis of MEN1 pedigrees has placed the MEN1 locus within the 8-cM region between D11S480 and D11S546. The markers on this map will be useful for prenatal or presymptomatic diagnosis of individuals in families that segregate a mutant allele of the MEN1 gene.

  5. 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.

  6. Identification of novel hereditary cancer genes by whole exome sequencing.

    PubMed

    Sokolenko, Anna P; Suspitsin, Evgeny N; Kuligina, Ekatherina Sh; Bizin, Ilya V; Frishman, Dmitrij; Imyanitov, Evgeny N

    2015-12-28

    Whole exome sequencing (WES) provides a powerful tool for medical genetic research. Several dozens of WES studies involving patients with hereditary cancer syndromes have already been reported. WES led to breakthrough in understanding of the genetic basis of some exceptionally rare syndromes; for example, identification of germ-line SMARCA4 mutations in patients with ovarian hypercalcemic small cell carcinomas indeed explains a noticeable share of familial aggregation of this disease. However, studies on common cancer types turned out to be more difficult. In particular, there is almost a dozen of reports describing WES analysis of breast cancer patients, but none of them yet succeeded to reveal a gene responsible for the significant share of missing heritability. Virtually all components of WES studies require substantial improvement, e.g. technical performance of WES, interpretation of WES results, mode of patient selection, etc. Most of contemporary investigations focus on genes with autosomal dominant mechanism of inheritance; however, recessive and oligogenic models of transmission of cancer susceptibility also need to be considered. It is expected that the list of medically relevant tumor-predisposing genes will be rapidly expanding in the next few years. PMID:26427841

  7. Identification of a germ-line mutation in the p53 gene in a patient with an intracranial ependymoma

    SciTech Connect

    Metzger, A.K.; Duyk, G.; Daneshvar, L.; Edwards, M.S.B.; Cogen, P.H. ); Sheffield, V.C. )

    1991-09-01

    The authors detected a germ-line mutation of the p53 gene in a patient with a malignant ependymoma of the posterior fossa. This mutation, which was found at codon 242, resulted in an amino acid substitution in a highly conserved site of exon 7 of the p53 gene; the same mutation was found in both the germ-line and tumor tissue. This is the most common region of previously described somatic p53 mutations in tumor specimens and of the germ-line p53 mutations in patients with the Li-Fraumeni cancer syndrome. Evaluation of the patient's family revealed several direct maternal and paternal relatives who had died at a young age from different types of cancer. The association of a germ-line p53 mutation with an intracranial malignancy and a strong family history of cancer suggests that p53 gene mutations predispose a person to malignancy and, like retinoblastoma mutations, may be inherited.

  8. Multivariate detection of gene-gene interactions

    E-print Network

    Washington at Seattle, University of

    interactions is crucial to obtaining a more complete picture of complex diseases. It is thought that gene-gene-mediated disease. Interactions among genes are de...ned as pheno- typic e¤ects that di¤er from those observed and ongoing e¤orts have centered on disease associations with single genes (a single nucleotide polymorphism

  9. Molecular screening of the LPCAT1 gene in patients with retinitis pigmentosa without defined mutations in known retinitis pigmentosa genes.

    PubMed

    Wu, Juan; Wang, Hong-Ting; Huang, Xiu-Feng; Lei, Xin-Lan; Lu, Qin-Kang; Jin, Zi-Bing

    2015-10-01

    Retinitis pigmentosa (RP) is an inherited retinopathy, which affects the photoreceptors in the retina. Lysophosphatidylcholine acyltransferase (LPCAT) is a critical phospholipid biosynthesis enzyme, which promotes the conversion of lysophosphatidylcholine into phosphatidylcholine in the remodeling pathway of PC biosynthesis. A previous study reported a homozygous insertion in the LPCAT1 gene in mice exhibiting retinal degeneration (rd11). However, whether genetic mutations in LPCAT1 predispose individuals to RP remains to be elucidated. Therefore, the aim of the present study was to investigate whether LPCAT1 mutations exist in patients with RP. A total of 50 unrelated patients diagnosed with either a sporadic or recessive inheritance pattern of RP were recruited in the present study. All of the patients were comprehensively screened for genes associated with the predisposition of RP, and no pathogenic mutations were identified. Reverse transcription-polymerase chain reaction and Sanger sequencing were performed to investigate the coding regions and exon?intron boundaries of the LPCAT1 gene in the recruited patients. In total, three genetic variations in the coding regions, which lead to amino acid changes, were identified. Although two of these mutations were predicted to be pathogenic, co?segregation analysis in the pedigrees excluded these as disease?causing mutations. In addition, the LPCAT1 gene was screen in a panel of RP patients who exhibited no identifiable mutations in any of the known RP?associated genes. No disease?causing mutations in the LPCAT1 gene were identified, indicating that LPCAT1 either does not confer a genetic predisposition to RP, or that the incidence of mutations in LPCAT1 is particularly rare in patients with RP. PMID:26260533

  10. Pleiotropic genes for metabolic syndrome and inflammation

    PubMed Central

    Kraja, Aldi T.; Chasman, Daniel I.; North, Kari E.; Reiner, Alexander P.; Yanek, Lisa R.; Kilpeläinen, Tuomas O.; Smith, Jennifer A.; Dehghan, Abbas; Dupuis, Josée; Johnson, Andrew D.; Feitosa, Mary F.; Tekola-Ayele, Fasil; Chu, Audrey Y.; Nolte, Ilja M.; Dastani, Zari; Morris, Andrew; Pendergrass, Sarah A.; Sun, Yan V.; Ritchie, Marylyn D.; Vaez, Ahmad; Lin, Honghuang; Ligthart, Symen; Marullo, Letizia; Rohde, Rebecca; Shao, Yaming; Ziegler, Mark A.; Im, Hae Kyung; Schnabel, Renate B.; Jørgensen, Torben; Jørgensen, Marit E.; Hansen, Torben; Pedersen, Oluf; Stolk, Ronald P.; Snieder, Harold; Hofman, Albert; Uitterlinden, Andre G.; Franco, Oscar H.; Ikram, M. Arfan; Richards, J. Brent; Rotimi, Charles; Wilson, James G.; Lange, Leslie; Ganesh, Santhi K.; Nalls, Mike; Rasmussen-Torvik, Laura J.; Pankow, James S.; Coresh, Josef; Tang, Weihong; Kao, W.H. Linda; Boerwinkle, Eric; Morrison, Alanna C.; Ridker, Paul M.; Becker, Diane M.; Rotter, Jerome I.; Kardia, Sharon L.R.; Loos, Ruth J.F.; Larson, Martin G.; Hsu, Yi-Hsiang; Province, Michael A.; Tracy, Russell; Voight, Benjamin F.; Vaidya, Dhananjay; O’Donnell, Christopher; Benjamin, Emelia J.; Alizadeh, Behrooz Z.; Prokopenko, Inga; Meigs, James B.; Borecki, Ingrid B.

    2014-01-01

    Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation. PMID:24981077

  11. A deep vein thrombosis caused by 20209C>T mutation in homozygosis of the prothrombin gene in a Caucasian patient

    PubMed Central

    Álvarez, Silvia Izquierdo; Ollero, Eva Barrio; Llinares Sanjuan, Francisco Miguel; Martínez, Fabiola Lorente; Calvo Martín, María Teresa

    2014-01-01

    Introduction: Additional nucleotide substitutions in the 3?-untranslated region of prothrombin gene could explain some thrombotic events and also adverse pregnancy outcomes. We describe the first case of a homozygous 20209C>T mutation as the cause of deep vein thrombosis in a Spanish patient. Case and methods: The 56-year-old male patient with a partial tear of the Achilles tendon developed calf (tibial) deep vein thrombosis after immobilization and was treated with an anticoagulant. To determine if the deep vein thrombosis was of genetic origin, a peripheral blood DNA sample was analysed for the presence of the three most frequent mutations associated with thrombotic events: factor V Leiden (1691G>A), prothrombin (20210G>A) and methylene tetrahydrofolate reductase (677C>T). The presence or absence of the normal allele of prothrombin could not be determined using the PTH-FV-MTHFR StripAssay (Vienna Lab). Results: Comprehensive analysis showed that the patient had a variant interfering with the polymerase chain reaction product, we sequenced the entire prothrombin gene and found that the patient had a homozygous C>T mutation at position 20209; this interfered with the polymerase chain reaction product, which needs a C at this position to be able to bind to the wild-type probe present in the test strip. Conclusion: The homozygous 20209C>T mutation and the presence of the mutation 677C>T in heterozygosity explained the patient’s deep vein thrombosis because the combination of mutations would increase the risk of thrombosis. Suitable genetic counselling should be provided to the patient and first-degree relatives as it important to detect prothrombin gene variants that could increase risk for thrombotic events. PMID:24627725

  12. Study design: Evaluating gene–environment interactions in the etiology of breast cancer – the WECARE study

    PubMed Central

    Bernstein, Jonine L; Langholz, Bryan; Haile, Robert W; Bernstein, Leslie; Thomas, Duncan C; Stovall, Marilyn; Malone, Kathleen E; Lynch, Charles F; Olsen, Jørgen H; Anton-Culver, Hoda; Shore, Roy E; Boice, John D; Berkowitz, Gertrud S; Gatti, Richard A; Teitelbaum, Susan L; Smith, Susan A; Rosenstein, Barry S; Børresen-Dale, Anne-Lise; Concannon, Patrick; Thompson, W Douglas

    2004-01-01

    Introduction Deficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated. Design To examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses. Conclusions Our study design improves the potential for detecting gene–environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case–control sets and enhanced our ability to detect radiation–genotype interactions. PMID:15084244

  13. Compare Gene Profiles

    SciTech Connect

    2014-05-31

    Compare Gene Profiles (CGP) performs pairwise gene content comparisons among a relatively large set of related bacterial genomes. CGP performs pairwise BLAST among gene calls from a set of input genome and associated annotation files, and combines the results to generate lists of common genes, unique genes, homologs, and genes from each genome that differ substantially in length from corresponding genes in the other genomes. CGP is implemented in Python and runs in a Linux environment in serial or parallel mode.

  14. Hemophilia and Gene Therapy

    E-print Network

    Brutlag, Doug

    Hemophilia and Gene Therapy Jackie Chu June 4, 2008 #12;Overview Hemophilia, the disease Gene therapy Hemophilia as a target for gene therapy Gene delivery systems Clinical trials New methods Future of gene therapy for hemophilia #12;Hemophilia, the disease X-linked, recessive bleeding disorder

  15. Disabled-2 heterozygous mice are predisposed to endometrial and ovarian tumorigenesis and exhibit sex-biased embryonic lethality in a p53-null background.

    PubMed

    Yang, Dong-Hua; Fazili, Zia; Smith, Elizabeth R; Cai, Kathy Qi; Klein-Szanto, Andres; Cohen, Cynthia; Horowitz, Ira R; Xu, Xiang-Xi

    2006-07-01

    Disabled-2 (Dab2) is a phosphoprotein involved in cellular signal transduction and endocytic trafficking. The expression of Dab2 is frequently lost or suppressed in several epithelial tumors, and studies of its cellular function and growth suppressive activity when re-expressed in cancer cells led to the suggestion that Dab2 is a tumor suppressor. A role for Dab2 in epithelial cell positioning organization was derived from study of knockout mice: homozygous deletion of dab2 results in early embryonic lethality due to the disorganization of the primitive endoderm, the first epithelium in early embryos. We now report that dab2 heterozygous mice develop uterine hyperplasia and ovarian preneoplastic morphological changes at a high frequency. Crossing into a p53(-/-) background unexpectedly produced few female dab2(+/-):p53(-/-) mice, while the male dab2(+/-):p53(-/-) were born at the expected Mendelian frequency. The tumor-prone phenotype of dab2(+/-) mice provides additional support for a role of human Dab2 as a tumor suppressor, and the sex-biased embryonic lethality suggests a genetic interaction between p53 and dab2 genes in female mice. PMID:16816378

  16. Frequent NF2 gene transcript mutations in sporadic meningiomas and vestibular schwannomas

    SciTech Connect

    Deprez, R.H.L.; Groen, N.A.; Zwarthoff, E.C.; Hagemeijer, A.; Van Drunen, E.; Bootsma, D.; Koper, J.W.; Avezaat, C.J.J. ); Bianchi, A.B.; Seizinger, B.R. )

    1994-06-01

    The gene for the hereditary disorder neurofibromatosis type 2 (NF2), which predisposes for benign CNS tumors such as vestibular schwannomas and meningiomas, has been assigned to chromosome 22 and recently has been isolated. Mutations in the NF2 gene were found in both sporadic meningiomas and vestibular schwannomas. However, so far only 6 of the 16 exons of the gene have been analyzed. In order to extend the analysis of an involvement of the NF2 gene in the sporadic counterparts of these NF2-related tumors, the authors have used reverse transcriptase-PCR amplification followed by SSCP and DNA sequence analysis to screen for mutations in the coding region of the NF2 gene. Analysis of the NF2 gene transcript in 53 unrelated patients with meningiomas and vestibular schwannomas revealed mutations in 32% of the sporadic meningiomas (n = 44), in 50% of the sporadic vestibular schwannomas (n = 4), in 100% of the tumors found in NF2 patients (n = 2), and in one of three tumors from multiple-meningioma patients. Of the 18 tumors in which a mutation in the NF2 gene transcript was observed and the copy number of chromosome 22 could be established, 14 also showed loss of (parts of) chromosome 22. This suggests that in sporadic meningiomas and NF2-associated tumors the NF2 gene functions as a recessive tumor-suppressor gene. The mutations detected resulted mostly in frameshifts, predicting truncations starting within the N-terminal half of the putative protein. 23 refs., 2 figs. 3 tabs.

  17. A systems approach identifies networks and genes linking sleep and stress: implications for neuropsychiatric disorders.

    PubMed

    Jiang, Peng; Scarpa, Joseph R; Fitzpatrick, Karrie; Losic, Bojan; Gao, Vance D; Hao, Ke; Summa, Keith C; Yang, He S; Zhang, Bin; Allada, Ravi; Vitaterna, Martha H; Turek, Fred W; Kasarskis, Andrew

    2015-05-01

    Sleep dysfunction and stress susceptibility are comorbid complex traits that often precede and predispose patients to a variety of neuropsychiatric diseases. Here, we demonstrate multilevel organizations of genetic landscape, candidate genes, and molecular networks associated with 328 stress and sleep traits in a chronically stressed population of 338 (C57BL/6J × A/J) F2 mice. We constructed striatal gene co-expression networks, revealing functionally and cell-type-specific gene co-regulations important for stress and sleep. Using a composite ranking system, we identified network modules most relevant for 15 independent phenotypic categories, highlighting a mitochondria/synaptic module that links sleep and stress. The key network regulators of this module are overrepresented with genes implicated in neuropsychiatric diseases. Our work suggests that the interplay among sleep, stress, and neuropathology emerges from genetic influences on gene expression and their collective organization through complex molecular networks, providing a framework for interrogating the mechanisms underlying sleep, stress susceptibility, and related neuropsychiatric disorders. PMID:25921536

  18. Impact of the IL-10 Promoter Gene Polymorphisms in the Severity of Chronic Hepatitis B Infection

    PubMed Central

    Ghaleh Baghi, Sahand; Alavian, Seyed Moayed; Mehrnoush, Leila; Salimi, Shima

    2015-01-01

    Background: Interleukin-10 (IL-10) is an important anti-inflammatory cytokine. The polymorphisms of its promoter gene have been considered to be related with the chronicity of hepatitis B infection. Objectives: The aim of this study was to evaluate the polymorphisms at different positions in the IL-10 promoter gene in patients with chronic hepatitis B. Patients and Methods: Totally, 166 patients with chronic hepatitis B infection were enrolled. Genotypes at different positions (i.e. -819, - 592, and - 1082) in the IL-10 gene promoter were determined. Results: The C/A genotype at position -592, C/T genotype at position -819, and GCC/ATA haplotype of the IL-10 gene promoter were significantly more common in the patients with cirrhosis. The genotypes were significantly different between the hepatitis B e antigen (HBeAg)-negative and HBeAg-positive patients at position -592 (C/A and C/C), position -819 (C/C and C/T), and position -1082 (A/A and G/A). Conclusions: Some IL-10 promoter gene polymorphisms predisposed the infected hepatitis B virus cases to cirrhosis in our study population. PMID:26300930

  19. Genomic Copy Number Variation Affecting Genes Involved in the Cell Cycle Pathway: Implications for Somatic Mosaicism

    PubMed Central

    Iourov, Ivan Y.; Vorsanova, Svetlana G.; Zelenova, Maria A.; Korostelev, Sergei A.; Yurov, Yuri B.

    2015-01-01

    Somatic genome variations (mosaicism) seem to represent a common mechanism for human intercellular/interindividual diversity in health and disease. However, origins and mechanisms of somatic mosaicism remain a matter of conjecture. Recently, it has been hypothesized that zygotic genomic variation naturally occurring in humans is likely to predispose to nonheritable genetic changes (aneuploidy) acquired during the lifetime through affecting cell cycle regulation, genome stability maintenance, and related pathways. Here, we have evaluated genomic copy number variation (CNV) in genes implicated in the cell cycle pathway (according to Kyoto Encyclopedia of Genes and Genomes/KEGG) within a cohort of patients with intellectual disability, autism, and/or epilepsy, in which the phenotype was not associated with genomic rearrangements altering this pathway. Benign CNVs affecting 20 genes of the cell cycle pathway were detected in 161 out of 255 patients (71.6%). Among them, 62 individuals exhibited >2 CNVs affecting the cell cycle pathway. Taking into account the number of individuals demonstrating CNV of these genes, a support for this hypothesis appears to be presented. Accordingly, we speculate that further studies of CNV burden across the genes implicated in related pathways might clarify whether zygotic genomic variation generates somatic mosaicism in health and disease. PMID:26421275

  20. Genetic variants conferring susceptibility to Alzheimer’s disease in the general population; do they also predispose to dementia in Down’s syndrome

    PubMed Central

    2014-01-01

    Background Down’s syndrome (DS) is caused by either complete or partial triplication of chromosome 21, affecting approximately 1/1000 live births, and it is widely accepted that individuals with DS are more likely to develop dementia of Alzheimer’s disease (DAD) compared with the general population. Recent collaborative genome-wide association studies of large case control data sets of individuals with and without Alzhemier’s disease (AD) have revealed new risk variants for dementia, as well as confirming previously identified risk variants. In this study, nine AD-derived SNPs, near or within the CR1 (rs3818361), BIN1 (rs744373), CD2AP (rs9349407), EPHA1 (rs11767557), CLU (rs1532278), MS4A6A/4A (rs610932), PICALM (rs561655), ABCA7 (rs3764650) and CD33 (rs3865444) genes were genotyped in 295 individuals with DS. Results There were no significant associations between these nine GWAS-derived SNPs and DAD in British Caucasian individuals with DS. Interestingly the CR1 rs3818361 variant appeared to be associated with mortality in our cohort, particularly in the subjects without dementia. To our knowledge, this is the first time that this variant has been implicated as a determinant of mortality and the finding warrants further investigation in other cohorts with DS. Conclusions This study shows negative associations of nine AD-derived SNPs with DAD in DS. This may be due to the modest size of our cohort, which may indicate that our study is insufficiently powered to pick up such associations. We cannot conclusively exclude a role for these SNPs in DAD in DS. Clearly, efforts to investigate genetic variants with small effects on disease risk require a much larger cohort of individuals with DS. In fact, we hypothesize that a sample size of 4465 individuals with DS would be needed to determine the role in DAD in DS of the nine AD-derived SNPs investigated in this study. We therefore recommend that all national and international clinics with access to individuals with DS should contribute DNA samples to form DS consortia. PMID:24438528

  1. Colitis-associated colon cancer: Is it in your genes?

    PubMed

    Van Der Kraak, Lauren; Gros, Philippe; Beauchemin, Nicole

    2015-11-01

    Colitis-associated colorectal cancer (CA-CRC) is the cause of death in 10%-15% of inflammatory bowel disease (IBD) patients. CA-CRC results from the accumulation of mutations in intestinal epithelial cells and progresses through a well-characterized inflammation to dysplasia to carcinoma sequence. Quantitative estimates of overall CA-CRC risks are highly variable ranging from 2% to 40% depending on IBD severity, duration and location, with IBD duration being the most significant risk factor associated with CA-CRC development. Recently, studies have identified IBD patients with similar patterns of colonic inflammation, but that differ with respect to CA-CRC development, suggesting a role for additional non-inflammatory risk factors in CA-CRC development. One suggestion is that select IBD patients carry polymorphisms in various low penetrance disease susceptibility genes, which pre-dispose them to CA-CRC development, although these loci have proven difficult to identify in human genome-wide association studies. Mouse models of CA-CRC have provided a viable alternative for the discovery, validation and study of individual genes in CA-CRC pathology. In this review, we summarize the current CA-CRC literature with a strong focus on genetic pre-disposition and highlight an emerging role for mouse models in the search for CA-CRC risk alleles. PMID:26556996

  2. Colitis-associated colon cancer: Is it in your genes?

    PubMed Central

    Van Der Kraak, Lauren; Gros, Philippe; Beauchemin, Nicole

    2015-01-01

    Colitis-associated colorectal cancer (CA-CRC) is the cause of death in 10%-15% of inflammatory bowel disease (IBD) patients. CA-CRC results from the accumulation of mutations in intestinal epithelial cells and progresses through a well-characterized inflammation to dysplasia to carcinoma sequence. Quantitative estimates of overall CA-CRC risks are highly variable ranging from 2% to 40% depending on IBD severity, duration and location, with IBD duration being the most significant risk factor associated with CA-CRC development. Recently, studies have identified IBD patients with similar patterns of colonic inflammation, but that differ with respect to CA-CRC development, suggesting a role for additional non-inflammatory risk factors in CA-CRC development. One suggestion is that select IBD patients carry polymorphisms in various low penetrance disease susceptibility genes, which pre-dispose them to CA-CRC development, although these loci have proven difficult to identify in human genome-wide association studies. Mouse models of CA-CRC have provided a viable alternative for the discovery, validation and study of individual genes in CA-CRC pathology. In this review, we summarize the current CA-CRC literature with a strong focus on genetic pre-disposition and highlight an emerging role for mouse models in the search for CA-CRC risk alleles. PMID:26556996

  3. Folate receptor gene variants and neural tube defect occurrence

    SciTech Connect

    Finnell, R.; Greer, K.; Lammer, E.

    1994-09-01

    Recent epidemiological evidence shows that periconceptional use of folic acid supplements may prevent 40-50% of neural tube defects (NTDs). The FDA has subsequently recommended folic acid supplementation of all women of childbearing potential, even though the mechanism by which folic acid prevents NTDs is unknown. We investigated genetic variation of a candidate gene, the 5-methyltetrahydrofolate (5-MeTHF) receptor, that may mediate this preventive effect. The receptor concentrates folate within cells and we have localized its mRNA to neuroepithelial cells during neurulation. Our hypothesis is that dysfunctional 5-MeTHF receptors inadequately concentrate folate intracellularly, predisposing infants to NTDs. We have completed SSCP analysis on 3 of the 4 coding exons of the 5-MeTHF receptor gene of 474 infants participating in a large population-based epidemiological case-control study of NTDs in California; genotyping of another 500 infants is ongoing. Genomic DNA was extracted from residual blood spots from newborn screening samples of cases and controls. Genotyping was done blinded to case status. Polymorphisms have been detected for exons 4 and 5; fourteen percent of the infants have exon 5 polymorphisms. Data will be presented on the prevalence of 5-MeTHF receptor polymorphisms among cases and controls. Relationships among the polymorphisms and NTD occurrence may shed light on how folic acid supplementation prevents NTDs.

  4. Mice heterozygous for the ATM gene are more sensitive to both X-ray and heavy ion exposure than are wildtypes

    NASA Astrophysics Data System (ADS)

    Worgul, B. V.; Smilenov, L.; Brenner, D. J.; Vazquez, M.; Hall, E. J.

    Previous studies have shown that the eyes of ATM heterozygous mice exposed to low-LET radiation (X-rays) are significantly more susceptible to the development of cataracts than are those of wildtype mice. The findings, as well as others, run counter to the assumption underpinning current radiation safety guidelines, that individuals are all equally sensitive to the biological effects of radiation. A question, highly relevant to human space activities is whether or not, in similar fashion there may exist a genetic predisposition to high-LET radiation damage. Mice haplodeficient for the ATM gene and wildtypes were exposed to 325 mGy of 1 GeV/amu 56Fe ions at the AGS facility of Brookhaven National Laboratory. The fluence was equivalent to 1 ion per lens epithelial cell nuclear area. Controls consisted of irradiated wildtype as well as unirradiated wildtype and heterozygous mice. Prevalence analyses for stage 0.5-3.0 cataracts indicated that not only cataract onset but also progression were accelerated in the mice haplo-deficient for the ATM gene. The data show that heterozygosity for the ATM gene predisposes the eye to the cataractogenic influence of heavy ions and suggest that ATM heterozygotes in the human population may also be radiosensitive. This may have to be considered in the selection of individuals who will be exposed to both HZE particles and low-LET radiation as they may be predisposed to increased late normal tissue damage.

  5. Gene doping: gene delivery for olympic victory.

    PubMed

    Gould, David

    2013-08-01

    With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called 'gene doping'. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place. PMID:23082866

  6. Autism and Genes

    ERIC Educational Resources Information Center

    National Institutes of Health, 2005

    2005-01-01

    This document defines and discusses autism and how genes play a role in the condition. Answers to the following questions are covered: (1) What are genes? (2) What is autism? (3) What causes autism? (4) Why study genes to learn about autism? (5) How do researchers look for the genes involved in autism? (screen the whole genome; conduct cytogenetic…

  7. Compare Gene Profiles

    Energy Science and Technology Software Center (ESTSC)

    2014-05-31

    Compare Gene Profiles (CGP) performs pairwise gene content comparisons among a relatively large set of related bacterial genomes. CGP performs pairwise BLAST among gene calls from a set of input genome and associated annotation files, and combines the results to generate lists of common genes, unique genes, homologs, and genes from each genome that differ substantially in length from corresponding genes in the other genomes. CGP is implemented in Python and runs in a Linuxmore »environment in serial or parallel mode.« less

  8. Multicentric origin of hemochromatosis gene (HFE) mutations.

    PubMed Central

    Rochette, J; Pointon, J J; Fisher, C A; Perera, G; Arambepola, M; Arichchi, D S; De Silva, S; Vandwalle, J L; Monti, J P; Old, J M; Merryweather-Clarke, A T; Weatherall, D J; Robson, K J

    1999-01-01

    Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, >80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are present, C282Y and H63D. The clinical significance of this second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease. The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies>5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends gene has been the subject of selection pressure. These selection pressures could be due to infectious diseases, environmental conditions, or other genetic disorders such as anemia. PMID:10090890

  9. Sleeping Beauty Transposon Mutagenesis as a Tool for Gene Discovery in the NOD Mouse Model of Type 1 Diabetes.

    PubMed

    Elso, Colleen M; Chu, Edward P F; Alsayb, May A; Mackin, Leanne; Ivory, Sean T; Ashton, Michelle P; Bröer, Stefan; Silveira, Pablo A; Brodnicki, Thomas C

    2015-01-01

    A number of different strategies have been used to identify genes for which genetic variation contributes to type 1 diabetes (T1D) pathogenesis. Genetic studies in humans have identified >40 loci that affect the risk for developing T1D, but the underlying causative alleles are often difficult to pinpoint or have subtle biological effects. A complementary strategy to identifying "natural" alleles in the human population is to engineer "artificial" alleles within inbred mouse strains and determine their effect on T1D incidence. We describe the use of the Sleeping Beauty (SB) transposon mutagenesis system in the nonobese diabetic (NOD) mouse strain, which harbors a genetic background predisposed to developing T1D. Mutagenesis in this system is random, but a green fluorescent protein (GFP)-polyA gene trap within the SB transposon enables early detection of mice harboring transposon-disrupted genes. The SB transposon also acts as a molecular tag to, without additional breeding, efficiently identify mutated genes and prioritize mutant mice for further characterization. We show here that the SB transposon is functional in NOD mice and can produce a null allele in a novel candidate gene that increases diabetes incidence. We propose that SB transposon mutagenesis could be used as a complementary strategy to traditional methods to help identify genes that, when disrupted, affect T1D pathogenesis. PMID:26438296

  10. Gene polymorphisms as risk factors for predicting the cardiovascular manifestations in Marfan syndrome. Role of folic acid metabolism enzyme gene polymorphisms in Marfan syndrome.

