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Sample records for r462q rnasel variant

  1. Identification of viral infections in the prostate and evaluation of their association with cancer

    PubMed Central

    2010-01-01

    Background Several viruses with known oncogenic potential infect prostate tissue, among these are the polyomaviruses BKV, JCV, and SV40; human papillomaviruses (HPVs), and human cytomegalovirus (HCMV) infections. Recently, the Xenotropic Murine Leukemia Virus-related gammaretrovirus (XMRV) was identified in prostate tissue with a high prevalence observed in prostate cancer (PC) patients homozygous for the glutamine variant of the RNASEL protein (462Q/Q). Association studies with the R462Q allele and non-XMRV viruses have not been reported. We assessed associations between prostate cancer, prostate viral infections, and the RNASEL 462Q allele in Mexican cancer patients and controls. Methods 130 subjects (55 prostate cancer cases and 75 controls) were enrolled in the study. DNA and RNA isolated from prostate tissues were screened for the presence of viral genomes. Genotyping of the RNASEL R462Q variant was performed by Taqman method. Results R/R, R/Q, and Q/Q frequencies for R462Q were 0.62, 0.38, and 0.0 for PC cases and 0.69, 0.24, and 0.07 for controls, respectively. HPV sequences were detected in 11 (20.0%) cases and 4 (5.3%) controls. XMRV and HCMV infections were detected in one and six control samples, respectively. The risk of PC was significantly increased (Odds Ratio = 3.98; 95% CI: 1.17-13.56, p = 0.027) by infection of the prostatic tissue with HPV. BKV, JCV, and SV40 sequences were not detected in any of the tissue samples examined. Conclusions We report a positive association between PC and HPV infection. The 462Q/Q RNASEL genotype was not represented in our PC cases; thus, its interaction with prostate viral infections and cancer could not be evaluated. PMID:20576103

  2. Functional role of R462 in the degradation of hyaluronan catalyzed by hyaluronate lyase from Streptococcus pneumoniae.

    PubMed

    Li, Fengxue; Xu, Dingguo

    2015-08-01

    Hyaluronan lyase from Streptococcus pneumoniae can degrade hyaluronic acid, which is one of the major components in the extracellular matrix. Hyaluronan can regulate water balance, osmotic pressure, and act as an ion exchange resin. Followed by our recent work on the catalytic reaction mechanism and substrate binding mode, we in this work further investigate the functional role of active site arginine residue, R462, in the degradation of hyaluronan. The site directed mutagenesis simulation of R462A and R462Q were modeled using a combined quantum mechanical and molecular mechanical method. The overall substrate binding features upon mutations do not have significant changes. The energetic profiles for the reaction processes are essentially the same as that in wild type enzyme, but significant activation barrier height changes can be observed. Both mutants were shown to accelerate the overall enzymatic activity, e.g., R462A can reduce the barrier height by about 2.8 kcal mol(-1), while R462Q reduces the activation energy by about 2.9 kcal mol(-1). Consistent with the active site model calculated using density functional theory, our results can support that the positive charge on R462 guanidino side chain group plays a negative role in the catalysis. Finally, the functional role of R462 was proposed to facilitate the formation of initial enzyme-substrate complex, but not in the subsequent catalytic degradation reaction. Graphical Abstract Degradation of hyaluronan catalyzed by hyaluronate lyase from Streptococcus pneumoniae.

  3. The IL23R R381Q Gene Variant Protects against Immune-Mediated Diseases by Impairing IL-23-Induced Th17 Effector Response in Humans

    PubMed Central

    Di Meglio, Paola; Di Cesare, Antonella; Laggner, Ute; Chu, Chung-Ching; Napolitano, Luca; Villanova, Federica; Tosi, Isabella; Capon, Francesca; Trembath, Richard C.; Peris, Ketty; Nestle, Frank O.

    2011-01-01

    IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohn's disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A) and common (G) allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies. PMID:21364948

  4. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans.

    PubMed

    Di Meglio, Paola; Di Cesare, Antonella; Laggner, Ute; Chu, Chung-Ching; Napolitano, Luca; Villanova, Federica; Tosi, Isabella; Capon, Francesca; Trembath, Richard C; Peris, Ketty; Nestle, Frank O

    2011-02-22

    IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohn's disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A) and common (G) allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies.

  5. A PYY Q62P variant linked to human obesity

    SciTech Connect

    Ahituv, Nadav; Kavaslar, Nihan; Schackwitz, Wendy

    2005-06-27

    Members of the pancreatic polypeptide family and the irreceptors have been implicated in the control of food intake in rodents and humans. To investigate whether nucleotide changes in these candidate genes result in abnormal weight in humans, we sequenced the coding exons and splice sites of seven family members (NPY, PYY, PPY, NPY1R, NPY2R, NPY4R, and NPY5R) in a large cohort of extremely obese (n=379) and lean (n=378) individuals. In total we found eleven rare non-synonymous variants, four of which exhibited familial segregation, NPY1R L53P and PPY P63L with leanness and NPY2R D42G and PYY Q62P with obesity. Functional analysismore » of the obese variants revealed NPY2R D42G to have reduced cell surface expression, while previous cell culture based studies indicated variant PYY Q62P to have altered receptor binding selectivity and we show that it fails to reduce food intake through mouse peptide injection experiments. These results support that rare non-synonymous variants within these genes can alter susceptibility to human body mass index extremes.« less

  6. The Cannabinoid Receptor 2 Q63R Variant Modulates the Relationship between Childhood Obesity and Age at Menarche.

    PubMed

    Bellini, Giulia; Grandone, Anna; Torella, Marco; Miraglia del Giudice, Emanuele; Nobili, Bruno; Perrone, Laura; Maione, Sabatino; Rossi, Francesca

    2015-01-01

    The ovary is an important site where gene variants modulate pubertal timing. The cannabinoid receptor 2 (CB2) is expressed in the ovary, plays a role in folliculogenesis and ovulation, and can be modulated by estrogens. Obesity is strictly associated with early menarche and is characterized by sex hormone and endocannabinoid derangement. In this study, we investigated the role of the CB2 receptor in determining the age at menarche in obese girls. We studied a cohort of 240 obese girls (age 11.9±3 years; BMI z-score 2.8±0.8). The age at menarche (if it had already occurred) was recorded at the time of the visit or via phonecall. The CNR2 rs35761398 polymorphism, which leads to the CB2 Q63R variant, was detected by the TaqMan assay. In total, 105 patients were homozygous for the R63-coding allele (RR), 113 were QR and 22 were QQ. Variance analysis revealed a significantly earlier age of menarche in subjects carrying the Q63 allele, which was also found after adjusting for BMI z-score (11±1.2 vs. 11.6±1.2 years, p = 0.0003). Logistic regression analysis demonstrated that patients homozygous for the Q allele had a 2.2-fold higher risk (odds ratio = 2.2; CI1.1-3.4; p = 0.02) of presenting with an early menarche (age at menarche <12 years). We demonstrated for the first time the association between the CB2 Q63R functional variant and the age at menarche in a cohort of Italian obese girls.

  7. Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q

    PubMed Central

    Marinovic-Terzic, Ivana; Yoshioka-Yamashita, Atsuko; Shimodaira, Hideki; Avdievich, Elena; Hunton, Irina C.; Kolodner, Richard D.; Edelmann, Winfried; Wang, Jean Y. J.

    2008-01-01

    Mismatch repair (MMR) corrects replication errors during DNA synthesis. The mammalian MMR proteins also activate cell cycle checkpoints and apoptosis in response to persistent DNA damage. MMR-deficient cells are resistant to cisplatin, a DNA cross-linking agent used in chemotherapy, because of impaired activation of apoptotic pathways. It is shown that postmeiotic segregation 2 (PMS2), an MMR protein, is required for cisplatin-induced activation of p73, a member of the p53 family of transcription factors with proapoptotic activity. The human PMS2 is highly polymorphic, with at least 12 known nonsynonymous codon changes identified. We show here that the PMS2(R20Q) variant is defective in activating p73-dependent apoptotic response to cisplatin. When expressed in Pms2-deficient mouse fibroblasts, human PMS2(R20Q) but not PMS2 interfered with the apoptotic response to cisplatin. Correspondingly, PMS2 but not PMS2(R20Q) enhanced the cytotoxic effect of cisplatin measured by clonogenic survival. Because PMS2(R20Q) lacks proapoptotic activity, this polymorphic allele may modulate tumor responses to cisplatin among cancer patients. PMID:18768816

  8. Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q.

    PubMed

    Marinovic-Terzic, Ivana; Yoshioka-Yamashita, Atsuko; Shimodaira, Hideki; Avdievich, Elena; Hunton, Irina C; Kolodner, Richard D; Edelmann, Winfried; Wang, Jean Y J

    2008-09-16

    Mismatch repair (MMR) corrects replication errors during DNA synthesis. The mammalian MMR proteins also activate cell cycle checkpoints and apoptosis in response to persistent DNA damage. MMR-deficient cells are resistant to cisplatin, a DNA cross-linking agent used in chemotherapy, because of impaired activation of apoptotic pathways. It is shown that postmeiotic segregation 2 (PMS2), an MMR protein, is required for cisplatin-induced activation of p73, a member of the p53 family of transcription factors with proapoptotic activity. The human PMS2 is highly polymorphic, with at least 12 known nonsynonymous codon changes identified. We show here that the PMS2(R20Q) variant is defective in activating p73-dependent apoptotic response to cisplatin. When expressed in Pms2-deficient mouse fibroblasts, human PMS2(R20Q) but not PMS2 interfered with the apoptotic response to cisplatin. Correspondingly, PMS2 but not PMS2(R20Q) enhanced the cytotoxic effect of cisplatin measured by clonogenic survival. Because PMS2(R20Q) lacks proapoptotic activity, this polymorphic allele may modulate tumor responses to cisplatin among cancer patients.

  9. Characterization of the equine 2'-5' oligoadenylate synthetase 1 (OAS1) and ribonuclease L (RNASEL) innate immunity genes

    PubMed Central

    Rios, Jonathan J; Perelygin, Andrey A; Long, Maureen T; Lear, Teri L; Zharkikh, Andrey A; Brinton, Margo A; Adelson, David L

    2007-01-01

    Background The mammalian OAS/RNASEL pathway plays an important role in antiviral host defense. A premature stop-codon within the murine Oas1b gene results in the increased susceptibility of mice to a number of flaviviruses, including West Nile virus (WNV). Mutations in either the OAS1 or RNASEL genes may also modulate the outcome of WNV-induced disease or other viral infections in horses. Polymorphisms in the human OAS gene cluster have been previously utilized for case-control analysis of virus-induced disease in humans. No polymorphisms have yet been identified in either the equine OAS1 or RNASEL genes for use in similar case-control studies. Results Genomic sequence for equine OAS1 was obtained from a contig assembly generated from a shotgun subclone library of CHORI-241 BAC 100I10. Specific amplification of regions of the OAS1 gene from 13 horses of various breeds identified 33 single nucleotide polymorphisms (SNP) and two microsatellites. RNASEL cDNA sequences were determined for 8 mammals and utilized in a phylogenetic analysis. The chromosomal location of the RNASEL gene was assigned by FISH to ECA5p17-p16 using two selected CHORI-241 BAC clones. The horse genomic RNASEL sequence was assembled. Specific amplification of regions of the RNASEL gene from 13 horses identified 31 SNPs. Conclusion In this report, two dinucleotide microsatellites and 64 single nucleotide polymorphisms within the equine OAS1 and RNASEL genes were identified. These polymorphisms are the first to be reported for these genes and will facilitate future case-control studies of horse susceptibility to infectious diseases. PMID:17822564

  10. The Roles of RNase-L in Antimicrobial Immunity and the Cytoskeleton-Associated Innate Response

    PubMed Central

    Ezelle, Heather J.; Malathi, Krishnamurthy; Hassel, Bret A.

    2016-01-01

    The interferon (IFN)-regulated endoribonuclease RNase-L is involved in multiple aspects of the antimicrobial innate immune response. It is the terminal component of an RNA cleavage pathway in which dsRNA induces the production of RNase-L-activating 2-5A by the 2′-5′-oligoadenylate synthetase. The active nuclease then cleaves ssRNAs, both cellular and viral, leading to downregulation of their expression and the generation of small RNAs capable of activating retinoic acid-inducible gene-I (RIG-I)-like receptors or the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome. This leads to IFNβ expression and IL-1β activation respectively, in addition to broader effects on immune cell function. RNase-L is also one of a growing number of innate immune components that interact with the cell cytoskeleton. It can bind to several cytoskeletal proteins, including filamin A, an actin-binding protein that collaborates with RNase-L to maintain the cellular barrier to viral entry. This antiviral activity is independent of catalytic function, a unique mechanism for RNase-L. We also describe here the interaction of RNase-L with the E3 ubiquitin ligase and scaffolding protein, ligand of nump protein X (LNX), a regulator of tight junction proteins. In order to better understand the significance and context of these novel binding partners in the antimicrobial response, other innate immune protein interactions with the cytoskeleton are also discussed. PMID:26760998

  11. The Roles of RNase-L in Antimicrobial Immunity and the Cytoskeleton-Associated Innate Response.

    PubMed

    Ezelle, Heather J; Malathi, Krishnamurthy; Hassel, Bret A

    2016-01-08

    The interferon (IFN)-regulated endoribonuclease RNase-L is involved in multiple aspects of the antimicrobial innate immune response. It is the terminal component of an RNA cleavage pathway in which dsRNA induces the production of RNase-L-activating 2-5A by the 2'-5'-oligoadenylate synthetase. The active nuclease then cleaves ssRNAs, both cellular and viral, leading to downregulation of their expression and the generation of small RNAs capable of activating retinoic acid-inducible gene-I (RIG-I)-like receptors or the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome. This leads to IFNβ expression and IL-1β activation respectively, in addition to broader effects on immune cell function. RNase-L is also one of a growing number of innate immune components that interact with the cell cytoskeleton. It can bind to several cytoskeletal proteins, including filamin A, an actin-binding protein that collaborates with RNase-L to maintain the cellular barrier to viral entry. This antiviral activity is independent of catalytic function, a unique mechanism for RNase-L. We also describe here the interaction of RNase-L with the E3 ubiquitin ligase and scaffolding protein, ligand of nump protein X (LNX), a regulator of tight junction proteins. In order to better understand the significance and context of these novel binding partners in the antimicrobial response, other innate immune protein interactions with the cytoskeleton are also discussed.

  12. Contrasting roles of the ABCG2 Q141K variant in prostate cancer

    SciTech Connect

    Sobek, Kathryn M.; Cummings, Jessica L.; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA

    plan. - Highlights: • The presence of ABCG2 Q141K variant decreases time to PSA recurrence. • Cells expressing the Q141K variant retain more folic acid than wild type. • Cells expressing the Q141K variant are more sensitive to docetaxel. • ABCG2 protein is repressed miR-519c and/or miR-520h in prostate cancer cell lines.« less

  13. Is RNASEL:p.Glu265* a modifier of early-onset breast cancer risk for carriers of high-risk mutations?

    PubMed

    Nguyen-Dumont, Tú; Teo, Zhi L; Hammet, Fleur; Roberge, Alexis; Mahmoodi, Maryam; Tsimiklis, Helen; Park, Daniel J; Pope, Bernard J; Lonie, Andrew; Kapuscinski, Miroslav K; Mahmood, Khalid; Goldgar, David E; Giles, Graham G; Winship, Ingrid; Hopper, John L; Southey, Melissa C

    2018-02-08

    Breast cancer risk for BRCA1 and BRCA2 pathogenic mutation carriers is modified by risk factors that cluster in families, including genetic modifiers of risk. We considered genetic modifiers of risk for carriers of high-risk mutations in other breast cancer susceptibility genes. In a family known to carry the high-risk mutation PALB2:c.3113G>A (p.Trp1038*), whole-exome sequencing was performed on germline DNA from four affected women, three of whom were mutation carriers. RNASEL:p.Glu265* was identified in one of the PALB2 carriers who had two primary invasive breast cancer diagnoses before 50 years. Gene-panel testing of BRCA1, BRCA2, PALB2 and RNASEL in the Australian Breast Cancer Family Registry identified five carriers of RNASEL:p.Glu265* in 591 early onset breast cancer cases. Three of the five women (60%) carrying RNASEL:p.Glu265* also carried a pathogenic mutation in a breast cancer susceptibility gene compared with 30 carriers of pathogenic mutations in the 586 non-carriers of RNASEL:p.Glu265* (5%) (p < 0.002). Taqman genotyping demonstrated that the allele frequency of RNASEL:p.Glu265* was similar in affected and unaffected Australian women, consistent with other populations. Our study suggests that RNASEL:p.Glu265* may be a genetic modifier of risk for early-onset breast cancer predisposition in carriers of high-risk mutations. Much larger case-case and case-control studies are warranted to test the association observed in this report.

  14. The common variant Q192R at the paraoxonase 1 (PON1) gene and its activity are responsible for a portion of the altered antioxidant status in type 2 diabetes.

    PubMed

    Zargari, Mehryar; Sharafeddin, Fahimeh; Mahrooz, Abdolkarim; Alizadeh, Ahad; Masoumi, Parisa

    2016-08-01

    In this study, we investigated the effects of paraoxonase 1 (PON1) activities and the variant PON1-Q192R on the ferric reducing ability of plasma (FRAP) and total thiol. In addition, we examined the distribution of genotypes of this variant and the relationship of the genotypes with age in patients with type 2 diabetes (T2D). A total of 115 patients with T2D were enrolled in this study. Paraoxonase activity (PON-para) and arylesterase activity (PON-aryl) were determined using spectrophotometric assays. The distribution of the Q192R genotypes was determined by the double substrate method. The antioxidant status was evaluated by determining FRAP and total thiol. The frequencies of Q and R allozyme were 0.78 and 0.22, respectively. The multivariate analysis identified a significant association between the variables PON1-Q192R (Wilks' λ = 0.85, P = 0.002) and PON-aryl (Wilks' λ = 0.896, P = 0.017), with FRAP and total thiol. The significant difference observed for PON1-Q192R and PON-aryl is primarily due to the changes in FRAP levels (η(2 )= 0.127, P = 0.002 for PON1-Q192R; η(2 )= 0.083, P = 0.011 for PON-aryl). The interaction PON1-Q192R-PON-aryl increased the effect sizes from 8 to 19% for FRAP. Only in R-carrying genotypes, there were significant correlations between both PON-para/HDL (r = -0.574, P < 0.001) and PON-aryl/HDL (r = -0.577, P < 0.001) with age. Our data suggest that the variant PON1-Q192R and PON1 activity, particularly PON-aryl, influenced the antioxidant status in T2D. The interaction of this variant and PON1 activity increased the effect size on the antioxidant capacity. Moreover, the presence of the R allozyme may potentiate the effects of age on susceptibility to cardiovascular diseases in T2D. © 2016 by the Society for Experimental Biology and Medicine.

  15. Polymorphic Variants 279R and 668Q Augment Activity of Matrix Metalloproteinase-9 in Breath Condensates of Children with Asthma.

    PubMed

    Grzela, Katarzyna; Zagórska, Wioletta; Krejner, Alicja; Litwiniuk, Malgorzata; Zawadzka-Krajewska, Anna; Kulus, Marek; Grzela, Tomasz

    2017-04-01

    Matrix metalloproteinase (MMP)-9 is involved in pathophysiology of asthma, mainly asthma-associated airway remodeling. Exhaled breath condensates (EBC) of asthmatics contain increased amounts of MMP-9 with activity higher, than in healthy controls. The increased activity of MMP-9 may originate from its excessive production and activation, but may also result from variations in MMP-9 structure, which are determined by single nucleotide polymorphisms (SNPs). In this pilot study we aimed to assess the possible influence of two functional MMP-9 polymorphisms, Q279R and R668Q, on enzymatic activity of MMP-9, measured in EBC of asthmatic children. The concentration and activity of MMP-9 were analyzed in EBC of 20 children with allergic asthma using specific standard ELISA and novel immunoenzymatic activity assay. The SNPs of MMP-9 were assessed using real-time PCR-based genotyping test. We have found that MMP-9 concentration in breath condensates of children with stable asthma was slightly higher in ELISA, than in the activity assay. Moreover, these results and activity-to-amount ratio have revealed some relationship with a presence of specific 279R and/or 668Q MMP-9 gene variants. Our observation suggests that at least in some patients MMP-9 hyperactivity may result from genetic predisposition, determined by polymorphic variants of MMP-9 gene. Moreover, it supports previous reports postulating significance of MMP-9 in pathogenesis of asthma. However, this issue still requires further studies.

  16. Full activation of RNaseL in animal cells requires binding of 2-5A within ankyrin repeats 6 to 9 of this interferon-inducible enzyme.

    PubMed

    Díaz-Guerra, M; Rivas, C; Esteban, M

    1999-02-01

    To define protein domains important for activation of the interferon (IFN)-induced enzyme 2-5A-dependent RNaseL, we have generated vaccinia virus (VV) recombinants able to express in cultured cells truncated forms of this protein and compared their biologic activities with those producing the wild-type enzyme, with and without coexpression of 2-5A synthetase. Our results show that full activation of RNaseL requires binding of 2-5A oligonucleotides within amino acid positions 212-339, corresponding to ankyrin repeats 6 to 9. The protein kinase and ribonuclease domains of RNaseL, amino acids 340-741, are sufficient for a constitutively active enzyme that is unresponsive to excess 2-5A. These results demonstrate in vivo the importance of the ankyrin domains in the biologic function of RNaseL. We suggest that ankyrin repeats act as key modulators of RNaseL activity.

  17. Association between lower frequency of R381Q variant (rs11209026) in IL-23 receptor gene and increased risk of recurrent spontaneous abortion (RSA).

    PubMed

    Abdollahi, Elham; Tavasolian, Fataneh; Ghasemi, Nasrin; Mirghanizadeh, Seyed Ali; Azizi, Mohammdareza; Ghoryani, Mohsen; Samadi, Morteza

    2015-01-01

    Recurrent spontaneous abortion (RSA) is defined as three or more consecutive spontaneous abortions before the 20th week of gestation. The purpose of the present study was to investigate the association between a functional single nucleotide polymorphism (SNP) in the interleukin (IL)-23 receptor gene (IL-23R; rs11209026, 1142 G wild type → A reduced function, Arg381Gln, R381Q) and RSA. For the study, 200 RSA patients (confirmed using established diagnostic criteria) and 200 normal individuals in fertility and infertility centers in the cities of Yazd and Isfahan were recruited during a period from 2012-2013. Using PCR-RFLP, the R381Q variant was screened for in the IL-23R gene of the patients and controls. The results indicated there were significant differences in the frequency of this genetic variant in the patients versus the healthy controls, i.e. 2% and 7.5%, respectively (p value = 0.01; odds ratio = 0.25; CI = 95%). No significant difference was found for the G allelic frequency in patients with RSA and in the control group (p = 0.60). The A allelic frequency was significantly different between the two groups (p = 0.01). Based on these findings, it is concluded that the frequency of single nucleotide polymorphism in the IL-23 receptor (R381Q) in patients with recurrent spontaneous abortion (RSA) is less than that found in normal control women.

  18. Clinical features and functional significance of the P369S/R408Q variant in pyrin, the familial Mediterranean fever protein.

    PubMed

    Ryan, J G; Masters, S L; Booty, M G; Habal, N; Alexander, J D; Barham, B K; Remmers, E F; Barron, K S; Kastner, D L; Aksentijevich, I

    2010-07-01

    Familial Mediterranean fever (FMF) is caused by mutations in MEFV, which encodes pyrin. The nature of substitutions P369S and R408Q in exon 3 remains unclear. Exon 3 encoding pyrin's B-box domain is necessary for interactions with proline serine threonine phosphatase interacting protein 1 (PSTPIP1). The aim was to characterise the phenotype of patients with these substitutions and to determine their functional significance. A database of genetic tests undertaken at the US National Institutes of Health was interrogated. Symptoms and signs were classified according to Tel-Hashomer criteria. Coimmunoprecipitation techniques were employed to determine the variants' effects on pyrin/PSTPIP1 interactions. A total of 40 symptomatic and 4 asymptomatic family members with these substitutions were identified. P369S and R408Q were found in cis, and cosegregated in all patients sequenced. Clinical details were available on 22 patients. In all, 5 patients had symptoms and signs fulfilling a clinical diagnosis of FMF, and 15 received colchicine. In patients not achieving the criteria, trials of anti-tumour necrosis factor (TNF) agents resulted in partial or no benefit; resolution of symptoms was noted in those receiving anakinra. The carrier frequency was higher in the patient cohort than in controls but was not statistically significant. Coimmunoprecipitation studies demonstrated that these pyrin variants did not affect binding to PSTPIP1. P369S/R408Q substitutions are associated with a highly variable phenotype, and are infrequently associated with typical FMF symptoms, however a trial of colchicine is warranted in all. Functional and modelling studies suggest that these substitutions do not significantly affect pyrin's interaction with PSTPIP1. This study highlights the need for caution in interpreting genetic tests in patients with atypical symptoms.

  19. Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant.

    PubMed

    Krakoff, Jonathan; Ma, Lijun; Kobes, Sayuko; Knowler, William C; Hanson, Robert L; Bogardus, Clifton; Baier, Leslie J

    2008-12-01

    Humans with functional variants in the melanocortin 4 receptor (MC4R) are obese, hyperphagic, and hyperinsulinemic but have been reported to have no difference in energy expenditure. We investigated the association of two MC4R variants, Arg165Gln (R165Q) and A insertion at nucleotide 100 (NT100), with adiposity in 3,074 full-heritage Pima Indians, a subset of whom had metabolic measures including 24-h energy expenditure (n = 252) and resting metabolic rate (RMR) (n = 364). Among the 3,074 subjects, 43 were heterozygous for R165Q and 14 for NT100 (frequency = 0.007 and 0.002). Mean (+/- SD) BMI was higher among subjects with R165Q (39.3 +/- 8.6 kg/m(2)) or NT100 (41.2 +/- 7.8) than subjects without either variant (37.1 +/- 8.4) (P = 0.04 and 0.02, adjusted for age, sex, and birth year and accounting for family membership). The 24-h energy expenditure (four with NT100; three with R165Q) or RMR (six with NT100; two with R165Q) was lower in heterozygous subjects but only met statistical significance when heterozygous subjects were combined and compared with subjects without either variant: least-squares means, 2,163 kcal/24 h (95% CI 2,035-2,291) vs. 2,307 kcal/24 h (2,285-2,328), P = 0.03 for 24-h energy expenditure, and 1,617 kcal/24 h (1,499-1,734) vs. 1,754 kcal/24 h (1,736-1,772), P = 0.02 for RMR; adjusted for age, sex, fat-free mass, and fat mass). For RMR, this difference persisted, even after accounting for family membership. Pima Indians heterozygous for R165Q or NT100 in MC4R have higher BMIs and lower energy expenditure (by approximately 140 kcal/day), indicating that lower energy expenditure was a component of the increased adiposity.