    PubMed

    Benke, Kálmán; Ágg, Bence; Mátyás, Gábor; Szokolai, Viola; Harsányi, Gergely; Szilveszter, Bálint; Odler, Balázs; Pólos, Miklós; Maurovich-Horvat, Pál; Radovits, Tamás; Merkely, Béla; Nagy, Zsolt B; Szabolcs, Zoltán

    2015-10-01

    Folic acid metabolism enzyme polymorphisms are believed to be responsible for the elevation of homocysteine (HCY) concentration in the blood plasma, correlating with the pathogenesis of aortic aneurysms and aortic dissection. We studied 71 Marfan patients divided into groups based on the severity of cardiovascular involvement: no intervention required (n=27, Group A); mild involvement requiring intervention (n=17, Group B); severe involvement (n=27, Group C) subdivided into aortic dilatation (n=14, Group C1) and aortic dissection (n=13, Group C2), as well as 117 control subjects. We evaluated HCY, folate, vitamin B12 and the polymorphisms of methylenetetrahydrofolate reductase (MTHFR;c.665C>T and c.1286A>C), methionine synthase (MTR;c.2756A>G) and methionine synthase reductase (MTRR;c.66A>G). Multiple comparisons showed significantly higher levels of HCY in Group C2 compared to Groups A, B, C1 and control group (p<0.0001, p<0.0001, p=0.001 and p=0.003, respectively). Folate was lower in Group C2 than in Groups A, B, C1 and control subjects (p<0.0001, p=0.02, p<0.0001 and p<0.0001, respectively). Group C2 had the highest prevalence of homozygotes for all four gene polymorphisms. Multivariate logistic regression analysis revealed that HCY plasma level was an independent risk factor for severe cardiovascular involvement (Group C; odds ratio [OR] 1.85, 95% confidence interval [CI] 1.28-2.67, p=0.001) as well as for aortic dissection (Group C2; OR 2.49, 95%CI 1.30-4.78, p=0.006). In conclusion, severe cardiovascular involvement in Marfan patients, and especially aortic dissection, is associated with higher HCY plasma levels and prevalence of homozygous genotypes of folic acid metabolism enzymes than mild or no cardiovascular involvement. These results suggest that impaired folic acid metabolism has an important role in the development and remodelling of the extracellular matrix of the aorta. PMID:26063524

  11. Influences of Gestational Obesity on Associations between Genotypes and Gene Expression Levels in Offspring following Maternal Gastrointestinal Bypass Surgery for Obesity

    PubMed Central

    Guénard, Frédéric; Lamontagne, Maxime; Bossé, Yohan; Deshaies, Yves; Cianflone, Katherine; Kral, John G.; Marceau, Picard; Vohl, Marie-Claude

    2015-01-01

    Maternal obesity and excess gestational weight gain with compromised metabolic fitness predispose offspring to lifelong obesity and its comorbidities. We demonstrated that compared to offspring born before maternal gastrointestinal bypass surgery (BMS) those born after (AMS) were less obese, with less cardiometabolic risk reflected in the expression and methylation of diabetes, immune and inflammatory pathway genes. Here we examine relationships between gestational obesity and offspring gene variations on expression levels. Methods Whole-genome genotyping and gene expression analyses in blood of 22 BMS and 23 AMS offspring from 19 mothers were conducted using Illumina HumanOmni-5-Quad and HumanHT-12 v4 Expression BeadChips, respectively. Using PLINK we analyzed interactions between offspring gene variations and maternal surgical status on offspring gene expression levels. Altered biological functions and pathways were identified and visualized using DAVID and Ingenuity Pathway Analysis. Results Significant interactions (p ? 1.22x10-12) were found for 525 among the 16,060 expressed transcripts: 1.9% of tested SNPs were involved. Gene function and pathway analysis demonstrated enrichment of transcription and of cellular metabolism functions and overrepresentation of cellular stress and signaling, immune response, inflammation, growth, proliferation and development pathways. Conclusion We suggest that impaired maternal gestational metabolic fitness interacts with offspring gene variations modulating gene expression levels, providing potential mechanisms explaining improved cardiometabolic risk profiles of AMS offspring related to ameliorated maternal lipid and carbohydrate metabolism. PMID:25603303

  12. Association study between the dopamine D4 receptor gene and schizophrenia

    SciTech Connect

    Petronis, A.; Macciardi, F.; Athanassiades, A.; Paterson, A.D.

    1995-10-09

    The dopamine D4 receptor is of major interest in schizophrenia research due to its high affinity for the atypical neuroleptic clozapine and a high degree of variability in the receptor gene (DRD4). Although several genetic linkage analyses performed on schizophrenia multiplex families from different regions of the world have either excluded or failed to prove that DRD4 is a major genetic factor for the development of schizophrenia, analyses for moderate predisposing effects are still of significant interest. We performed a study examining differences in allele frequencies of 4 different DRD4 polymorphisms in schizophrenia patients and age, sex, and ethnic origin matched controls. None of these 4 polymorphisms showed evidence for genetic association with schizophrenia, although a trend towards excess of the allele with 7 repeats in the (48){sub n} bp exon III polymorphism was observed. Complexities in the DRD4 genetic investigation and further analytic approaches are discussed. 18 refs., 2 tabs.

  13. Genetic similarity between cancers and comorbid Mendelian diseases identifies candidate driver genes

    PubMed Central

    Melamed, Rachel D.; Emmett, Kevin J.; Madubata, Chioma; Rzhetsky, Andrey; Rabadan, Raul

    2015-01-01

    Despite large-scale cancer genomics studies, key somatic mutations driving cancer, and their functional roles, remain elusive. Here we propose that analysis of comorbidities of Mendelian diseases with cancers provides a novel, systematic way to discover new cancer genes. If germline genetic variation in Mendelian loci predisposes bearers to common cancers, the same loci may harbor cancer-associated somatic variation. Compilations of clinical records spanning over 100 million patients provide an unprecedented opportunity to assess clinical associations between Mendelian diseases and cancers. We systematically compare these comorbidities against recurrent somatic mutations from more than five thousand patients across many cancers. Using multiple measures of genetic similarity, we show that a Mendelian disease and comorbid cancer indeed have genetic alterations of significant functional similarity. This result provides a basis to identify candidate drivers in cancers including melanoma and glioblastoma. Some Mendelian diseases demonstrate “pan-cancer” comorbidity and shared genetics across cancers. PMID:25926297

  14. Gene symbol precision.

    PubMed

    Bennani-Baiti, Barbara; Bennani-Baiti, Idriss M

    2012-01-10

    Several gene databases, including heavily used ones such as the National Center for Biotechnology Information (NCBI) database, erroneously assign, on occasion, literature references to genes or proteins. These mistakes are mostly due to an overlap in gene aliases, whereby two distinct genes share a pseudonym. This is particularly confusing when the gene products have also biological properties in common, are part of signaling pathways that cross-talk to one another, or are regulated by the same effectors. We present examples spanning several research fields including apoptosis, ubiquitin-dependent degradation, signaling by Notch, Wnt, and small G proteins, transporters of glutathione conjugates of electrophiles, and mitochondrial and ribosomal RNA genes. To solve the problem, we argue in favor of including Entrez gene numbers in papers submitted for publication as unique gene identifiers to allow precise identification of genes and species studied. PMID:22019431

  15. Gene–Environment Interaction in Major Depression: Focus on Experience-Dependent Biological Systems

    PubMed Central

    Lopizzo, Nicola; Bocchio Chiavetto, Luisella; Cattane, Nadia; Plazzotta, Giona; Tarazi, Frank I.; Pariante, Carmine M.; Riva, Marco A.; Cattaneo, Annamaria

    2015-01-01

    Major depressive disorder (MDD) is a multifactorial and polygenic disorder, where multiple and partially overlapping sets of susceptibility genes interact each other and with the environment, predisposing individuals to the development of the illness. Thus, MDD results from a complex interplay of vulnerability genes and environmental factors that act cumulatively throughout individual’s lifetime. Among these environmental factors, stressful life experiences, especially those occurring early in life, have been suggested to exert a crucial impact on brain development, leading to permanent functional changes that may contribute to lifelong risk for mental health outcomes. In this review, we will discuss how genetic variants (polymorphisms, SNPs) within genes operating in neurobiological systems that mediate stress response and synaptic plasticity, can impact, by themselves, the vulnerability risk for MDD; we will also consider how this MDD risk can be further modulated when gene?×?environment interaction is taken into account. Finally, we will discuss the role of epigenetic mechanisms, and in particular of DNA methylation and miRNAs expression changes, in mediating the effect of the stress on the vulnerability risk to develop MDD. Taken together, we aim to underlie the role of genetic and epigenetic processes involved in stress- and neuroplasticity-related biological systems on the development of MDD after exposure to early life stress, thereby building the basis for future research and clinical interventions. PMID:26005424

  16. Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series.

    PubMed Central

    Summerfield, J. A.; Sumiya, M.; Levin, M.; Turner, M. W.

    1997-01-01

    OBJECTIVE: To determine the extent to which mutations in the mannose binding protein gene predispose to childhood infection. DESIGN: Clinical details and genotype of mannose binding protein determined in consecutive children attending a paediatric department. SETTING: Inner city hospital paediatric service in London. SUBJECTS: 617 children attending hospital between October 1993 and August 1995. MAIN OUTCOME MEASURE: Infection as the cause for attendance or admission in relation to mutations in the mannose binding protein gene. RESULTS: The prevalence of mutations in the mannose binding protein gene in children with infection (146/345) was about twice that in children without infection (64/272) (P < 0.0001). Increased susceptibility to infection was found in both heterozygotic and homozygotic children. 13 out of 17 children homozygotic for variant alleles presented with strikingly severe infections, including 6 with septicaemia. CONCLUSIONS: The findings suggest that mutations in the mannose binding protein gene are an important risk factor for infections in children. Screening for such mutations should be included in the investigation of severe or frequent infections. PMID:9154025

  17. Genetic Background Modulates Gene Expression Profile Induced by Skin Irradiation in Ptch1 Mice

    SciTech Connect

    Galvan, Antonella; Noci, Sara; Mancuso, Mariateresa; Pazzaglia, Simonetta; Saran, Anna; Dragani, Tommaso A.

    2008-12-01

    Purpose: Ptch1 germ-line mutations in mice predispose to radiation-induced basal cell carcinoma of the skin, with tumor incidence modulated by the genetic background. Here, we examined the possible mechanisms underlying skin response to radiation in F1 progeny of Ptch1{sup neo67/+} mice crossed with either skin tumor-susceptible (Car-S) or -resistant (Car-R) mice and X-irradiated (3 Gy) at 2 days of age or left untreated. Methods and Materials: We conducted a gene expression profile analysis in mRNA samples extracted from the skin of irradiated or control mice, using Affymetrix whole mouse genome expression array. Confirmation of the results was done using real-time reverse-transcriptase polymerase chain reaction. Results: Analysis of the gene expression profile of normal skin of F1 mice at 4 weeks of age revealed a similar basal profile in the nonirradiated mice, but alterations in levels of 71 transcripts in irradiated Ptch1{sup neo67/+} mice of the Car-R cross and modulation of only eight genes in irradiated Ptch1{sup neo67/+} mice of the Car-S cross. Conclusions: These results indicate that neonatal irradiation causes a persistent change in the gene expression profile of the skin. The tendency of mice genetically resistant to skin tumorigenesis to show a more complex pattern of transcriptional response to radiation than do genetically susceptible mice suggests a role for this response in genetic resistance to basal cell tumorigenesis.

  18. Speciation genes in plants

    PubMed Central

    Rieseberg, Loren H.; Blackman, Benjamin K.

    2010-01-01

    Background Analyses of speciation genesgenes that contribute to the cessation of gene flow between populations – can offer clues regarding the ecological settings, evolutionary forces and molecular mechanisms that drive the divergence of populations and species. This review discusses the identities and attributes of genes that contribute to reproductive isolation (RI) in plants, compares them with animal speciation genes and investigates what these genes can tell us about speciation. Scope Forty-one candidate speciation genes were identified in the plant literature. Of these, seven contributed to pre-pollination RI, one to post-pollination, prezygotic RI, eight to hybrid inviability, and 25 to hybrid sterility. Genes, gene families and genetic pathways that were frequently found to underlie the evolution of RI in different plant groups include the anthocyanin pathway and its regulators (pollinator isolation), S RNase-SI genes (unilateral incompatibility), disease resistance genes (hybrid necrosis), chimeric mitochondrial genes (cytoplasmic male sterility), and pentatricopeptide repeat family genes (cytoplasmic male sterility). Conclusions The most surprising conclusion from this review is that identities of genes underlying both prezygotic and postzygotic RI are often predictable in a broad sense from the phenotype of the reproductive barrier. Regulatory changes (both cis and trans) dominate the evolution of pre-pollination RI in plants, whereas a mix of regulatory mutations and changes in protein-coding genes underlie intrinsic postzygotic barriers. Also, loss-of-function mutations and copy number variation frequently contribute to RI. Although direct evidence of positive selection on speciation genes is surprisingly scarce in plants, analyses of gene family evolution, along with theoretical considerations, imply an important role for diversifying selection and genetic conflict in the evolution of RI. Unlike in animals, however, most candidate speciation genes in plants exhibit intraspecific polymorphism, consistent with an important role for stochastic forces and/or balancing selection in development of RI in plants. PMID:20576737

  19. Gene Ontology Driven Classification of Gene

    E-print Network

    Spang, Rainer

    evaluation on leukemia · Limitations and future work · Conclusions #12;Introduction 23-Jul-02 3 / 17Claudio · Identifier, name, description · Children (other GO nodes) · Probe-set annotations · One logistic regression genes and direct children) #12;GO driven gene expression classification 23-Jul-02 7 / 17Claudio Lottaz

  20. From Gene Networks to Gene Function

    PubMed Central

    Schlitt, Thomas; Palin, Kimmo; Rung, Johan; Dietmann, Sabine; Lappe, Michael; Ukkonen, Esko; Brazma, Alvis

    2003-01-01

    We propose a novel method to identify functionally related genes based on comparisons of neighborhoods in gene networks. This method does not rely on gene sequence or protein structure homologies, and it can be applied to any organism and a wide variety of experimental data sets. The character of the predicted gene relationships depends on the underlying networks;they concern biological processes rather than the molecular function. We used the method to analyze gene networks derived from genome-wide chromatin immunoprecipitation experiments, a large-scale gene deletion study, and from the genomic positions of consensus binding sites for transcription factors of the yeast Saccharomyces cerevisiae. We identified 816 functional relationships between 159 genes and show that these relationships correspond to protein–protein interactions, co-occurrence in the same protein complexes, and/or co-occurrence in abstracts of scientific articles. Our results suggest functions for seven previously uncharacterized yeast genes: KIN3 and YMR269W may be involved in biological processes related to cell growth and/or maintenance, whereas IES6, YEL008W, YEL033W, YHL029C, YMR010W, and YMR031W-A are likely to have metabolic functions. PMID:14656964

  1. Human Gene Therapy: Genes without Frontiers?

    ERIC Educational Resources Information Center

    Simon, Eric J.

    2002-01-01

    Describes the latest advancements and setbacks in human gene therapy to provide reference material for biology teachers to use in their science classes. Focuses on basic concepts such as recombinant DNA technology, and provides examples of human gene therapy such as severe combined immunodeficiency syndrome, familial hypercholesterolemia, and…

  2. P2X7 gene polymorphisms do not appear to be a susceptibility gene locus in sporadic cases of systemic lupus erythematosus.

    PubMed

    Forchap, S L; Anandacoomarasamy, A; Wicks, J; Di Virgilio, F; Baricordi, O R; Rubbini, M; Trotta, F; Wiley, J; Manolios, N

    2008-11-01

    The P2X(7) receptor is a ligand-gated cation-selective channel that mediates ATP-induced apoptosis of cells of the immune system. A loss-of-function single nucleotide polymorphism (SNP) at position 1513 (1513 A-->C) of the P2X(7) gene has recently been identified in both healthy and chronic lymphocytic leukemia (CLL) B-cells, translating into a loss of P2X(7)-mediated apoptosis in these cells. This antiapoptotic effect results in increased B-cell numbers, thereby potentially contributing to the survival of B-CLL clones. It was hypothesized that prolonged cell survival may also predispose to induction of autoimmunity. The objective of this study is to analyze the role of the P2X(7) receptor and its loss-of-function 1513 A-->C polymorphism (SNP) in the development of systemic lupus erythematosus (SLE). DNA samples obtained from patients with sporadic SLE were analyzed for the presence of the 1513 A-->C polymorphism using polymerase chain reaction (PCR) amplification and then direct sequencing. No significant difference in allele frequencies (1513 A-->C polymorphism) between sporadic cases of SLE and controls was found. A loss-of-function SNP at position 1513 (1513 A-->C) of the P2X(7) gene does not appear to be a susceptibility gene locus for the development of sporadic SLE. PMID:18937793

  3. Gene Carlson Oral History

    E-print Network

    Carlson, Gene; Shriner, Clint

    2009-12-10

    Oral history interview with Gene Carlson conducted by Clint Shriner on December 10, 2009. In this interview, Gene Carlson, lead pastor at Westlink Christian Church, discusses the formative experiences that resulted in his decision to join...

  4. Proto-genes and de novo gene birth

    E-print Network

    Carvunis, Anne-Ruxandra

    Novel protein-coding genes can arise either through re-organization of pre-existing genes or de novo. Processes involving re-organization of pre-existing genes, notably after gene duplication, have been extensively described. ...

  5. Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

    PubMed Central

    Cuchet-Lourenço, Delphine; Wu, Changxin; Lo, Kitty; Maes, Mailis; Alisaac, Ali; Stebbings, Emma; Liu, Jimmy Z.; Kopanitsa, Liliya; Ignatyeva, Olga; Balabanova, Yanina; Nikolayevskyy, Vladyslav; Baessmann, Ingelore; Thye, Thorsten; Meyer, Christian G.; Nürnberg, Peter; Horstmann, Rolf D.; Drobniewski, Francis; Plagnol, Vincent; Barrett, Jeffrey C.; Nejentsev, Sergey

    2015-01-01

    Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 pulmonary TB patients and 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 (P = 2.6 × 10?11 for rs4733781; P = 1.0 × 10?10 for rs10956514). Dendritic cells (DCs) showed high level of ASAP1 expression, which was reduced after M. tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in M. tuberculosis-infected DCs may lead to their impaired migration, suggesting a potential novel mechanism that predisposes to TB. PMID:25774636

  6. Sandro Rusconi Gene transfer

    E-print Network

    Málaga, Universidad de

    Sandro Rusconi aaaaaa UNIFR Rusconi 2003 Gene transfer: limits and potential as doping vehicle Geneva 30.09.03 AISTS 'genes & sport' workshop 1972-75 Primary school teacher (Locarno, Switzerland) 1975 on 'molecular medicine' & molecular doping: applications and problems, Gene-based doping applications

  7. Sandro Rusconi Gene transfer

    E-print Network

    Málaga, Universidad de

    Sandro Rusconi UNIFR Rusconi 2003 Gene transfer: limits and potential as doping vehicle Geneva 30.09.03 AISTS 'genes & sport' workshop 1972-75 Primary school teacher (Locarno, Switzerland) 1975-79 Graduation medicine' & molecular doping: applications and problems, Gene-based doping applications, comparison

  8. Reading and Generalist Genes

    ERIC Educational Resources Information Center

    Haworth, Claire M. A.; Meaburn, Emma L.; Harlaar, Nicole; Plomin, Robert

    2007-01-01

    Twin-study research suggests that many (but not all) of the same genes contribute to genetic influence on diverse learning abilities and disabilities, a hypothesis called "generalist genes". This generalist genes hypothesis was tested using a set of 10 DNA markers (single nucleotide polymorphisms [SNPs]) found to be associated with early reading…

  9. CANCER OF THE RESPIRATORY TRACT: PREDISPOSING FACTORS

    EPA Science Inventory

    This volume documents the proceedings of the U.S. Environmental Protection Agency-sponsored symposium 'Tumor Promotion and Enhancement in the Etiology of Human and Experimental Respiratory Tract Carcinogenesis,' held in Williamsburg, VA in June 1984. In order to determine the nec...

  10. 32 CFR 644.391 - Predisposal conference.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... involved, the Major Air Command will take the initiative in convening the conference. In any cases... operations are phased out. This will do much to lessen the impact of the installation's closing on the... prior to phase out of military operations. In these cases, the DE has responsibility to insure, to...

  11. Endogenous Estradiol and Testosterone may Predispose toward Atherogenic Lipid Profile, but Higher Blood Level of Testosterone is Associated with Lower Number of Stenoses in the Coronary Arteries of Men with Coronary Disease

    PubMed Central

    Wranicz, Jerzy Krzysztof; Cygankiewicz, Iwona; Kula, Piotr; Walczak-Jedrzejowska, Renata; Slowikowska-Hilczer, Jolanta; Kula, Krzysztof

    2006-01-01

    Objectives: To assess the correlations between blood levels of sex steroid hormones and blood lipid profile or the degree of coronary artery stenosis in men with coronary artery disease (CAD). Methods: 111 men with stable CAD, aged 36-73 yrs, unselected for the coexisting clinical coronary risk factors were prospectively studied. Degree of coronary stenosis was assessed angiographically using different indices. Total cholesterol (T-Ch), high density lipoproteins cholesterol (HDL-Ch), low density lipoproteins cholesterol (LDL-Ch), triglicerydes (TG), testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA-S), and sex hormone binding globulin (SHBG) were measured in the blood. Free testosterone index (FTI) was calculated. Results: A positive, significant correlations were found between blood concentrations of estradiol and T-Ch (r=0.29, p<0.01) or LDL-Ch (r=0.34, p<0.005) as well as between FTI and blood LDL-Ch (r=0.23, p<0.05). Blood level of estradiol negatively correlated with HDL-Ch/T-Ch ratio (r=-0.21, p<0.05). While blood levels of T-Ch correlated positively with 3 out of 5 applied here indices of coronary stenosis, blood LDL-Ch with two of them. In turn, blood level of testosterone negatively correlated with one index of coronary stenosis (r=-0.26, p<0.05). Conclusion: In men with CAD, plasma estradiol concentrations are predictive for T-Ch, LDL-Ch and HDL-Ch/TCh ratio, and FTI for LDL-Ch. Regression analyses indicated that while sex steroid hormones may predispose toward atherogenic lipid profile and are predictive for the number and degree of coronary artery stenosis, higher blood level of total testosterone was associated with the lower number of stenosis in the coronary arteries. Hence, endogenous testosterone may have beneficial effect on coronary arteries. PMID:23674975

  12. Evolution of Gene Expression after Gene Amplification

    PubMed Central

    Garcia, Nelson; Zhang, Wei; Wu, Yongrui; Messing, Joachim

    2015-01-01

    We took a rather unique approach to investigate the conservation of gene expression of prolamin storage protein genes across two different subfamilies of the Poaceae. We took advantage of oat plants carrying single maize chromosomes in different cultivars, called oat–maize addition (OMA) lines, which permitted us to determine whether regulation of gene expression was conserved between the two species. We found that ?-zeins are expressed in OMA7.06, which carries maize chromosome 7 even in the absence of the trans-acting maize prolamin-box-binding factor (PBF), which regulates their expression. This is likely because oat PBF can substitute for the function of maize PBF as shown in our transient expression data, using a ?-zein promoter fused to green fluorescent protein (GFP). Despite this conservation, the younger, recently amplified prolamin genes in maize, absent in oat, are not expressed in the corresponding OMAs. However, maize can express the oldest prolamin gene, the wheat high-molecular weight glutenin Dx5 gene, even when maize Pbf is knocked down (through PbfRNAi), and/or another maize transcription factor, Opaque-2 (O2) is knocked out (in maize o2 mutant). Therefore, older genes are conserved in their regulation, whereas younger ones diverged during evolution and eventually acquired a new repertoire of suitable transcriptional activators. PMID:25912045

  13. Immunoglobulin ? Gene Rearrangement Can Precede ? Gene Rearrangement

    DOE PAGESBeta

    Berg, Jörg; Mcdowell, Mindy; Jäck, Hans-Martin; Wabl, Matthias

    1990-01-01

    Immunoglobulin genes are generated during differentiation of B lymphocytes by joining gene segments. A mouse pre-B cell contains a functional immunoglobulin heavy-chain gene, but no light-chain gene. Although there is only one heavy-chain locus, there are two lightchain loci: ? and ? .It has been reported that ? loci in the germ-line configuration are never (in man) or very rarely (in the mouse) present in cells with functionally rearranged ? -chain genes. Two explanations have been proposed to explain this: (a) the ordered rearrangement theory, which postulatesmore »that light-chain gene rearrangement in the pre-B cell is first attempted at the ? locus, and that only upon failure to produce a functional ? chain is there an attempt to rearrange the ? locus; and (b) the stochastic theory, which postulates that rearrangement at the ? locus proceeds at a rate that is intrinsically much slower than that at the ? locus. We show here that ? -chain genes are generated whether or not the ? locus has lost its germ-line arrangement, a result that is compatible only with the stochastic theory. « less

  14. Connectionist Approaches for Predicting Mouse Gene Function from Gene Expression

    E-print Network

    Bonner, Anthony

    Therapy. Identifying gene function based on gene expression data is much easier in prokaryotes than ways, especially in Gene Therapy [5]. Identifying gene function in prokaryotes is much easier thanConnectionist Approaches for Predicting Mouse Gene Function from Gene Expression Emad Andrews

  15. Genes Help Set Menopause Timing

    MedlinePLUS

    ... rights reserved. More Health News on: Genes and Gene Therapy Menopause Recent Health News Related MedlinePlus Health Topics Genes and Gene Therapy Menopause About MedlinePlus Site Map FAQs Contact Us ...

  16. Gene hunting in autoinflammation

    PubMed Central

    2013-01-01

    Steady progress in our understanding of the genetic basis of autoinflammatory diseases has been made over the past 16 years. Since the discovery of the familial Mediterranean fever gene MEFV (also known as marenostrin) in 1997, 18 other genes responsible for monogenic autoinflammatory diseases have been identified to date. The discovery of these genes was made through the utilisation of many genetic mapping techniques, including next generation sequencing platforms. This review article clearly describes the gene hunting approaches, methods of data analysis and the technological platforms used, which has relevance to all those working within the field of gene discovery for Mendelian disorders. PMID:24070009

  17. Is There a Predisposition Gene for Ewing's Sarcoma?

    PubMed Central

    Randall, R. L.; Lessnick, S. L.; Jones, K. B.; Gouw, L. G.; Cummings, J. E.; Cannon-Albright, L.; Schiffman, J. D.

    2010-01-01

    Ewing's sarcoma is a highly malignant tumor of children and young adults. The molecular mechanisms that underlie Ewing's Sarcoma development are beginning to be understood. For example, most cases of this disease harbor somatic chromosomal translocations that fuse the EWSR1 gene on chromosome 22 with members of the ETS family. While some cooperative genetic events have been identified, such as mutations in TP53 or deletions of the CDKN2A locus, these appear to be absent in the vast majority of cases. It is therefore uncertain whether EWS/ETS translocations are the only consistently present alteration in this tumor, or whether there are other recurrent abnormalities yet to be discovered. One method to discover such mutations is to identify familial cases of Ewing's sarcoma and to then map the susceptibility locus using traditional genetic mapping techniques. Although cases of sibling pairs with Ewing's sarcoma exist, familial cases of Ewing's sarcoma have not been reported. While Ewing's sarcoma has been reported as a 2nd malignancy after retinoblastoma, significant associations of Ewing's sarcoma with classic tumor susceptibility syndromes have not been identified. We will review the current evidence, or lack thereof, regarding the potential of a heritable condition predisposing to Ewing's sarcoma. PMID:20300555

  18. Regulated Gene Therapy.

    PubMed

    Breger, Ludivine; Wettergren, Erika Elgstrand; Quintino, Luis; Lundberg, Cecilia

    2016-01-01

    Gene therapy represents a promising approach for the treatment of monogenic and multifactorial neurological disorders. It can be used to replace a missing gene and mutated gene or downregulate a causal gene. Despite the versatility of gene therapy, one of the main limitations lies in the irreversibility of the process: once delivered to target cells, the gene of interest is constitutively expressed and cannot be removed. Therefore, efficient, safe and long-term gene modification requires a system allowing fine control of transgene expression.Different systems have been developed over the past decades to regulate transgene expression after in vivo delivery, either at transcriptional or post-translational levels. The purpose of this chapter is to give an overview on current regulatory system used in the context of gene therapy for neurological disorders. Systems using external regulation of transgenes using antibiotics are commonly used to control either gene expression using tetracycline-controlled transcription or protein levels using destabilizing domain technology. Alternatively, specific promoters of genes that are regulated by disease mechanisms, increasing expression as the disease progresses or decreasing expression as disease regresses, are also examined. Overall, this chapter discusses advantages and drawbacks of current molecular methods for regulated gene therapy in the central nervous system. PMID:26611578

  19. Alteration of the alkaloid profile in genetically modified tobacco reveals a role of methylenetetrahydrofolate reductase in nicotine N-demethylation.

    PubMed

    Hung, Chiu-Yueh; Fan, Longjiang; Kittur, Farooqahmed S; Sun, Kehan; Qiu, Jie; Tang, She; Holliday, Bronwyn M; Xiao, Bingguang; Burkey, Kent O; Bush, Lowell P; Conkling, Mark A; Roje, Sanja; Xie, Jiahua

    2013-02-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of the tetrahydrofolate (THF)-mediated one-carbon (C1) metabolic network. This enzyme catalyzes the reduction of 5,10-methylene-THF to 5-methyl-THF. The latter donates its methyl group to homocysteine, forming methionine, which is then used for the synthesis of S-adenosyl-methionine, a universal methyl donor for numerous methylation reactions, to produce primary and secondary metabolites. Here, we demonstrate that manipulating tobacco (Nicotiana tabacum) MTHFR gene (NtMTHFR1) expression dramatically alters the alkaloid profile in transgenic tobacco plants by negatively regulating the expression of a secondary metabolic pathway nicotine N-demethylase gene, CYP82E4. Quantitative real-time polymerase chain reaction and alkaloid analyses revealed that reducing NtMTHFR expression by RNA interference dramatically induced CYP82E4 expression, resulting in higher nicotine-to-nornicotine conversion rates. Conversely, overexpressing NtMTHFR1 suppressed CYP82E4 expression, leading to lower nicotine-to-nornicotine conversion rates. However, the reduced expression of NtMTHFR did not affect the methionine and S-adenosyl-methionine levels in the knockdown lines. Our finding reveals a new regulatory role of NtMTHFR1 in nicotine N-demethylation and suggests that the negative regulation of CYP82E4 expression may serve to recruit methyl groups from nicotine into the C1 pool under C1-deficient conditions. PMID:23221678

  20. Bioinformatic and Genetic Association Analysis of MicroRNA Target Sites in One-Carbon Metabolism Genes

    PubMed Central

    Stone, Nicole; Pangilinan, Faith; Molloy, Anne M.; Shane, Barry; Scott, John M.; Ueland, Per Magne; Mills, James L.; Kirke, Peader N.; Sethupathy, Praveen; Brody, Lawrence C.

    2011-01-01

    One-carbon metabolism (OCM) is linked to DNA synthesis and methylation, amino acid metabolism and cell proliferation. OCM dysfunction has been associated with increased risk for various diseases, including cancer and neural tube defects. MicroRNAs (miRNAs) are ?22 nt RNA regulators that have been implicated in a wide array of basic cellular processes, such as differentiation and metabolism. Accordingly, mis-regulation of miRNA expression and/or activity can underlie complex disease etiology. We examined the possibility of OCM regulation by miRNAs. Using computational miRNA target prediction methods and Monte-Carlo based statistical analyses, we identified two candidate miRNA “master regulators” (miR-22 and miR-125) and one candidate pair of “master co-regulators” (miR-344-5p/484 and miR-488) that may influence the expression of a significant number of genes involved in OCM. Interestingly, miR-22 and miR-125 are significantly up-regulated in cells grown under low-folate conditions. In a complementary analysis, we identified 15 single nucleotide polymorphisms (SNPs) that are located within predicted miRNA target sites in OCM genes. We genotyped these 15 SNPs in a population of healthy individuals (age 18–28, n?=?2,506) that was previously phenotyped for various serum metabolites related to OCM. Prior to correction for multiple testing, we detected significant associations between TCblR rs9426 and methylmalonic acid (p ?=? 0.045), total homocysteine levels (tHcy) (p ?=? 0.033), serum B12 (p < 0.0001), holo transcobalamin (p < 0.0001) and total transcobalamin (p < 0.0001); and between MTHFR rs1537514 and red blood cell folate (p < 0.0001). However, upon further genetic analysis, we determined that in each case, a linked missense SNP is the more likely causative variant. Nonetheless, our Monte-Carlo based in silico simulations suggest that miRNAs could play an important role in the regulation of OCM. PMID:21765920

  1. The homeobox gene CDX2 in colorectal carcinoma: a genetic analysis

    PubMed Central

    Sivagnanasundaram, S; Islam, I; Talbot, I; Drummond, F; Walters, J R F; Edwards, Y H

    2001-01-01

    Accumulation of mutations in tumour suppressor genes and oncogenes has been proposed to underlie the initiation and progression of sporadic colorectal cancer (CRC). Evidence is accumulating to suggest that the caudal homeobox gene CDX2 is implicated in the pathogenesis of CRC. The CDX2 transcription factor is expressed in intestinal epithelium and is markedly down-regulated in colon tumours. Furthermore, Cdx2 heterozygous null mice develop multiple intestinal tumours. In this present study, we have investigated CDX2 as a potential candidate gene for sporadic CRC by a thorough search of all exons and exon/intron boundaries for DNA polymorphisms and rare variants in a panel of CRC tumours. 6 polymorphisms were identified and the haplotypes determined. In addition two rare variants were found, one of which was only identified in DNA from a CRC case. Loss of heterozygosity was observed in 3 out of 28 informative CRC cases. A possible association between particular haplotypes and tumour progression was also suggested by the data. In addition a preliminary analysis of the relative expression of CDX2 alleles in tumour/normal tissue suggested some variation in the levels, however further analysis is required before any conclusions can be drawn. While CDX2 mutations predisposing to sporadic CRC have not been identified, this study has established that loss of CDX2 contributes towards the progression of some sporadic CRC tumours. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11161380

  2. A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes

    PubMed Central

    Hansen, Maren F; Neckmann, Ulrike; Lavik, Liss A S; Vold, Trine; Gilde, Bodil; Toft, Ragnhild K; Sjursen, Wenche

    2014-01-01

    The purpose of this study was to develop a massive parallel sequencing (MPS) workflow for diagnostic analysis of mismatch repair (MMR) genes using the GS Junior system (Roche). A pathogenic variant in one of four MMR genes, (MLH1, PMS2, MSH6, and MSH2), is the cause of Lynch Syndrome (LS), which mainly predispose to colorectal cancer. We used an amplicon-based sequencing method allowing specific and preferential amplification of the MMR genes including PMS2, of which several pseudogenes exist. The amplicons were pooled at different ratios to obtain coverage uniformity and maximize the throughput of a single-GS Junior run. In total, 60 previously identified and distinct variants (substitutions and indels), were sequenced by MPS and successfully detected. The heterozygote detection range was from 19% to 63% and dependent on sequence context and coverage. We were able to distinguish between false-positive and true-positive calls in homopolymeric regions by cross-sample comparison and evaluation of flow signal distributions. In addition, we filtered variants according to a predefined status, which facilitated variant annotation. Our study shows that implementation of MPS in routine diagnostics of LS can accelerate sample throughput and reduce costs without compromising sensitivity, compared to Sanger sequencing. PMID:24689082

  3. Do Housekeeping Genes Exist?

    PubMed Central

    Sun, Bingyun

    2015-01-01

    The searching of human housekeeping (HK) genes has been a long quest since the emergence of transcriptomics, and is instrumental for us to understand the structure of genome and the fundamentals of biological processes. The resolved genes are frequently used in evolution studies and as normalization standards in quantitative gene-expression analysis. Within the past 20 years, more than a dozen HK-gene studies have been conducted, yet none of them sampled human tissues completely. We believe an integration of these results will help remove false positive genes owing to the inadequate sampling. Surprisingly, we only find one common gene across 15 examined HK-gene datasets comprising 187 different tissue and cell types. Our subsequent analyses suggest that it might not be appropriate to rigidly define HK genes as expressed in all tissue types that have diverse developmental, physiological, and pathological states. It might be beneficial to use more robustly identified HK functions for filtering criteria, in which the representing genes can be a subset of genome. These genes are not necessarily the same, and perhaps need not to be the same, everywhere in our body. PMID:25970694

  4. Protection genes in nucleus accumbens shell affect vulnerability to nicotine self-administration across isogenic strains of adolescent rat.

    PubMed

    Chen, Hao; Luo, Rui; Gong, Suzhen; Matta, Shannon G; Sharp, Burt M

    2014-01-01

    Classical genetic studies show the heritability of cigarette smoking is 0.4-0.6, and that multiple genes confer susceptibility and resistance to smoking. Despite recent advances in identifying genes associated with smoking behaviors, the major source of this heritability and its impact on susceptibility and resistance are largely unknown. Operant self-administration (SA) of intravenous nicotine is an established model for smoking behavior. We recently confirmed that genetic factors exert strong control over nicotine intake in isogenic rat strains. Because the processing of afferent dopaminergic signals by nucleus accumbens shell (AcbS) is critical for acquisition and maintenance of motivated behaviors reinforced by nicotine, we hypothesized that differential basal gene expression in AcbS accounts for much of the strain-to-strain variation in nicotine SA. We therefore sequenced the transcriptome of AcbS samples obtained by laser capture microdissection from 10 isogenic adolescent rat strains and compared all RNA transcript levels with behavior. Weighted gene co-expression network analysis, a systems biology method, found 12 modules (i.e., unique sets of genes that covary across all samples) that correlated (p<0.05) with amount of self-administered nicotine; 9 of 12 correlated negatively, implying a protective role. PCR confirmed selected genes from these modules. Chilibot, a literature mining tool, identified 15 genes within 1 module that were nominally associated with cigarette smoking, thereby providing strong support for the analytical approach. This is the first report demonstrating that nicotine intake by adolescent rodents is associated with the expression of specific genes in AcbS of the mesolimbic system, which controls motivated behaviors. These findings provide new insights into genetic mechanisms that predispose or protect against tobacco addiction. PMID:24465966

  5. The gap gene network

    PubMed Central

    2010-01-01

    Gap genes are involved in segment determination during the early development of the fruit fly Drosophila melanogaster as well as in other insects. This review attempts to synthesize the current knowledge of the gap gene network through a comprehensive survey of the experimental literature. I focus on genetic and molecular evidence, which provides us with an almost-complete picture of the regulatory interactions responsible for trunk gap gene expression. I discuss the regulatory mechanisms involved, and highlight the remaining ambiguities and gaps in the evidence. This is followed by a brief discussion of molecular regulatory mechanisms for transcriptional regulation, as well as precision and size-regulation provided by the system. Finally, I discuss evidence on the evolution of gap gene expression from species other than Drosophila. My survey concludes that studies of the gap gene system continue to reveal interesting and important new insights into the role of gene regulatory networks in development and evolution. PMID:20927566

  6. Gene expression data analysis.

    PubMed

    Brazma, A; Vilo, J

    2001-08-01

    Microarrays are one of the latest breakthroughs in experimental molecular biology, which allow monitoring of gene expression for tens of thousands of genes in parallel and are already producing huge amounts of valuable data. Analysis and handling of such data is becoming one of the major bottlenecks in the utilization of the technology. The raw microarray data are images, which have to be transformed into gene expression matrices, tables where rows represent genes, columns represent various samples such as tissues or experimental conditions, and numbers in each cell characterize the expression level of the particular gene in the particular sample. These matrices have to be analyzed further if any knowledge about the underlying biological processes is to be extracted. In this paper we concentrate on discussing bioinformatics methods used for such analysis. We briefly discuss supervised and unsupervised data analysis and its applications, such as predicting gene function classes and cancer classification as well as some possible future directions. PMID:11580977

  7. Mammalian suppressor genes

    SciTech Connect

    Sharp, P.A.; Capecchi, M.R.; Raj Bhandary, U.L.; Laski, F.A.

    1987-08-18

    A method is described of suppressing a nonsense codon in a gene for production of a protein of interest in mammalian cells, the method comprising: (a) preparing an oligonucleotide primer comprising a region complementary to the nonsense codon; (b) preparing a DNA template for production of a tRNA molecule; (c) forming a suppressor gene from the template and primer by site specific mutagenesis; and (d) transforming the suppressor gene into a mammalian cell, whereby the nonsense codon will be suppressed.

  8. Green genes gleaned.

    PubMed

    Beale, Samuel I

    2005-07-01

    A recent paper by Ayumi Tanaka and colleagues identifying an Arabidopsis thaliana gene for 3,8-divinyl(proto)chlorophyllide 8-vinyl reductase brings a satisfying conclusion to the hunt for genes encoding enzymes for the steps in the chlorophyll biosynthetic pathway. Now, at least in angiosperm plants represented by Arabidopsis, genes for all 15 steps in the pathway from glutamyl-tRNA to chlorophylls a and b have been identified. PMID:15951223

  9. The Gene for May-Hegglin Anomaly Localizes to a <1-Mb Region on Chromosome 22q12.3-13.1

    PubMed Central

    Martignetti, John A.; Heath, Karen E.; Harris, Juliette; Bizzaro, Nicola; Savoia, Anna; Balduini, Carlo L.; Desnick, Robert J.

    2000-01-01

    The May-Hegglin anomaly (MHA) is an autosomal dominant platelet disorder of unknown etiology. It is characterized by thrombocytopenia, giant platelets, and leukocyte inclusion bodies, and affected heterozygotes are predisposed to bleeding episodes. The MHA gene has recently been localized, by means of linkage analysis, to a 13.6-cM region on chromosome 22, and the complete chromosome 22 sequence has been reported. We recently performed a genome scan for the MHA gene in 29 members of a large, multigenerational Italian family, and we now confirm that the MHA locus is on chromosome 22q12.3-13.1. The maximal two-point LOD score of 4.50 was achieved with the use of marker D22S283, at a recombination fraction of .05. Haplotype analysis narrowed the MHA critical region to 6.6 cM between markers D22S683 and D22S1177. It is of note that the chromosome 22 sequence allowed all markers to be ordered correctly, identified all the candidate genes and predicted genes, and specifically determined the physical size of the MHA region to be 0.7 Mb. These results significantly narrow the region in which the MHA gene is located, and they represent the first use of chromosome 22 data to positionally clone a disease gene. PMID:10739770

  10. History of gene therapy.

    PubMed

    Wirth, Thomas; Parker, Nigel; Ylä-Herttuala, Seppo

    2013-08-10

    Two decades after the initial gene therapy trials and more than 1700 approved clinical trials worldwide we not only have gained much new information and knowledge regarding gene therapy in general, but also learned to understand the concern that has persisted in society. Despite the setbacks gene therapy has faced, success stories have increasingly emerged. Examples for these are the positive recommendation for a gene therapy product (Glybera) by the EMA for approval in the European Union and the positive trials for the treatment of ADA deficiency, SCID-X1 and adrenoleukodystrophy. Nevertheless, our knowledge continues to grow and during the course of time more safety data has become available that helps us to develop better gene therapy approaches. Also, with the increased understanding of molecular medicine, we have been able to develop more specific and efficient gene transfer vectors which are now producing clinical results. In this review, we will take a historical view and highlight some of the milestones that had an important impact on the development of gene therapy. We will also discuss briefly the safety and ethical aspects of gene therapy and address some concerns that have been connected with gene therapy as an important therapeutic modality. PMID:23618815

  11. Selecting Informative Genes from Microarray Dataset by Incorporating Gene Ontology

    E-print Network

    Buffalo, State University of New York

    Selecting Informative Genes from Microarray Dataset by Incorporating Gene Ontology Xian Xu Aidong 14224, USA xianxu,azhang@cse.buffalo.edu Abstract Selecting informative genes from microarray experi, namely large num- ber of genes and limited number of samples, the statistical soundness of gene selection

  12. Essential Genes Are More Evolutionarily Conserved Than Are Nonessential Genes

    E-print Network

    Jordan, King

    Essential Genes Are More Evolutionarily Conserved Than Are Nonessential Genes in Bacteria I. King The "knockout-rate" prediction holds that essential genes should be more evolutionarily conserved than are nonessential genes. This is because negative (purifying) selection acting on essential genes is expected

  13. Analysis of Gene Order Evolution beyond Single-Copy Genes

    E-print Network

    El-Mabrouk, Nadia

    -chromosomal rearrangement events, which do not change gene content, but may radically alter gene order. InferringAnalysis of Gene Order Evolution beyond Single-Copy Genes Nadia El-Mabrouk D´epartement d genomics based on representation of genomes as ordered sequences of signed genes. We specifically focus

  14. Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study

    PubMed Central

    2013-01-01

    Background Preterm birth (PTB) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. This study was designed to identify genetic variation associated with PTB in oxytocin pathway genes whose role in parturition is well known. Methods To identify common genetic variants predisposing to PTB, we genotyped 16 single nucleotide polymorphisms (SNPs) in the oxytocin (OXT), oxytocin receptor (OXTR), and leucyl/cystinyl aminopeptidase (LNPEP) genes in 651 case infants from the U.S. and one or both of their parents. In addition, we examined the role of rare genetic variation in susceptibility to PTB by conducting direct sequence analysis of OXTR in 1394 cases and 1112 controls from the U.S., Argentina, Denmark, and Finland. This study was further extended to maternal triads (maternal grandparents-mother of a case infant, N=309). We also performed in vitro analysis of selected rare OXTR missense variants to evaluate their functional importance. Results Maternal genetic effect analysis of the SNP genotype data revealed four SNPs in LNPEP that show significant association with prematurity. In our case–control sequence analysis, we detected fourteen coding variants in exon 3 of OXTR, all but four of which were found in cases only. Of the fourteen variants, three were previously unreported novel rare variants. When the sequence data from the maternal triads were analyzed using the transmission disequilibrium test, two common missense SNPs (rs4686302 and rs237902) in OXTR showed suggestive association for three gestational age subgroups. In vitro functional assays showed a significant difference in ligand binding between wild-type and two mutant receptors. Conclusions Our study suggests an association between maternal common polymorphisms in LNPEP and susceptibility to PTB. Maternal OXTR missense SNPs rs4686302 and rs237902 may have gestational age-dependent effects on prematurity. Most of the OXTR rare variants identified do not appear to significantly contribute to the risk of PTB, but those shown to affect receptor function in our in vitro study warrant further investigation. Future studies with larger sample sizes are needed to confirm the findings of this study. PMID:23889750

  15. An Image-Based Genetic Assay Identifies Genes in T1D Susceptibility Loci Controlling Cellular Antiviral Immunity in Mouse

    PubMed Central

    Liao, Juan; Jijon, Humberto B.; Kim, Ira R.; Goel, Gautam; Doan, Aivi; Sokol, Harry; Bauer, Hermann; Herrmann, Bernhard G.; Lassen, Kara G.; Xavier, Ramnik J.

    2014-01-01

    The pathogenesis of complex diseases, such as type 1 diabetes (T1D), derives from interactions between host genetics and environmental factors. Previous studies have suggested that viral infection plays a significant role in initiation of T1D in genetically predisposed individuals. T1D susceptibility loci may therefore be enriched in previously uncharacterized genes functioning in antiviral defense pathways. To identify genes involved in antiviral immunity, we performed an image-based high-throughput genetic screen using short hairpin RNAs (shRNAs) against 161 genes within T1D susceptibility loci. RAW 264.7 cells transduced with shRNAs were infected with GFP-expressing herpes simplex virus type 1 (HSV-1) and fluorescent microscopy was performed to assess the viral infectivity by fluorescence reporter activity. Of the 14 candidates identified with high confidence, two candidates were selected for further investigation, Il27 and Tagap. Administration of recombinant IL-27 during viral infection was found to act synergistically with interferon gamma (IFN-?) to activate expression of type I IFNs and proinflammatory cytokines, and to enhance the activities of interferon regulatory factor 3 (IRF3). Consistent with a role in antiviral immunity, Tagap-deficient macrophages demonstrated increased viral replication, reduced expression of proinflammatory chemokines and cytokines, and decreased production of IFN-?. Taken together, our unbiased loss-of-function genetic screen identifies genes that play a role in host antiviral immunity and delineates roles for IL-27 and Tagap in the production of antiviral cytokines. PMID:25268627

  16. Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk

    PubMed Central

    Duncan, Emma L.; Danoy, Patrick; Kemp, John P.; Leo, Paul J.; McCloskey, Eugene; Nicholson, Geoffrey C.; Eastell, Richard; Prince, Richard L.; Eisman, John A.; Jones, Graeme; Sambrook, Philip N.; Reid, Ian R.; Dennison, Elaine M.; Wark, John; Richards, J. Brent; Uitterlinden, Andre G.; Spector, Tim D.; Esapa, Chris; Cox, Roger D.; Brown, Steve D. M.; Thakker, Rajesh V.; Addison, Kathryn A.; Bradbury, Linda A.; Center, Jacqueline R.; Cooper, Cyrus; Cremin, Catherine; Estrada, Karol; Felsenberg, Dieter; Glüer, Claus-C.; Hadler, Johanna; Henry, Margaret J.; Hofman, Albert; Kotowicz, Mark A.; Makovey, Joanna; Nguyen, Sing C.; Nguyen, Tuan V.; Pasco, Julie A.; Pryce, Karena; Reid, David M.; Rivadeneira, Fernando; Roux, Christian; Stefansson, Kari; Styrkarsdottir, Unnur; Thorleifsson, Gudmar; Tichawangana, Rumbidzai; Evans, David M.; Brown, Matthew A.

    2011-01-01

    Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55–85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n?=?1055, or ?4.0 to ?1.5, n?=?900), with replication in cohorts of women drawn from the general population (n?=?20,898). The study replicates 21 of 26 known BMD–associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies. PMID:21533022

  17. 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

  18. High Incidence of ACE/PAI-1 in Association to a Spectrum of Other Polymorphic Cardiovascular Genes Involving PBMCs Proinflammatory Cytokines in Hypertensive Hypercholesterolemic Patients: Reversibility with a Combination of ACE Inhibitor and Statin

    PubMed Central

    Mouawad, Charbel; Haddad, Katia; Hamoui, Samar; Azar, Albert; Fajloun, Ziad; Makdissy, Nehman

    2015-01-01

    Cardiovascular diseases (CVDs) are significantly high in the Lebanese population with the two most predominant forms being atherosclerosis and venous thrombosis. The purpose of our study was to assess the association of a spectrum of CVD related genes and combined state of hypertension hypercholesterolemia (HH) in unrelated Lebanese. Twelve polymorphisms were studied by multiplex PCR and reverse hybridization of DNA from 171 healthy individuals and 144 HH subjects. Two genes were significantly associated with HH: ACE (OR: 9.20, P<0.0001) and PAI-1 (OR: 2.29, P = 0.007), respectively with the occurrence of the risky alleles “Del” and “4G”. The frequencies of the Del and 4G alleles were found to be 0.98 and 0.90 in the HH group versus 0.84 and 0.79 in the healthy group, respectively. Serum ACE activity and PAI-I increased significantly with Del/Del and 4G/5G genotypes. The co-expression of Del/4G(+/+) was detected in 113 out of 171 (66.0%) controls and 125 out of 144 (86.8%) HH subjects. Del/4G(-/-) was detected in only 6 (3.5%) controls and undetected in the HH group. Three venous thrombosis related genes [FV(Leiden), MTHFR(A1298C) and FXIII(V34L)] were significantly related to the prominence of the co-expression of Del/4G(+/+). A range of 2 to 8 combined polymorphisms co-expressed per subject where 5 mutations were the most detected. In Del/4G(+/+) subjects, peripheral blood mononuclear cells (PBMCs) produced significant elevated levels of IFN-? and TNF-? contrary to IL-10, and no variations occurred for IL-4. ACE inhibitor (ramipril) in combination with statin (atorvastatin) and not alone reversed significantly the situation. This first report from Lebanon sheds light on an additional genetic predisposition of a complex spectrum of genes involved in CVD and suggests that the most requested gene FVL by physicians may not be sufficient to diagnose eventual future problems that can occur in the cardiovascular system. Subjects expressing the double mutations (Del/4G) are at high risk for the onset of CVDs. PMID:25973747

  19. Library Generation by Gene Shuffling

    PubMed Central

    Meyer, Adam J.; Ellefson, JaredW.; Ellington, Andrew D.

    2014-01-01

    This unit describes the process of gene shuffling (also known as sexual PCR). Gene shuffling is a facile method for the generation of sequence libraries containing the information from a family of related genes. Essentially, related genes are fragmented by DNase I digestion and reassembled by primerless PCR. The resulting chimeric genes can then be screened or selected for a desired function. PMID:24510437

  20. 4. AERIAL VIEW OF GENE WASH RESERVOIR AND GENE CAMP ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    4. AERIAL VIEW OF GENE WASH RESERVOIR AND GENE CAMP LOOKING SOUTHWEST. DAM AND SPILLWAY VISIBLE IN BOTTOM OF PHOTO. - Gene Wash Reservoir & Dam, 2 miles west of Parker Dam, Parker Dam, San Bernardino County, CA

  1. GENE EXPRESSION NETWORKS

    EPA Science Inventory

    "Gene expression network" is the term used to describe the interplay, simple or complex, between two or more gene products in performing a specific cellular function. Although the delineation of such networks is complicated by the existence of multiple and subtle types of intera...

  2. Ocular Gene Therapy.

    PubMed

    Campbell, J Peter; McFarland, Trevor J; Stout, J Timothy

    2016-01-01

    Ocular gene therapy involves the introduction of an exogenous gene product to a host's cellular and genetic machinery for endogenous production of a desired gene product. The eye represents an ideal target organ due to its easy visibility and accessibility, and several trials have demonstrated proof-of-principle safety and efficacy in a subtype of Leber's congenital amaurosis. There are numerous ongoing clinical trials exploring gene therapy in other retinal diseases. In autosomal recessively inherited retinal degenerations, the introduced gene product replaces a known genetically deficient gene product and provides restoration of function. In other disease states, such as neovascular age-related macular degeneration, the delivered gene product modulates existing proteins within a cell, such as vascular endothelial growth factor, for a desired therapeutic effect. This latter approach may have broader applications in other diseases such as diabetes and other retinal vascular diseases that are as yet unrealized. This review summarizes the current state of clinical research in ocular gene therapy focusing on those diseases in which the technology has reached clinical trials. PMID:26502313

  3. Gene expression profiles from discordant monozygotic twins suggest that molecular pathways are shared among multiple systemic autoimmune diseases

    PubMed Central

    2011-01-01

    Introduction The objective of this study is to determine if multiple systemic autoimmune diseases (SAID) share gene expression pathways that could provide insights into pathogenic mechanisms common to these disorders. Methods RNA microarray analyses (Agilent Human 1A(V2) 20K oligo arrays) were used to quantify gene expression in peripheral blood cells from 20 monozygotic (MZ) twin pairs discordant for SAID. Six affected probands with systemic lupus erythematosus (SLE), six with rheumatoid arthritis (RA), eight with idiopathic inflammatory myopathies (IIM), and their same-gendered unaffected twins, were enrolled. Comparisons were made between discordant twin pairs and these were also each compared to 40 unrelated control subjects (matched 2:1 to each twin by age, gender and ethnicity) using statistical and molecular pathway analyses. Relative quantitative PCR was used to verify independently measures of differential gene expression assessed by microarray analysis. Results Probands and unrelated, matched controls differed significantly in gene expression for 104 probes corresponding to 92 identifiable genes (multiple-comparison adjusted P values < 0.1). Differentially expressed genes involved several overlapping pathways including immune responses (16%), signaling pathways (24%), transcription/translation regulators (26%), and metabolic functions (15%). Interferon (IFN)-response genes (IFI27, OASF, PLSCR1, EIF2AK2, TNFAIP6, and TNFSF10) were up-regulated in probands compared to unrelated controls. Many of the abnormally expressed genes played regulatory roles in multiple cellular pathways. We did not detect any probes expressed differentially in comparisons among the three SAID phenotypes. Similarly, we found no significant differences in gene expression when comparing probands to unaffected twins or unaffected twins to unrelated controls. Gene expression levels for unaffected twins appeared intermediate between that of probands and unrelated controls for 6535 probes (32% of the total probes) as would be expected by chance. By contrast, in unaffected twins intermediate ordering was observed for 84 of the 104 probes (81%) whose expression differed significantly between probands and unrelated controls. Conclusions Alterations in expression of a limited number of genes may influence the dysregulation of numerous, integrated immune response, cell signaling and regulatory pathways that are common to a number of SAID. Gene expression profiles in peripheral blood suggest that for genes in these critical pathways, unaffected twins may be in a transitional or intermediate state of immune dysregulation between twins with SAID and unrelated controls, perhaps predisposing them to the development of SAID given the necessary and sufficient environmental exposures. PMID:21521520

  4. Gene promoters dictate histone occupancy within genes.

    PubMed

    Perales, Roberto; Erickson, Benjamin; Zhang, Lian; Kim, Hyunmin; Valiquett, Elan; Bentley, David

    2013-10-01

    Spt6 is a transcriptional elongation factor and histone chaperone that reassembles transcribed chromatin. Genome-wide H3 mapping showed that Spt6 preferentially maintains nucleosomes within the first 500 bases of genes and helps define nucleosome-depleted regions in 5' and 3' flanking sequences. In Spt6-depleted cells, H3 loss at 5' ends correlates with reduced pol II density suggesting enhanced transcription elongation. Consistent with its 'Suppressor of Ty' (Spt) phenotype, Spt6 inactivation caused localized H3 eviction over 1-2 nucleosomes at 5' ends of Ty elements. H3 displacement differed between genes driven by promoters with 'open'/DPN and 'closed'/OPN chromatin conformations with similar pol II densities. More eviction occurred on genes with 'closed' promoters, associated with 'noisy' transcription. Moreover, swapping of 'open' and 'closed' promoters showed that they can specify distinct downstream patterns of histone eviction/deposition. These observations suggest a novel function for promoters in dictating histone dynamics within genes possibly through effects on transcriptional bursting or elongation rate. PMID:24013117

  5. Virtual Gene: Using Correlations Between Genes to Select Informative Genes on Microarray Datasets

    E-print Network

    Buffalo, State University of New York

    Virtual Gene: Using Correlations Between Genes to Select Informative Genes on Microarray Datasets State University of New York at Buffalo, Buffalo, NY 14260, USA Abstract. Gene Selection is one class of most used data analysis algorithms on microarray datasets. The goal of gene selection algorithms

  6. Genes from scratch – the evolutionary fate of de novo genes

    PubMed Central

    Schlötterer, Christian

    2015-01-01

    Although considered an extremely unlikely event, many genes emerge from previously noncoding genomic regions. This review covers the entire life cycle of such de novo genes. Two competing hypotheses about the process of de novo gene birth are discussed as well as the high death rate of de novo genes. Despite the high death rate, some de novo genes are retained and remain functional, even in distantly related species, through their integration into gene networks. Further studies combining gene expression with ribosome profiling in multiple populations across different species will be instrumental for an improved understanding of the evolutionary processes operating on de novo genes. PMID:25773713

  7. Gene expression data analysis.

    PubMed

    Brazma, A; Vilo, J

    2000-08-25

    Microarrays are one of the latest breakthroughs in experimental molecular biology, which allow monitoring of gene expression for tens of thousands of genes in parallel and are already producing huge amounts of valuable data. Analysis and handling of such data is becoming one of the major bottlenecks in the utilization of the technology. The raw microarray data are images, which have to be transformed into gene expression matrices--tables where rows represent genes, columns represent various samples such as tissues or experimental conditions, and numbers in each cell characterize the expression level of the particular gene in the particular sample. These matrices have to be analyzed further, if any knowledge about the underlying biological processes is to be extracted. In this paper we concentrate on discussing bioinformatics methods used for such analysis. We briefly discuss supervised and unsupervised data analysis and its applications, such as predicting gene function classes and cancer classification. Then we discuss how the gene expression matrix can be used to predict putative regulatory signals in the genome sequences. In conclusion we discuss some possible future directions. PMID:10967323

  8. The gene tree delusion.

    PubMed

    Springer, Mark S; Gatesy, John

    2016-01-01

    Higher-level relationships among placental mammals are mostly resolved, but several polytomies remain contentious. Song et al. (2012) claimed to have resolved three of these using shortcut coalescence methods (MP-EST, STAR) and further concluded that these methods, which assume no within-locus recombination, are required to unravel deep-level phylogenetic problems that have stymied concatenation. Here, we reanalyze Song et al.'s (2012) data and leverage these re-analyses to explore key issues in systematics including the recombination ratchet, gene tree stoichiometry, the proportion of gene tree incongruence that results from deep coalescence versus other factors, and simulations that compare the performance of coalescence and concatenation methods in species tree estimation. Song et al. (2012) reported an average locus length of 3.1kb for the 447 protein-coding genes in their phylogenomic dataset, but the true mean length of these loci (start codon to stop codon) is 139.6kb. Empirical estimates of recombination breakpoints in primates, coupled with consideration of the recombination ratchet, suggest that individual coalescence genes (c-genes) approach ?12bp or less for Song et al.'s (2012) dataset, three to four orders of magnitude shorter than the c-genes reported by these authors. This result has general implications for the application of coalescence methods in species tree estimation. We contend that it is illogical to apply coalescence methods to complete protein-coding sequences. Such analyses amalgamate c-genes with different evolutionary histories (i.e., exons separated by >100,000bp), distort true gene tree stoichiometry that is required for accurate species tree inference, and contradict the central rationale for applying coalescence methods to difficult phylogenetic problems. In addition, Song et al.'s (2012) dataset of 447 genes includes 21 loci with switched taxonomic names, eight duplicated loci, 26 loci with non-homologous sequences that are grossly misaligned, and numerous loci with >50% missing data for taxa that are misplaced in their gene trees. These problems were compounded by inadequate tree searches with nearest neighbor interchange branch swapping and inadvertent application of substitution models that did not account for among-site rate heterogeneity. Sixty-six gene trees imply unrealistic deep coalescences that exceed 100 million years (MY). Gene trees that were obtained with better justified models and search parameters show large increases in both likelihood scores and congruence. Coalescence analyses based on a curated set of 413 improved gene trees and a superior coalescence method (ASTRAL) support a Scandentia (treeshrews)+Glires (rabbits, rodents) clade, contradicting one of the three primary systematic conclusions of Song et al. (2012). Robust support for a Perissodactyla+Carnivora clade within Laurasiatheria is also lost, contradicting a second major conclusion of this study. Song et al.'s (2012) MP-EST species tree provided the basis for circular simulations that led these authors to conclude that the multispecies coalescent accounts for 77% of the gene tree conflicts in their dataset, but many internal branches of their MP-EST tree are stunted by an order of magnitude or more due to wholesale gene tree reconstruction errors. An independent assessment of branch lengths suggests the multispecies coalescent accounts for ?15% of the conflicts among Song et al.'s (2012) 447 gene trees. Unfortunately, Song et al.'s (2012) flawed phylogenomic dataset has been used as a model for additional simulation work that suggests the superiority of shortcut coalescence methods relative to concatenation. Investigator error was passed on to the subsequent simulation studies, which also incorporated further logical errors that should be avoided in future simulation studies. Illegitimate branch length switches in the simulation routines unfairly protected coalescence methods from their Achilles' heel, high gene tree reconstruction error at short internodes. These simulations therefore provide no

  9. The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity.

    PubMed

    Dudek, Michal; Gossan, Nicole; Yang, Nan; Im, Hee-Jeong; Ruckshanthi, Jayalath P D; Yoshitane, Hikari; Li, Xin; Jin, Ding; Wang, Ping; Boudiffa, Maya; Bellantuono, Ilaria; Fukada, Yoshitaka; Boot-Handford, Ray P; Meng, Qing-Jun

    2016-01-01

    Osteoarthritis (OA) is the most prevalent and debilitating joint disease, and there are currently no effective disease-modifying treatments available. Multiple risk factors for OA, such as aging, result in progressive damage and loss of articular cartilage. Autonomous circadian clocks have been identified in mouse cartilage, and environmental disruption of circadian rhythms in mice predisposes animals to OA-like damage. However, the contribution of the cartilage clock mechanisms to the maintenance of tissue homeostasis is still unclear. Here, we have shown that expression of the core clock transcription factor BMAL1 is disrupted in human OA cartilage and in aged mouse cartilage. Furthermore, targeted Bmal1 ablation in mouse chondrocytes abolished their circadian rhythm and caused progressive degeneration of articular cartilage. We determined that BMAL1 directs the circadian expression of many genes implicated in cartilage homeostasis, including those involved in catabolic, anabolic, and apoptotic pathways. Loss of BMAL1 reduced the levels of phosphorylated SMAD2/3 (p-SMAD2/3) and NFATC2 and decreased expression of the major matrix-related genes Sox9, Acan, and Col2a1, but increased p-SMAD1/5 levels. Together, these results define a regulatory mechanism that links chondrocyte BMAL1 to the maintenance and repair of cartilage and suggest that circadian rhythm disruption is a risk factor for joint diseases such as OA. PMID:26657859

  10. The 'Pokemon' (ZBTB7) Gene: No Evidence of Association with Sporadic Breast Cancer.

    PubMed

    Salas, Antonio; Vega, Ana; Milne, Roger L; García-Magariños, Manuel; Ruibal, Alvaro; Benítez, Javier; Carracedo, Angel

    2008-01-01

    It has been proposed that the excess of familiar risk associated with breast cancer could be explained by the cumulative effect of multiple weakly predisposing alleles. The transcriptional repressor FBI1, also known as Pokemon, has recently been identified as a critical factor in oncogenesis. This protein is encoded by the ZBTB7 gene. Here we aimed to determine whether polymorphisms in ZBTB7 are associated with breast cancer risk in a sample of cases and controls collected in hospitals from North and Central Spanish patients. We genotyped 15 SNPs in ZBTB7, including the flanking regions, with an average coverage of 1 SNP/2.4 Kb, in 360 sporadic breast cancer cases and 402 controls. Comparison of allele, genotype and haplotype frequencies between cases and controls did not reveal associations using Pearson's chi-square test and a permutation procedure to correct for multiple test. In this, the first study of the ZBTB7 gene in relation to, sporadic breast cancer, we found no evidence of an association. PMID:21892298

  11. Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene.