  20. Clinical features and functional significance of the P369S/R408Q variant in pyrin, the familial Mediterranean fever protein

    PubMed Central

    Ryan, JG; Masters, SL; Booty, MG; Habal, N; Alexander, JD; Barham, BK; Remmers, EF; Barron, KS; Kastner, DL; Aksentijevich, I

    2013-01-01

    Objectives Familial Mediterranean fever (FMF) is caused by mutations in MEFV, which encodes pyrin. The nature of substitutions P369S and R408Q in exon 3 remains unclear. Exon 3 encoding pyrin’s B-box domain is necessary for interactions with PSTPIP1. We aimed to characterize the phenotype of patients with these substitutions and to determine their functional significance. Methods A database of genetic tests undertaken in our institution was interrogated. Symptoms and signs were classified according to Tel-Hashomer criteria. Co-immunoprecipation techniques were employed to determine the variants’ effects on pyrin/PSTPIP1 interactions. Results We identified 40 symptomatic and 4 asymptomatic family members with these substitutions. P369S and R408Q were found in cis, and co-segregated in all patients sequenced. Clinical details were available on 22 patients. Five patients had symptoms and signs fulfilling a clinical diagnosis of FMF. Fourteen received colchicine. In patients not reaching the criteria, trials of anti-TNF agents resulted in partial or no benefit; resolution of symptoms was noted in those receiving anakinra. The carrier frequency was higher in the patient cohort than in controls but was not statistically significant. Co-immunoprecipitation studies demonstrated that these pyrin variants did not affect binding to PSTPIP1. Conclusions P369S/R408Q substitutions are associated with a highly variable phenotype, and are infrequently associated with typical FMF symptoms, however a trial of colchicine is warranted in all. Functional and modeling studies suggest that these substitutions do not significantly affect pyrin’s interaction with PSTPIP1. This study highlights the need for caution in interpreting genetic tests in patients with atypical symptoms. PMID:19934105

  1. A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

    PubMed Central

    Gudmundsson, Julius; Sulem, Patrick; Gudbjartsson, Daniel F.; Masson, Gisli; Agnarsson, Bjarni A.; Benediktsdottir, Kristrun R.; Sigurdsson, Asgeir; Magnusson, Olafur Th.; Gudjonsson, Sigurjon A.; Magnusdottir, Droplaug N.; Johannsdottir, Hrefna; Helgadottir, Hafdis Th.; Stacey, Simon N.; Jonasdottir, Adalbjorg; Olafsdottir, Stefania B.; Thorleifsson, Gudmar; Jonasson, Jon G.; Tryggvadottir, Laufey; Navarrete, Sebastian; Fuertes, Fernando; Helfand, Brian T.; Hu, Qiaoyan; Csiki, Irma E.; Mates, Ioan N.; Jinga, Viorel; Aben, Katja K. H.; van Oort, Inge M.; Vermeulen, Sita H.; Donovan, Jenny L.; Hamdy, Freddy C.; Ng, Chi-Fai; Chiu, Peter K.F.; Lau, Kin-Mang; Ng, Maggie C.Y.; Gulcher, Jeffrey R.; Kong, Augustine; Catalona, William J.; Mayordomo, Jose I.; Einarsson, Gudmundur V.; Barkardottir, Rosa B.; Jonsson, Eirikur; Mates, Dana; Neal, David E.; Kiemeney, Lambertus A.; Thorsteinsdottir, Unnur; Rafnar, Thorunn; Stefansson, Kari

    2013-01-01

    Western countries, prostate cancer is the most prevalent cancer of men, and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. In the present study we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. One variant was found to be associated with prostate cancer in European populations: rs188140481[A] (OR = 2.90, Pcomb = 6.2×10−34) located on 8q24, with an average risk allele control frequency of 0.54%. This variant is only very weakly correlated (r2 ≤ 0.06) with previously reported risk variants on 8q24, and remains significant after adjustment for all of them. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for the previously described HOXB13 mutation (rs138213197[T]), confirming it as prostate cancer risk variant in populations from all over Europe. PMID:23104005

  2. 22q11.2 deletion carriers and schizophrenia-associated novel variants.

    PubMed

    Balan, S; Iwayama, Y; Toyota, T; Toyoshima, M; Maekawa, M; Yoshikawa, T

    2014-01-01

    The penetrance of schizophrenia risk in carriers of the 22q11.2 deletion is high but incomplete, suggesting the possibility of additional genetic defects. We performed whole exome sequencing on two individuals with 22q11.2 deletion, one with schizophrenia and the other who was psychosis-free. The results revealed novel genetic variants related to neuronal function exclusively in the person with schizophrenia (frameshift: KAT8, APOH and SNX31; nonsense: EFCAB11 and CLVS2). This study paves the way towards a more complete understanding of variant dose and genetic architecture in schizophrenia.

  3. Common variants at 12q15 and 12q24 are associated with infant head circumference.

    PubMed

    Taal, H Rob; Pourcain, Beate St; Thiering, Elisabeth; Das, Shikta; Mook-Kanamori, Dennis O; Warrington, Nicole M; Kaakinen, Marika; Kreiner-Møller, Eskil; Bradfield, Jonathan P; Freathy, Rachel M; Geller, Frank; Guxens, Mònica; Cousminer, Diana L; Kerkhof, Marjan; Timpson, Nicholas J; Ikram, M Arfan; Beilin, Lawrence J; Bønnelykke, Klaus; Buxton, Jessica L; Charoen, Pimphen; Chawes, Bo Lund Krogsgaard; Eriksson, Johan; Evans, David M; Hofman, Albert; Kemp, John P; Kim, Cecilia E; Klopp, Norman; Lahti, Jari; Lye, Stephen J; McMahon, George; Mentch, Frank D; Müller, Martina; O'Reilly, Paul F; Prokopenko, Inga; Rivadeneira, Fernando; Steegers, Eric A P; Sunyer, Jordi; Tiesler, Carla; Yaghootkar, Hanieh; Breteler, Monique M B; Debette, Stephanie; Fornage, Myriam; Gudnason, Vilmundur; Launer, Lenore J; van der Lugt, Aad; Mosley, Thomas H; Seshadri, Sudha; Smith, Albert V; Vernooij, Meike W; Blakemore, Alexandra If; Chiavacci, Rosetta M; Feenstra, Bjarke; Fernandez-Benet, Julio; Grant, Struan F A; Hartikainen, Anna-Liisa; van der Heijden, Albert J; Iñiguez, Carmen; Lathrop, Mark; McArdle, Wendy L; Mølgaard, Anne; Newnham, John P; Palmer, Lyle J; Palotie, Aarno; Pouta, Annneli; Ring, Susan M; Sovio, Ulla; Standl, Marie; Uitterlinden, Andre G; Wichmann, H-Erich; Vissing, Nadja Hawwa; DeCarli, Charles; van Duijn, Cornelia M; McCarthy, Mark I; Koppelman, Gerard H; Estivill, Xavier; Hattersley, Andrew T; Melbye, Mads; Bisgaard, Hans; Pennell, Craig E; Widen, Elisabeth; Hakonarson, Hakon; Smith, George Davey; Heinrich, Joachim; Jarvelin, Marjo-Riitta; Jaddoe, Vincent W V

    2012-04-15

    To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.

  4. Common variants at 12q15 and 12q24 are associated with infant head circumference

    PubMed Central

    Warrington, Nicole M; Kaakinen, Marika; Kreiner-Møller, Eskil; Bradfield, Jonathan P; Freathy, Rachel M; Geller, Frank; Guxens, Mònica; Cousminer, Diana L; Kerkhof, Marjan; Timpson, Nicholas J; Ikram, M Arfan; Beilin, Lawrence J; Bønnelykke, Klaus; Buxton, Jessica L; Charoen, Pimphen; Chawes, Bo Lund Krogsgaard; Eriksson, Johan; Evans, David M; Hofman, Albert; Kemp, John P; Kim, Cecilia E; Klopp, Norman; Lahti, Jari; Lye, Stephen J; McMahon, George; Mentch, Frank D; Müller, Martina; O’Reilly, Paul F; Prokopenko, Inga; Rivadeneira, Fernando; Steegers, Eric A P; Sunyer, Jordi; Tiesler, Carla; Yaghootkar, Hanieh; Breteler, Monique M B; Debette, Stephanie; Fornage, Myriam; Gudnason, Vilmundur; Launer, Lenore J; van der Lugt, Aad; Mosley, Thomas H; Seshadri, Sudha; Smith, Albert V; Vernooij, Meike W; Blakemore, Alexandra IF; Chiavacci, Rosetta M; Feenstra, Bjarke; Fernandez-Benet, Julio; Grant, Struan F A; Hartikainen, Anna-Liisa; van der Heijden, Albert J; Iñiguez, Carmen; Lathrop, Mark; McArdle, Wendy L; Mølgaard, Anne; Newnham, John P; Palmer, Lyle J; Palotie, Aarno; Pouta, Annneli; Ring, Susan M; Sovio, Ulla; Standl, Marie; Uitterlinden, Andre G; Wichmann, H-Erich; Vissing, Nadja Hawwa; DeCarli, Charles; van Duijn, Cornelia M; McCarthy, Mark I; Koppelman, Gerard H.; Estivill, Xavier; Hattersley, Andrew T; Melbye, Mads; Bisgaard, Hans; Pennell, Craig E; Widen, Elisabeth; Hakonarson, Hakon; Smith, George Davey; Heinrich, Joachim; Jarvelin, Marjo-Riitta; Jaddoe, Vincent W V

    2013-01-01

    To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association (GWA) studies (N=10,768 from European ancestry enrolled in pregnancy/birth cohorts) and followed up three lead signals in six replication studies (combined N=19,089). Rs7980687 on chromosome 12q24 (P=8.1×10−9), and rs1042725 on chromosome 12q15 (P=2.8×10−10) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height1, their effects on infant head circumference were largely independent of height (P=3.8×10−7 for rs7980687, P=1.3×10−7 for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P=3.9×10−6). SNPs correlated to the 17q21 signal show genome-wide association with adult intra cranial volume2, Parkinson’s disease and other neurodegenerative diseases3-5, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life. PMID:22504419

  5. ACVR1 p.Q207E causes classic fibrodysplasia ossificans progressiva and is functionally distinct from the engineered constitutively active ACVR1 p.Q207D variant

    PubMed Central

    Haupt, Julia; Deichsel, Alexandra; Stange, Katja; Ast, Cindy; Bocciardi, Renata; Ravazzolo, Roberto; Di Rocco, Maja; Ferrari, Paola; Landi, Antonio; Kaplan, Frederick S.; Shore, Eileen M.; Reissner, Carsten; Seemann, Petra

    2014-01-01

    Fibrodysplasia ossificans progressiva (FOP) is a disabling genetic disorder of progressive heterotopic ossification (HO). Here, we report a patient with an ultra-rare point mutation [c.619C>G, p.Q207E] located in a codon adjacent to the most common FOP mutation [c.617G>A, p.R206H] of Activin A Receptor, type 1 (ACVR1) and that affects the same intracellular amino acid position in the GS activation domain as the engineered constitutively active (c.a.) variant p.Q207D. It was predicted that both mutations at residue 207 have similar functional effects by introducing a negative charge. Transgenic p.Q207D-c.a. mice have served as a model for FOP HO in several in vivo studies. However, we found that the engineered ACVR1Q207D−c.a. is significantly more active than the classic FOP mutation ACVR1R206H when overexpressed in chicken limbs and in differentiation assays of chondrogenesis, osteogenesis and myogenesis. Importantly, our studies reveal that the ACVR1Q207E resembles the classic FOP receptor in these assays, not the engineered ACVR1Q207D−c.a.. Notably, reporter gene assays revealed that both naturally occurring FOP receptors (ACVR1R206H and ACVR1Q207E) were activated by BMP7 and were sensitive to deletion of the ligand binding domain, whereas the engineered ACVR1Q207D−c.a. exhibited ligand independent activity. We performed an in silico analysis and propose a structural model for p.Q207D-c.a. that irreversibly relocates the GS domain into an activating position, where it becomes ligand independent. We conclude that the engineered p.Q207D-c.a. mutation has severe limitations as a model for FOP, whereas the naturally occurring mutations p.R206H and p.Q207E facilitate receptor activation, albeit in a reversible manner. PMID:24852373

  6. Clinical dose effect and functional consequences of R92Q in two families presenting with a TRAPS/PFAPA-like phenotype.