    PubMed

    Cascón, Alberto; Comino-Méndez, Iñaki; Currás-Freixes, María; de Cubas, Aguirre A; Contreras, Laura; Richter, Susan; Peitzsch, Mirko; Mancikova, Veronika; Inglada-Pérez, Lucía; Pérez-Barrios, Andrés; Calatayud, María; Azriel, Sharona; Villar-Vicente, Rosa; Aller, Javier; Setién, Fernando; Moran, Sebastian; Garcia, Juan F; Río-Machín, Ana; Letón, Rocío; Gómez-Graña, Álvaro; Apellániz-Ruiz, María; Roncador, Giovanna; Esteller, Manel; Rodríguez-Antona, Cristina; Satrústegui, Jorgina; Eisenhofer, Graeme; Urioste, Miguel; Robledo, Mercedes

    2015-05-01

    Disruption of the Krebs cycle is a hallmark of cancer. IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers. We describe a paraganglioma family carrying a germline mutation in MDH2, which encodes a Krebs cycle enzyme. Whole-exome sequencing was applied to tumor DNA obtained from a man age 55 years diagnosed with multiple malignant paragangliomas. Data were analyzed with the two-sided Student's t and Mann-Whitney U tests with Bonferroni correction for multiple comparisons. Between six- and 14-fold lower levels of MDH2 expression were observed in MDH2-mutated tumors compared with control patients. Knockdown (KD) of MDH2 in HeLa cells by shRNA triggered the accumulation of both malate (mean ± SD: wild-type [WT] = 1±0.18; KD = 2.24±0.17, P = .043) and fumarate (WT = 1±0.06; KD = 2.6±0.25, P = .033), which was reversed by transient introduction of WT MDH2 cDNA. Segregation of the mutation with disease and absence of MDH2 in mutated tumors revealed MDH2 as a novel pheochromocytoma/paraganglioma susceptibility gene. PMID:25766404

  12. Intrauterine growth restriction affects hippocampal dual specificity phosphatase 5 gene expression and epigenetic characteristics

    PubMed Central

    Ke, Xingrao; McKnight, Robert A.; Caprau, Diana; O'Grady, Shannon; Fu, Qi; Yu, Xing; Callaway, Christopher W.; Albertine, Kurt H.

    2011-01-01

    Intrauterine growth retardation (IUGR) predisposes humans toward hippocampal morbidities, such as impaired learning and memory. Hippocampal dual specificity phosphatase 5 (DUSP5) may be involved in these morbidities because DUSP5 regulates extracellular signal-regulated kinase phosphorylation (Erk). In the rat, IUGR causes postnatal changes in hippocampal gene expression and epigenetic characteristics. However, the impact of IUGR upon hippocampal DUSP5 expression and epigenetic characteristics is not known. We therefore hypothesized that IUGR affects hippocampal 1) DUSP5 expression, DNA CpG methylation, and histone code, and 2) erk1/2 phosphorylation in a well-characterized rat model of IUGR. We found that IUGR significantly decreased DUSP5 expression in the day of life (DOL) 0 and 21 male rat, while decreasing only DUSP5 protein levels in the DOL21 female rat. Fluorescent in situ hybridization and immunohistochemistry analyses localized the changes in DUSP5 mRNA and protein, many of which occurred in the dentate gyrus. IUGR also caused sex-specific differences in DNA CpG methylation and histone code in two sites of the hippocampal DUSP5 gene, a 5?-flanking specificity protein-1 (SP1) site and exon 2. Finally, when IUGR decreased DUSP5 protein levels, Erk phosphorylation increased. We conclude that IUGR affects hippocampal DUSP5 expression and epigenetic characteristics in a sex-specific manner. PMID:21828247

  13. GeneCards Version 3: the human gene integrator

    PubMed Central

    Safran, Marilyn; Dalah, Irina; Alexander, Justin; Rosen, Naomi; Iny Stein, Tsippi; Shmoish, Michael; Nativ, Noam; Bahir, Iris; Doniger, Tirza; Krug, Hagit; Sirota-Madi, Alexandra; Olender, Tsviya; Golan, Yaron; Stelzer, Gil; Harel, Arye; Lancet, Doron

    2010-01-01

    GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73 000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards’ unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene’s functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite. Database URL: www.genecards.org PMID:20689021

  14. Identification of four soybean reference genes for gene expression normalization

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Gene expression analysis requires the use of reference genes stably expressed independently of specific tissues or environmental conditions. Housekeeping genes (e.g., actin, tubulin, ribosomal, polyubiquitin and elongation factor 1-alpha) are commonly used as reference genes with the assumption tha...

  15. Gene Mutations Gene a finite segment of DNA specified

    E-print Network

    Massey, Thomas N.

    Mutation only appear in both parents contribute the same gene. · It may take generations for a recessive a large amount of DNA. · This allows expression of recessive genes on the X chromosome. · There are moreModule 5 Gene Mutations · Gene ­ a finite segment of DNA specified by an exact sequence of bases

  16. Functional Grouping of Genes Using Spectral Clustering and Gene Ontology

    E-print Network

    Zell, Andreas

    Functional Grouping of Genes Using Spectral Clustering and Gene Ontology Nora Speer, Holger amounts of biological data. During the analysis of such data the need for a functional grouping of genes arises. In this paper, we propose a new method based on spectral clustering for the partitioning of genes

  17. A Gene Scrapbook A Tribute to Gene Loh

    E-print Network

    A Gene Scrapbook A Tribute to Gene Loh on the Occasion of His Retirement Feb 22, 2003 #12;The Early of Technology, 1961 #12;The Missing Years Not much is known about Gene's whereabouts between 1961 until his (probably kelp) for transport by sea. #12;Why did Gene leave Cornell? He got tired of shoveling all

  18. 5. OVERHEAD VIEW OF GENE CAMP LOOKING SOUTH. GENE PUMP ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    5. OVERHEAD VIEW OF GENE CAMP LOOKING SOUTH. GENE PUMP PLANT IS AT CENTER WITH ADMINISTRATIVE COMPLEX IN FOREGROUND AND RESIDENTIAL AREA BEYOND PLANT. - Gene Pump Plant, South of Gene Wash Reservoir, 2 miles west of Whitsett Pump Plant, Parker Dam, San Bernardino County, CA

  19. "Bad genes" & criminal responsibility.

    PubMed

    González-Tapia, María Isabel; Obsuth, Ingrid

    2015-01-01

    The genetics of the accused is trying to break into the courts. To date several candidate genes have been put forward and their links to antisocial behavior have been examined and documented with some consistency. In this paper, we focus on the so called "warrior gene", or the low-activity allele of the MAOA gene, which has been most consistently related to human behavior and specifically to violence and antisocial behavior. In preparing this paper we had two objectives. First, to summarize and analyze the current scientific evidence, in order to gain an in depth understanding of the state of the issue and determine whether a dominant line of generally accepted scientific knowledge in this field can be asserted. Second, to derive conclusions and put forward recommendations related to the use of genetic information, specifically the presence of the low-activity genotype of the MAOA gene, in modulation of criminal responsibility in European and US courts. PMID:25708001

  20. Reading and Generalist Genes.

    PubMed

    Haworth, Claire M A; Meaburn, Emma L; Harlaar, Nicole; Plomin, Robert

    2007-12-01

    Twin-study research suggests that many (but not all) of the same genes contribute to genetic influence on diverse learning abilities and disabilities, a hypothesis called generalist genes. This generalist genes hypothesis was tested using a set of 10 DNA markers (single nucleotide polymorphisms [SNPs]) found to be associated with early reading ability in a study of 4,258 7-year-old children that screened 100,000 SNPs. Using the same sample, we show that this early reading SNP set also correlates with other aspects of literacy, components of mathematics, and more general cognitive abilities. These results provide support for the generalist genes hypothesis. Although the effect size of the current SNP set is small, such SNP sets could eventually be used to predict genetic risk for learning disabilities as well as to prescribe genetically tailored intervention and prevention programs. PMID:20383260

  1. Microfluidic gene synthesis

    E-print Network

    Kong, David Sun, 1979-

    2008-01-01

    The ability to synthesize custom de novo DNA constructs rapidly, accurately, and inexpensively is highly desired by researchers, as synthetic genes and longer DNA constructs are enabling to numerous powerful applications ...

  2. Multiple effects of an additional growth hormone gene in adult sheep.

    PubMed

    Adams, N R; Briegel, J R

    2005-08-01

    Molecular genetics provides an increasing capacity to modulate the function of individual genes, but the practical implications of these technologies are still poorly understood. This study examined adult Merino or Merino-cross sheep that had an additional copy of the ovine GH gene with a modified metal-lothionine promoter, which resulted in a doubling of the plasma concentration of GH. Previous work showed that up to the age of 18 mo, GH sheep grew faster and had less s.c. fat, with only minor effects on fleece production. The present paper describes characteristics of reproduction, wool production, and animal health of these sheep during the following 2 yr of adult life. Ewes with the GH gene had a greater ovulation rate (1.78 vs. 1.35; P <0.05), but bore fewer lambs, apparently due to greater fetal loss after mating. Grease fleece weight was increased (P <0.05) due mainly to a greater content of suint (9.1 vs. 7.7 +/- 0.4%, P <0.01), which was associated with a deeper color of the raw wool. Effects on clean fleece weight and fiber diameter were not consistent between years. The GH sheep had swollen metatarsal and metacarpal joints, which was associated with a need for more frequent hoof-trimming, and more GH than control sheep died during the experiment (P <0.001). All of these changes are consistent with previously reported effects of increased plasma GH. Results of this study show that increased activity of a single gene (GH) affected several production characteristics and predisposed the animals to a number of distinct health problems, some of which developed after the normal age of genetic selection. PMID:16024706

  3. Higher Vulnerability and Stress Sensitivity of Neuronal Precursor Cells Carrying an Alpha-Synuclein Gene Triplication

    PubMed Central

    Flierl, Adrian; Oliveira, Luís M. A.; Falomir-Lockhart, Lisandro J.; Mak, Sally K.; Hesley, Jayne; Soldner, Frank; Arndt-Jovin, Donna J.; Jaenisch, Rudolf; Langston, J. William; Jovin, Thomas M.; Schüle, Birgitt

    2014-01-01

    Parkinson disease (PD) is a multi-factorial neurodegenerative disorder with loss of dopaminergic neurons in the substantia nigra and characteristic intracellular inclusions, called Lewy bodies. Genetic predisposition, such as point mutations and copy number variants of the SNCA gene locus can cause very similar PD-like neurodegeneration. The impact of altered ?-synuclein protein expression on integrity and developmental potential of neuronal stem cells is largely unexplored, but may have wide ranging implications for PD manifestation and disease progression. Here, we investigated if induced pluripotent stem cell-derived neuronal precursor cells (NPCs) from a patient with Parkinson’s disease carrying a genomic triplication of the SNCA gene (SNCA-Tri). Our goal was to determine if these cells these neuronal precursor cells already display pathological changes and impaired cellular function that would likely predispose them when differentiated to neurodegeneration. To achieve this aim, we assessed viability and cellular physiology in human SNCA-Tri NPCs both under normal and environmentally stressed conditions to model in vitro gene-environment interactions which may play a role in the initiation and progression of PD. Human SNCA-Tri NPCs displayed overall normal cellular and mitochondrial morphology, but showed substantial changes in growth, viability, cellular energy metabolism and stress resistance especially when challenged by starvation or toxicant challenge. Knockdown of ?-synuclein in the SNCA-Tri NPCs by stably expressed short hairpin RNA (shRNA) resulted in reversal of the observed phenotypic changes. These data show for the first time that genetic alterations such as the SNCA gene triplication set the stage for decreased developmental fitness, accelerated aging, and increased neuronal cell loss. The observation of this “stem cell pathology” could have a great impact on both quality and quantity of neuronal networks and could provide a powerful new tool for development of neuroprotective strategies for PD. PMID:25390032

  4. Classification of genes based on gene expression analysis

    NASA Astrophysics Data System (ADS)

    Angelova, M.; Myers, C.; Faith, J.

    2008-05-01

    Systems biology and bioinformatics are now major fields for productive research. DNA microarrays and other array technologies and genome sequencing have advanced to the point that it is now possible to monitor gene expression on a genomic scale. Gene expression analysis is discussed and some important clustering techniques are considered. The patterns identified in the data suggest similarities in the gene behavior, which provides useful information for the gene functionalities. We discuss measures for investigating the homogeneity of gene expression data in order to optimize the clustering process. We contribute to the knowledge of functional roles and regulation of E. coli genes by proposing a classification of these genes based on consistently correlated genes in expression data and similarities of gene expression patterns. A new visualization tool for targeted projection pursuit and dimensionality reduction of gene expression data is demonstrated.

  5. Classification of genes based on gene expression analysis

    SciTech Connect

    Angelova, M. Myers, C. Faith, J.

    2008-05-15

    Systems biology and bioinformatics are now major fields for productive research. DNA microarrays and other array technologies and genome sequencing have advanced to the point that it is now possible to monitor gene expression on a genomic scale. Gene expression analysis is discussed and some important clustering techniques are considered. The patterns identified in the data suggest similarities in the gene behavior, which provides useful information for the gene functionalities. We discuss measures for investigating the homogeneity of gene expression data in order to optimize the clustering process. We contribute to the knowledge of functional roles and regulation of E. coli genes by proposing a classification of these genes based on consistently correlated genes in expression data and similarities of gene expression patterns. A new visualization tool for targeted projection pursuit and dimensionality reduction of gene expression data is demonstrated.

  6. Gene Expression and Physiological Changes of Different Populations of the Long-Lived Bivalve Arctica islandica under Low Oxygen Conditions

    PubMed Central

    Philipp, Eva E. R.; Wessels, Wiebke; Gruber, Heike; Strahl, Julia; Wagner, Anika E.; Ernst, Insa M. A.; Rimbach, Gerald; Kraemer, Lars; Schreiber, Stefan; Abele, Doris; Rosenstiel, Philip

    2012-01-01

    The bivalve Arctica islandica is extremely long lived (>400 years) and can tolerate long periods of hypoxia and anoxia. European populations differ in maximum life spans (MLSP) from 40 years in the Baltic to >400 years around Iceland. Characteristic behavior of A. islandica involves phases of metabolic rate depression (MRD) during which the animals burry into the sediment for several days. During these phases the shell water oxygen concentrations reaches hypoxic to anoxic levels, which possibly support the long life span of some populations. We investigated gene regulation in A. islandica from a long-lived (MLSP 150 years) German Bight population and the short-lived Baltic Sea population, experimentally exposed to different oxygen levels. A new A. islandica transcriptome enabled the identification of genes important during hypoxia/anoxia events and, more generally, gene mining for putative stress response and (anti-) aging genes. Expression changes of a) antioxidant defense: Catalase, Glutathione peroxidase, manganese and copper-zinc Superoxide dismutase; b) oxygen sensing and general stress response: Hypoxia inducible factor alpha, Prolyl hydroxylase and Heat-shock protein 70; and c) anaerobic capacity: Malate dehydrogenase and Octopine dehydrogenase, related transcripts were investigated. Exposed to low oxygen, German Bight individuals suppressed transcription of all investigated genes, whereas Baltic Sea bivalves enhanced gene transcription under anoxic incubation (0 kPa) and, further, decreased these transcription levels again during 6 h of re-oxygenation. Hypoxic and anoxic exposure and subsequent re-oxygenation in Baltic Sea animals did not lead to increased protein oxidation or induction of apoptosis, emphasizing considerable hypoxia/re-oxygenation tolerance in this species. The data suggest that the energy saving effect of MRD may not be an attribute of Baltic Sea A. islandica chronically exposed to high environmental variability (oxygenation, temperature, salinity). Contrary, higher physiological flexibility and stress hardening may predispose these animals to perform a pronounced stress response at the expense of life span. PMID:23028566

  7. GeneCards Version 3: the human gene integrator.

    PubMed

    Safran, Marilyn; Dalah, Irina; Alexander, Justin; Rosen, Naomi; Iny Stein, Tsippi; Shmoish, Michael; Nativ, Noam; Bahir, Iris; Doniger, Tirza; Krug, Hagit; Sirota-Madi, Alexandra; Olender, Tsviya; Golan, Yaron; Stelzer, Gil; Harel, Arye; Lancet, Doron

    2010-01-01

    GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73,000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards' unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene's functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite. Database URL: www.genecards.org. PMID:20689021

  8. Neoplasms Associated with Germline and Somatic NF1 Gene Mutations

    PubMed Central

    Patil, Sachin

    2012-01-01

    Introduction. Neurofibromatosis 1 is a tumor predisposition genetic syndrome with autosomal dominant inheritance and virtually 100% penetrance by the age of 5 years. NF1 results from a loss-of-function mutation in the NF1 gene, resulting in decreased levels of neurofibromin in the cell. Neurofibromin is a negative regulator of various intracellular signaling pathways involved in the cellular proliferation. Although the loss of heterozygosity in the NF1 gene may predispose NF1 patients to certain malignancies, additional genetic alterations are a prerequisite for their development. The precise nature of these additional genetic alterations is not well defined, and genetic testing of all malignancies in NF1 patients becomes an essential component of future research in this subset of patients. In addition to germline NF1 mutations, alteration of the somatic NF1 gene is associated with sporadic malignancies such as adenocarcinoma of the colon, myelodysplastic syndrome, and anaplastic astrocytoma. Materials and Methods. A comprehensive English and non-English language search for all articles pertinent to malignancies associated with NF1 was conducted using PubMed, a search engine provided by the U.S. National Library of Medicine and the National Institutes of Health. Key words searched included the following: “malignancies associated with NF1”, “tumors associated with NF1”, and “NF1 and malignancies”. A comprehensive analysis in terms age and mode of presentation, investigation and therapeutic modalities, and outcome of the published data was performed and compared with similar information on the sporadic cases. Results. Malignancies in NF1 patients typically occur at an earlier age and, with an exception of optic pathway gliomas, certain types of malignancies carry a poor prognosis compared with their sporadic counterparts. Malignancies are the leading cause of death in NF1 patients, resulting in a 10- to 15-year decreased life expectancy compared with the general population. Conclusions. The lack of well-defined screening tests for early detection and the nonspecific clinical presentation contributes to a poorer outcome in malignancies associated with NF1. Small study group size, mixed patient population, and a lack of uniformity in reporting research results make comparison of treatment outcome for this group difficult. An International Consensus Meeting to address and recommend best practices for screening, diagnosis, management, and follow-up of malignancies associated with NF1 is needed. PMID:22240541

  9. Gene Therapy Current Methods and

    E-print Network

    Brutlag, Doug

    Gene Therapy Current Methods and Research for Cystic Fibrosis Alexis Wallen June 4, 2001 #12;What membrane · "Subtle defects in pulmonary function" #12;Gene Therapy for CF · General Principles of gene therapy is to cure disease by altering the genome to include or exclude a desired set of genes

  10. Gene Center Munich Genzentrum Mnchen

    E-print Network

    Frey, Erwin

    Gene Center Munich Genzentrum München Symposium December 1, 2010 'From Genes to Networks ­ Systems:50 ­ 12:50 Prof. Dr. Ulrike Gaul (Alexander von Humboldt Professor, LMU Munich) "Decoding regulatory gene. Patrick Cramer (LMU Munich) "Global mechanisms of gene transcription" 14:30 ­ 15:10 Prof. Dr. Gertrud

  11. Frequency of Genotype With ?F508 Mutation in CFTR Gene Among Iranian Cystic Fibrosis Patients With Pancreatic Insufficiency

    PubMed Central

    Khodadad, Ahmad; Elahi, Elaheh; Bani Hassani, Setareh Sadat; Rouhani, Pejman; Sadeghi, Bamdad; Rezaei, Nima

    2015-01-01

    Background: Cystic fibrosis (CF) is the most prevalent lethal autosomal recessive disease with a broad spectrum of phenotypes. Mutation of ?F508 in the CFTR gene is the most important and lethal mutation in CF, which contains 70% of all predisposing mutations for CF worldwide. Objectives: Determining frequency of genotypes with ?F508 mutation in CFTR gene, and evaluation of correlation between genotype and phenotype of Iranian patients with CF. Patients and Methods: Thirty six patients were included in this cross sectional study. ?F508 mutations in both alleles of the CFTR gene were checked. Results: Among 36 pediatric patients, ?F508 mutation was detected in 9 (25%) patients; 2 patients were heterozygous, and 7 patients homozygous for this mutation. From overall 72 tracked alleles, 11 (15.2%) were found to have ?F508 mutations. Differences in prevalence of dyspnea and bronchiectasis were significant in homozygote group, compared with non-mutated group for ?F508. Conclusions: It seems that more ?F508 mutated alleles lead to more severe symptoms of CF. PMID:26635942

  12. Polymorphic variants of GSTM1, GSTT1, and GSTP1 genes in childhood acute leukemias: A preliminary study in Argentina.

    PubMed

    Weich, N; Nuñez, M C; Galimberti, G; Elena, G; Acevedo, S; Larripa, I; Fundia, A F

    2015-10-01

    Background and Aim Despite recent major advances in leukemia research, the etiopathogenesis of childhood leukemias remains far elusive. Individual predisposing factors, including polymorphisms in detoxification enzymes, have been implicated in the molecular pathogenesis and heterogeneity of the disease. Genetic polymorphisms of glutathione S-transferases (GSTs) that alter enzyme activity could be an additional factor that increases the risk of acute leukemia, but data are lacking in Argentina. We assessed the association of GST polymorphisms and the susceptibility to childhood leukemia in Argentina by conducting an exploratory case-control study and correlated patients' genotype to clinical and biological features. Methods Deletion polymorphisms in GSTM1 and GSTT1 genes and the single nucleotide polymorphism in GSTP1 c.313A>G (rs1695; p.105Ile>Val) were genotyped by PCR-RFLP in 36 patients and 133 healthy individuals. Results GSTM1-null genotype was associated with a lower risk of developing acute leukemia (P = 0.013; OR: 0.31; CI: 0.12-0.80), while GSTP1-GG variants displayed an increased risk (P = 0.01; OR: 3.9; CI: 1.85-8.2). However, no differences were found for GSTT1 gene. Conclusion These preliminary results, to be validated in a larger population from Argentina, suggest that the development of pediatric leukemia may be differentially influenced by polymorphic variants in GST genes. PMID:25799091

  13. How old is my gene?

    PubMed

    Capra, John A; Stolzer, Maureen; Durand, Dannie; Pollard, Katherine S

    2013-11-01

    Gene functions, interactions, disease associations, and ecological distributions are all correlated with gene age. However, it is challenging to estimate the intricate series of evolutionary events leading to a modern-day gene and then to reduce this history to a single age estimate. Focusing on eukaryotic gene families, we introduce a framework that can be used to compare current strategies for quantifying gene age, discuss key differences between these methods, and highlight several common problems. We argue that genes with complex evolutionary histories do not have a single well-defined age. As a result, care must be taken to articulate the goals and assumptions of any analysis that uses gene age estimates. Recent algorithmic advances offer the promise of gene age estimates that are fast, accurate, and consistent across gene families. This will enable a shift to integrated genome-wide analyses of all events in gene evolutionary histories in the near future. PMID:23915718

  14. How old is my gene?

    PubMed Central

    Capra, John A.; Stolzer, Maureen; Durand, Dannie; Pollard, Katherine S.

    2013-01-01

    Gene functions, interactions, disease associations, and ecological distributions are all correlated with gene age. However, it is challenging to estimate the intricate series of evolutionary events leading to a modern day gene and then reduce this history to a single age estimate. Focusing on eukaryotic gene families, we introduce a framework in which to compare current strategies for quantifying gene age, discuss key differences between these methods, and highlight several common problems. We argue that genes with complex evolutionary histories do not have a single well-defined age. As a result, care must be taken to articulate the goals and assumptions of any analysis that uses gene age estimates. Recent algorithmic advances offer the promise of gene age estimates that are fast, accurate, and consistent across gene families. This will enable a shift to integrated genome-wide analyses of all events in gene evolutionary histories in the near future. PMID:23915718

  15. FunGene: the functional gene pipeline and repository

    PubMed Central

    Fish, Jordan A.; Chai, Benli; Wang, Qiong; Sun, Yanni; Brown, C. Titus; Tiedje, James M.; Cole, James R.

    2013-01-01

    Ribosomal RNA genes have become the standard molecular markers for microbial community analysis for good reasons, including universal occurrence in cellular organisms, availability of large databases, and ease of rRNA gene region amplification and analysis. As markers, however, rRNA genes have some significant limitations. The rRNA genes are often present in multiple copies, unlike most protein-coding genes. The slow rate of change in rRNA genes means that multiple species sometimes share identical 16S rRNA gene sequences, while many more species share identical sequences in the short 16S rRNA regions commonly analyzed. In addition, the genes involved in many important processes are not distributed in a phylogenetically coherent manner, potentially due to gene loss or horizontal gene transfer. While rRNA genes remain the most commonly used markers, key genes in ecologically important pathways, e.g., those involved in carbon and nitrogen cycling, can provide important insights into community composition and function not obtainable through rRNA analysis. However, working with ecofunctional gene data requires some tools beyond those required for rRNA analysis. To address this, our Functional Gene Pipeline and Repository (FunGene; http://fungene.cme.msu.edu/) offers databases of many common ecofunctional genes and proteins, as well as integrated tools that allow researchers to browse these collections and choose subsets for further analysis, build phylogenetic trees, test primers and probes for coverage, and download aligned sequences. Additional FunGene tools are specialized to process coding gene amplicon data. For example, FrameBot produces frameshift-corrected protein and DNA sequences from raw reads while finding the most closely related protein reference sequence. These tools can help provide better insight into microbial communities by directly studying key genes involved in important ecological processes. PMID:24101916

  16. Genome-wide CNV analysis in 221 unrelated patients and targeted high-throughput sequencing reveal novel causative candidate genes for colorectal adenomatous polyposis.

    PubMed

    Horpaopan, Sukanya; Spier, Isabel; Zink, Alexander M; Altmüller, Janine; Holzapfel, Stefanie; Laner, Andreas; Vogt, Stefanie; Uhlhaas, Siegfried; Heilmann, Stefanie; Stienen, Dietlinde; Pasternack, Sandra M; Keppler, Kathleen; Adam, Ronja; Kayser, Katrin; Moebus, Susanne; Draaken, Markus; Degenhardt, Franziska; Engels, Hartmut; Hofmann, Andrea; Nöthen, Markus M; Steinke, Verena; Perez-Bouza, Alberto; Herms, Stefan; Holinski-Feder, Elke; Fröhlich, Holger; Thiele, Holger; Hoffmann, Per; Aretz, Stefan

    2015-03-15

    To uncover novel causative genes in patients with unexplained adenomatous polyposis, a model disease for colorectal cancer, we performed a genome-wide analysis of germline copy number variants (CNV) in a large, well characterized APC and MUTYH mutation negative patient cohort followed by a targeted next generation sequencing (NGS) approach. Genomic DNA from 221 unrelated German patients was genotyped on high-resolution SNP arrays. Putative CNVs were filtered according to stringent criteria, compared with those of 531 population-based German controls, and validated by qPCR. Candidate genes were prioritized using in silico, expression, and segregation analyses, data mining and enrichment analyses of genes and pathways. In 27% of the 221 unrelated patients, a total of 77 protein coding genes displayed rare, nonrecurrent, germline CNVs. The set included 26 candidates with molecular and cellular functions related to tumorigenesis. Targeted high-throughput sequencing found truncating point mutations in 12% (10/77) of the prioritized genes. No clear evidence was found for autosomal recessive subtypes. Six patients had potentially causative mutations in more than one of the 26 genes. Combined with data from recent studies of early-onset colorectal and breast cancer, recurrent potential loss-of-function alterations were detected in CNTN6, FOCAD (KIAA1797), HSPH1, KIF26B, MCM3AP, YBEY and in three genes from the ARHGAP family. In the canonical Wnt pathway oncogene CTNNB1 (?-catenin), two potential gain-of-function mutations were found. In conclusion, the present study identified a group of rarely affected genes which are likely to predispose to colorectal adenoma formation and confirmed previously published candidates for tumor predisposition as etiologically relevant. PMID:25219767

  17. Virus induced gene silencing of Arabidopsis gene homologues in wheat identify genes conferring improved drought tolerance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In a non-model staple crop like wheat, functional validation of potential drought stress responsive genes identified in Arabidopsis could provide gene targets for wheat breeding. Virus induced gene silencing (VIGS) of genes of interest can overcome the inherent problems of polyploidy and limited tra...

  18. GeneTIER: prioritization of candidate disease genes using tissue-specific gene expression profiles

    PubMed Central

    Antanaviciute, Agne; Daly, Catherine; Crinnion, Laura A.; Markham, Alexander F.; Watson, Christopher M.; Bonthron, David T.; Carr, Ian M.

    2015-01-01

    Motivation: In attempts to determine the genetic causes of human disease, researchers are often faced with a large number of candidate genes. Linkage studies can point to a genomic region containing hundreds of genes, while the high-throughput sequencing approach will often identify a great number of non-synonymous genetic variants. Since systematic experimental verification of each such candidate gene is not feasible, a method is needed to decide which genes are worth investigating further. Computational gene prioritization presents itself as a solution to this problem, systematically analyzing and sorting each gene from the most to least likely to be the disease-causing gene, in a fraction of the time it would take a researcher to perform such queries manually. Results: Here, we present Gene TIssue Expression Ranker (GeneTIER), a new web-based application for candidate gene prioritization. GeneTIER replaces knowledge-based inference traditionally used in candidate disease gene prioritization applications with experimental data from tissue-specific gene expression datasets and thus largely overcomes the bias toward the better characterized genes/diseases that commonly afflict other methods. We show that our approach is capable of accurate candidate gene prioritization and illustrate its strengths and weaknesses using case study examples. Availability and Implementation: Freely available on the web at http://dna.leeds.ac.uk/GeneTIER/. Contact: umaan@leeds.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25861967

  19. Engineered Gene Circuits

    NASA Astrophysics Data System (ADS)

    Hasty, Jeff

    2003-03-01

    Uncovering the structure and function of gene regulatory networks has become one of the central challenges of the post-genomic era. Theoretical models of protein-DNA feedback loops and gene regulatory networks have long been proposed, and recently, certain qualitative features of such models have been experimentally corroborated. This talk will focus on model and experimental results that demonstrate how a naturally occurring gene network can be used as a ``parts list'' for synthetic network design. The model formulation leads to computational and analytical approaches relevant to nonlinear dynamics and statistical physics, and the utility of such a formulation will be demonstrated through the consideration of specific design criteria for several novel genetic devices. Fluctuations originating from small molecule-number effects will be discussed in the context of model predictions, and the experimental validation of these stochastic effects underscores the importance of internal noise in gene expression. Potential biotech applications will be highlighted within the framework of cellular control schemes. Specifically, the coupling of an oscillating cellular process to a synthetic oscillator will be considered, and the resulting model behavior will be analyzed in the context of synchronization. The underlying methodology highlights the utility of engineering-based methods in the design of synthetic gene regulatory networks.

  20. Mice heterozygous for the ATM gene are more sensitive to heavy ions exposure than are wildtypes

    NASA Astrophysics Data System (ADS)

    Worgul, B.; Smilenov, L.; Brenner, D.; Vazquez, M.; Hall, E.

    Previous studies have shown that the eyes of atm heterozygous mice exposed to Low LET radiation (X-rays) are more susceptible to the development of cataracts than are those of wildtype mice. The findings, as well as others, run counter to the assumption underpinning current radiation safety guidelines, that individuals are all equally sensitive to the biological effects of radiation. A question, highly relevant to human space activities is whether or not, in similar fashion there may exist a genetic predisposition to High LET radiation damage. Again the lens and, its primary radiopathy, cataract, were used to assay for the effects of ATM deficiency in a late-responding tissue. Together with those of wildtypes, the eyes of AT heterozygous knockout mice were exposed to 325 mGy of 1 GEV/amu 56Fe ions at the AGS facility of Brookhaven National Laboratory. The fluence was equivalent to 1 ion per nuclear area. As was the case in the earlier X-ray studies all irradiations were done on the 28th day after birth. Controls consisted of wildtype irradiated as well as unirradiated wildtype and heterozygotes. Ten mice from each group were examined weekly by conventional slitlamp biomicroscopy for a total of 35 weeks. The time required for prevalence to reach 50% (T50) as an endpoint for each stage indicated that not only cataract onset but also progression were accelerated in the mice haplo-deficient for the atm gene. For example the T50 for definitive cataract onset (stage 1) in the atm heterozygotes was 10 weeks whereas 17 weeks were required for the wildtypes. Similarly at the conclusion of the experiment (35 weeks), 40% of the lenses of allele-deficient mice had progressed to stage 3 (near fully opaque and obviously visually debilitating), while only one lens (5%) from the wildtype irradiated eyes achieved that stage. The data show that heterozygosity for the atm gene predisposes the eye to the cataractogenic influence of heavy ions and suggest that AT heterozygotes in the human population may also be radiosensitive. This may have to be considered in the selection of individuals who will be exposed to both HZE particles and Low-LET radiation as they may be predisposed to increased late normal tissue damage. Supported by NASA Grant NAG 9-1148 and Research to Prevent Blindness, Inc.

  1. Characterizing gene family evolution

    PubMed Central

    Liberles, David A.

    2008-01-01

    Gene families are widely used in comparative genomics, molecular evolution, and in systematics. However, they are constructed in different manners, their data analyzed and interpreted differently, with different underlying assumptions, leading to sometimes divergent conclusions. In systematics, concepts like monophyly and the dichotomy between homoplasy and homology have been central to the analysis of phylogenies. We critique the traditional use of such concepts as applied to gene families and give examples of incorrect inferences they may lead to. Operational definitions that have emerged within functional genomics are contrasted with the common formal definitions derived from systematics. Lastly, we question the utility of layers of homology and the meaning of homology at the character state level in the context of sequence evolution. From this, we move forward to present an idealized strategy for characterizing gene family evolution for both systematic and functional purposes, including recent methodological improvements. PMID:19461954

  2. Beyond the Gene

    PubMed Central

    Fox Keller, Evelyn; Harel, David

    2007-01-01

    This paper is a response to the increasing difficulty biologists find in agreeing upon a definition of the gene, and indeed, the increasing disarray in which that concept finds itself. After briefly reviewing these problems, we propose an alternative to both the concept and the word gene—an alternative that, like the gene, is intended to capture the essence of inheritance, but which is both richer and more expressive. It is also clearer in its separation of what the organism statically is (what it tangibly inherits) and what it dynamically does (its functionality and behavior). Our proposal of a genetic functor, or genitor, is a sweeping extension of the classical genotype/phenotype paradigm, yet it appears to be faithful to the findings of contemporary biology, encompassing many of the recently emerging—and surprisingly complex—links between structure and functionality. PMID:18043738

  3. Alphaviruses in Gene Therapy

    PubMed Central

    Lundstrom, Kenneth

    2015-01-01

    Alphavirus vectors present an attractive approach for gene therapy applications due to the rapid and simple recombinant virus particle production and their broad range of mammalian host cell transduction. Mainly three types of alphavirus vectors, namely naked RNA, recombinant particles and DNA/RNA layered vectors, have been subjected to preclinical studies with the goal of achieving prophylactic or therapeutic efficacy, particularly in oncology. In this context, immunization with alphavirus vectors has provided protection against challenges with tumor cells. Moreover, alphavirus intratumoral and systemic delivery has demonstrated substantial tumor regression and significant prolonged survival rates in various animal tumor models. Recent discoveries of the strong association of RNA interference and disease have accelerated gene therapy based approaches, where alphavirus-based gene delivery can play an important role. PMID:25961488

  4. Gene therapy in pancreatic cancer

    PubMed Central

    Liu, Si-Xue; Xia, Zhong-Sheng; Zhong, Ying-Qiang

    2014-01-01

    Pancreatic cancer (PC) is a highly lethal disease and notoriously difficult to treat. Only a small proportion of PC patients are eligible for surgical resection, whilst conventional chemoradiotherapy only has a modest effect with substantial toxicity. Gene therapy has become a new widely investigated therapeutic approach for PC. This article reviews the basic rationale, gene delivery methods, therapeutic targets and developments of laboratory research and clinical trials in gene therapy of PC by searching the literature published in English using the PubMed database and analyzing clinical trials registered on the Gene Therapy Clinical Trials Worldwide website (http://www. wiley.co.uk/genmed/ clinical). Viral vectors are main gene delivery tools in gene therapy of cancer, and especially, oncolytic virus shows brighter prospect due to its tumor-targeting property. Efficient therapeutic targets for gene therapy include tumor suppressor gene p53, mutant oncogene K-ras, anti-angiogenesis gene VEGFR, suicide gene HSK-TK, cytosine deaminase and cytochrome p450, multiple cytokine genes and so on. Combining different targets or combination strategies with traditional chemoradiotherapy may be a more effective approach to improve the efficacy of cancer gene therapy. Cancer gene therapy is not yet applied in clinical practice, but basic and clinical studies have demonstrated its safety and clinical benefits. Gene therapy will be a new and promising field for the treatment of PC. PMID:25309069

  5. Multidimensional gene search with Genehopper

    PubMed Central

    Munz, Matthias; Tönnies, Sascha; Balke, Wolf-Tilo; Simon, Eric

    2015-01-01

    The high abundance of genetic information enables researchers to gain new insights from the comparison of human genes according to their similarities. However, existing tools that allow the exploration of such gene-to-gene relationships, apply each similarity independently. To make use of multidimensional scoring, we developed a new search engine named Genehopper. It can handle two query types: (i) the typical use case starts with a term-to-gene search, i.e. an optimized full-text search for an anchor gene of interest. The web-interface can handle one or more terms including gene symbols and identifiers of Ensembl, UniProt, EntrezGene and RefSeq. (ii) When the anchor gene is defined, the user can explore its neighborhood by a gene-to-gene search as the weighted sum of nine normalized gene similarities based on sequence homology, protein domains, mRNA expression profiles, Gene Ontology Annotation, gene symbols and other features. Each weight can be adjusted by the user, allowing flexible customization of the gene search. All implemented similarities have a low pairwise correlation (max r2 = 0.4) implying a low linear dependency, i.e. any change in a single weight has an effect on the ranking. Thus, we treated them as separate dimensions in the search space. Genehopper is freely available at http://genehopper.ifis.cs.tu-bs.de. PMID:25990726

  6. Multidimensional gene search with Genehopper.

    PubMed

    Munz, Matthias; Tönnies, Sascha; Balke, Wolf-Tilo; Simon, Eric

    2015-07-01

    The high abundance of genetic information enables researchers to gain new insights from the comparison of human genes according to their similarities. However, existing tools that allow the exploration of such gene-to-gene relationships, apply each similarity independently. To make use of multidimensional scoring, we developed a new search engine named Genehopper. It can handle two query types: (i) the typical use case starts with a term-to-gene search, i.e. an optimized full-text search for an anchor gene of interest. The web-interface can handle one or more terms including gene symbols and identifiers of Ensembl, UniProt, EntrezGene and RefSeq. (ii) When the anchor gene is defined, the user can explore its neighborhood by a gene-to-gene search as the weighted sum of nine normalized gene similarities based on sequence homology, protein domains, mRNA expression profiles, Gene Ontology Annotation, gene symbols and other features. Each weight can be adjusted by the user, allowing flexible customization of the gene search. All implemented similarities have a low pairwise correlation (max r(2) = 0.4) implying a low linear dependency, i.e. any change in a single weight has an effect on the ranking. Thus, we treated them as separate dimensions in the search space. Genehopper is freely available at http://genehopper.ifis.cs.tu-bs.de. PMID:25990726

  7. Origin of?Genes

    PubMed Central

    Gilbert, Walter; de Souza, Sandro J.; Long, Manyuan

    1997-01-01

    We discuss two tests of the hypothesis that the first genes were assembled from exons. The hypothesis of exon shuffling in the progenote predicts that intron phases will be correlated so that exons will be an integer number of codons and predicts that the exons will be correlated with compact regions of polypeptide chain. These predictions have been tested on ancient conserved proteins (proteins without introns in prokaryotes but with introns in eukaryotes) and hold with high statistical significance. We conclude that introns are correlated with compact features of proteins 15-, 22-, or 30-amino acid residues long, as was predicted by “The Exon Theory of Genes.” PMID:9223251

  8. Phospholipid – Driven gene regulation

    PubMed Central

    Musille, Paul M.; Kohn, Jeffrey A.; Ortlund, Eric A.

    2013-01-01

    Phospholipids (PLs), well known for their fundamental role in cellular structure, play critical signaling roles via their derivatives and cleavage products acting as second messengers in signaling cascades. Recent work has shown that intact PLs act as signaling molecules in their own right by modulating the activity of nuclear hormone transcription factors responsible for tuning genes involved in metabolism, lipid flux, steroid synthesis and inflammation. As such, PLs have been classified as novel hormones. This review highlights recent work in PL-driven gene regulation with a focus on the unique structural features of phospholipid-sensing transcription factors and what sets them apart from well known soluble phospholipid transporters. PMID:23333623

  9. Genes and Vocal Learning

    PubMed Central

    White, Stephanie A.

    2009-01-01

    Could a mutation in a single gene be the evolutionary lynchpin supporting the development of human language? A rare mutation in the molecule known as FOXP2 discovered in a human family seemed to suggest so, and its sequence phylogeny reinforced a Chomskian view that language emerged wholesale in humans. Spurred by this discovery, research in primates, rodents and birds suggests that FoxP2 and other language-related genes are interactors in the neuromolecular networks that underlie subsystems of language, such symbolic understanding, vocal learning and theory of mind. The whole picture will only come together through comparative and integrative study into how the human language singularity evolved. PMID:19913899

  10. Association Between Upstream Purine Complexes of Human Caveolin-1 Gene and Schizophrenia in Qazvin Province of Iran

    PubMed Central

    Najafipour, Reza; Heidari, Abolfazl; Alizadeh, Safar Ali; Ghafelebashi, Hannaneh; Rashvand, Zahra; Javadi, Amir; Moradi, Mohammad; Afshar, Hosein

    2014-01-01

    Background: Caveolin is a multifunctional and scaffolding membrane protein, which involves cholesterol trafficking to plasma lipid microdomain. It organizes and targets synaptic parts of the neurotransmitter and neurotrophic receptor signaling pathways. Caveolins are encoded by CAV-1, 2 and 3 genes. Disruption of the CAV1 would likely ruin the neuronal signaling, which leads to symptoms of schizophrenia in predisposed individuals. Objectives: The upper area of CAV-1 gene is highly conserved and can have a regulatory role in neurodegenerative diseases. This study was designed to find out the possible association of polymorphisms of this area and schizophrenia. Patients and Methods: In a case-control study, 254 blood samples were obtained from 127 patients with schizophrenia and 127 well matched controls referred to 22 Bahman Hospital of Qazvin University of Medical Sciences (QUMS) in Qazvin province, Iran, using simple random sampling method. After extracting DNA, the upper region of the human CAV1- gene was amplified by PCR in all collected samples. The products were visualized by silver staining in 10% polyacrylamide gel and then sequenced. Results: We detected nine homozygotes in patients and 15 in control subjects. Homozygosity was 7.08% and 11.8% in cases and control, respectively. Nine types homozygote haplotype were detected in upper region of the CAV1 gene in cases and controls. Three haplotypes were common in cases and controls; four haplotypes were seen in controls only and two in cases. Conclusions: Our findings implied a significant correlation between some haplotypes of upper region of CAV1 gene and schizophrenia. Existence of some haplotypes and lack of another in CAV1 upstream can suggest a significant correlation between schizophrenia and some haplotypes. PMID:25763243

  11. Laminar and Dorsoventral Molecular Organization of the Medial Entorhinal Cortex Revealed by Large-scale Anatomical Analysis of Gene Expression

    PubMed Central

    Ramsden, Helen L.; Sürmeli, Gül?en; McDonagh, Steven G.; Nolan, Matthew F.

    2015-01-01

    Neural circuits in the medial entorhinal cortex (MEC) encode an animal’s position and orientation in space. Within the MEC spatial representations, including grid and directional firing fields, have a laminar and dorsoventral organization that corresponds to a similar topography of neuronal connectivity and cellular properties. Yet, in part due to the challenges of integrating anatomical data at the resolution of cortical layers and borders, we know little about the molecular components underlying this organization. To address this we develop a new computational pipeline for high-throughput analysis and comparison of in situ hybridization (ISH) images at laminar resolution. We apply this pipeline to ISH data for over 16,000 genes in the Allen Brain Atlas and validate our analysis with RNA sequencing of MEC tissue from adult mice. We find that differential gene expression delineates the borders of the MEC with neighboring brain structures and reveals its laminar and dorsoventral organization. We propose a new molecular basis for distinguishing the deep layers of the MEC and show that their similarity to corresponding layers of neocortex is greater than that of superficial layers. Our analysis identifies ion channel-, cell adhesion- and synapse-related genes as candidates for functional differentiation of MEC layers and for encoding of spatial information at different scales along the dorsoventral axis of the MEC. We also reveal laminar organization of genes related to disease pathology and suggest that a high metabolic demand predisposes layer II to neurodegenerative pathology. In principle, our computational pipeline can be applied to high-throughput analysis of many forms of neuroanatomical data. Our results support the hypothesis that differences in gene expression contribute to functional specialization of superficial layers of the MEC and dorsoventral organization of the scale of spatial representations. PMID:25615592

  12. Interleukin-6 C-572G gene polymorphism and coronary artery disease in Asian: a meta-analysis of 2511 subjects.

    PubMed

    Li, Yan-Yan; Zhou, Chuan-Wei; Xu, Jian; Qian, Yun; Wang, Xiang-Ming

    2015-01-01

    The interleukin-6 (IL-6) C-572G gene polymorphism has been suggested to be associated with the increased coronary artery disease (CAD) risk, but the study results are still debatable. To explore the association between IL-6 C-572G gene polymorphism and CAD in the Asian population, the current meta-analysis involving 2511 subjects from 7 separate studies was conducted. The combined odds ratio (ORs) for the association between IL-6 C-572G gene polymorphism and CAD and their corresponding 95% confidence intervals (95% CIs) were assessed by random or fixed effect model. A significant association between IL-6 C-572G gene polymorphism and CAD was found in the Asian population under an allelic (OR: 1.50, 95% CI: 1.30-1.71, P<0.00001), recessive (OR: 2.221, 95% CI: 1.444-3.417, P=1.0×10(-10)) dominant (OR: 1.313, 95% CI: 1.188-1.451, P=1.0×10(-10)), homozygous (OR: 2.454, 95% CI: 1.606-3.751, P=1.0×10(-10)), heterozygous (OR: 3.01, 95% CI:1.99-4.55, P<0.00001) and additive genetic models (OR: 1.372, 95% CI: 1.231-1.528, P=1.0×10(-10)). In the Asian population, the IL-6 C-572G gene polymorphism was indicated to be correlated with CAD susceptibility. The carriers of -572G allele might be predisposed to CAD risk. PMID:26309552

  13. CD14 gene-159C/T polymorphism and coronary artery disease: a meta-analysis involving 4467 subjects

    PubMed Central

    Li, Yan-Yan; Wang, Xiang-Ming; Zhou, Chuan-Wei; Xu, Jian; Qian, Yun

    2015-01-01

    Background: The cluster of differentiation antigen 14 (CD14) gene-159C/T polymorphism has been implied to be associated with coronary artery disease (CAD) susceptibility. However, the separate studies results are still conflicting between each other. Objective and methods: To investigate the relationship between CD14 gene-159C/T polymorphism and CAD, a meta-analysis including 4467 subjects from 7 individual studies was performed. The random or fixed effect models were used to evaluate the pooled odds ratios (ORs) and their corresponding 95% confidence intervals. Results: There was a significant association between CD14 gene -159C/T polymorphism and CAD in the whole population under allelic (OR: 1.280, 95% CI: 1.000-1.630, P=0.05), recessive (OR: 1.760, 95% CI: 1.120-2.750, P=0.01), homozygous (OR: 1.693, 95% CI: 1.008-2.843, P=0.046), and additive genetic models (OR: 1.278, 95% CI: 1.000-1.633, P=0.050). No significant association was found between them under dominant (OR: 0.580, 95% CI: 0.310-1.110, P=0.10) and heterozygous genetic models (OR: 1.334, 95% CI: 0.870-2.045, P=0.186). In the subgroup analysis, a significant association was detected in Chinese population (P<0.05), while there was no significant association in the Caucasian subgroup (P>0.05). Conclusions: CD14 gene -159C/T polymorphism was significantly associated with CAD susceptibility, particularly in the Chinese population. The person with T allele of CD14 gene -159C/T polymorphism might predispose to CAD. There was no distinct association between them in the Caucasian subgroup. PMID:26550125

  14. TAP1 I333V gene polymorphism and type 1 diabetes mellitus: a meta-analysis of 2248 cases

    PubMed Central

    Li, Yan-Yan; Gao, Wei; Pang, Si-Si; Min, Xiao-Yan; Yang, Zhi-Jian; Wang, Hui; Lu, Xin-Zheng; Wang, Lian-Sheng; Wang, Xiang-Ming; Qian, Yun; Zhou, Chuan-Wei; Wu, Jun; Chen, Ai-Ling

    2014-01-01

    Transporter associated with antigen processing 1 (TAP1) I333V gene polymorphism has been suggested to be associated with type 1 diabetes mellitus (T1DM) susceptibility. However, the results from individual studies are inconsistent. To explore the association of TAP1 I333V gene polymorphisms with T1DM, a meta-analysis involving 2246 cases from 13 individual studies was conducted. The pooled odd ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were evaluated by a fixed-effect model. A significant relationship was observed between TAP1 I333V gene polymorphism and T1DM in allelic (OR: 1.35, 95% CI: 1.08–1.68, P = 0.007), dominant (OR: 1.462, 95% CI: 1.094–1.955, P = 0.010), homozygous (OR: 1.725, 95% CI: 1.082–2.752, P = 0.022), heterozygous (OR: 1.430, 95% CI: 1.048–1.951, P = 0.024) and additive (OR: 1.348, 95% CI: 1.084–1.676, P = 0.007) genetic models. No significant association between TAP1 I333V gene polymorphism and T1DM was detected in a recessive genetic model (OR: 1.384, 95% CI: 0.743–2.579, P = 0.306) in the entire population, especially among Caucasians. No significant association between them was found in an Asian or African population. TAP1 I333V gene polymorphism was significantly associated with increased T1DM risk. V allele carriers might be predisposed to T1DM susceptibility. PMID:24655325

  15. A Customized Pigmentation SNP Array Identifies a Novel SNP Associated with Melanoma Predisposition in the SLC45A2 Gene

    PubMed Central

    Alonso, Santos; Boyano, M. Dolores; Peña-Chilet, Maria; Pita, Guillermo; Aviles, Jose A.; Mayor, Matias; Gomez-Fernandez, Cristina; Casado, Beatriz; Martin-Gonzalez, Manuel; Izagirre, Neskuts; De la Rua, Concepcion; Asumendi, Aintzane; Perez-Yarza, Gorka; Arroyo-Berdugo, Yoana; Boldo, Enrique; Lozoya, Rafael; Torrijos-Aguilar, Arantxa; Pitarch, Ana; Pitarch, Gerard; Sanchez-Motilla, Jose M.; Valcuende-Cavero, Francisca; Tomas-Cabedo, Gloria; Perez-Pastor, Gemma; Diaz-Perez, Jose L.; Gardeazabal, Jesus; de Lizarduy, Iñigo Martinez; Sanchez-Diez, Ana; Valdes, Carlos; Pizarro, Angel; Casado, Mariano; Carretero, Gregorio; Botella-Estrada, Rafael; Nagore, Eduardo; Lazaro, Pablo; Lluch, Ana; Benitez, Javier; Martinez-Cadenas, Conrado; Ribas, Gloria

    2011-01-01

    As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date. PMID:21559390

  16. Optimal Reference Genes for Gene Expression Normalization in Trichomonas vaginalis

    PubMed Central

    dos Santos, Odelta; de Vargas Rigo, Graziela; Frasson, Amanda Piccoli; Macedo, Alexandre José; Tasca, Tiana

    2015-01-01

    Trichomonas vaginalis is the etiologic agent of trichomonosis, the most common non-viral sexually transmitted disease worldwide. This infection is associated with several health consequences, including cervical and prostate cancers and HIV acquisition. Gene expression analysis has been facilitated because of available genome sequences and large-scale transcriptomes in T. vaginalis, particularly using quantitative real-time polymerase chain reaction (qRT-PCR), one of the most used methods for molecular studies. Reference genes for normalization are crucial to ensure the accuracy of this method. However, to the best of our knowledge, a systematic validation of reference genes has not been performed for T. vaginalis. In this study, the transcripts of nine candidate reference genes were quantified using qRT-PCR under different cultivation conditions, and the stability of these genes was compared using the geNorm and NormFinder algorithms. The most stable reference genes were ?-tubulin, actin and DNATopII, and, conversely, the widely used T. vaginalis reference genes GAPDH and ?-tubulin were less stable. The PFOR gene was used to validate the reliability of the use of these candidate reference genes. As expected, the PFOR gene was upregulated when the trophozoites were cultivated with ferrous ammonium sulfate when the DNATopII, ?-tubulin and actin genes were used as normalizing gene. By contrast, the PFOR gene was downregulated when the GAPDH gene was used as an internal control, leading to misinterpretation of the data. These results provide an important starting point for reference gene selection and gene expression analysis with qRT-PCR studies of T. vaginalis. PMID:26393928

  17. Differentially Coexpressed Genes

    E-print Network

    Spang, Rainer

    Fine-tuning #12;Do these pattern exist in real data ? Acute Lymphoblastic Leukemia · About 1/3 of all compared cytogenetically normal children to those with the phil+ translocation Yeoh EJ, RossMEet al. (2002) Classication, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene

  18. Gene electrotransfer clinical trials.

    PubMed

    Heller, Richard; Heller, Loree C

    2015-01-01

    Plasmid or non-viral gene therapy offers an alternative to classic viral gene delivery that negates the need for a biological vector. In this case, delivery is enhanced by a variety of approaches including lipid or polymer conjugation, particle-mediated delivery, hydrodynamic delivery, ultrasound or electroporation. Electroporation was originally used as a laboratory tool to deliver DNA to bacterial and mammalian cells in culture. Electrode development allowed this technique to be modified for in vivo use. After preclinical therapeutic studies, clinical delivery of cell impermeant chemotherapeutic agents progressed to clinical delivery of plasmid DNA. One huge benefit of this delivery technique is its malleability. The pulse protocol used for plasmid delivery can be fine-tuned to control the levels and duration of subsequent transgene expression. This fine-tuning allows transgene expression to be tailored to each therapeutic application. Effective and appropriate expression induces the desired clinical response that is a critical component for any gene therapy. This chapter focuses on clinical trials using in vivo electroporation or electrotransfer as a plasmid delivery method. The first clinical trial was initiated in 2004, and now more than fifty trials use electric fields for gene delivery. Safety and tolerability has been demonstrated by several groups, and early clinical efficacy results are promising in both cancer therapeutic and infectious disease vaccine applications. PMID:25620013

  19. GENE EXPRESSION PROFILING

    Technology Transfer Automated Retrieval System (TEKTRAN)

    DNA microarray technology is fast becoming a standard tool for gene expression analysis. The laboratory methods and protocols for array construction, processing, and hybridization are well established. Many of the initial plant genome sequencing projects are providing large sets of expressed seque...

  20. Inferring Horizontal Gene Transfer

    PubMed Central

    Lassalle, Florent; Dessimoz, Christophe

    2015-01-01

    Horizontal or Lateral Gene Transfer (HGT or LGT) is the transmission of portions of genomic DNA between organisms through a process decoupled from vertical inheritance. In the presence of HGT events, different fragments of the genome are the result of different evolutionary histories. This can therefore complicate the investigations of evolutionary relatedness of lineages and species. Also, as HGT can bring into genomes radically different genotypes from distant lineages, or even new genes bearing new functions, it is a major source of phenotypic innovation and a mechanism of niche adaptation. For example, of particular relevance to human health is the lateral transfer of antibiotic resistance and pathogenicity determinants, leading to the emergence of pathogenic lineages [1]. Computational identification of HGT events relies upon the investigation of sequence composition or evolutionary history of genes. Sequence composition-based ("parametric") methods search for deviations from the genomic average, whereas evolutionary history-based ("phylogenetic") approaches identify genes whose evolutionary history significantly differs from that of the host species. The evaluation and benchmarking of HGT inference methods typically rely upon simulated genomes, for which the true history is known. On real data, different methods tend to infer different HGT events, and as a result it can be difficult to ascertain all but simple and clear-cut HGT events. PMID:26020646

  1. Naming genes beyond Caenorhabditis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The nomenclature of genes in Caenorhabditis elegans is based on long-standing, successful guidelines established in the late 1970s. Over time these guidelines have matured into a comprehensive, systematic nomenclature that is easy to apply, descriptive and therefore highly informative. Recently, a f...