    PubMed

    Grandemange, Sylvie; Cabasson, Sébastien; Sarrabay, Guillaume; Pène, Jérôme; Rittore, Cécile; Sanchez, Elodie; Chastang, Marie-Caroline; Guyon, Gaël; Pillet, Pascal; Touitou, Isabelle

    2017-03-01

    TNF receptor-associated syndrome (TRAPS) is a dominantly inherited autoinflammatory condition caused by mutations in the TNFRSF1A gene. The mechanism underlying the variable expressivity of the common variant R92Q (rs4149584; c.362G>A; p.Arg121Gln) is unclear and is of critical importance for patient care and genetic counseling. This study evaluated the impact of the number of R92Q mutations in two unique unrelated families. Two patients with undefined but clear autoinflammatory symptoms were referred for genetic diagnosis. Blood samples were collected from the available family members to screen autoinflammatory genes and assess key steps of the TNFR1-mediated signaling pathway using flow cytometry and ex vivo culture. R92Q homozygosity was demonstrated for the two probands. In family 1, the segregation analysis revealed TRAPS-like symptoms in all carriers, with a more severe presentation in the proband, whereas in family 2, the heterozygous parents were totally asymptomatic, suggesting recessive transmission. Functional studies revealed a nonclassical pathogenesis of TRAPS in the two probands and suggested a compensatory mechanism without clear dose effect. We observed for the first time a possible clinical dose effect of R92Q. This work highlights the importance of familial studies to reconcile the contradictory reports published on the pathogenicity of this variant.

  7. Q192R polymorphism in the PON1 gene and familial hypercholesterolemia in a Saudi population.

    PubMed

    Alharbi, Khalid Khalaf; Alnbaheen, May Salem; Alharbi, Fawiziah Khalaf; Hasanato, Rana M; Khan, Imran Ali

    2017-01-01

    Familial hypercholesterolemia (FH) is an autosomal dominant condition characterized by abnormal levels of low-density lipoprotein (LDL) in the blood. FH is a risk factor for atherosclerosis and cardiovascular disease. The relationship between the paraoxonase 1 (PON1) gene, atherosclerosis and coronary artery disease has not been studied in Saudi patients. To investigate the genetic associations of the Q192R polymorphism in the PON1 gene with FH in Saudi patients. Case-control study. Tertiary care center, Riyadh. Two hundred Saudi patients were enrolled in this study, including 100 patients with FH and 100 healthy controls, during the period from January 2012 to March 2013. Serum was separated from coagulated blood (3 mL) and used for analysis of lipid profiles. Genomic DNA was isolated from anticoagulant-treated blood (2 mL). Genotyping for the Q192R polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism analysis, followed by 3% agarose gel electrophoresis. The strength of association between the Q192R polymorphism and FH in the Saudi population. We confirmed that QR versus QQ (odds ratio [OR]: 1.55; 95% confidence interval [CI]: 1.05-3.43; P=.03), QR+RR versus QQ (OR: 1.98; 95% CI: 1.13-3.49; P=.01), and R versus Q (OR: 1.68; 95% CI: 1.09- 2.59; P=.01) in the Q192R polymorphism were associated with FH in the Saudi population. In conclusion, the Q192R polymorphism in the PON1 gene is associated with FH in the Saudi population. Our results confirmed that the R allele, QR, and dominant model genotypes were associated with FH. Only a single variant (Q192R) was analyzed, and the medical and family histories of the patients were not known.

  8. Proximal 15q familial euchromatic variant and PWS/AS critical region duplication in the same patient: a cytogenetic pitfall.

    PubMed

    Carelle-Calmels, Nadège; Girard-Lemaire, Françoise; Guérin, Eric; Bieth, Eric; Rudolf, Gabrielle; Biancalana, Valérie; Pecheur, Hélène; Demil, Houria; Schneider, Thierry; de Saint-Martin, Anne; Caron, Olivier; Legrain, Michèle; Gaston, Valérie; Flori, Elisabeth

    2008-01-01

    Cytogenetically detectable elongation of the 15q proximal region can be associated with Prader-Willi/Angelman critical region interstitial duplications or with inherited juxtacentromeric euchromatic variants. The first category has been reported in association with developmental delay and autistic disorders. These pathogenic recurrent duplications are more frequently of maternal origin and originate from unequal meiotic crossovers between chromosome 15 low-copy repeats. 15q juxtacentromeric euchromatic variants reflect polymorphic copy number variations of segments containing pseudogenes and usually segregate without apparent phenotypic consequence. Pathogenic relevant 15q11-q13 duplications are not distinguishable from the innocuous euchromatic variants with conventional cytogenetic methods. We report cytogenetic and molecular studies of a patient with hypotonia, developmental delay and epilepsy, carrying, on the same chromosome 15, both a de novo 15q11-q13 interstitial duplication and an inherited 15q juxtacentromeric amplification from maternal origin. The duplication, initially suspected by fluorescent in situ hybridization (FISH), has been confirmed by molecular studies. The 15q juxtacentromeric region amplification, which segregates in the family for at least three generations, has been confirmed by FISH using BAC probes overlapping the NF1 and GABRA5 pseudogenes. This report emphasizes the importance to distinguish proximal 15q polymorphic variants from clinically significant duplications. In any patient with inherited 15q proximal variant but unexplained developmental delay suggesting 15q11-q13 pathology, a pathogenic rearrangement has to be searched with adapted strategies, in order to detect deletions as well as duplications of this region.

  9. Search for copy number variants in chromosomes 15q11-q13 and 22q11.2 in obsessive compulsive disorder

    PubMed Central

    2010-01-01

    Background Obsessive-compulsive disorder (OCD) is a clinically and etiologically heterogeneous syndrome. The high frequency of obsessive-compulsive symptoms reported in subjects with the 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) or Prader-Willi syndrome (15q11-13 deletion of the paternally derived chromosome), suggests that gene dosage effects in these chromosomal regions could increase risk for OCD. Therefore, the aim of this study was to search for microrearrangements in these two regions in OCD patients. Methods We screened the 15q11-13 and 22q11.2 chromosomal regions for genomic imbalances in 236 patients with OCD using multiplex ligation-dependent probe amplification (MLPA). Results No deletions or duplications involving 15q11-13 or 22q11.2 were identified in our patients. Conclusions Our results suggest that deletions/duplications of chromosomes 15q11-13 and 22q11.2 are rare in OCD. Despite the negative findings in these two regions, the search for copy number variants in OCD using genome-wide array-based methods is a highly promising approach to identify genes of etiologic importance in the development of OCD. PMID:20565924

  10. Search for copy number variants in chromosomes 15q11-q13 and 22q11.2 in obsessive compulsive disorder.

    PubMed

    Delorme, Richard; Moreno-De-Luca, Daniel; Gennetier, Aurélie; Maier, Wolfgang; Chaste, Pauline; Mössner, Rainald; Grabe, Hans Jörgen; Ruhrmann, Stephan; Falkai, Peter; Mouren, Marie-Christine; Leboyer, Marion; Wagner, Michael; Betancur, Catalina

    2010-06-21

    Obsessive-compulsive disorder (OCD) is a clinically and etiologically heterogeneous syndrome. The high frequency of obsessive-compulsive symptoms reported in subjects with the 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) or Prader-Willi syndrome (15q11-13 deletion of the paternally derived chromosome), suggests that gene dosage effects in these chromosomal regions could increase risk for OCD. Therefore, the aim of this study was to search for microrearrangements in these two regions in OCD patients. We screened the 15q11-13 and 22q11.2 chromosomal regions for genomic imbalances in 236 patients with OCD using multiplex ligation-dependent probe amplification (MLPA). No deletions or duplications involving 15q11-13 or 22q11.2 were identified in our patients. Our results suggest that deletions/duplications of chromosomes 15q11-13 and 22q11.2 are rare in OCD. Despite the negative findings in these two regions, the search for copy number variants in OCD using genome-wide array-based methods is a highly promising approach to identify genes of etiologic importance in the development of OCD.

  11. Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1–q35.3 susceptibility locus identified by whole-exome sequencing

    PubMed Central

    Karolak, Justyna A; Gambin, Tomasz; Pitarque, Jose A; Molinari, Andrea; Jhangiani, Shalini; Stankiewicz, Pawel; Lupski, James R; Gajecka, Marzena

    2017-01-01

    Keratoconus (KTCN) is a protrusion and thinning of the cornea, resulting in impairment of visual function. The extreme genetic heterogeneity makes it difficult to discover factors unambiguously influencing the KTCN phenotype. In this study, we used whole-exome sequencing (WES) and Sanger sequencing to reduce the number of candidate genes at the 5q31.1–q35.3 locus and to prioritize other potentially relevant variants in an Ecuadorian family with KTCN. We applied WES in two affected KTCN individuals from the Ecuadorian family that showed a suggestive linkage between the KTCN phenotype and the 5q31.1–q35.3 locus. Putative variants identified by WES were further evaluated in this family using Sanger sequencing. Exome capture discovered a total of 173 rare (minor allele frequency <0.001 in control population) nonsynonymous variants in both affected individuals. Among them, 16 SNVs were selected for further evaluation. Segregation analysis revealed that variants c.475T>G in SKP1, c.671G>A in PROB1, and c.527G>A in IL17B in the 5q31.1–q35.3 linkage region, and c.850G>A in HKDC1 in the 10q22 locus completely segregated with the phenotype in the studied KTCN family. We demonstrate that a combination of various techniques significantly narrowed the studied genomic region and reduced the list of the putative exonic variants. Moreover, since this locus overlapped two other chromosomal regions previously recognized in distinct KTCN studies, our findings suggest that this 5q31.1–q35.3 locus might be linked with KTCN. PMID:27703147

  12. Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk

    PubMed Central

    Rafnar, Thorunn; Sulem, Patrick; Besenbacher, Soren; Gudbjartsson, Daniel F.; Zanon, Carlo; Gudmundsson, Julius; Stacey, Simon N.; Kostic, Jelena P.; Thorgeirsson, Thorgeir E.; Thorleifsson, Gudmar; Bjarnason, Hjordis; Skuladottir, Halla; Gudbjartsson, Tomas; Isaksson, Helgi J.; Isla, Dolores; Murillo, Laura; García-Prats, Maria D.; Panadero, Angeles; Aben, Katja K.H.; Vermeulen, Sita H.; van der Heijden, Henricus F.M.; Feser, William; Miller, York E.; Bunn, Paul A.; Kong, Augustine; Wolf, Holly J.; Franklin, Wilbur A.; Mayordomo, Jose I; Kiemeney, Lambertus A.; Jonsson, Steinn; Thorsteinsdottir, Unnur; Stefansson, Kari

    2010-01-01

    Genome-wide association studies (GWAS) have identified three genomic regions, at 15q24-25.1, 5p15.33 and 6p21.33, which associate with risk of lung cancer. Large meta-analyses of GWA data have failed to find additional associations of genome-wide significance. In this study, we sought to confirm 7 variants with suggestive association to lung cancer (P<10−5) in a recently published meta-analysis. In a GWA dataset of 1,447 lung cancer cases and 36,256 controls in Iceland, three correlated variants on 15q15.2 (rs504417, rs11853991 and rs748404) showed a significant association with lung cancer whereas rs4254535 on 2p14, rs1530057 on 3p24.1, rs6438347 on 3q13.31 and rs1926203 on 10q23.31 did not. The most significant variant, rs748404, was genotyped in additional 1,299 lung cancer cases and 4,102 controls from the Netherlands, Spain and the USA and the results combined with published GWAS data. In this analysis, the T allele of rs748404 reached genome-wide significance (OR=1.15, P=1.1×10−9). Another variant at the same locus, rs12050604, showed association with lung cancer (OR=1.09, 3.6×10−6) and remained significant after adjustment for rs748404 and vice versa. rs748404 is located 140 kb centromeric of the TP53BP1 gene that has been implicated in lung cancer risk. Two fully correlated, non-synonymous coding variants in TP53BP1, rs2602141 (Q1136K) and rs560191 (E353D), showed association with lung cancer in our sample set; however, this association did not remain significant after adjustment for rs748404. Our data show that one or more lung cancer risk variants of genome-wide significance and distinct from the coding variants in TP53BP1 are located at 15q15.2. PMID:21303977

  13. Variants on 8q24 and prostate cancer risk in Chinese population: a meta-analysis.

    PubMed

    Ren, Xiao-Qiang; Zhang, Jian-Guo; Xin, Shi-Yong; Cheng, Tao; Li, Liang; Ren, Wei-Hua

    2015-01-01

    Previous studies have identified 8q24 as an important region to prostate cancer (PCa) susceptibility. The aim of this study was to investigate the role of six genetic variants on 8q24 (rs1447295, A; rs6983267, G; rs6983561, C; rs7837688, T; rs10090154, T and rs16901979, A) on PCa risk in Chinese population. Online electronic databases were searched to retrieve related articles concerning the association between 8q24 variants and PCa risk in men of Chinese population published between 2000 and 2014. Odds ratio (ORs) with its 95% correspondence interval (CI) were employed to assess the strength of association. Total eleven case-control studies were screened out, including 2624 PCa patients and 2438 healthy controls. Our results showed that three risk alleles of rs1447295 A (OR=1.35, 95% CI=1.19-1.53, P<0.00001), rs6983561 C (C vs. A: OR=1.41, 95% CI=1.21-1.63, P<0.00001) and rs10090154 T (T vs. C: OR=1.48, 95% CI=1.22-1.80, P<0.00001) on8q24 were significantly associated with PCa risk in Chinese population. Furthermore, genotypes of rs1447295, AA+AC; rs6983561, CC+AC and CC; rs10090154, TT+TC; and rs16901979, AA were associated with PCa as well (P<0.01). No association was found between rs6983267, rs7837688 and PCa risk. In conclusions, variants including rs1447295, rs6983561, rs10090154 and rs16901979 on 8q24 might be associated with PCa risk in Chinese population, indicating these four variations may contribute risk to this disease. This meta-analysis was the first study to assess the role of 8q24 variants on PCa risk in Chinese population.