  2. IBMFS - gene mutations

    Cancer.gov

    A "mutation" is a change in a gene that prevents it from working properly. A "germline" mutation is a change that occurs in the egg or the sperm, or both, and is passed from one parent or both parents to the child.

  3. Genes and Vocal Learning

    ERIC Educational Resources Information Center

    White, Stephanie A.

    2010-01-01

    Could a mutation in a single gene be the evolutionary lynchpin supporting the development of human language? A rare mutation in the molecule known as FOXP2 discovered in a human family seemed to suggest so, and its sequence phylogeny reinforced a Chomskian view that language emerged wholesale in humans. Spurred by this discovery, research in…

  4. GENES REGULATING CHOLESTEROL METABOLISM

    E-print Network

    Brutlag, Doug

    GENES REGULATING CHOLESTEROL METABOLISM Chau Vu Bio 118 #12;FUNCTIONS OF CHOLESTEROL Maintain atherosclerosis #12;SYNTHESIS OF CHOLESTEROL Occurs in cytoplasm and microsomes acetyl-CoA ­ starting material OF CHOLESTEROL #12;REGULATION OF CHOLESTEROL Synthesis and dietary intake: Normal Adult: produce1g/day; consume

  5. Ultrasound mediated gene transfection

    NASA Astrophysics Data System (ADS)

    Williamson, Rene G.; Apfel, Robert E.; Brandsma, Janet L.

    2002-05-01

    Gene therapy is a promising modality for the treatment of a variety of human diseases both inherited and acquired, such as cystic fibrosis and cancer. The lack of an effective, safe method for the delivery of foreign genes into the cells, a process known as transfection, limits this effort. Ultrasound mediated gene transfection is an attractive method for gene delivery since it is a noninvasive technique, does not introduce any viral particles into the host and can offer very good temporal and spatial control. Previous investigators have shown that sonication increases transfection efficiency with and without ultrasound contrast agents. The mechanism is believed to be via a cavitation process where collapsing bubble nuclei permeabilize the cell membrane leading to increased DNA transfer. The research is focused on the use of pulsed wave high frequency focused ultrasound to transfect DNA into mammalian cells in vitro and in vivo. A better understanding of the mechanism behind the transfection process is also sought. A summary of some in vitro results to date will be presented, which includes the design of a sonication chamber that allows us to model the in vivo case more accurately.

  6. Your Genes, Your Choices

    MedlinePLUS

    ... to science literacy and the public understanding of science. Through its Directorate for Education and Human Resources Programs, AAAS has been a ... Your Genes, Your Choices is a publication of Science + Literacy for Health, a project of ... for Education and Human Resources . The publication was funded by ...

  7. Gene Manipulation In Cereals

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aluminum, the most abundant metal on earth, is detrimental to plant growth and agricultural production. There are about 2.5 billion hectares of acid soils high in aluminum around the world. Molecular markers linked to aluminum tolerance gene complexes in rye would be of value in marker-mediated ge...

  8. Gene-Environment Interdependence

    ERIC Educational Resources Information Center

    Rutter, Michael

    2007-01-01

    Behavioural genetics was initially concerned with partitioning population variance into that due to genetics and that due to environmental influences. The implication was that the two were separate and it was assumed that gene-environment interactions were usually of so little importance that they could safely be ignored. Theoretical…

  9. Germ line variation in nucleotide excision repair genes and lung cancer risk in smokers

    PubMed Central

    Sakoda, Lori C; Loomis, Melissa M; Doherty, Jennifer A; Julianto, Liberto; Barnett, Matt J; Neuhouser, Marian L; Thornquist, Mark D; Weiss, Noel S; Goodman, Gary E; Chen, Chu

    2012-01-01

    Since nucleotide excision repair (NER) is primarily responsible for detecting and removing bulky DNA lesions induced by tobacco smoke in the respiratory tract, single nucleotide polymorphisms (SNPs) in NER protein-encoding genes may influence lung cancer risk, particularly in smokers. Studies testing this hypothesis have produced inconsistent results, with most analyzing a few SNPs in relatively small population samples. In a study nested in the Beta- Carotene and Retinol Efficacy Trial, we examined 79 tag and previously reported risk-associated SNPs in the ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, LIG1, POLE, XPA, and XPC genes in 744 lung cancer cases and 1,477 controls, all of whom were non-Hispanic white smokers. Using logistic regression, odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to estimate lung cancer risk associated with SNP genotypes and haplotypes, adjusting for case-control matching factors. Lung cancer risk was modestly associated with LIG1 rs156640 (OR per G allele, 1.23; 95% CI, 1.08-1.40), rs156641 (OR per A allele, 1.23; 95% CI, 1.08-1.40), and rs8100261 (OR per A allele, 0.83; 95% CI, 0.76-0.98); XPA rs3176658 (OR per A allele, 0.83; 95% CI, 0.69-1.00); and ERCC2 rs50871 (OR per C allele, 1.15; 95% CI: 1.01-1.30). Associations with LIG1 and XPA, but not ERCC2, haplotypes were found. The results of this study and others suggest that inherited variants in LIG1 and possibly other NER genes may predispose to smokingrelated lung cancer. Given that chance likely accounts for one or more of the associations observed, replication of our findings is needed. PMID:22493747

  10. Post-mortem Whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series.

    PubMed

    Narula, Nupoor; Tester, David J; Paulmichl, Anna; Maleszewski, Joseph J; Ackerman, Michael J

    2015-04-01

    Annually, thousands of sudden deaths in individuals under 35 years remain unexplained following comprehensive medico-legal autopsy. Previously, post-mortem genetic analysis by Sanger sequencing of four major cardiac channelopathy genes revealed that approximately one-fourth of these autopsy-negative sudden unexplained death in the young (SUDY) cases harbored an underlying mutation. However, there are now over 100 sudden death-predisposing cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes. Here, we set out to determine whether post-mortem whole exome sequencing (WES) is an efficient strategy to detect ultra-rare, potentially pathogenic variants. We performed post-mortem WES and gene-specific analysis of 117 sudden death-susceptibility genes for 14 consecutively referred Caucasian SUDY victims (average age at death 17.4 ± 8.6 years) to identify putative SUDY-associated mutations. On average, each SUDY case had 12,758 ± 2,016 non-synonymous variants, of which 79 ± 15 localized to these 117 genes. Overall, eight ultra-rare variants (seven missense, one in-frame insertion) absent in three publically available exome databases were identified in six genes (three in TTN, and one each in CACNA1C, JPH2, MYH7, VCL, RYR2) in seven of 14 cases (50 %). Of the seven missense alterations, two (T171M-CACNA1C, I22160T-TTN) were predicted damaging by three independent in silico tools. Although WES and gene-specific surveillance is an efficient means to detect rare genetic variants that might underlie the pathogenic cause of death, accurate interpretation of each variant is challenging. Great restraint and caution must be exercised otherwise families may be informed prematurely and incorrectly that the root cause has been found. PMID:25500949

  11. GENE METHYLATION CHANGES IN TUMOR SUPPRESSOR GENES INDUCED BY ARSENIC

    EPA Science Inventory

    The choice of a dose-response model used for extrapolation can be influenced by knowledge of mechanism of action. We have already showed that arsenic affects methylation of the human p53 gene promoter. Evidence that genes other than the p53 tumor suppressor gene are affected woul...

  12. The Gene Ontology (GO) database and informatics Gene Ontology Consortium*

    E-print Network

    The Gene Ontology (GO) database and informatics resource Gene Ontology Consortium* GO-EBI, EMBL and Accepted September 12, 2003 ABSTRACT The Gene Ontology (GO) project (http://www. geneontology and sequences. Many model organism databases and genome annotation groups use the GO and contribute

  13. [Gene pool and gene geography of the USSR population].

    PubMed

    Rychkov, Iu G; Balanovskaia, E V

    1992-01-01

    Gene pool and gene geography are discussed from the point of view of their conceptual history beginning from the original concept of A.S. Serebrovski? (1928). Difference between the present-day gene geography and gene geography of gene pool is accentuated: the former only represents a portion of the latter. Historical and territorial integrity of the USSR population gene pool, in conjunction with its huge diversity, is the main problem being analysed by various means of computerized genetic cartography. Coupled with the gene frequency mapping, following methods were also used: mapping of average heterozygosity, of interpopulation differentiation, of principal component scores and mapping of geographical trend for each mapped genetic parameter. The work is based on 100 allelic genes and haplotypes from 30 independent loci studied on the average in 225 local populations. Statistical analysis of gene geographical maps is based on 3975 nodes of regular cartographic net for the USSR territory. The wind rose of systematic changes in the USSR gene pool has three main geographic orientations: W-E, SW-NE and S-N. At the same time, there are only two main systematic forces of gene pool evolution: the force of social history with predominant W-E orientation and the force of natural history with predominant S-N orientation of their actions. The heterozygosity level of gene pool declines strictly in accordance with the resultant in the SW-NE direction. PMID:1582574

  14. Spectral Clustering Gene Ontology Terms to Group Genes by Function

    E-print Network

    Zell, Andreas

    Spectral Clustering Gene Ontology Terms to Group Genes by Function Nora Speer, Christian Spieth throughput me- thods like DNA microarrays, biologists are capable of producing huge amounts of data. During the analysis of such data the need for a group- ing of the genes according to their biological function arises

  15. Proto-genes and de novo gene birth

    PubMed Central

    Carvunis, Anne-Ruxandra; Rolland, Thomas; Wapinski, Ilan; Calderwood, Michael A.; Yildirim, Muhammed A.; Simonis, Nicolas; Charloteaux, Benoit; Hidalgo, César A.; Barbette, Justin; Santhanam, Balaji; Brar, Gloria A.; Weissman, Jonathan S.; Regev, Aviv; Thierry-Mieg, Nicolas; Cusick, Michael E.; Vidal, Marc

    2012-01-01

    Novel protein-coding genes can arise either through re-organization of pre-existing genes or de novo1,2. Processes involving re-organization of pre-existing genes, notably following gene duplication, have been extensively described1,2. In contrast, de novo gene birth remains poorly understood, mainly because translation of sequences devoid of genes, or “non-genic” sequences, is expected to produce insignificant polypeptides rather than proteins with specific biological functions1,3-6. Here, we formalize an evolutionary model according to which functional genes evolve de novo through transitory proto-genes4 generated by widespread translational activity in non-genic sequences. Testing this model at genome-scale in Saccharomyces cerevisiae, we detect translation of hundreds of short species-specific open reading frames (ORFs) located in non-genic sequences. These translation events appear to provide adaptive potential7, as suggested by their differential regulation upon stress and by signatures of retention by natural selection. In line with our model, we establish that S. cerevisiae ORFs can be placed within an evolutionary continuum ranging from non-genic sequences to genes. We identify ~1,900 candidate proto-genes among S. cerevisiae ORFs and find that de novo gene birth from such a reservoir may be more prevalent than sporadic gene duplication. Our work illustrates that evolution exploits seemingly dispensable sequences to generate adaptive functional innovation. PMID:22722833

  16. Intervention in gene regulatory networks 

    E-print Network

    Choudhary, Ashish

    2006-10-30

    In recent years Boolean Networks (BN) and Probabilistic Boolean Networks (PBN) have become popular paradigms for modeling gene regulation. A PBN is a collection of BNs in which the gene state vector transitions according to the rules of one...

  17. Chapter 15: Disease Gene Prioritization

    PubMed Central

    Bromberg, Yana

    2013-01-01

    Disease-causing aberrations in the normal function of a gene define that gene as a disease gene. Proving a causal link between a gene and a disease experimentally is expensive and time-consuming. Comprehensive prioritization of candidate genes prior to experimental testing drastically reduces the associated costs. Computational gene prioritization is based on various pieces of correlative evidence that associate each gene with the given disease and suggest possible causal links. A fair amount of this evidence comes from high-throughput experimentation. Thus, well-developed methods are necessary to reliably deal with the quantity of information at hand. Existing gene prioritization techniques already significantly improve the outcomes of targeted experimental studies. Faster and more reliable techniques that account for novel data types are necessary for the development of new diagnostics, treatments, and cure for many diseases. PMID:23633938

  18. Regulation of eucaryotic gene expression

    SciTech Connect

    Brent, R.; Ptashne, M.S

    1989-05-23

    This patent describes a method of regulating the expression of a gene in a eucaryotic cell. The method consists of: providing in the eucaryotic cell, a peptide, derived from or substantially similar to a peptide of a procaryotic cell able to bind to DNA upstream from or within the gene, the amount of the peptide being sufficient to bind to the gene and thereby control expression of the gene.

  19. Deconstructing cell determination: proneural genes

    E-print Network

    Montpellier II, Université

    involved in the development of sense organs in Drosophila, which itself has been the starting point genes in vertebrates. The first event leading to the formation of a sense organ in flies: for example, the genes achaete and scute confer the competence to form external sense organs, while the gene

  20. Independent Gene Discovery and Testing

    ERIC Educational Resources Information Center

    Palsule, Vrushalee; Coric, Dijana; Delancy, Russell; Dunham, Heather; Melancon, Caleb; Thompson, Dennis; Toms, Jamie; White, Ashley; Shultz, Jeffry

    2010-01-01

    A clear understanding of basic gene structure is critical when teaching molecular genetics, the central dogma and the biological sciences. We sought to create a gene-based teaching project to improve students' understanding of gene structure and to integrate this into a research project that can be implemented by instructors at the secondary level…

  1. Evolutionary Origin of Orphan Genes

    E-print Network

    Evolutionary Origin of Orphan Genes Diethard Tautz, Max-Planck Institute for Evolutionary Biology Orphangenesaregenesthatoccurinspecificevolutionary lineages without similarity to genes outside of these lin- eages and have, therefore, alternatively been named taxonomically restricted genes. They were so far con- sidered to emerge through

  2. Clinical Perspective Genes Associated with

    E-print Network

    Oliver, Douglas L.

    Clinical Perspective Genes Associated with Alcohol Dependence There is good evidence from studies, hundreds of genes likely are involved in this complex disorder, with each variant contributing only a very small effect. Therefore, identifying individual risk genes is difficult. Using a new approach

  3. PLANT MORPHOGENESIS AND KNOX GENES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    KNOX genes function in plant meristems, which produce leaves and stems. Three recent studies show that the dwarf phenotype, brevipedicellus, is caused by a recessive mutation in a KNOX gene. A fourth study shows that misexpression of KNOX genes leads to novel features that may have selective value....

  4. Eukaryotic Gene Prediction Kelli Davies

    E-print Network

    Eukaryotic Gene Prediction Kelli Davies 2009 December 12 Introduction: The advent of large in 1977, that of a small bacteriophage consisting of 11 genes over 5.4kb of DNA. In the bacteriophage, coding genes comprise 95% of the genome.1 Since then, numerous prokaryotic and eukaryotic genomes have

  5. From SNPs to Genes: Disease Association at the Gene Level

    PubMed Central

    Lehne, Benjamin; Lewis, Cathryn M.; Schlitt, Thomas

    2011-01-01

    Interpreting Genome-Wide Association Studies (GWAS) at a gene level is an important step towards understanding the molecular processes that lead to disease. In order to incorporate prior biological knowledge such as pathways and protein interactions in the analysis of GWAS data it is necessary to derive one measure of association for each gene. We compare three different methods to obtain gene-wide test statistics from Single Nucleotide Polymorphism (SNP) based association data: choosing the test statistic from the most significant SNP; the mean test statistics of all SNPs; and the mean of the top quartile of all test statistics. We demonstrate that the gene-wide test statistics can be controlled for the number of SNPs within each gene and show that all three methods perform considerably better than expected by chance at identifying genes with confirmed associations. By applying each method to GWAS data for Crohn's Disease and Type 1 Diabetes we identified new potential disease genes. PMID:21738570

  6. A Genomewide Scan for Loci Predisposing to Type 2 Diabetes in a U.K. Population (The Diabetes UK Warren 2 Repository): Analysis of 573 Pedigrees Provides Independent Replication of a Susceptibility Locus on Chromosome 1q

    PubMed Central

    Wiltshire, Steven; Hattersley, Andrew T.; Hitman, Graham A.; Walker, Mark; Levy, Jonathan C.; Sampson, Michael; O’Rahilly, Stephen; Frayling, Timothy M.; Bell, John I.; Lathrop, G. Mark; Bennett, Amanda; Dhillon, Ranjit; Fletcher, Christopher; Groves, Christopher J.; Jones, Elizabeth; Prestwich, Philip; Simecek, Nikol; Rao, Pamidighantam V. Subba; Wishart, Marie; Foxon, Richard; Howell, Simon; Smedley, Damian; Cardon, Lon R.; Menzel, Stephan; McCarthy, Mark I.

    2001-01-01

    Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores ?1.18 (P?.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest. PMID:11484155

  7. Gene Therapy and Children (For Parents)

    MedlinePLUS

    ... Kids Deal With Bullies Pregnant? What to Expect Gene Therapy and Children KidsHealth > Parents > Doctors & Hospitals > Medical Tests & ... by a "bad" gene. Continue Two Types of Gene Therapy The two forms of gene therapy are: Somatic ...

  8. Genetics Home Reference: What is gene therapy?

    MedlinePLUS

    ... Precision Medicine Next Handbook > Gene Therapy > What is gene therapy? Gene therapy is an experimental technique that uses ... have no other cures. For general information about gene therapy: MedlinePlus from the National Library of Medicine offers ...

  9. Biometrics 000, 000000 DOI: 000 Powerful tests for detecting a gene effect in the presence of possible gene-gene

    E-print Network

    Maity, Arnab

    Biometrics 000, 000­000 DOI: 000 000 0000 Powerful tests for detecting a gene effect in the presence of possible gene-gene interactions using garrote kernel machines Arnab Maity Department a gene effect on a continuous outcome in the presence of possible gene-gene interactions (epistasis

  10. Graphene based gene transfection

    NASA Astrophysics Data System (ADS)

    Feng, Liangzhu; Zhang, Shuai; Liu, Zhuang

    2011-03-01

    Graphene as a star in materials research has been attracting tremendous attentions in the past few years in various fields including biomedicine. In this work, for the first time we successfully use graphene as a non-toxic nano-vehicle for efficient gene transfection. Graphene oxide (GO) is bound with cationic polymers, polyethyleneimine (PEI) with two different molecular weights at 1.2 kDa and 10 kDa, forming GO-PEI-1.2k and GO-PEG-10k complexes, respectively, both of which are stable in physiological solutions. Cellular toxicity tests reveal that our GO-PEI-10k complex exhibits significantly reduced toxicity to the treated cells compared to the bare PEI-10k polymer. The positively charged GO-PEI complexes are able to further bind with plasmid DNA (pDNA) for intracellular transfection of the enhanced green fluorescence protein (EGFP) gene in HeLa cells. While EGFP transfection with PEI-1.2k appears to be ineffective, high EGFP expression is observed using the corresponding GO-PEI-1.2k as the transfection agent. On the other hand, GO-PEI-10k shows similar EGFP transfection efficiency but lower toxicity compared with PEI-10k. Our results suggest graphene to be a novel gene delivery nano-vector with low cytotoxicity and high transfection efficiency, promising for future applications in non-viral based gene therapy.Graphene as a star in materials research has been attracting tremendous attentions in the past few years in various fields including biomedicine. In this work, for the first time we successfully use graphene as a non-toxic nano-vehicle for efficient gene transfection. Graphene oxide (GO) is bound with cationic polymers, polyethyleneimine (PEI) with two different molecular weights at 1.2 kDa and 10 kDa, forming GO-PEI-1.2k and GO-PEG-10k complexes, respectively, both of which are stable in physiological solutions. Cellular toxicity tests reveal that our GO-PEI-10k complex exhibits significantly reduced toxicity to the treated cells compared to the bare PEI-10k polymer. The positively charged GO-PEI complexes are able to further bind with plasmid DNA (pDNA) for intracellular transfection of the enhanced green fluorescence protein (EGFP) gene in HeLa cells. While EGFP transfection with PEI-1.2k appears to be ineffective, high EGFP expression is observed using the corresponding GO-PEI-1.2k as the transfection agent. On the other hand, GO-PEI-10k shows similar EGFP transfection efficiency but lower toxicity compared with PEI-10k. Our results suggest graphene to be a novel gene delivery nano-vector with low cytotoxicity and high transfection efficiency, promising for future applications in non-viral based gene therapy. Electronic supplementary information (ESI) available: Thickness distribution of GO and GO-PEI; IR and TGA data; and confocal images of HeLa cells treated with bare EGFP pDNA and GO + pDNA. See DOI: 10.1039/c0nr00680g

  11. Brains, genes, and primates.

    PubMed

    Izpisua Belmonte, Juan Carlos; Callaway, Edward M; Caddick, Sarah J; Churchland, Patricia; Feng, Guoping; Homanics, Gregg E; Lee, Kuo-Fen; Leopold, David A; Miller, Cory T; Mitchell, Jude F; Mitalipov, Shoukhrat; Moutri, Alysson R; Movshon, J Anthony; Okano, Hideyuki; Reynolds, John H; Ringach, Dario; Sejnowski, Terrence J; Silva, Afonso C; Strick, Peter L; Wu, Jun; Zhang, Feng

    2015-05-01

    One of the great strengths of the mouse model is the wide array of genetic tools that have been developed. Striking examples include methods for directed modification of the genome, and for regulated expression or inactivation of genes. Within neuroscience, it is now routine to express reporter genes, neuronal activity indicators, and opsins in specific neuronal types in the mouse. However, there are considerable anatomical, physiological, cognitive, and behavioral differences between the mouse and the human that, in some areas of inquiry, limit the degree to which insights derived from the mouse can be applied to understanding human neurobiology. Several recent advances have now brought into reach the goal of applying these tools to understanding the primate brain. Here we describe these advances, consider their potential to advance our understanding of the human brain and brain disorders, discuss bioethical considerations, and describe what will be needed to move forward. PMID:25950631

  12. Genes and addiction.

    PubMed

    Nestler, E J

    2000-11-01

    Drug addiction, like all psychiatric disorders, is defined solely in behavioural terms. For example, addiction can be considered a loss of control over drug-taking, or compulsive drug-seeking and -taking despite horrendous consequences. Abnormal behaviours are a consequence of aberrant brain function, which means that it is a tangible goal to identify the biological underpinnings of addiction. The genetic basis of addiction encompasses two broad areas of enquiry. One of these is the identification of genetic variation in humans that partly determines susceptibility to addiction. The other is the use of animal models to investigate the role of specific genes in mediating the development of addiction. Whereas recent advances in this latter effort are heartening, a major challenge remains: to understand how the many genes implicated in rodent models interact to yield as complex a phenotype as addiction. PMID:11062465

  13. Alphaviruses in gene therapy.

    PubMed

    Lundstrom, Kenneth

    2009-06-01

    Alphaviruses are enveloped single stranded RNA viruses, which as gene therapy vectors provide high-level transient gene expression. Semliki Forest virus (SFV), Sindbis virus (SIN) and Venezuelan Equine Encephalitis (VEE) virus have been engineered as efficient replication-deficient and -competent expression vectors. Alphavirus vectors have frequently been used as vehicles for tumor vaccine generation. Moreover, SFV and SIN vectors have been applied for intratumoral injections in animals implanted with tumor xenografts. SIN vectors have demonstrated natural tumor targeting, which might permit systemic vector administration. Another approach for systemic delivery of SFV has been to encapsulate replication-deficient viral particles in liposomes, which can provide passive targeting to tumors and allow repeated administration without host immune responses. This approach has demonstrated safe delivery of encapsulated SFV particles to melanoma and kidney carcinoma patients in a phase I trial. Finally, the prominent neurotropism of alphaviruses make them attractive for the treatment of CNS-related diseases. PMID:21994535

  14. Endochondral ossification pathway genes and postmenopausal osteoporosis: Association and specific allele related serum bone sialoprotein levels in Han Chinese.

    PubMed

    Zhang, Yunzhi; Liu, Haiyan; Zhang, Chen; Zhang, Tianxiao; Zhang, Bo; Li, Lu; Chen, Gang; Fu, Dongke; Wang, KunZheng

    2015-01-01

    Osteoporosis is a systemic skeletal disorder characterized by reduced bone mineral density (BMD) and disrupted bone architecture, predisposing the patient to increased fracture risk. Evidence from early genetic epidemiological studies has indicated a major role for genetics in the development of osteoporosis and the variation in BMD. In this study, we focused on two key genes in the endochondral ossification pathway, IBSP and PTHLH. Over 9,000 postmenopausal Han Chinese women were recruited, and 54 SNPs were genotyped. Two significant SNPs within IBSP, rs1054627 and rs17013181, were associated with BMD and postmenopausal osteoporosis by the two-stage strategy, and rs17013181 was also significantly associated with serum IBSP levels. Moreover, one haplotype (rs12425376-rs10843047-rs42294) covering the 5' end of PTHLH was associated with postmenopausal osteoporosis. Our results provide evidence for the association of these two key endochondral ossification pathway genes with BMD and osteoporosis in postmenopausal Han Chinese women. Combined with previous findings, we provide evidence that a particular SNP in IBSP has an allele-specific effect on mRNA levels, which would, in turn, reflect serum IBSP levels. PMID:26568273

  15. Endochondral ossification pathway genes and postmenopausal osteoporosis: Association and specific allele related serum bone sialoprotein levels in Han Chinese

    PubMed Central

    Zhang, Yunzhi; Liu, Haiyan; Zhang, Chen; Zhang, Tianxiao; Zhang, Bo; Li, Lu; Chen, Gang; Fu, Dongke; Wang, KunZheng

    2015-01-01

    Osteoporosis is a systemic skeletal disorder characterized by reduced bone mineral density (BMD) and disrupted bone architecture, predisposing the patient to increased fracture risk. Evidence from early genetic epidemiological studies has indicated a major role for genetics in the development of osteoporosis and the variation in BMD. In this study, we focused on two key genes in the endochondral ossification pathway, IBSP and PTHLH. Over 9,000 postmenopausal Han Chinese women were recruited, and 54 SNPs were genotyped. Two significant SNPs within IBSP, rs1054627 and rs17013181, were associated with BMD and postmenopausal osteoporosis by the two-stage strategy, and rs17013181 was also significantly associated with serum IBSP levels. Moreover, one haplotype (rs12425376-rs10843047-rs42294) covering the 5’ end of PTHLH was associated with postmenopausal osteoporosis. Our results provide evidence for the association of these two key endochondral ossification pathway genes with BMD and osteoporosis in postmenopausal Han Chinese women. Combined with previous findings, we provide evidence that a particular SNP in IBSP has an allele-specific effect on mRNA levels, which would, in turn, reflect serum IBSP levels. PMID:26568273

  16. Xeroderma pigmentosum variant: complementary molecular approaches to detect a 13 base pair deletion in the DNA polymerase eta gene.

    PubMed

    Hentosh, Patricia; Benjamin, Tirania; Hall, Lavinia; Leap, Shannon; Loescher, Jessica; Poyner, Elizabeth; Sundin, Tabetha; Whittle, Mary; Wilkinson, Sandra; Peffley, Dennis M

    2011-10-01

    Deficiencies of DNA polymerase eta-an enzyme mediating replication past UV-induced DNA damage-predispose individuals to xeroderma pigmentosum variant (XPV) and result in a high incidence of skin cancers. We designed, developed and assessed several complementary molecular approaches to detect a genetically inherited deletion within DNA polymerase eta. RNA was reverse transcribed from XPV fibroblasts and from normal human cells, and standard polymerase chain reaction (PCR) was conducted on the cDNA targeting a region with a 13 base pair deletion within the polymerase eta gene. PCR products were subjected to restriction fragment length polymorphism (RFLP) analysis and cycle DNA sequencing. The deletion was found to eliminate a BsrGI restriction site and affected the number of resultant fragments visualized after gel electrophoresis. Cycle sequencing of polymerase eta-specific amplicons from XPV and normal cells provided a second approach for detecting the mutation. Additionally, the use of a fluorescent nucleic acid dye-EvaGreen-in real-time PCR and melt curve analysis distinguished normal and XPV patient-derived amplicons as well as heteroduplexes that represent heterozygotic carriers without the need for high resolution melt analysis-compatible software. Our approaches are easily adaptable by diagnostic laboratories that screen for or verify genetically inherited disorders and identify carriers of a defective gene. PMID:21640722

  17. Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile.

    PubMed

    Cramer-Morales, Kimberly; Nieborowska-Skorska, Margaret; Scheibner, Kara; Padget, Michelle; Irvine, David A; Sliwinski, Tomasz; Haas, Kimberly; Lee, Jaewoong; Geng, Huimin; Roy, Darshan; Slupianek, Artur; Rassool, Feyruz V; Wasik, Mariusz A; Childers, Wayne; Copland, Mhairi; Müschen, Markus; Civin, Curt I; Skorski, Tomasz

    2013-08-15

    Homologous recombination repair (HRR) protects cells from the lethal effect of spontaneous and therapy-induced DNA double-stand breaks. HRR usually depends on BRCA1/2-RAD51, and RAD52-RAD51 serves as back-up. To target HRR in tumor cells, a phenomenon called "synthetic lethality" was applied, which relies on the addiction of cancer cells to a single DNA repair pathway, whereas normal cells operate 2 or more mechanisms. Using mutagenesis and a peptide aptamer approach, we pinpointed phenylalanine 79 in RAD52 DNA binding domain I (RAD52-phenylalanine 79 [F79]) as a valid target to induce synthetic lethality in BRCA1- and/or BRCA2-deficient leukemias and carcinomas without affecting normal cells and tissues. Targeting RAD52-F79 disrupts the RAD52-DNA interaction, resulting in the accumulation of toxic DNA double-stand breaks in malignant cells, but not in normal counterparts. In addition, abrogation of RAD52-DNA interaction enhanced the antileukemia effect of already-approved drugs. BRCA-deficient status predisposing to RAD52-dependent synthetic lethality could be predicted by genetic abnormalities such as oncogenes BCR-ABL1 and PML-RAR, mutations in BRCA1 and/or BRCA2 genes, and gene expression profiles identifying leukemias displaying low levels of BRCA1 and/or BRCA2. We believe this work may initiate a personalized therapeutic approach in numerous patients with tumors displaying encoded and functional BRCA deficiency. PMID:23836560

  18. A germline mutation in SRRM2, a splicing factor gene, is implicated in papillary thyroid carcinoma predisposition

    PubMed Central

    Tomsic, Jerneja; He, Huiling; Akagi, Keiko; Liyanarachchi, Sandya; Pan, Qun; Bertani, Blake; Nagy, Rebecca; Symer, David E.; Blencowe, Benjamin J.; Chapelle, Albert de la

    2015-01-01

    Papillary thyroid carcinoma (PTC) displays strong but so far largely uncharacterized heritability. Here we studied genetic predisposition in a family with six affected individuals. We genotyped all available family members and conducted whole exome sequencing of blood DNA from two affected individuals. Haplotype analysis and other genetic criteria narrowed our list of candidates to a germline variant in the serine/arginine repetitive matrix 2 gene (SRRM2). This heterozygous variant, c.1037C?>?T (Ser346Phe or S346F; rs149019598) cosegregated with PTC in the family. It was not found in 138 other PTC families. It was found in 7/1,170 sporadic PTC cases and in 0/1,404 controls (p?=?0.004). The encoded protein SRRM2 (also called SRm300) is part of the RNA splicing machinery. To evaluate the possibility that the S346F missense mutation affects alternative splicing, we compared RNA-Seq data in leukocytes from three mutation carriers and three controls. Significant differences in alternative splicing were identified for 1,642 exons, of which a subset of 7 exons was verified experimentally. The results confirmed a higher ratio of inclusion of exons in mutation carriers. These data suggest that the S346F mutation in SRRM2 predisposes to PTC by affecting alternative splicing of unidentified downstream target genes. PMID:26135620

  19. Pure genes, pure genius.

    PubMed

    McKnight, Steven L

    2012-09-14

    The 2012 Albert Lasker Special Achievement Award in Medical Science will be shared by Donald Brown and Tom Maniatis for their scientific work leading to the purification and study of single genes by physical and molecular biological methodologies. Brown and Maniatis are also recognized for their extraordinary commitment and generosity in promoting the careers of young scientists. The impact of these accomplishments has transformed biological and medical science over the past four decades. PMID:22980972

  20. Gene Expression in Bone

    NASA Astrophysics Data System (ADS)

    D'Ambrogio, A.

    Skeletal system has two main functions, to provide mechanical integrity for both locomotion and protection and to play an important role in mineral homeostasis. There is extensive evidence showing loss of bone mass during long-term Space-Flights. The loss is due to a break in the equilibrium between the activity of osteoblasts (the cells that forms bone) and the activity of osteoclasts (the cells that resorbs bone). Surprisingly, there is scanty information about the possible altered gene expression occurring in cells that form bone in microgravity.(Just 69 articles result from a "gene expression in microgravity" MedLine query.) Gene-chip or microarray technology allows to screen thousands of genes at the same time: the use of this technology on samples coming from cells exposed to microgravity could provide us with many important informations. For example, the identification of the molecules or structures which are the first sensors of the mechanical stress derived from lack of gravity, could help in understanding which is the first event leading to bone loss due to long-term exposure to microgravity. Consequently, this structure could become a target for a custom-designed drug. It is evident that bone mass loss, observed during long-time stay in Space, represents an accelerated model of what happens in aging osteoporosis. Therefore, the discovery and design of drugs able to interfere with the bone-loss process, could help also in preventing negative physiological processes normally observed on Earth. Considering the aims stated above, my research is designed to:

  1. DETECTING CANCER-RELATED GENES AND GENE-GENE INTERACTIONS BY MACHINE LEARNING METHODS

    E-print Network

    Han, Bing

    2011-12-31

    an integrative method based on the bootstrapping K-S test to evaluate a large number of microarray datasets. The experimental results demonstrate that my method can find meaningful alterations in gene relations. For gene-gene interaction detection, I propose...

  2. Silencing of stat4 gene inhibits cell proliferation and invasion of colorectal cancer cells.

    PubMed

    Cheng, J M; Yao, M R; Zhu, Q; Wu, X Y; Zhou, J; Tan, W L; Zhan, S H

    2015-01-01

    Signal transducers and activators of transcription (STAT) play critical roles in development, proliferation, and immune defense. However the consequences of STAT hyperactivity can predispose to diseases, including colorectal cancer. In the present study, we aimed to evaluate the function of STAT4 in human colorectal cancer (CRC). The expression of STAT4 was examined by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was carried out to investigate the effects of lentivirus-mediated STAT4 shRNA (Lv-shSTAT4) on cell proliferation and invasive potential indicated by MTT and Transwell assays in CRC cell lines (SW480 and Caco2). As a consequence, it was found that the expression of STAT4 protein was significantly increased in CRC tissues compared with that in adjacent non-cancerous tissues (ANCT) (71.1% vs 44.4%, P=0.015), and was related with the Duke?s staging and depth of invasion in CRC patients (P=0.022; P=0.001). Silencing of STAT4 gene suppressed cell proliferation and invasion of CRC cells. Taken together, these findings demonstrate that increased expression of STAT4 is positively correlated with the depth of invasion in CRC patients, and inhibition of STAT4 expression represses the growth and invasion of CRC cells, suggesting that STAT4 may be a promising therapeutic target for the treatment of CRC. PMID:25864744

  3. Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus

    PubMed Central

    Lechner, Judith; Porter, Louise F.; Rice, Aine; Vitart, Veronique; Armstrong, David J.; Schorderet, Daniel F.; Munier, Francis L.; Wright, Alan F.; Inglehearn, Chris F.; Black, Graeme C.; Simpson, David A.; Manson, Forbes; Willoughby, Colin E.

    2014-01-01

    Keratoconus, a common inherited ocular disorder resulting in progressive corneal thinning, is the leading indication for corneal transplantation in the developed world. Genome-wide association studies have identified common SNPs 100 kb upstream of ZNF469 strongly associated with corneal thickness. Homozygous mutations in ZNF469 and PR domain-containing protein 5 (PRDM5) genes result in brittle cornea syndrome (BCS) Types 1 and 2, respectively. BCS is an autosomal recessive generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Some individuals with heterozygous PRDM5 mutations demonstrate a carrier ocular phenotype, which includes a mildly reduced corneal thickness, keratoconus and blue sclera. We hypothesized that heterozygous variants in PRDM5 and ZNF469 predispose to the development of isolated keratoconus. We found a significant enrichment of potentially pathologic heterozygous alleles in ZNF469 associated with the development of keratoconus (P = 0.00102) resulting in a relative risk of 12.0. This enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients represents a significant mutational load and highlights ZNF469 as the most significant genetic factor responsible for keratoconus identified to date. PMID:24895405

  4. Gender-dependent association of a ?(2)-adrenergic gene variant with obesity parameters in Malaysian Malays.

    PubMed

    Apalasamy, Yamunah Devi; Ming, Moy Foong; Rampal, Sanjay; Bulgiba, Awang; Mohamed, Zahurin

    2015-03-01

    Recent findings have shown that the rs1042714 (Gln27Glu) single-nucleotide polymorphism (SNP) on the ?2-adrenoceptor gene may predispose to obesity. The findings from other studies carried on different populations, however, have been inconsistent. The authors investigated the association between the rs1042714 SNP with obesity-related parameters. DNA of 672 Malaysian Malays was analyzed using real-time polymerase chain reaction. Univariate and multivariate linear regression analyses revealed significant associations between rs1042714 and diastolic blood pressure in the pooled Malaysian Malay subjects under additive and recessive models. After gender stratification, however, a significant association was found between the rs1042714 and triglyceride and the rs1042714 and log-transformed high-density lipoprotein cholesterol levels in Malaysian Malay men. No significant association was found between the SNP and log-transformed body mass index. This polymorphism may have an important role in the development of obesity-related traits in Malaysian Malays. Gender is an effect modifier for the effect of the rs1042714 polymorphism on obesity-related traits in Malaysian Malays. PMID:22199155

  5. Single-nucleotide polymorphisms in pigment genes and nonmelanoma skin cancer predisposition: a systematic review.

    PubMed

    Binstock, M; Hafeez, F; Metchnikoff, C; Arron, S T

    2014-10-01

    Nonmelanoma skin cancer (NMSC) is the most common cancer in the U.S.A. The two most common NMSCs are basal cell carcinoma and squamous cell carcinoma. The associations of single-nucleotide polymorphisms (SNPs) in pigmentation pathway genes with NMSC are not well characterized. There is a series of epidemiological studies that have tested these relationships, but there is no recent summary of these findings. To explain overarching trends, we undertook a systematic review of published studies. The summarized data support the concept that specific SNPs in the pigmentation pathway are of importance for the pathogenesis of NMSC. The SNPs with the most promising evidence include MC1R rs1805007(T) (Arg151Cys) and rs1805008(T) (Arg160Trp), and ASIP AH haplotype [rs4911414(T) and rs1015362(G)]. There are a few other SNPs found in TYR, OCA2 and SLC45A2 that may show additional correlation after future research. With additional research there is potential for the translation of future findings to the clinic in the form of SNP screenings, where patients at high risk for NMSC can be identified beyond their phenotype by genotypically screening for predisposing SNPs. PMID:25319428

  6. nanosheets for gene therapy

    NASA Astrophysics Data System (ADS)

    Kou, Zhongyang; Wang, Xin; Yuan, Renshun; Chen, Huabin; Zhi, Qiaoming; Gao, Ling; Wang, Bin; Guo, Zhaoji; Xue, Xiaofeng; Cao, Wei; Guo, Liang

    2014-10-01

    A new class of two-dimensional (2D) nanomaterial, transition metal dichalcogenides (TMDCs) such as MoS2, MoSe2, WS2, and WSe2 which have fantastic physical and chemical properties, has drawn tremendous attention in different fields recently. Herein, we for the first time take advantage of the great potential of MoS2 with well-engineered surface as a novel type of 2D nanocarriers for gene delivery and therapy of cancer. In our system, positively charged MoS2-PEG-PEI is synthesized with lipoic acid-modified polyethylene glycol (LA-PEG) and branched polyethylenimine (PEI). The amino end of positively charged nanomaterials can bind to the negatively charged small interfering RNA (siRNA). After detection of physical and chemical characteristics of the nanomaterial, cell toxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Polo-like kinase 1 (PLK1) was investigated as a well-known oncogene, which was a critical regulator of cell cycle transmission at multiple levels. Through knockdown of PLK1 with siRNA carried by novel nanovector, qPCR and Western blot were used to measure the interfering efficiency; apoptosis assay was used to detect the transfection effect of PLK1. All results showed that the novel nanocarrier revealed good biocompatibility, reduced cytotoxicity, as well as high gene-carrying ability without serum interference, thus would have great potential for gene delivery and therapy.

  7. GENE DELIVERY TO BONE

    PubMed Central

    Evans, C. H.

    2012-01-01

    Gene delivery to bone is useful both as an experimental tool and as a potential therapeutic strategy. Among its advantages over protein delivery are the potential for directed, sustained and regulated expression of authentically processed, nascent proteins. Although no clinical trials have been initiated, there is a substantial pre-clinical literature documenting the successful transfer of genes to bone, and their intraosseous expression. Recombinant vectors derived from adenovirus, retrovirus and lentivirus, as well as non-viral vectors, have been used for this purpose. Both ex vivo and in vivo strategies, including gene-activated matrices, have been explored. Ex vivo delivery has often employed mesenchymal stem cells (MSCs), partly because of their ability to differentiate into osteoblasts. MSCs also have the potential to home to bone after systemic administration, which could serve as a useful way to deliver transgenes in a disseminated fashion for the treatment of diseases affecting the whole skeleton, such as osteoporosis or osteogenesis imperfecta. Local delivery of osteogenic transgenes, particularly those encoding bone morphogenetic proteins, has shown great promise in a number of applications where it is necessary to regenerate bone. These include healing large segmental defects in long bones and the cranium, as well as spinal fusion and treating avascular necrosis. PMID:22480730

  8. Venom evolution through gene duplications.

    PubMed

    Wong, Emily S W; Belov, Katherine

    2012-03-15

    Venoms contain highly complex mixtures that typically include hundreds of different components and have evolved independently in a diverse range of animals including platypuses, shrews, snakes, lizards, fishes, echinoderms, spiders, wasps, centipedes, sea snails, cephalopods, jellyfish and sea anemones. Many venom genes evolved through gene duplication. Gene duplication occurs in all domains of life and provides the raw substrate from which novel function arise. In this review, we focus on the role that gene duplication has played in the origin and diversification of venom genes. We outline the selective advantages of venom gene duplicates and the role that selection has played in the retention of these duplicates. We use toxin gene intermediates to help trace the evolution of toxin innovation. We also focus on other genomic processes, such as exon and domain duplications, in venom evolution. Finally, we conclude by focusing on the use of high throughput sequencing technology in understanding venom evolution. PMID:22285376

  9. Progress in gene targeting and gene therapy for retinitis pigmentosa

    SciTech Connect

    Farrar, G.J.; Humphries, M.M.; Erven, A.

    1994-09-01

    Previously, we localized disease genes involved in retinitis pigmentosa (RP), an inherited retinal degeneration, close to the rhodopsin and peripherin genes on 3q and 6p. Subsequently, we and others identified mutations in these genes in RP patients. Currently animal models for human retinopathies are being generated using gene targeting by homologous recombination in embryonic stem (ES) cells. Genomic clones for retinal genes including rhodopsin and peripherin have been obtained from a phage library carrying mouse DNA isogenic with the ES cell line (CC1.2). The peripherin clone has been sequenced to establish the genomic structure of the mouse gene. Targeting vectors for rhodopsin and peripherin including a neomycin cassette for positive selection and thymidine kinase genes enabling selection against random intergrants are under construction. Progress in vector construction will be presented. Simultaneously we are developing systems for delivery of gene therapies to retinal tissues utilizing replication-deficient adenovirus (Ad5). Efficacy of infection subsequent to various methods of intraocular injection and with varying viral titers is being assayed using an adenovirus construct containing a CMV promoter LacZ fusion as reporter and the range of tissues infected and the level of duration of LacZ expression monitored. Viral constructs with the LacZ reporter gene under the control of retinal specific promoters such as rhodopsin and IRBP cloned into pXCJL.1 are under construction. An update on developments in photoreceptor cell-directed expression of virally delivered genes will be presented.

  10. Serotonin transporter, sex, and hypoxia: microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH

    PubMed Central

    White, Kevin; Loughlin, Lynn; Maqbool, Zakia; Nilsen, Margaret; McClure, John; Dempsie, Yvonne; Baker, Andrew H.

    2011-01-01

    Pulmonary arterial hypertension (PAH) is up to threefold more prevalent in women than men. Female mice overexpressing the serotonin transporter (SERT; SERT+ mice) exhibit PAH and exaggerated hypoxia-induced PAH, whereas male SERT+ mice remain unaffected. To further investigate these sex differences, microarray analysis was performed in the pulmonary arteries of normoxic and chronically hypoxic female and male SERT+ mice. Quantitative RT-PCR analysis was employed for validation of the microarray data. In relevant groups, immunoblotting was performed for genes of interest (CEBP?, CYP1B1, and FOS). To translate clinical relevance to our findings, CEBP?, CYP1B1, and FOS mRNA and protein expression was assessed in pulmonary artery smooth muscle cells (PASMCs) derived from idiopathic PAH (IPAH) patients and controls. In female SERT+ mice, multiple pathways with relevance to PAH were altered. This was also observed in chronically hypoxic female SERT+ mice. We selected 10 genes of interest for qRT-PCR analysis (FOS, CEBP?, CYP1B1, MYL3, HAMP2, LTF, PLN, NPPA, UCP1, and C1S), and 100% concordance was reported. Protein expression of three selected genes, CEBP?, CYP1B1, FOS, was also upregulated in female SERT+ mice. Serotonin and 17?-estradiol increased CEBP?, CYP1B1, and FOS protein expression in PASMCs. In addition, CEBP?, CYP1B1, and FOS mRNA and protein expression was also increased in PASMCs derived from IPAH patients. Here, we have identified a number of genes that may predispose female SERT+ mice to PAH, and these findings may also be relevant to human PAH. PMID:21303932

  11. Evidence for major gene inheritance of Alzheimer disease in families of patients with and without Apolipoprotein E {epsilon}4

    SciTech Connect

    Rao, V.S.; Auerbach, S.A.; Farrer, L.A.

    1996-09-01

    Apolipoprotein E (APOE) genotype is the single most important determinant to the common form of Alzheimer disease (AD) yet identified. Several studies show that family history of AD is not entirely accounted for by APOE genotype. Also, there is evidence for an interaction between APOE genotype and gender. We carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission which account for the influences of APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and Mendelian inheritance were rejected. Transmission of AD in families of probands with at least one {epsilon}4 allele best fit a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking E4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. Our results also suggest that susceptibility to AD differs between men and women regardless of the proband`s APOE status. Assuming a dominant model, AD appears to be completely penetrant in women, whereas only 62%-65% of men with predisposing genotypes develop AD. However, parameter estimates from the arbitrary major gene model suggests that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, are consistent with the hypothesis of an interaction between genes and other biological factors affecting disease susceptibility. 76 refs., 4 tabs.

  12. Evidence for major gene inheritance of Alzheimer disease in families of patients with and without apolipoprotein E epsilon 4.

    PubMed Central

    Rao, V. S.; Cupples, A.; van Duijn, C. M.; Kurz, A.; Green, R. C.; Chui, H.; Duara, R.; Auerbach, S. A.; Volicer, L.; Wells, J.; van Broeckhoven, C.; Growdon, J. H.; Haines, J. L.; Farrer, L. A.

    1996-01-01

    Apolipoprotein E (APOE) genotype is the single most important determinant to the common form of Alzheimer disease (AD) yet identified. Several studies show that family history of AD is not entirely accounted for by APOE genotype. Also, there is evidence for an interaction between APOE genotype and gender. We carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission which account for the influences of APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and Mendelian inheritance were rejected. Transmission of AD in families of probands with at least one epsilon 4 allele best fit a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking epsilon 4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. Our results also suggest that susceptibility to AD differs between men and women regardless of the proband's APOE status. Assuming a dominant model, AD appears to be completely penetrant in women, whereas only 62%-65% of men with predisposing genotypes develop AD. However, parameter estimates from the arbitrary major gene model suggests that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, are consistent with the hypothesis of an interaction between genes and other biological factors affecting disease susceptibility. PMID:8751868

  13. Lack of association between polymorphisms of the DNA base excision repair genes MUTYH and hOGG1 and keratoconus in a Polish subpopulation

    PubMed Central

    Synowiec, Ewelina; Wójcik, Katarzyna A.; Czubatka, Anna; Polakowski, Piotr; Izdebska, Justyna; Szaflik, Jerzy; B?asiak, Janusz

    2015-01-01

    Introduction Keratoconus (KC) is a non-inflammatory thinning of the cornea and a leading indication for corneal transplantation. Oxidative stress plays a role in the pathogenesis of this disease. The products of the hOGG1 and MUTYH genes play an important role in the repair of oxidatively modified DNA in the base excision repair pathway. We hypothesized that variability in these genes may change susceptibility to oxidative stress and predispose individuals to the development of KC. We investigated the possible association between the c.977C>G polymorphism of the hOGG1 gene (rs1052133) and the c.972G>C polymorphism of the MUTYH gene (rs3219489) and KC occurrence as well as the modulation of this association by some KC risk factors. Material and methods A total of 205 patients with KC and 220 controls were included in this study. The polymorphisms were genotyped with polymerase chain reaction (PCR) restriction fragment length polymorphism and PCR-confronting two-pair primer techniques. Differences in genotype and allele frequency distributions were evaluated using the ?2 test, and KC risk was estimated with an unconditional multiple logistic regression with and without adjustment for co-occurrence of visual impairment, allergies, sex and family history for KC. Results We did not find any association between the genotypes and combined genotypes of the c.977C>G polymorphism of the hOGG1 gene and the c.972G>C polymorphism of the MUTYH gene and the occurrence of KC. Conclusions Our findings suggest that the c.977C>G-hOGG1 polymorphism and the c.972G>C-MUTYH polymorphism may not be linked with KC occurrence in this Polish subpopulation. PMID:26528356

  14. Wandering spleen: 'presentation in adolescent with high thrombotic risk'.

    PubMed

    Tchidjou, Hyppolite K; Castelluzzo, Maria A; Messia, Virginia; Luciani, Matteo; Monti, Lidia; Grimaldi, Chiara; Bernardi, Stefania; D'Argenio, Patrizia

    2014-07-01

    The term 'wandering spleen' refers to an abnormal hypermobility of the spleen, which may be congenital or acquired. The absence or abnormal laxity of splenic ligaments combined with an abnormally long and mobile vascular pedicle predispose to complications such as torsion of the splenic pedicle, infarction and splenic vein thrombosis. The clinical presentation of such disease is highly variable. In this case, we describe an asymptomatic case of wandering spleen in high thrombotic risk patients with cavernoma of splenic vein and infarction of the spleen. Physical examination was normal except the enlarged and no tender consistency spleen palpable at left iliac fossa. Ultrasonography revealed enlarged spleniform mass below its normal position suggesting vascular impairment and subsequently has been confirmed by colour Doppler ultrasound and computed tomography. The family history was positive for ischemic thrombotic vascular diseases and the screening for thrombotic risk has revealed hyperhomocysteinemia, thrombophilic homozygous gene mutations for factor V (H1299R) and MTHFR (C677T). For high thrombotic risk, prophylaxis postsplenectomy was suggested according to the international recommendations with subcutaneous low molecular weight heparin, associated with a preventive treatment with acetyl salicylic acid and folic acid along with B-vitamin. This case report may be helpful for clinicians involved in the care of splenectomized patients, because it has shown the importance of an appropriate pre and postoperative antithrombotic management to reduce as soon as possible the risk of thrombotic events in such patients after splenectomy. PMID:24509326

  15. Alternative Gene Form Discovery and Candidate Gene Selection from Gene Indexing?Projects

    PubMed Central

    Burke, John; Wang, Hui; Hide, Winston; Davison, Daniel B.

    1998-01-01

    Several efforts are under way to partition single-read expressed sequence tag (EST), as well as full-length transcript data, into large-scale gene indices, where transcripts are in common index classes if and only if they share a common progenitor gene. Accurate gene indexing facilitates gene expression studies, as well as inexpensive and early gene sequence discovery through assembly of ESTs that are derived from genes that have not been sequenced by classical methods. We extend, correct, and enhance the information obtained from index groups by splitting index classes into subclasses based on sequence dissimilarity (diversity). Two applications of this are highlighted in this report. First it is shown that our method can ameliorate the damage that artifacts, such as chimerism, inflict on index integrity. Additionally, we demonstrate how the organization imposed by an effective subpartition can greatly increase the sensitivity of gene expression studies by accounting for the existence and tissue- or pathology-specific regulation of novel gene isoforms and polymorphisms. We apply our subpartitioning treatment to the UniGene gene indexing project to measure a marked increase in information quality and abundance (in terms of assembly length and insertion/deletion error) after treatment and demonstrate cases where new levels of information concerning differential expression of alternate gene forms, such as regulated alternative splicing, are discovered. [Tables 2 and 3 can be viewed in their entirety as Online Supplements at http://www.genome.org.] PMID:9521931

  16. Rare Copy Number Variants Observed in Hereditary Breast Cancer Cases Disrupt Genes in Estrogen Signaling and TP53 Tumor Suppression Network

    PubMed Central

    Pylkäs, Katri; Vuorela, Mikko; Otsukka, Meeri; Kallioniemi, Anne; Jukkola-Vuorinen, Arja; Winqvist, Robert

    2012-01-01

    Breast cancer is the most common cancer in women in developed countries, and the contribution of genetic susceptibility to breast cancer development has been well-recognized. However, a great proportion of these hereditary predisposing factors still remain unidentified. To examine the contribution of rare copy number variants (CNVs) in breast cancer predisposition, high-resolution genome-wide scans were performed on genomic DNA of 103 BRCA1, BRCA2, and PALB2 mutation negative familial breast cancer cases and 128 geographically matched healthy female controls; for replication an independent cohort of 75 similarly mutation negative young breast cancer patients was used. All observed rare variants were confirmed by independent methods. The studied breast cancer cases showed a consistent increase in the frequency of rare CNVs when compared to controls. Furthermore, the biological networks of the disrupted genes differed between the two groups. In familial cases the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity, including DNA double-strand break repair (P?=?0.0211). Biological network analysis in the two independent breast cancer cohorts showed that the disrupted genes were closely related to estrogen signaling and TP53 centered tumor suppressor network. These results suggest that rare CNVs represent an alternative source of genetic variation influencing hereditary risk for breast cancer. PMID:22737080

  17. Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells.

    PubMed

    Diouf, Barthelemy; Cheng, Qing; Krynetskaia, Natalia F; Yang, Wenjian; Cheok, Meyling; Pei, Deqing; Fan, Yiping; Cheng, Cheng; Krynetskiy, Evgeny Y; Geng, Hui; Chen, Siying; Thierfelder, William E; Mullighan, Charles G; Downing, James R; Hsieh, Peggy; Pui, Ching-Hon; Relling, Mary V; Evans, William E

    2011-10-01

    DNA mismatch repair enzymes (for example, MSH2) maintain genomic integrity, and their deficiency predisposes to several human cancers and to drug resistance. We found that leukemia cells from a substantial proportion of children (?11%) with newly diagnosed acute lymphoblastic leukemia have low or undetectable MSH2 protein levels, despite abundant wild-type MSH2 mRNA. Leukemia cells with low levels of MSH2 contained partial or complete somatic deletions of one to four genes that regulate MSH2 degradation (FRAP1 (also known as MTOR), HERC1, PRKCZ and PIK3C2B); we also found these deletions in individuals with adult acute lymphoblastic leukemia (16%) and sporadic colorectal cancer (13.5%). Knockdown of these genes in human leukemia cells recapitulated the MSH2 protein deficiency by enhancing MSH2 degradation, leading to substantial reduction in DNA mismatch repair and increased resistance to thiopurines. These findings reveal a previously unrecognized mechanism whereby somatic deletions of genes regulating MSH2 degradation result in undetectable levels of MSH2 protein in leukemia cells, DNA mismatch repair deficiency and drug resistance. PMID:21946537

  18. Human AZU-1 gene, variants thereof and expressed gene products

    DOEpatents

    Chen, Huei-Mei; Bissell, Mina

    2004-06-22

    A human AZU-1 gene, mutants, variants and fragments thereof. Protein products encoded by the AZU-1 gene and homologs encoded by the variants of AZU-1 gene acting as tumor suppressors or markers of malignancy progression and tumorigenicity reversion. Identification, isolation and characterization of AZU-1 and AZU-2 genes localized to a tumor suppressive locus at chromosome 10q26, highly expressed in nonmalignant and premalignant cells derived from a human breast tumor progression model. A recombinant full length protein sequences encoded by the AZU-1 gene and nucleotide sequences of AZU-1 and AZU-2 genes and variant and fragments thereof. Monoclonal or polyclonal antibodies specific to AZU-1, AZU-2 encoded protein and to AZU-1, or AZU-2 encoded protein homologs.

  19. Improvements to cardiovascular gene ontology.

    PubMed

    Lovering, Ruth C; Dimmer, Emily C; Talmud, Philippa J

    2009-07-01

    Gene Ontology (GO) provides a controlled vocabulary to describe the attributes of genes and gene products in any organism. Although one might initially wonder what relevance a 'controlled vocabulary' might have for cardiovascular science, such a resource is proving highly useful for researchers investigating complex cardiovascular disease phenotypes as well as those interpreting results from high-throughput methodologies. GO enables the current functional knowledge of individual genes to be used to annotate genomic or proteomic datasets. In this way, the GO data provides a very effective way of linking biological knowledge with the analysis of the large datasets of post-genomics research. Consequently, users of high-throughput methodologies such as expression arrays or proteomics will be the main beneficiaries of such annotation sets. However, as GO annotations increase in quality and quantity, groups using small-scale approaches will gradually begin to benefit too. For example, genome wide association scans for coronary heart disease are identifying novel genes, with previously unknown connections to cardiovascular processes, and the comprehensive annotation of these novel genes might provide clues to their cardiovascular link. At least 4000 genes, to date, have been implicated in cardiovascular processes and an initiative is underway to focus on annotating these genes for the benefit of the cardiovascular community. In this article we review the current uses of Gene Ontology annotation to highlight why Gene Ontology should be of interest to all those involved in cardiovascular research. PMID:19046747

  20. Reverse engineering transcriptional gene networks.

    PubMed

    Belcastro, Vincenzo; di Bernardo, Diego

    2014-01-01

    The aim of this chapter is a step-by-step guide on how to infer gene networks from gene expression profiles. The definition of a gene network is given in Subheading 1, where the different types of networks are discussed. The chapter then guides the readers through a data-gathering process in order to build a compendium of gene expression profiles from a public repository. Gene expression profiles are then discretized and a statistical relationship between genes, called mutual information (MI), is computed. Gene pairs with insignificant MI scores are then discarded by applying one of the described pruning steps. The retained relationships are then used to build up a Boolean adjacency matrix used as input for a clustering algorithm to divide the network into modules (or communities). The gene network can then be used as a hypothesis generator for discovering gene function and analyzing gene signatures. Some case studies are presented, and an online web-tool called Netview is described. PMID:24233783

  1. Imprinting genes associated with endometriosis

    PubMed Central

    Kobayashi, Hiroshi

    2014-01-01

    Purpose: Much work has been carried out to investigate the genetic and epigenetic basis of endometriosis and proposed that endometriosis has been described as an epigenetic disease. The purpose of this study was to extract the imprinting genes that are associated with endometriosis development. Methods: The information on the imprinting genes can be accessed publicly from a web-based interface at http://www.geneimprint.com/site/genes-by-species. Results: In the current version, the database contains 150 human imprinted genes derived from the literature. We searched gene functions and their roles in particular biological processes or events, such as development and pathogenesis of endometriosis. From the genomic imprinting database, we picked 10 genes that were highly associated with female reproduction; prominent among them were paternally expressed genes (DIRAS3, BMP8B, CYP1B1, ZFAT, IGF2, MIMT1, or MIR296) and maternally expressed genes (DVL1, FGFRL1, or CDKN1C). These imprinted genes may be associated with reproductive biology such as endometriosis, pregnancy loss, decidualization process and preeclampsia. Discussion: This study supports the possibility that aberrant epigenetic dysregulation of specific imprinting genes may contribute to endometriosis predisposition. PMID:26417259

  2. Broker genes in human disease.

    PubMed

    Cai, James J; Borenstein, Elhanan; Petrov, Dmitri A

    2010-01-01

    Genes that underlie human disease are important subjects of systems biology research. In the present study, we demonstrate that Mendelian and complex disease genes have distinct and consistent protein-protein interaction (PPI) properties. We show that five different network properties can be reduced to two independent metrics when applied to the human PPI network. These two metrics largely coincide with the degree (number of connections) and the clustering coefficient (the number of connections among the neighbors of a particular protein). We demonstrate that disease genes have simultaneously unusually high degree and unusually low clustering coefficient. Such genes can be described as brokers in that they connect many proteins that would not be connected otherwise. We show that these results are robust to the effect of gene age and inspection bias variation. Notably, genes identified in genome-wide association study (GWAS) have network patterns that are almost indistinguishable from the network patterns of nondisease genes and significantly different from the network patterns of complex disease genes identified through non-GWAS means. This suggests either that GWAS focused on a distinct set of diseases associated with an unusual set of genes or that mapping of GWAS-identified single nucleotide polymorphisms onto the causally affected neighboring genes is error prone. PMID:20937604

  3. Broker Genes in Human Disease

    PubMed Central

    Cai, James J.; Borenstein, Elhanan; Petrov, Dmitri A.