  14. Decreased cyclooxygenase inhibition by aspirin in polymorphic variants of human prostaglandin H synthase-1

    PubMed Central

    Liu, Wen; Poole, Elizabeth M.; Ulrich, Cornelia M.; Kulmacz, Richard J.

    2012-01-01

    Objectives Aspirin, a major anti-platelet and cancer preventing drug, irreversibly blocks the cyclooxygenase activity of prostaglandin H synthase-1 (PGHS-1). Considerable differences in aspirin effectiveness are observed between individuals, and some of this variability may be due to PGHS-1 protein variants. Our overall aim is to determine which, if any, of the known variants in the mature PGHS-1 protein lead to functional alterations in cyclooxygenase catalysis or inhibition by aspirin. The present study targeted four PGHS-1 variants: R53H, R108Q, L237M and V481I. Methods Wildtype human PGHS-1 and the four polymorphic variants were expressed as histidine-tagged, homodimeric proteins in insect cells using baculovirus vectors, solubilized with detergent, and purified by affinity chromatography. The purified proteins were characterized in vitro to evaluate cyclooxygenase and peroxidase catalytic parameters and the kinetics of cyclooxygenase inhibition by aspirin and NS-398. Results Compared to wildtype, several variants exhibited a higher COX/POX ratio (up to 1.5-fold, for R108Q), an elevated arachidonate Km (up to 1.9-fold, for R108Q), and/or a lower aspirin reactivity (up to 60% less, for R108Q). The decreased aspirin reactivity in R108Q reflected both a 70% increase in the Ki for aspirin and a 30% decrease in the rate constant for acetyl group transfer to the protein. Computational modeling of the brief aspirin pulses experienced by PGHS-1 in circulating platelets during daily aspirin dosing predicted that the 60% lower aspirin reactivity in R108Q gives a 15-fold increase in surviving cyclooxygenase activity; smaller, ~2-fold increases in surviving cyclooxygenase activity were predicted for L237M and V481I. NS-398 competitively inhibited cyclooxygenase catalysis of the wildtype (Ki = 6 μM) and inhibited cyclooxygenase inactivation by 1.0 mM aspirin in both wildtype (IC50 = 0.8 μM) and R108Q (IC50 = 2.1 μM). Conclusions Of the four PGHS-1 variants examined, R108

  15. Functional consequences of a novel variant of PCSK1.

    PubMed

    Pickett, Lindsay A; Yourshaw, Michael; Albornoz, Valeria; Chen, Zijun; Solorzano-Vargas, R Sergio; Nelson, Stanley F; Martín, Martín G; Lindberg, Iris

    2013-01-01

    Common single nucleotide polymorphisms (SNPs) in proprotein convertase subtilisin/kexin type 1 with modest effects on PC1/3 in vitro have been associated with obesity in five genome-wide association studies and with diabetes in one genome-wide association study. We here present a novel SNP and compare its biosynthesis, secretion and catalytic activity to wild-type enzyme and to SNPs that have been linked to obesity. A novel PC1/3 variant introducing an Arg to Gln amino acid substitution at residue 80 (within the secondary cleavage site of the prodomain) (rs1799904) was studied. This novel variant was selected for analysis from the 1000 Genomes sequencing project based on its predicted deleterious effect on enzyme function and its comparatively more frequent allele frequency. The actual existence of the R80Q (rs1799904) variant was verified by Sanger sequencing. The effects of this novel variant on the biosynthesis, secretion, and catalytic activity were determined; the previously-described obesity risk SNPs N221D (rs6232), Q665E/S690T (rs6234/rs6235), and the Q665E and S690T SNPs (analyzed separately) were included for comparative purposes. The novel R80Q (rs1799904) variant described in this study resulted in significantly detrimental effects on both the maturation and in vitro catalytic activity of PC1/3. Our findings that this novel R80Q (rs1799904) variant both exhibits adverse effects on PC1/3 activity and is prevalent in the population suggests that further biochemical and genetic analysis to assess its contribution to the risk of metabolic disease within the general population is warranted.

  16. R102Q mutation shifts the salt-bridge network and reduces the structural flexibility of human neuronal calcium sensor-1 protein.

    PubMed

    Zhu, Yuzhen; Wu, Ying; Luo, Yin; Zou, Yu; Ma, Buyong; Zhang, Qingwen

    2014-11-20

    Neuronal calcium sensor-1 (NCS-1) protein has a variety of different neuronal functions and interacts with multiple binding partners mostly through a large solvent-exposed hydrophobic crevice (HC). A single R102Q mutation in human NCS-1 protein was demonstrated to be associated with autism disease. Solution NMR study reported that this R102Q mutant had long-range chemical shift effects on the HC and the C-terminal tail (L3). To understand the influence of the R102Q mutation on the HC and L3 of NCS-1, we have investigated the conformational dynamics and the structural flexibility of wild type (WT) NCS-1 and its R102Q mutant by conducting extensive all-atom molecular dynamics (MD) simulations. On the basis of six independent 450 ns MD simulations, we have found that the R102Q mutation in NCS-1 protein (1) dramatically reduces the flexibility of loops L2 and L3, (2) facilitates L3 in a more extended state to occupy the hydrophobic crevice to a larger extent, (3) significantly affects the intersegment salt bridges, and (4) changes the subspace of the free energy landscape of NCS-1 protein. Analysis of the salt bridge network in both WT and the R102Q variant demonstrates that the R102Q-mutation-induced salt bridge alternations play a critical role on the reduced flexibility of L2 and L3. These results reveal the important role of salt bridges on the structural properties of NCS-1 protein and that R102Q mutation disables the dynamic relocation of C-terminus, which may block the binding of NCS-1 protein to its receptors. This study may provide structural insights into the autistic spectrum disorder associated with R102Q mutation.

  17. R248Q mutation--Beyond p53-DNA binding.

    PubMed

    Ng, Jeremy W K; Lama, Dilraj; Lukman, Suryani; Lane, David P; Verma, Chandra S; Sim, Adelene Y L

    2015-12-01

    R248 in the DNA binding domain (DBD) of p53 interacts directly with the minor groove of DNA. Earlier nuclear magnetic resonance (NMR) studies indicated that the R248Q mutation resulted in conformation changes in parts of DBD far from the mutation site. However, how information propagates from the mutation site to the rest of the DBD is still not well understood. We performed a series of all-atom molecular dynamics (MD) simulations to dissect sterics and charge effects of R248 on p53-DBD conformation: (i) wild-type p53 DBD; (ii) p53 DBD with an electrically neutral arginine side-chain; (iii) p53 DBD with R248A; (iv) p53 DBD with R248W; and (v) p53 DBD with R248Q. Our results agree well with experimental observations of global conformational changes induced by the R248Q mutation. Our simulations suggest that both charge- and sterics are important in the dynamics of the loop (L3) where the mutation resides. We show that helix 2 (H2) dynamics is altered as a result of a change in the hydrogen bonding partner of D281. In turn, neighboring L1 dynamics is altered: in mutants, L1 predominantly adopts the recessed conformation and is unable to interact with the major groove of DNA. We focused our attention the R248Q mutant that is commonly found in a wide range of cancer and observed changes at the zinc-binding pocket that might account for the dominant negative effects of R248Q. Furthermore, in our simulations, the S6/S7 turn was more frequently solvent exposed in R248Q, suggesting that there is a greater tendency of R248Q to partially unfold and possibly lead to an increased aggregation propensity. Finally, based on the observations made in our simulations, we propose strategies for the rescue of R248Q mutants. © 2015 Wiley Periodicals, Inc.

  18. 40 CFR Appendixes Q-R to Part 51 - [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 2 2013-07-01 2013-07-01 false [Reserved] Q Appendixes Q-R to Part 51 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS REQUIREMENTS FOR PREPARATION, ADOPTION, AND SUBMITTAL OF IMPLEMENTATION PLANS Appendixes Q-R to Part 51 [Reserved] ...

  19. 40 CFR Appendixes Q-R to Part 51 - [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 2 2014-07-01 2014-07-01 false [Reserved] Q Appendixes Q-R to Part 51 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS REQUIREMENTS FOR PREPARATION, ADOPTION, AND SUBMITTAL OF IMPLEMENTATION PLANS Appendixes Q-R to Part 51 [Reserved] ...

  20. 40 CFR Appendixes Q-R to Part 51 - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 2 2010-07-01 2010-07-01 false [Reserved] Q Appendixes Q-R to Part 51 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS REQUIREMENTS FOR PREPARATION, ADOPTION, AND SUBMITTAL OF IMPLEMENTATION PLANS Appendixes Q-R to Part 51 [Reserved] ...

  1. 40 CFR Appendixes Q-R to Part 51 - [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 2 2011-07-01 2011-07-01 false [Reserved] Q Appendixes Q-R to Part 51 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS REQUIREMENTS FOR PREPARATION, ADOPTION, AND SUBMITTAL OF IMPLEMENTATION PLANS Appendixes Q-R to Part 51 [Reserved] ...

  2. 40 CFR Appendixes Q-R to Part 51 - [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 2 2012-07-01 2012-07-01 false [Reserved] Q Appendixes Q-R to Part 51 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS REQUIREMENTS FOR PREPARATION, ADOPTION, AND SUBMITTAL OF IMPLEMENTATION PLANS Appendixes Q-R to Part 51 [Reserved] ...

  3. Functional Consequences of a Novel Variant of PCSK1

    PubMed Central

    Pickett, Lindsay A.; Yourshaw, Michael; Albornoz, Valeria; Chen, Zijun; Solorzano-Vargas, R. Sergio; Nelson, Stanley F.; Martín, Martín G.; Lindberg, Iris

    2013-01-01

    Background Common single nucleotide polymorphisms (SNPs) in proprotein convertase subtilisin/kexin type 1 with modest effects on PC1/3 in vitro have been associated with obesity in five genome-wide association studies and with diabetes in one genome-wide association study. We here present a novel SNP and compare its biosynthesis, secretion and catalytic activity to wild-type enzyme and to SNPs that have been linked to obesity. Methodology/Principal Findings A novel PC1/3 variant introducing an Arg to Gln amino acid substitution at residue 80 (within the secondary cleavage site of the prodomain) (rs1799904) was studied. This novel variant was selected for analysis from the 1000 Genomes sequencing project based on its predicted deleterious effect on enzyme function and its comparatively more frequent allele frequency. The actual existence of the R80Q (rs1799904) variant was verified by Sanger sequencing. The effects of this novel variant on the biosynthesis, secretion, and catalytic activity were determined; the previously-described obesity risk SNPs N221D (rs6232), Q665E/S690T (rs6234/rs6235), and the Q665E and S690T SNPs (analyzed separately) were included for comparative purposes. The novel R80Q (rs1799904) variant described in this study resulted in significantly detrimental effects on both the maturation and in vitro catalytic activity of PC1/3. Conclusion/Significance Our findings that this novel R80Q (rs1799904) variant both exhibits adverse effects on PC1/3 activity and is prevalent in the population suggests that further biochemical and genetic analysis to assess its contribution to the risk of metabolic disease within the general population is warranted. PMID:23383060

  4. Novel pathways revealed in P. fluorescens Q2-87 and Q8r1-96

    USDA-ARS?s Scientific Manuscript database

    Pseudomonas fluorescens Q2-87 and Q8r1-96, both from a take-all decline field in Quincy, Washington, U.S.A., are almost indistinguishable in vitro, but only strain Q8r1-96 exhibits the “premier” phenotype distinguished by highly aggressive wheat root colonizing ability essential for the natural dise...

  5. Variants of glycoside hydrolases

    DOEpatents

    Teter, Sarah; Ward, Connie; Cherry, Joel; Jones, Aubrey; Harris, Paul; Yi, Jung

    2013-02-26

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  6. Variants of glycoside hydrolases

    DOEpatents

    Teter, Sarah [Davis, CA; Ward, Connie [Hamilton, MT; Cherry, Joel [Davis, CA; Jones, Aubrey [Davis, CA; Harris, Paul [Carnation, WA; Yi, Jung [Sacramento, CA

    2011-04-26

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  7. Variants of glycoside hydrolases

    DOEpatents

    Teter, Sarah; Ward, Connie; Cherry, Joel; Jones, Aubrey; Harris, Paul; Yi, Jung

    2017-07-11

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  8. Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer

    PubMed Central

    Zheng, Wei; Michailidou, Kyriaki; Ghoussaini, Maya; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Lush, Michael; Milne, Roger L.; Shu, Xiao-Ou; Beesley, Jonathan; Kar, Siddhartha; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Zhao, Zhiguo; Guo, Xingyi; Benitez, Javier; Beeghly-Fadiel, Alicia; Blot, William; Bogdanova, Natalia V.; Bojesen, Stig E.; Brauch, Hiltrud; Brenner, Hermann; Brinton, Louise; Broeks, Annegien; Brüning, Thomas; Burwinkel, Barbara; Cai, Hui; Canisius, Sander; Chang-Claude, Jenny; Choi, Ji-Yeob; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Devilee, Peter; Droit, Arnaud; Dork, Thilo; Fasching, Peter A.; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gaborieau, Valerie; García-Closas, Montserrat; Giles, Graham G.; Guenel, Pascal; Haiman, Christopher A.; Hamann, Ute; Hartman, Mikael; Miao, Hui; Hollestelle, Antoinette; Hopper, John L.; Hsiung, Chia-Ni; Ito, Hidemi; Jakubowska, Anna; Johnson, Nichola; Torres, Diana; Kabisch, Maria; Kang, Daehee; Khan, Sofia; Knight, Julia A.; Kosma, Veli-Matti; Lambrechts, Diether; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Le Marchand, Loic; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; McLean, Catriona; Meindl, Alfons; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Nord, Silje; Børresen-Dale, Anne-Lise; Olson, Janet E.; Orr, Nick; van den Ouweland, Ans M.W.; Peterlongo, Paolo; Putti, Thomas Choudary; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Shen, Chen-Yang; Hou, Ming-Feng; Shrubsole, Matha J; Southey, Melissa C.; Swerdlow, Anthony; Teo, Soo Hwang; Thienpont, Bernard; Toland, Amanda E.; Tollenaar, Robert A.E.M.; Tomlinson, Ian; Truong, Therese; Tseng, Chiu-chen; Wen, Wanqing; Winqvist, Robert; Wu, Anna H.; Yip, Cheng Har; Zamora, Pilar M.; Zheng, Ying; Floris, Giuseppe; Cheng, Ching-Yu; Hooning, Maartje J.; Martens, John W.M.; Seynaeve, Caroline; Kristensen, Vessela N.; Hall, Per; Pharoah, Paul D.P.; Simard, Jacques; Chenevix-Trench, Georgia; Dunning, Alison M.; Antoniou, Antonis C.; Easton, Douglas F.; Cai, Qiuyin; Long, Jirong

    2016-01-01

    Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. We conducted a fine-mapping study across 2.06 Mb (chr8:127,561,724 −129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium. We found three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional P = 5.8 × 10−6), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional P = 1.1 × 10−6), and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional P = 1.1 × 10−4). Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas, and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r2 = 0.77), were putatively functional variants for two of the five independent association signals. Our results highlight multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry. PMID:27087578

  9. Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer.

    PubMed

    Shi, Jiajun; Zhang, Yanfeng; Zheng, Wei; Michailidou, Kyriaki; Ghoussaini, Maya; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Lush, Michael; Milne, Roger L; Shu, Xiao-Ou; Beesley, Jonathan; Kar, Siddhartha; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W; Zhao, Zhiguo; Guo, Xingyi; Benitez, Javier; Beeghly-Fadiel, Alicia; Blot, William; Bogdanova, Natalia V; Bojesen, Stig E; Brauch, Hiltrud; Brenner, Hermann; Brinton, Louise; Broeks, Annegien; Brüning, Thomas; Burwinkel, Barbara; Cai, Hui; Canisius, Sander; Chang-Claude, Jenny; Choi, Ji-Yeob; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Darabi, Hatef; Devilee, Peter; Droit, Arnaud; Dork, Thilo; Fasching, Peter A; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gaborieau, Valerie; García-Closas, Montserrat; Giles, Graham G; Guenel, Pascal; Haiman, Christopher A; Hamann, Ute; Hartman, Mikael; Miao, Hui; Hollestelle, Antoinette; Hopper, John L; Hsiung, Chia-Ni; Ito, Hidemi; Jakubowska, Anna; Johnson, Nichola; Torres, Diana; Kabisch, Maria; Kang, Daehee; Khan, Sofia; Knight, Julia A; Kosma, Veli-Matti; Lambrechts, Diether; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Le Marchand, Loic; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; McLean, Catriona; Meindl, Alfons; Muir, Kenneth; Neuhausen, Susan L; Nevanlinna, Heli; Nord, Silje; Børresen-Dale, Anne-Lise; Olson, Janet E; Orr, Nick; van den Ouweland, Ans M W; Peterlongo, Paolo; Putti, Thomas Choudary; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Marjanka K; Schmutzler, Rita K; Shen, Chen-Yang; Hou, Ming-Feng; Shrubsole, Matha J; Southey, Melissa C; Swerdlow, Anthony; Teo, Soo Hwang; Thienpont, Bernard; Toland, Amanda E; Tollenaar, Robert A E M; Tomlinson, Ian; Truong, Therese; Tseng, Chiu-Chen; Wen, Wanqing; Winqvist, Robert; Wu, Anna H; Yip, Cheng Har; Zamora, Pilar M; Zheng, Ying; Floris, Giuseppe; Cheng, Ching-Yu; Hooning, Maartje J; Martens, John W M; Seynaeve, Caroline; Kristensen, Vessela N; Hall, Per; Pharoah, Paul D P; Simard, Jacques; Chenevix-Trench, Georgia; Dunning, Alison M; Antoniou, Antonis C; Easton, Douglas F; Cai, Qiuyin; Long, Jirong

    2016-09-15

    Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2)  = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry. © 2016 UICC.

  10. Factor VII R353Q genetic polymorphism is associated with altered warfarin sensitivity among CYP2C9 *1/*1 carriers.

    PubMed

    Mlynarsky, Liat; Bejarano-Achache, Idit; Muszkat, Mordechai; Caraco, Yoseph

    2012-05-01

    Warfarin responsiveness is characterized by marked interindividual variability. A major portion of this variability is attributed to CYP2C9 and VKORC1 polymorphisms, but almost 50% is still unaccounted for. This paper reports the first prospective study on the association between factor VII R353Q polymorphism and warfarin responsiveness during induction. Genotyping for factor VII R353Q and 323D/I polymorphisms was performed in a cohort consisting of 374 patients (198 CYP2C9*1/*1) treated with warfarin who were prospectively followed from warfarin initiation. Compared with *1/*1-R/R and *1/*1-R/Q genotype carriers, *1/*1-Q/Q homozygotes achieved higher International Normalized Ratio (INR) values while consuming lower warfarin doses. The greater sensitivity was illustrated by 82.1% higher Warfarin Sensitivity Index During Induction (WSIDI) (0.14 ± 0.11 vs. 0.08 ± 0.50 mg⁻¹ Mann-Whitney, P = 0.043). Multiple regression analysis consisting of both genetic and nongenetic factors explained 26% of WSIDI variability, with R353Q genetic polymorphism having a modest yet significant effect and accounting for 1.7% of the overall variability. Moreover, the incidence of overanticoagulation (i.e., INR > 4) was 6.94-fold higher among *1/*1-Q/Q vs. *1/*1-R/R&R/Q carriers during warfarin induction (Pearson chi-square, P = 0.005). These findings were not accounted for by a chance difference in the distribution of VKORC1 genotypes. Analysis of these parameters among the entire cohort, including CYP2C9*2 and CYP2C9*3 variant allele carriers, did not reach statistical significance. Warfarin responsiveness during induction was unrelated to factor VII 323D/I genetic polymorphism. The response to warfarin during induction is influenced by factor VII R353Q polymorphism. The prospective use of this polymorphism, along with CYP2C9 and VKORC1, may enhance the accuracy of warfarin loading. However, the impact of R353Q polymorphism on overall warfarin response is subtle, and it is therefore

  11. A Novel Four-Way Complex Variant Translocation Involving Chromosome 46,XY,t(4;9;19;22)(q25:q34;p13.3;q11.2) in a Chronic Myeloid Leukemia Patient

    PubMed Central

    Asif, Muhammad; Jamal, Mohammad Sarwar; Khan, Abdul Rehman; Naseer, Muhammad Imran; Hussain, Abrar; Choudhry, Hani; Malik, Arif; Khan, Shahida Aziz; Mahmoud, Maged Mostafa; Ali, Ashraf; Iram, Saima; Kamran, Kashif; Iqbal, Asim; Abduljaleel, Zainularifeen; Pushparaj, Peter Natesan; Rasool, Mahmood

    2016-01-01

    Philadelphia (Ph) chromosome (9;22)(q34;q11) is well established in more than 90% of chronic myeloid leukemia (CML) patients, and the remaining 5–8% of CML patients show variant and complex translocations, with the involvement of third, fourth, or fifth chromosome other than 9;22. However, in very rare cases, the fourth chromosome is involved. Here, we found a novel case of four-way Ph+ chromosome translocation involving 46,XY,t(4;9;19;22)(q25:q34;p13.3;q11.2) with CML in the chronic phase. Complete blood cell count of the CML patient was carried out to obtain total leukocytes count, hemoglobin, and platelets. Fluorescence in situ hybridization technique was used for the identification of BCR–ABL fusion gene, and cytogenetic test for the confirmation of Ph (9;22)(q34;q11) and the mechanism of variant translocation in the bone marrow. The patient is successfully treated with a dose of 400 mg/day imatinib mesylate (Gleevec). We observed a significant decrease in white blood cell count of 11.7 × 109/L after 48-month follow-up. Patient started feeling better generally. There was a reduction in the swelling of the body, fatigue, and anxiety. PMID:27303656

  12. Impaired dacarbazine activation and 7-ethoxyresorufin deethylation in vitro by polymorphic variants of CYP1A1 and CYP1A2: implications for cancer therapy.

    PubMed

    Lewis, Benjamin C; Korprasertthaworn, Porntipa; Miners, John O

    2016-10-01

    To extend our understanding of how interindividual variability mediates the efficacy of cancer treatment. The kinetics of dacarbazine (DTIC) N-demethylation by the most frequent polymorphic variants of CYP1A1 (T461N, I462V) and CYP1A2 (F186L, D348N, I386F, R431W, R456H) were characterized, along with kinetic parameters for the O-deethylation of the prototypic CYP1A substrate 7-ethoxyresorufin, using recombinant protein expression and high-performance liquid chromatographic techniques. A reduction of ∼30% in the catalytic efficiencies (measured as in-vitro intrinsic clearance, CLint) was observed for DTIC N-demethylation by the two CYP1A1 variants relative to wild type. Although a modest increase in the CLint value for DTIC N-demethylation was observed for the CYP1A2 D348N variant relative to the wild type, the CLint for the F186L variant was reduced and the I386F, R431W, and R456H variants all showed loss of catalytic function. Comparison of the kinetic data for DTIC N-demethylation and 7-ethoxyresorufin O-deethylation indicated that alterations in the kinetic parameters (Km, Vmax, CLint) observed with each of the CYP1A1 and CYP1A2 polymorphic variants were substrate dependent. These data indicate that cancer patients treated with DTIC who possess any of the CYP1A1-T461N and I462V variants or the CYP1A2-F186L, D348N, I386F, R431W, and R456H variants are likely to have decreased prodrug activation, and hence may respond less favorably to DTIC treatment compared with individuals with wild-type CYP1A alleles.

  13. Photocopy of floor plan of the C.B. & Q. R.R ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Photocopy of floor plan of the C.B. & Q. R.R roundhouse and locomotive shops. June 1980. - Chicago, Burlington & Quincy Railroad, Roundhouse & Shops, Broadway & Spring Streets, Aurora, Kane County, IL

  14. Functional Invalidation of Putative Sudden Infant Death Syndrome-Associated Variants in the KCNH2-Encoded Kv11.1 Channel.