    2010-01-01

    Genes that underlie human disease are important subjects of systems biology research. In the present study, we demonstrate that Mendelian and complex disease genes have distinct and consistent protein–protein interaction (PPI) properties. We show that five different network properties can be reduced to two independent metrics when applied to the human PPI network. These two metrics largely coincide with the degree (number of connections) and the clustering coefficient (the number of connections among the neighbors of a particular protein). We demonstrate that disease genes have simultaneously unusually high degree and unusually low clustering coefficient. Such genes can be described as brokers in that they connect many proteins that would not be connected otherwise. We show that these results are robust to the effect of gene age and inspection bias variation. Notably, genes identified in genome-wide association study (GWAS) have network patterns that are almost indistinguishable from the network patterns of nondisease genes and significantly different from the network patterns of complex disease genes identified through non-GWAS means. This suggests either that GWAS focused on a distinct set of diseases associated with an unusual set of genes or that mapping of GWAS-identified single nucleotide polymorphisms onto the causally affected neighboring genes is error prone. PMID:20937604

  4. Ancient origins of axial patterning genes: Hox genes and ParaHox genes in the Cnidaria.

    PubMed

    Finnerty, J R; Martindale, M Q

    1999-01-01

    Among the bilaterally symmetrical, triploblastic animals (the Bilateria), a conserved set of developmental regulatory genes are known to function in patterning the anterior-posterior (AP) axis. This set includes the well-studied Hox cluster genes, and the recently described genes of the ParaHox cluster, which is believed to be the evolutionary sister of the Hox cluster (Brooke et al. 1998). The conserved role of these axial patterning genes in animals as diverse as frogs and flies is believed to reflect an underlying homology (i.e., all bilaterians derive from a common ancestor which possessed an AP axis and the developmental mechanisms responsible for patterning the axis). However, the origin and early evolution of Hox genes and ParaHox genes remain obscure. Repeated attempts have been made to reconstruct the early evolution of Hox genes by analyzing data from the triphoblastic animals, the Bilateria (Schubert et al. 1993; Zhang and Nei 1996). A more precise dating of Hox origins has been elusive due to a lack of sufficient information from outgroup taxa such as the phylum Cnidaria (corals, hydras, jellyfishes, and sea anemones). In combination with outgroup taxa, another potential source of information about Hox origins is outgroup genes (e.g., the genes of the ParaHox cluster). In this article, we present cDNA sequences of two Hox-like genes (anthox2 and anthox6) from the sea anemone, Nematostella vectensis. Phylogenetic analysis indicates that anthox2 (= Cnox2) is homologous to the GSX class of ParaHox genes, and anthox6 is homologous to the anterior class of Hox genes. Therefore, the origin of Hox genes and ParaHox genes occurred prior to the evolutionary split between the Cnidaria and the Bilateria and predated the evolution of the anterior-posterior axis of bilaterian animals. Our analysis also suggests that the central Hox class was invented in the bilaterian lineage, subsequent to their split from the Cnidaria. PMID:11324016

  5. Identifying Driver Genes in Cancer by Triangulating Gene Expression, Gene Location, and Survival Data

    PubMed Central

    Rouam, Sigrid; Miller, Lance D; Karuturi, R Krishna Murthy

    2014-01-01

    Driver genes are directly responsible for oncogenesis and identifying them is essential in order to fully understand the mechanisms of cancer. However, it is difficult to delineate them from the larger pool of genes that are deregulated in cancer (ie, passenger genes). In order to address this problem, we developed an approach called TRIAngulating Gene Expression (TRIAGE through clinico-genomic intersects). Here, we present a refinement of this approach incorporating a new scoring methodology to identify putative driver genes that are deregulated in cancer. TRIAGE triangulates – or integrates – three levels of information: gene expression, gene location, and patient survival. First, TRIAGE identifies regions of deregulated expression (ie, expression footprints) by deriving a newly established measure called the Local Singular Value Decomposition (LSVD) score for each locus. Driver genes are then distinguished from passenger genes using dual survival analyses. Incorporating measurements of gene expression and weighting them according to the LSVD weight of each tumor, these analyses are performed using the genes located in significant expression footprints. Here, we first use simulated data to characterize the newly established LSVD score. We then present the results of our application of this refined version of TRIAGE to gene expression data from five cancer types. This refined version of TRIAGE not only allowed us to identify known prominent driver genes, such as MMP1, IL8, and COL1A2, but it also led us to identify several novel ones. These results illustrate that TRIAGE complements existing tools, allows for the identification of genes that drive cancer and could perhaps elucidate potential future targets of novel anticancer therapeutics. PMID:25949096

  6. Aberrant Gene Expression in Humans

    PubMed Central

    Yang, Ence; Ji, Guoli; Brinkmeyer-Langford, Candice L.; Cai, James J.

    2015-01-01

    Gene expression as an intermediate molecular phenotype has been a focus of research interest. In particular, studies of expression quantitative trait loci (eQTL) have offered promise for understanding gene regulation through the discovery of genetic variants that explain variation in gene expression levels. Existing eQTL methods are designed for assessing the effects of common variants, but not rare variants. Here, we address the problem by establishing a novel analytical framework for evaluating the effects of rare or private variants on gene expression. Our method starts from the identification of outlier individuals that show markedly different gene expression from the majority of a population, and then reveals the contributions of private SNPs to the aberrant gene expression in these outliers. Using population-scale mRNA sequencing data, we identify outlier individuals using a multivariate approach. We find that outlier individuals are more readily detected with respect to gene sets that include genes involved in cellular regulation and signal transduction, and less likely to be detected with respect to the gene sets with genes involved in metabolic pathways and other fundamental molecular functions. Analysis of polymorphic data suggests that private SNPs of outlier individuals are enriched in the enhancer and promoter regions of corresponding aberrantly-expressed genes, suggesting a specific regulatory role of private SNPs, while the commonly-occurring regulatory genetic variants (i.e., eQTL SNPs) show little evidence of involvement. Additional data suggest that non-genetic factors may also underlie aberrant gene expression. Taken together, our findings advance a novel viewpoint relevant to situations wherein common eQTLs fail to predict gene expression when heritable, rare inter-individual variation exists. The analytical framework we describe, taking into consideration the reality of differential phenotypic robustness, may be valuable for investigating complex traits and conditions. PMID:25617623

  7. Gene: a gene-centered information resource at NCBI.

    PubMed

    Brown, Garth R; Hem, Vichet; Katz, Kenneth S; Ovetsky, Michael; Wallin, Craig; Ermolaeva, Olga; Tolstoy, Igor; Tatusova, Tatiana; Pruitt, Kim D; Maglott, Donna R; Murphy, Terence D

    2015-01-01

    The National Center for Biotechnology Information's (NCBI) Gene database (www.ncbi.nlm.nih.gov/gene) integrates gene-specific information from multiple data sources. NCBI Reference Sequence (RefSeq) genomes for viruses, prokaryotes and eukaryotes are the primary foundation for Gene records in that they form the critical association between sequence and a tracked gene upon which additional functional and descriptive content is anchored. Additional content is integrated based on the genomic location and RefSeq transcript and protein sequence data. The content of a Gene record represents the integration of curation and automated processing from RefSeq, collaborating model organism databases, consortia such as Gene Ontology, and other databases within NCBI. Records in Gene are assigned unique, tracked integers as identifiers. The content (citations, nomenclature, genomic location, gene products and their attributes, phenotypes, sequences, interactions, variation details, maps, expression, homologs, protein domains and external databases) is available via interactive browsing through NCBI's Entrez system, via NCBI's Entrez programming utilities (E-Utilities and Entrez Direct) and for bulk transfer by FTP. PMID:25355515

  8. Gene: a gene-centered information resource at NCBI

    PubMed Central

    Brown, Garth R.; Hem, Vichet; Katz, Kenneth S.; Ovetsky, Michael; Wallin, Craig; Ermolaeva, Olga; Tolstoy, Igor; Tatusova, Tatiana; Pruitt, Kim D.; Maglott, Donna R.; Murphy, Terence D.

    2015-01-01

    The National Center for Biotechnology Information's (NCBI) Gene database (www.ncbi.nlm.nih.gov/gene) integrates gene-specific information from multiple data sources. NCBI Reference Sequence (RefSeq) genomes for viruses, prokaryotes and eukaryotes are the primary foundation for Gene records in that they form the critical association between sequence and a tracked gene upon which additional functional and descriptive content is anchored. Additional content is integrated based on the genomic location and RefSeq transcript and protein sequence data. The content of a Gene record represents the integration of curation and automated processing from RefSeq, collaborating model organism databases, consortia such as Gene Ontology, and other databases within NCBI. Records in Gene are assigned unique, tracked integers as identifiers. The content (citations, nomenclature, genomic location, gene products and their attributes, phenotypes, sequences, interactions, variation details, maps, expression, homologs, protein domains and external databases) is available via interactive browsing through NCBI's Entrez system, via NCBI's Entrez programming utilities (E-Utilities and Entrez Direct) and for bulk transfer by FTP. PMID:25355515

  9. Heterochromatic Genes in Drosophila: A Comparative Analysis of Two Genes

    PubMed Central

    Schulze, Sandra R.; McAllister, Bryant F.; Sinclair, Donald A. R.; Fitzpatrick, Kathleen A.; Marchetti, Marcella; Pimpinelli, Sergio; Honda, Barry M.

    2006-01-01

    Centromeric heterochromatin comprises ?30% of the Drosophila melanogaster genome, forming a transcriptionally repressive environment that silences euchromatic genes juxtaposed nearby. Surprisingly, there are genes naturally resident in heterochromatin, which appear to require this environment for optimal activity. Here we report an evolutionary analysis of two genes, Dbp80 and RpL15, which are adjacent in proximal 3L heterochromatin of D. melanogaster. DmDbp80 is typical of previously described heterochromatic genes: large, with repetitive sequences in its many introns. In contrast, DmRpL15 is uncharacteristically small. The orthologs of these genes were examined in D. pseudoobscura and D. virilis. In situ hybridization and whole-genome assembly analysis show that these genes are adjacent, but not centromeric in the genome of D. pseudoobscura, while they are located on different chromosomal elements in D. virilis. Dbp80 gene organization differs dramatically among these species, while RpL15 structure is conserved. A bioinformatic analysis in five additional Drosophila species demonstrates active repositioning of these genes both within and between chromosomal elements. This study shows that Dbp80 and RpL15 can function in contrasting chromatin contexts on an evolutionary timescale. The complex history of these genes also provides unique insight into the dynamic nature of genome evolution. PMID:16648646

  10. Gene Therapy for Cartilage Repair

    PubMed Central

    Madry, Henning; Orth, Patrick; Cucchiarini, Magali

    2011-01-01

    The concept of using gene transfer strategies for cartilage repair originates from the idea of transferring genes encoding therapeutic factors into the repair tissue, resulting in a temporarily and spatially defined delivery of therapeutic molecules to sites of cartilage damage. This review focuses on the potential benefits of using gene therapy approaches for the repair of articular cartilage and meniscal fibrocartilage, including articular cartilage defects resulting from acute trauma, osteochondritis dissecans, osteonecrosis, and osteoarthritis. Possible applications for meniscal repair comprise meniscal lesions, meniscal sutures, and meniscal transplantation. Recent studies in both small and large animal models have demonstrated the applicability of gene-based approaches for cartilage repair. Chondrogenic pathways were stimulated in the repair tissue and in osteoarthritic cartilage using genes for polypeptide growth factors and transcription factors. Although encouraging data have been generated, a successful translation of gene therapy for cartilage repair will require an ongoing combined effort of orthopedic surgeons and of basic scientists. PMID:26069580

  11. Genomewide search for type 2 diabetes susceptibility genes in four American populations.

    PubMed

    Ehm, M G; Karnoub, M C; Sakul, H; Gottschalk, K; Holt, D C; Weber, J L; Vaske, D; Briley, D; Briley, L; Kopf, J; McMillen, P; Nguyen, Q; Reisman, M; Lai, E H; Joslyn, G; Shepherd, N S; Bell, C; Wagner, M J; Burns, D K

    2000-06-01

    Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatments are available. Identification of biochemical or regulatory pathways involved in the disease syndrome could lead to innovative therapeutic interventions. One way to identify such pathways is the genetic analysis of families with multiple affected members where disease predisposing genes are likely to be segregating. We undertook a genomewide screen (389-395 microsatellite markers) in samples of 835 white, 591 Mexican American, 229 black, and 128 Japanese American individuals collected as part of the American Diabetes Association's GENNID study. Multipoint nonparametric linkage analyses were performed with diabetes, and diabetes or impaired glucose homeostasis (IH). Linkage to diabetes or IH was detected near markers D5S1404 (map position 77 cM, LOD = 2.80), D12S853 (map position 82 cM, LOD = 2.81) and GATA172D05 (X-chromosome map position 130 cM, LOD = 2.99) in whites, near marker D3S2432 (map position 51 cM, LOD = 3.91) in Mexican Americans, and near marker D10S1412 (map position 14 cM, LOD = 2.39) in African Americans mainly collected in phase 1 of the study. Further analyses showed evidence for interactions between the chromosome 5 locus and region on chromosome 12 containing the MODY 3 gene (map position 132 cM) and between the X-chromosome locus and region near D12S853 (map position 82 cM) in whites. Although these results were not replicated in samples collected in phase 2 of the GENNID study, the region on chromosome 12 was replicated in samples from whites described by Bektas et al. (1999). PMID:10793009

  12. DNA Methyl Transferase (DNMT) Gene Polymorphisms Could Be a Primary Event in Epigenetic Susceptibility to Schizophrenia

    PubMed Central

    Saradalekshmi, Koramannil Radha; Neetha, Nanoth Vellichiramal; Sathyan, Sanish; Nair, Indu V.; Nair, Chandrasekharan M.; Banerjee, Moinak

    2014-01-01

    DNA methylation has been implicated in the etiopathology of various complex disorders. DNA methyltransferases are involved in maintaining and establishing new methylation patterns. The aim of the present study was to investigate the inherent genetic variations within DNA methyltransferase genes in predisposing to susceptibility to schizophrenia. We screened for polymorphisms in DNA methyltransferases, DNMT1, DNMT3A, DNMT3B and DNMT3L in 330 schizophrenia patients and 302 healthy controls for association with Schizophrenia in south Indian population. These polymorphisms were also tested for subgroup analysis with patient's gender, age of onset and family history. DNMT1 rs2114724 (genotype P?=?.004, allele P?=?0.022) and rs2228611 (genotype P?=?0.004, allele P?=?0.022) were found to be significantly associated at genotypic and allelic level with Schizophrenia in South Indian population. DNMT3B rs2424932 genotype (P?=?0.023) and allele (P?=?0.0063) increased the risk of developing schizophrenia in males but not in females. DNMT3B rs1569686 (genotype P?=?0.027, allele P?=?0.033) was found to be associated with early onset of schizophrenia and also with family history and early onset (genotype P?=?0.009). DNMT3L rs2070565 (genotype P?=?0.007, allele P?=?0.0026) confers an increased risk of developing schizophrenia at an early age in individuals with family history. In-silico prediction indicated functional relevance of these SNPs in regulating the gene. These observations might be crucial in addressing and understanding the genetic control of methylation level differences from ethnic viewpoint. Functional significance of genotype variations within the DNMTs indeed suggest that the genetic nature of methyltransferases should be considered while addressing epigenetic events mediated by methylation in Schizophrenia. PMID:24859147

  13. XLMR genes: Update 1996

    SciTech Connect

    Lubs, H.A.; Tranebjaerg, L.; Arena, J.F.

    1996-07-12

    A current list of all known forms of X-linked mental retardation (XLMR) and a slightly revised classification are presented. The number of known disorders has not increased because 6 disorders have been combined based on new molecular data or on clinical grounds and only 6 newly described XLMR disorders have been reported. Of the current 105 XLMR disorders, 34 have been mapped, and 18 disorders and 1 non-specific XLMR (FRAXE) have been cloned. The number of families with nonspecific XLMR with a LOD score of {ge}2.0 has more than doubled, with 42 (including FRAXE) now being known. A summary of the localization of presumed nonspecific mental retardation (MR) genes from well-studied X-chromosomal translocations and deletions is also included. Only 10-12 nonoverlapping loci are required to explain all localizations of non-specific MR from both approaches. These new trends mark the beginning of a significantly improved understanding of the role of genes on the X chromosome in producing MR. Continued close collaboration between clinical and molecular investigators will be required to complete the process. 105 refs., 2 figs., 6 tabs.

  14. Conotoxin Gene Superfamilies

    PubMed Central

    Robinson, Samuel D.; Norton, Raymond S.

    2014-01-01

    Conotoxins are the peptidic components of the venoms of marine cone snails (genus Conus). They are remarkably diverse in terms of structure and function. Unique potency and selectivity profiles for a range of neuronal targets have made several conotoxins valuable as research tools, drug leads and even therapeutics, and has resulted in a concerted and increasing drive to identify and characterise new conotoxins. Conotoxins are translated from mRNA as peptide precursors, and cDNA sequencing is now the primary method for identification of new conotoxin sequences. As a result, gene superfamily, a classification based on precursor signal peptide identity, has become the most convenient method of conotoxin classification. Here we review each of the described conotoxin gene superfamilies, with a focus on the structural and functional diversity present in each. This review is intended to serve as a practical guide to conotoxin superfamilies and to facilitate interpretation of the increasing number of conotoxin precursor sequences being identified by targeted-cDNA sequencing and more recently high-throughput transcriptome sequencing. PMID:25522317

  15. Genes of aging.

    PubMed

    Hamet, Pavel; Tremblay, Johanne

    2003-10-01

    According to developmental genetics theories, aging is a genetically programmed and controlled continuum of development and maturation. Being dynamic and malleable processes, development and aging are controlled not only by genes but also by environmental and epigenetic influences that predominate in the second half of life. Genetic mutations affect many phenotypes in flies, worms, rodents, and humans which share several diseases or their equivalents, including cancer, neurodegeneration, and infectious disorders as well as their susceptibility to them. Life span and stress resistance are closely linked. Oxidative stress actually constitutes a defined hypothesis of aging in that macromolecule oxidative damage accumulates with age and tends to be associated with life expectancy. DNA methylation, a force in the regulation of gene expression, is also one of the biomarkers of genetic damage. The mitotic clock of aging is marked, if not guided, by telomeres, essential genetic elements stabilizing natural chromosomic ends. The dream of humans to live longer, healthy lives is being tested by attempts to modify longevity in animal models, frequently by dietary manipulation. The quest continues to understand the mechanisms of healthy aging, one of the most compelling areas of research in the 21st century. PMID:14577056

  16. Peptide-based gene delivery.

    PubMed

    Mahat, R I; Monera, O D; Smith, L C; Rolland, A

    1999-04-01

    To achieve effective plasmid-based gene therapy, the control of cellular access and uptake, intracellular trafficking and nuclear retention of plasmids must be achieved. Inefficient endosomal release, cytoplasmic transport and nuclear entry of plasmids are amongst some of the key limiting factors in the use of plasmids for effective gene therapy. A number of non-viral gene delivery systems have been designed to overcome these limiting factors. The most common approach to protect and control plasmid distribution is to complex plasmids with cationic lipids or polymers through electrostatic interactions. Endosomal release of plasmids can be achieved, for instance, by using pH-sensitive lipids, inactivated viral particles, endosomolytic peptides and polymers. Among the least explored gene delivery systems are those that consist mainly of synthetic, short peptides. Peptides can be incorporated into multicomponent gene delivery complexes for specific purposes, such as for DNA condensation, cell-specific targeting, endosomolysis or nuclear transport. The aims of this review are to: (i) explore the conceptual and experimental aspects of peptide-DNA interactions; (ii) critically assess the possible use of peptides for efficient gene transfer; and (iii) present an overview on the use of peptides to enhance the effectiveness of other gene delivery systems. On balance, peptide-based gene delivery systems appear to have a significant potential as commercially viable gene delivery products. PMID:11715946

  17. Comparative genomics of metabolic pathways in Mycobacterium species: gene duplication, gene decay and lateral gene transfer.

    PubMed

    Marri, Pradeep Reddy; Bannantine, John P; Golding, Geoffrey B

    2006-11-01

    The genus Mycobacterium comprises significant pathogenic species that infect both humans and animals. One species within this genus, Mycobacterium tuberculosis, is the primary killer of humans resulting from bacterial infections. Five mycobacterial genomes belonging to four different species (M. tuberculosis, Mycobacterium bovis, Mycobacterium leprae and Mycobacterium avium ssp. paratuberculosis) have been sequenced to date and another 14 mycobacterial genomes are at various stages of completion. A comparative analysis of the gene products of key metabolic pathways revealed that the major differences among these species are in the gene products constituting the cell wall and the gene families encoding the acidic glycine-rich (PE/PPE/PGRS) proteins. Mycobacterium leprae has evolved by retaining a minimal gene set for most of the gene families, whereas M. avium ssp. paratuberculosis has acquired some of the virulence factors by lateral gene transfer. PMID:17064286

  18. Gene variations linked to lung cancer susceptibility in Asian women

    Cancer.gov

    An international group of scientists has identified three genetic regions that predispose Asian women who have never smoked to lung cancer. The finding provides further evidence that risk of lung cancer among never-smokers, especially Asian women, may be associated with certain unique inherited genetic characteristics that distinguishes it from lung cancer in smokers.

  19. Candidate reference genes for gene expression studies in water lily.

    PubMed

    Luo, Huolin; Chen, Sumei; Wan, Hongjian; Chen, Fadi; Gu, Chunsun; Liu, Zhaolei

    2010-09-01

    The selection of an appropriate reference gene(s) is a prerequisite for the proper interpretation of quantitative Real-Time polymerase chain reaction data. We report the evaluation of eight candidate reference genes across various tissues and treatments in the water lily by the two software packages geNorm and NormFinder. Across all samples, clathrin adaptor complexes medium subunit (AP47) and actin 11 (ACT11) emerged as the most suitable reference genes. Across different tissues, ACT11 and elongation factor 1-alpha (EF1alpha) exhibited a stable expression pattern. ACT11 and AP47 also stably expressed in roots subjected to various treatments, but in the leaves of the same plants the most stably expressed genes were ubiquitin-conjugating enzyme 16 (UBC16) and ACT11. PMID:20452325

  20. Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures.

    PubMed

    Ow, Ghim Siong; Ivshina, Anna V; Fuentes, Gloria; Kuznetsov, Vladimir A

    2014-01-01

    High-grade serous ovarian cancer (HG-SOC), a major histologic type of epithelial ovarian cancer (EOC), is a poorly-characterized, heterogeneous and lethal disease where somatic mutations of TP53 are common and inherited loss-of-function mutations in BRCA1/2 predispose to cancer in 9.5-13% of EOC patients. However, the overall burden of disease due to either inherited or sporadic mutations is not known. We performed bioinformatics analyses of mutational and clinical data of 334 HG-SOC tumor samples from The Cancer Genome Atlas to identify novel tumor-driving mutations, survival-significant patient subgroups and tumor subtypes potentially driven by either hereditary or sporadic factors. We identified a sub-cluster of high-frequency mutations in 22 patients and 58 genes associated with DNA damage repair, apoptosis and cell cycle. Mutations of CHEK2, observed with the highest intensity, were associated with poor therapy response and overall survival (OS) of these patients (P = 8.00e-05), possibly due to detrimental effect of mutations at the nuclear localization signal. A 21-gene mutational prognostic signature significantly stratifies patients into relatively low or high-risk subgroups with 5-y OS of 37% or 6%, respectively (P = 7.31e-08). Further analysis of these genes and high-risk subgroup revealed 2 distinct classes of tumors characterized by either germline mutations of genes such as CHEK2, RPS6KA2 and MLL4, or somatic mutations of other genes in the signature. Our results could provide improvement in prediction and clinical management of HG-SOC, facilitate our understanding of this complex disease, guide the design of targeted therapeutics and improve screening efforts to identify women at high-risk of hereditary ovarian cancers distinct from those associated with BRCA1/2 mutations. PMID:24879340

  1. Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures

    PubMed Central

    Ow, Ghim Siong; Ivshina, Anna V; Fuentes, Gloria; Kuznetsov, Vladimir A

    2014-01-01

    High-grade serous ovarian cancer (HG-SOC), a major histologic type of epithelial ovarian cancer (EOC), is a poorly-characterized, heterogeneous and lethal disease where somatic mutations of TP53 are common and inherited loss-of-function mutations in BRCA1/2 predispose to cancer in 9.5–13% of EOC patients. However, the overall burden of disease due to either inherited or sporadic mutations is not known.     We performed bioinformatics analyses of mutational and clinical data of 334 HG-SOC tumor samples from The Cancer Genome Atlas to identify novel tumor-driving mutations, survival-significant patient subgroups and tumor subtypes potentially driven by either hereditary or sporadic factors. We identified a sub-cluster of high-frequency mutations in 22 patients and 58 genes associated with DNA damage repair, apoptosis and cell cycle. Mutations of CHEK2, observed with the highest intensity, were associated with poor therapy response and overall survival (OS) of these patients (P = 8.00e-05), possibly due to detrimental effect of mutations at the nuclear localization signal. A 21-gene mutational prognostic signature significantly stratifies patients into relatively low or high-risk subgroups with 5-y OS of 37% or 6%, respectively (P = 7.31e-08). Further analysis of these genes and high-risk subgroup revealed 2 distinct classes of tumors characterized by either germline mutations of genes such as CHEK2, RPS6KA2 and MLL4, or somatic mutations of other genes in the signature. Our results could provide improvement in prediction and clinical management of HG-SOC, facilitate our understanding of this complex disease, guide the design of targeted therapeutics and improve screening efforts to identify women at high-risk of hereditary ovarian cancers distinct from those associated with BRCA1/2 mutations. PMID:24879340

  2. Effects of common haplotypes of the ileal sodium dependent bile acid transporter gene on the development of sporadic and familial colorectal cancer: A case control study

    PubMed Central

    Grünhage, Frank; Jungck, Matthias; Lamberti, Christoph; Keppeler, Hildegard; Becker, Ursula; Schulte-Witte, Hildegard; Plassmann, Dominik; Friedrichs, Nicolaus; Buettner, Reinhard; Aretz, Stefan; Sauerbruch, Tilman; Lammert, Frank

    2008-01-01

    Background The genetics of sporadic and non-syndromic familial colorectal cancer (CRC) is not well defined. However, genetic factors that promote the development of precursor lesions, i.e. adenomas, might also predispose to CRC. Recently, an association of colorectal adenoma with two variants (c.507C>T;p.L169L and c.511G>T;p.A171S) of the ileal sodium dependent bile acid transporter gene (SLC10A2) has been reported. Here, we reconstructed haplotypes of the SLC10A2 gene locus and tested for association with non-syndromic familial and sporadic CRC compared to 'hyper-normal' controls who displayed no colorectal polyps on screening colonoscopy. Methods We included 150 patients with sporadic CRC, 93 patients with familial CRC but exclusion of familial adenomatous polyposis and Lynch's syndrome, and 204 'hyper-normal' controls. Haplotype-tagging SLC10A2 gene variants were identified in the Hapmap database and genotyped using PCR-based 5' exonuclease assays with fluorescent dye-labelled probes. Haplotypes were reconstructed using the PHASE algorithm. Association testing was performed with both SNPs and reconstructed haplotypes. Results Minor allele frequencies of all SLC10A2 polymorphisms are within previously reported ranges, and no deviations from Hardy-Weinberg equilibrium are observed. However, we found no association with any of the SLC10A2 haplotypes with sporadic or familial CRC in our samples (all P values > 0.05). Conclusion Common variants of the SLC10A2 gene are not associated with sporadic or familial CRC. Hence, albeit this gene might be associated with early stages of colorectal neoplasia, it appears not to represent a major risk factor for progression to CRC. PMID:18644122

  3. In This Issue Gene Therapy ........................................1

    E-print Network

    Chen, Ying

    In This Issue · Gene Therapy ........................................1 · US / Australia Joint such as HIV may all be treatable in the future thanks to the field of research called gene therapy. A major challenge with gene therapy is the risks associated with gene delivery. Normally, genes are delivered across

  4. MRI-guided gene therapy Xiaoming Yanga

    E-print Network

    Atalar, Ergin

    Minireview MRI-guided gene therapy Xiaoming Yanga , Ergin Atalara,b,* a Department of Radiology gene expression. This review summarizes the current status of MRI- guided gene therapy. Ó 2006 resonance imaging; MRI-guided therapy; Gene therapy 1. Introduction Gene therapy is an exciting frontier

  5. Computing Gene Functional Similarity Using Combined Graphs

    E-print Network

    Al-Mubaid, Hisham

    way to explore the functional relationships between genes. We conducted the evaluation on a dataset gene functions and identifying gene disease associations are also based on GO. Gene ontologyComputing Gene Functional Similarity Using Combined Graphs Anurag Nagar Hisham Al-Mubaid Said

  6. REGULATORY GENES IN CREATING FLOWER COLOR PATTERNS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Differences in structural gene expression are responsible for a wide range of responses from human cancer to patterned flowers. Gene silencing is one of the ways in which gene expression is controlled. We have developed a model system to study gene silencing using a gene silencing mutation in Petun...

  7. Gene therapy for hemophilia

    PubMed Central

    Rogers, Geoffrey L.; Herzog, Roland W.

    2015-01-01