    PubMed

    Smith, Jennifer L; Tester, David J; Hall, Allison R; Burgess, Don E; Hsu, Chun-Chun; Claude Elayi, Samy; Anderson, Corey L; January, Craig T; Luo, Jonathan Z; Hartzel, Dustin N; Mirshahi, Uyenlinh L; Murray, Michael F; Mirshahi, Tooraj; Ackerman, Michael J; Delisle, Brian P

    2018-05-01

    Heterologous functional validation studies of putative long-QT syndrome subtype 2-associated variants clarify their pathological potential and identify disease mechanism(s) for most variants studied. The purpose of this study is to clarify the pathological potential for rare nonsynonymous KCNH2 variants seemingly associated with sudden infant death syndrome. Genetic testing of 292 sudden infant death syndrome cases identified 9 KCNH2 variants: E90K, R181Q, A190T, G294V, R791W, P967L, R1005W, R1047L, and Q1068R. Previous studies show R181Q-, P967L-, and R1047L-Kv11.1 channels function similar to wild-type Kv11.1 channels, whereas Q1068R-Kv11.1 channels accelerate inactivation gating. We studied the biochemical and biophysical properties for E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels expressed in human embryonic kidney 293 cells; examined the electronic health records of patients who were genotype positive for the sudden infant death syndrome-linked KCNH2 variants; and simulated their functional impact using computational models of the human ventricular action potential. Western blot and voltage-clamping analyses of cells expressing E90K-, G294V-, R791W-, and R1005W-Kv11.1 channels demonstrated these variants express and generate peak Kv11.1 current levels similar to cells expressing wild-type-Kv11.1 channels, but R791W- and R1005W-Kv11.1 channels accelerated deactivation and activation gating, respectively. Electronic health records of patients with the sudden infant death syndrome-linked KCNH2 variants showed that the patients had median heart rate-corrected QT intervals <480 ms and none had been diagnosed with long-QT syndrome or experienced cardiac arrest. Simulating the impact of dysfunctional gating variants predicted that they have little impact on ventricular action potential duration. We conclude that these rare Kv11.1 missense variants are not long-QT syndrome subtype 2-causative variants and therefore do not represent the pathogenic substrate for

  15. ABCC6 Gene Analysis in 20 Japanese Patients with Angioid Streaks Revealing Four Frequent and Two Novel Variants and Pseudodominant Inheritance

    PubMed Central

    Negishi, Yuya; Mizobuchi, Kei; Urashima, Mitsuyoshi; Nakano, Tadashi

    2017-01-01

    Purpose To report the spectrum of ABCC6 variants in Japanese patients with angioid streaks (AS). Patients and Methods This was a single-center cohort study. The medical records of 20 patients with AS from 18 unrelated Japanese families were retrospectively reviewed. Screening of the ABCC6 gene (exons 1 to 31) was performed using PCR-based Sanger sequencing. Results Eight ABCC6 variants were identified as candidate disease-causing variants. These eight variants included five known variants (p.Q378X, p.R419Q, p.V848CfsX83, p.R1114C, and p.R1357W), one previously reported variant (p.N428S) of unknown significance, and two novel variants (c.1939C>T [p.H647Y] and c.3374C>T [p.S1125F]); the three latter variants were determined to be variants of significance. The following four variants were frequently identified: p.V848CfsX83 (14/40 alleles, 35.0%), p.Q378X (7/40 alleles, 17.5%), p.R1357W (6/40 alleles, 15.0%), and p.R419Q (4/40 alleles, 10.0%). The ABCC6 variants were identified in compound heterozygous or homozygous states in 13 of 18 probands. Two families showed a pseudodominant inheritance pattern. Pseudoxanthoma elasticum was seen in 15 of 17 patients (88.2%) who underwent dermatological examination. Conclusions We identified disease-causing ABCC6 variants that were in homozygous or compound heterozygous states in 13 of 18 families (72.2%). Our results indicated that ABCC6 variants play a significant role in patients with AS in the Japanese population. PMID:28912966

  16. 38 CFR 4.62 - Circulatory disturbances.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Circulatory disturbances. 4.62 Section 4.62 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings The Musculoskeletal System § 4.62 Circulatory disturbances...

  17. 38 CFR 4.62 - Circulatory disturbances.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false Circulatory disturbances. 4.62 Section 4.62 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings The Musculoskeletal System § 4.62 Circulatory disturbances...

  18. 38 CFR 4.62 - Circulatory disturbances.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Circulatory disturbances. 4.62 Section 4.62 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings The Musculoskeletal System § 4.62 Circulatory disturbances...

  19. 38 CFR 4.62 - Circulatory disturbances.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Circulatory disturbances. 4.62 Section 4.62 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings The Musculoskeletal System § 4.62 Circulatory disturbances...

  20. 38 CFR 4.62 - Circulatory disturbances.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false Circulatory disturbances. 4.62 Section 4.62 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS SCHEDULE FOR RATING DISABILITIES Disability Ratings The Musculoskeletal System § 4.62 Circulatory disturbances...

  1. 7 CFR 3560.462 - Money laundering.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 15 2013-01-01 2013-01-01 false Money laundering. 3560.462 Section 3560.462 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, DEPARTMENT OF... Other Actions § 3560.462 Money laundering. The Agency will act in accordance with U.S. Code Title 18...

  2. 7 CFR 3560.462 - Money laundering.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 15 2012-01-01 2012-01-01 false Money laundering. 3560.462 Section 3560.462 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, DEPARTMENT OF... Other Actions § 3560.462 Money laundering. The Agency will act in accordance with U.S. Code Title 18...

  3. 7 CFR 3560.462 - Money laundering.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 15 2011-01-01 2011-01-01 false Money laundering. 3560.462 Section 3560.462 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, DEPARTMENT OF... Other Actions § 3560.462 Money laundering. The Agency will act in accordance with U.S. Code Title 18...

  4. 7 CFR 3560.462 - Money laundering.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 15 2014-01-01 2014-01-01 false Money laundering. 3560.462 Section 3560.462 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, DEPARTMENT OF... Other Actions § 3560.462 Money laundering. The Agency will act in accordance with U.S. Code Title 18...

  5. 7 CFR 3560.462 - Money laundering.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 15 2010-01-01 2010-01-01 false Money laundering. 3560.462 Section 3560.462 Agriculture Regulations of the Department of Agriculture (Continued) RURAL HOUSING SERVICE, DEPARTMENT OF... Other Actions § 3560.462 Money laundering. The Agency will act in accordance with U.S. Code Title 18...

  6. Combined Bicarbonate Conductance-Impairing Variants in CFTR and SPINK1 Are Associated with Chronic Pancreatitis in Patients without Cystic Fibrosis

    PubMed Central

    Schneider, Alexander; LaRusch, Jessica; Sun, Xiumei; Aloe, Amy; Lamb, Janette; Hawes, Robert; Cotton, Peter; Brand, Randall E.; Anderson, Michelle A.; Money, Mary E.; Banks, Peter A.; Lewis, Michele D.; Baillie, John; Sherman, Stuart; DiSario, James; Burton, Frank R.; Gardner, Timothy B.; Amann, Stephen T.; Gelrud, Andres; George, Ryan; Kassabian, Sirvart; Martinson, Jeremy; Slivka, Adam; Yadav, Dhiraj; Oruc, Nevin; Barmada, M. Michael; Frizzell, Raymond; Whitcomb, David C.

    2010-01-01

    Background & Aims Idiopathic chronic pancreatitis (ICP) is a complex inflammatory disorder associated with multiple genetic and environmental factors. In individuals without cystic fibrosis (CF), variants of CFTR that inhibit bicarbonate conductance but maintain chloride conductance might selectively impair secretion of pancreatic juice, leading to trypsin activation and pancreatitis. We investigated whether sequence variants in the gene encoding the pancreatic secretory trypsin inhibitor, SPINK1, further increase the risk of pancreatitis in these patients. Methods We screened patients with ICP (sporadic or familial) and controls for variants in SPINK1 associated with chronic pancreatitis (CP) risk (in exon 3) and in all 27 exons of CFTR. The final study group included 53 patients with sporadic ICP, 27 probands with familial ICP, and 150 unrelated controls, plus 503 controls for limited genotyping. CFTR wild-type (wt) and p.R75Q were cloned and expressed in HEK293 cells and relative conductances of HCO3− and Cl− were measured. Results SPINK1 variants were identified in 36% of subjects and 3% controls (odds ratio [OR]=16.5). One variant of CFTR that has not been associated with CF, p.R75Q, was found in 16% of subjects and 5.4% controls (OR=3.4). Co-inheritance of CFTR p.R75Q and SPINK1 variants occurred in 8.75% of patients and 0.15% controls (OR=62.5). Patch-clamp recordings of cells that expressed CFTR p.R75Q demonstrated normal chloride currents but significantly reduced bicarbonate currents (P=0.0001). Conclusions The CFTR variant p.R75Q causes a selective defect in bicarbonate conductance and increases risk for pancreatitis. Co-inheritance of CF-associated, and some not associated, CFTR variants with SPINK1 variants significantly increase risk of ICP. PMID:20977904

  7. 21 CFR 520.462 - Clorsulon drench.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Clorsulon drench. 520.462 Section 520.462 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.462 Clorsulon drench. (a...

  8. 21 CFR 520.462 - Clorsulon drench.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Clorsulon drench. 520.462 Section 520.462 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.462 Clorsulon drench. (a...

  9. 21 CFR 520.462 - Clorsulon drench.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Clorsulon drench. 520.462 Section 520.462 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.462 Clorsulon drench. (a...

  10. 21 CFR 520.462 - Clorsulon drench.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Clorsulon drench. 520.462 Section 520.462 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.462 Clorsulon drench. (a...

  11. 21 CFR 520.462 - Clorsulon drench.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Clorsulon drench. 520.462 Section 520.462 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.462 Clorsulon drench. (a...

  12. Association of COMT and PRODH gene variants with intelligence quotient (IQ) and executive functions in 22q11.2DS subjects.

    PubMed

    Carmel, Miri; Zarchi, Omer; Michaelovsky, Elena; Frisch, Amos; Patya, Miriam; Green, Tamar; Gothelf, Doron; Weizman, Abraham

    2014-09-01

    The 22q11.2 deletion syndrome (22q11.2DS) carries the highest genetic risk factor for the development of schizophrenia. We investigated the association of genetic variants in two schizophrenia candidate genes with executive function (EF) and IQ in 22q11.2DS individuals. Ninety two individuals with 22q11.2 deletion were studied for the genetic association between COMT and PRODH variants and EF and IQ. Subjects were divided into children (under 12 years old), adolescents (between 12 and 18 years old) and adults (older than 18 years), and genotyped for the COMT Val158Met (rs4680) and PRODH Arg185Trp (rs4819756) polymorphisms. The participants underwent psychiatric evaluation and EF assessment. Our main finding is a significant influence of the COMT Val158Met polymorphism on both IQ and EF performance. Specifically, 22q11.2DS subjects with Met allele displayed higher IQ scores in all age groups compared to Val carriers, reaching significance in both adolescents and adults. The Met allele carriers performed better than Val carriers in EF tasks, being statistically significant in the adult group. PRODH Arg185Trp variant did not affect IQ or EF in our 22q11.2DS cohort. In conclusion, functional COMT variant, but not PRODH, affects IQ and EF in 22q11.2DS subjects during neurodevelopment with a maximal effect at adulthood. Future studies should monitor the cognitive performance of the same individuals from childhood to old age. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Evaluation of the association between the TAS1R2 and TAS1R3 variants and food intake and nutritional status in children

    PubMed Central

    Melo, Silvia V.; Agnes, Grasiela; Vitolo, Márcia R.; Mattevi, Vanessa S.; Campagnolo, Paula D.B.; Almeida, Silvana

    2017-01-01

    Abstract Taste perception plays a key role in determining individual food preferences and dietary habits and may influence nutritional status. This study aimed to investigate the association of TAS1R2 (Ile191Val - rs35874116) and TAS1R3 (-1266 C/T - rs35744813) variants with food intake and nutritional status in children followed from birth until 7.7 years old. The nutritional status and food intake data of 312 children were collected at three developmental stages (1, 3.9 and 7.7 years old). DNA was extracted from blood samples and the polymorphisms were analyzed by real-time polymerase chain reactions (qPCR) using hydrolysis probes as the detection method. Food intake and nutritional status were compared among individuals with different single nucleotide polymorphism (SNP) genotypes. At 3.9 years old, children homozygous (Val/Val) for the TAS1R2 Ile191Val polymorphism ingested less sugar and sugar-dense foods than children who were *Ile carriers. This finding demonstrated that a genetic variant of the T1R2 taste receptor is associated with the intake of different amounts of high sugar-content foods in childhood. This association may provide new perspectives for studying dietary patterns and nutritional status in childhood. PMID:28497839

  14. Evaluation of the association between the TAS1R2 and TAS1R3 variants and food intake and nutritional status in children.

    PubMed

    Melo, Silvia V; Agnes, Grasiela; Vitolo, Márcia R; Mattevi, Vanessa S; Campagnolo, Paula D B; Almeida, Silvana

    2017-01-01

    Taste perception plays a key role in determining individual food preferences and dietary habits and may influence nutritional status. This study aimed to investigate the association of TAS1R2 (Ile191Val - rs35874116) and TAS1R3 (-1266 C/T - rs35744813) variants with food intake and nutritional status in children followed from birth until 7.7 years old. The nutritional status and food intake data of 312 children were collected at three developmental stages (1, 3.9 and 7.7 years old). DNA was extracted from blood samples and the polymorphisms were analyzed by real-time polymerase chain reactions (qPCR) using hydrolysis probes as the detection method. Food intake and nutritional status were compared among individuals with different single nucleotide polymorphism (SNP) genotypes. At 3.9 years old, children homozygous (Val/Val) for the TAS1R2 Ile191Val polymorphism ingested less sugar and sugar-dense foods than children who were *Ile carriers. This finding demonstrated that a genetic variant of the T1R2 taste receptor is associated with the intake of different amounts of high sugar-content foods in childhood. This association may provide new perspectives for studying dietary patterns and nutritional status in childhood.

  15. Association of sequence variants on chromosomes 20, 11, and 5 (20q13.33, 11q23.3, and 5p15.33) with glioma susceptibility in a Chinese population.

    PubMed

    Chen, Hongyan; Chen, Yuanyuan; Zhao, Yao; Fan, Weiwei; Zhou, Keke; Liu, Yanhong; Zhou, Liangfu; Mao, Ying; Wei, Qingyi; Xu, Jianfeng; Lu, Daru

    2011-04-15

    Two genome-wide association studies of glioma in European populations identified 14 genetic variants strongly associated with risk of glioma, but it is unknown whether these variants are associated with glioma risk in Asian populations. The authors genotyped these 14 variants in 976 glioma patients and 1,057 control subjects to evaluate their associations with risk of glioma, particularly high-grade glioma (glioblastoma; n = 312), in a Chinese population (2004-2009). Overall, the authors identified 3 susceptibility loci for glioma risk at 20q13.33 (RTEL1 rs6010620 (P = 2.79 × 10(-6))), 11q23.3 (PHLDB1 rs498872 (P = 3.8 × 10(-6))), and 5p15.33 (TERT rs2736100 (P = 3.69 × 10(-4))) in this study population; these loci were also associated with glioblastoma risk (20q13.33: RTEL1 rs6010620 (P = 3.57 × 10(-7)); 11q23.3: PHLDB1 rs498872 (P = 7.24 × 10(-3)); 5p15.33: TERT rs2736100 and TERT rs2736098 (P = 1.21 × 10(-4) and P = 2.84 × 10(-4), respectively)). This study provides further evidence for 3 glioma susceptibility regions at 20q13.33, 11q23.3, and 5p15.33 in Chinese populations.

  16. Moderate folic acid supplementation and MTHFD1-synthetase deficiency in mice, a model for the R653Q variant, result in embryonic defects and abnormal placental development.

    PubMed

    Christensen, Karen E; Hou, Wenyang; Bahous, Renata H; Deng, Liyuan; Malysheva, Olga V; Arning, Erland; Bottiglieri, Teodoro; Caudill, Marie A; Jerome-Majewska, Loydie A; Rozen, Rima

    2016-11-01

    Moderately high folic acid intake in pregnant women has led to concerns about deleterious effects on the mother and fetus. Common polymorphisms in folate genes, such as methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase (MTHFD1) R653Q, may modulate the effects of elevated folic acid intake. We investigated the effects of moderate folic acid supplementation on reproductive outcomes and assessed the potential interaction of the supplemented diet with MTHFD1-synthetase (Mthfd1S) deficiency in mice, which is a model for the R653Q variant. Female Mthfd1S +/+ and Mthfd1S +/- mice were fed a folic acid-supplemented diet (FASD) (5-fold higher than recommended) or control diets before mating and during pregnancy. Embryos and placentas were assessed for developmental defects at embryonic day 10.5 (E10.5). Maternal folate and choline metabolites and gene expression in folate-related pathways were examined. The combination of FASD and maternal MTHFD1-synthetase deficiency led to a greater incidence of defects in E10.5 embryos (diet × maternal genotype, P = 0.0016; diet × embryonic genotype, P = 0.054). The methylenetetrahydrofolate reductase (MTHFR) protein and methylation potential [ratio of S-adenosylmethionine (major methyl donor):S-adenosylhomocysteine) were reduced in maternal liver. Although 5-methyltetrahydrofolate (methylTHF) was higher in maternal circulation, the methylation potential was lower in embryos. The presence of developmental delays and defects in Mthfd1S +/- embryos was associated with placental defects (P = 0.003). The labyrinth layer failed to form properly in the majority of abnormal placentas, which compromised the integration of the maternal and fetal circulation and presumably the transfer of methylTHF and other nutrients. Moderately higher folate intake and MTHFD1-synthetase deficiency in pregnant mice result in a lower methylation potential in maternal liver and embryos and a greater

  17. Construction of general colored R matrices for the Yang-Baxter equation and q-boson realization of quantum algebra SL[sub q](2) when q is a root of unity

    SciTech Connect

    Ge, M.L.; Sun, C.P.; Xue, K.

    1992-10-20

    In this paper, through a general q-boson realization of quantum algebra sl[sub q](2) and its universal R matrix an operator R matrix with many parameters is obtained in terms of q-boson operators. Building finite-dimensional representations of q-boson algebra, the authors construct various colored R matrices associated with nongeneric representations of sl[sub q](2) with dimension-independent parameters. The nonstandard R matrices obtained by Lee-Couture and Murakami are their special examples.

  18. 18 CFR 46.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... plant equipment (316, 325, 335 and 346); Water wheels, turbines and generators (333); Fuel holders... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Definitions. 46.2 Section 46.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF...

  19. 18 CFR 46.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... plant equipment (316, 325, 335 and 346); Water wheels, turbines and generators (333); Fuel holders... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Definitions. 46.2 Section 46.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF...

  20. 18 CFR 46.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... plant equipment (316, 325, 335 and 346); Water wheels, turbines and generators (333); Fuel holders... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Definitions. 46.2 Section 46.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF...

  1. 18 CFR 46.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... plant equipment (316, 325, 335 and 346); Water wheels, turbines and generators (333); Fuel holders... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Definitions. 46.2 Section 46.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF...

  2. 18 CFR 46.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... plant equipment (316, 325, 335 and 346); Water wheels, turbines and generators (333); Fuel holders... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Definitions. 46.2 Section 46.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF...

  3. A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent and frequent in the Swedish population.

    PubMed

    Entesarian, Miriam; Carlsson, Birgit; Mansouri, Mahmoud Reza; Stattin, Eva-Lena; Holmberg, Eva; Golovleva, Irina; Stefansson, Hreinn; Klar, Joakim; Dahl, Niklas

    2009-03-01

    We identified a paracentric inversion of chromosome 10 [inv(10)(q11.22q21.1)] in 0.20% of Swedish individuals (15/7,439) referred for cytogenetic analysis. A retrospective analysis of 8,896 karyotypes from amniocenteses in Sweden revealed a carrier frequency of 0.079% (7/8,896) for the inversion. Cloning and detailed analysis of the inversion breakpoint regions show enrichment for interspersed repeat elements and AT-stretches. The centromeric breakpoint coincides with that of a predicted inversion from HapMap data, which suggests that this region is involved in several chromosome 10 variants. No known gene or predicted transcript are disrupted by the inversion which spans approximately 12 Mb. Carriers from four non-related Swedish families have identical inversion breakpoints and haplotype analysis confirmed that the rearrangement is identical by descent. Diagnosis was retrieved in 6 out of the 15 carriers referred for cytogenetic analysis. No consistent phenotype was found to be associated with the inversion. Our study demonstrates that the inv(10)(q11.22q21.1) is a rare and inherited chromosome variant with a broad geographical distribution in Sweden. 2009 Wiley-Liss, Inc.

  4. Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

    PubMed Central

    Glubb, Dylan M.; Johnatty, Sharon E.; Quinn, Michael C.J.; O’Mara, Tracy A.; Tyrer, Jonathan P.; Gao, Bo; Fasching, Peter A.; Beckmann, Matthias W.; Lambrechts, Diether; Vergote, Ignace; Velez Edwards, Digna R.; Beeghly-Fadiel, Alicia; Benitez, Javier; Garcia, Maria J.; Goodman, Marc T.; Thompson, Pamela J.; Dörk, Thilo; Dürst, Matthias; Modungo, Francesmary; Moysich, Kirsten; Heitz, Florian; du Bois, Andreas; Pfisterer, Jacobus; Hillemanns, Peter; Karlan, Beth Y.; Lester, Jenny; Goode, Ellen L.; Cunningham, Julie M.; Winham, Stacey J.; Larson, Melissa C.; McCauley, Bryan M.; Kjær, Susanne Krüger; Jensen, Allan; Schildkraut, Joellen M.; Berchuck, Andrew; Cramer, Daniel W.; Terry, Kathryn L.; Salvesen, Helga B.; Bjorge, Line; Webb, Penny M.; Grant, Peter; Pejovic, Tanja; Moffitt, Melissa; Hogdall, Claus K.; Hogdall, Estrid; Paul, James; Glasspool, Rosalind; Bernardini, Marcus; Tone, Alicia; Huntsman, David; Woo, Michelle; Group, AOCS; deFazio, Anna; Kennedy, Catherine J.; Pharoah, Paul D.P.; MacGregor, Stuart; Chenevix-Trench, Georgia

    2017-01-01

    We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p<1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci. PMID:29029385

  5. Functional characterization of four naturally occurring variants of human pregnane X receptor (PXR): one variant causes dramatic loss of both DNA binding activity and the transactivation of the CYP3A4 promoter/enhancer region.

    PubMed

    Koyano, Satoru; Kurose, Kouichi; Saito, Yoshiro; Ozawa, Shogo; Hasegawa, Ryuichi; Komamura, Kazuo; Ueno, Kazuyuki; Kamakura, Shiro; Kitakaze, Masafumi; Nakajima, Toshiharu; Matsumoto, Kenji; Akasawa, Akira; Saito, Hirohisa; Sawada, Jun-Ichi

    2004-01-01

    Metabolism of administered drugs is determined by expression and activity of many drug-metabolizing enzymes, such as the cytochrome P450 (P450s) family members. Pregnane X receptor (PXR) is a master transcriptional regulator of many drug/xenobiotic-metabolizing enzymes, including P450s and drug transporters. In this study, we describe the functional analysis of four naturally occurring human PXR (hPXR) variants (R98C, R148Q, R381W, and I403V) that we have recently identified. By a reporter gene assay using the CYP3A4 promoter/enhancer reporter in COS-7 or HepG2 cells, it was found that the R98C variant failed to transactivate the CYP3A4 reporter. The R381W and I403V variants also showed varying degrees of reduction in transactivation, depending on the dose of PXR activators, rifampicin, clotrimazole, and paclitaxel. The transcriptional activities of the R148Q variant were not significantly different from that of the wild-type hPXR. The electrophoretic mobility shift assay revealed that only the R98C variant lacked DNA binding. Furthermore, the cellular localization of the hPXR proteins was analyzed. All four variants as well as the wild-type hPXR localized exclusively to the nucleus, regardless of the presence or absence of rifampicin. These data suggest that the R98C, R381W, and I403V hPXR variants, especially R98C, may influence the expression of drug-metabolizing enzymes and transporters, which are transactivated by PXR.

  6. Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?

    PubMed

    Lovelock, Paul K; Spurdle, Amanda B; Mok, Myth T S; Farrugia, Daniel J; Lakhani, Sunil R; Healey, Sue; Arnold, Stephen; Buchanan, Daniel; Couch, Fergus J; Henderson, Beric R; Goldgar, David E; Tavtigian, Sean V; Chenevix-Trench, Georgia; Brown, Melissa A

    2007-01-01

    Many of the DNA sequence variants identified in the breast cancer susceptibility gene BRCA1 remain unclassified in terms of their potential pathogenicity. Both multifactorial likelihood analysis and functional approaches have been proposed as a means to elucidate likely clinical significance of such variants, but analysis of the comparative value of these methods for classifying all sequence variants has been limited. We have compared the results from multifactorial likelihood analysis with those from several functional analyses for the four BRCA1 sequence variants A1708E, G1738R, R1699Q, and A1708V. Our results show that multifactorial likelihood analysis, which incorporates sequence conservation, co-inheritance, segregation, and tumour immunohistochemical analysis, may improve classification of variants. For A1708E, previously shown to be functionally compromised, analysis of oestrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumour expression data significantly strengthened the prediction of pathogenicity, giving a posterior probability of pathogenicity of 99%. For G1738R, shown to be functionally defective in this study, immunohistochemistry analysis confirmed previous findings of inconsistent 'BRCA1-like' phenotypes for the two tumours studied, and the posterior probability for this variant was 96%. The posterior probabilities of R1699Q and A1708V were 54% and 69%, respectively, only moderately suggestive of increased risk. Interestingly, results from functional analyses suggest that both of these variants have only partial functional activity. R1699Q was defective in foci formation in response to DNA damage and displayed intermediate transcriptional transactivation activity but showed no evidence for centrosome amplification. In contrast, A1708V displayed an intermediate transcriptional transactivation activity and a normal foci formation response in response to DNA damage but induced centrosome amplification. These data highlight the need for a range of

  7. Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?

    PubMed Central

    Lovelock, Paul K; Spurdle, Amanda B; Mok, Myth TS; Farrugia, Daniel J; Lakhani, Sunil R; Healey, Sue; Arnold, Stephen; Buchanan, Daniel; Investigators, kConFab; Couch, Fergus J; Henderson, Beric R; Goldgar, David E; Tavtigian, Sean V; Chenevix-Trench, Georgia; Brown, Melissa A

    2007-01-01

    Introduction Many of the DNA sequence variants identified in the breast cancer susceptibility gene BRCA1 remain unclassified in terms of their potential pathogenicity. Both multifactorial likelihood analysis and functional approaches have been proposed as a means to elucidate likely clinical significance of such variants, but analysis of the comparative value of these methods for classifying all sequence variants has been limited. Methods We have compared the results from multifactorial likelihood analysis with those from several functional analyses for the four BRCA1 sequence variants A1708E, G1738R, R1699Q, and A1708V. Results Our results show that multifactorial likelihood analysis, which incorporates sequence conservation, co-inheritance, segregation, and tumour immunohistochemical analysis, may improve classification of variants. For A1708E, previously shown to be functionally compromised, analysis of oestrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumour expression data significantly strengthened the prediction of pathogenicity, giving a posterior probability of pathogenicity of 99%. For G1738R, shown to be functionally defective in this study, immunohistochemistry analysis confirmed previous findings of inconsistent 'BRCA1-like' phenotypes for the two tumours studied, and the posterior probability for this variant was 96%. The posterior probabilities of R1699Q and A1708V were 54% and 69%, respectively, only moderately suggestive of increased risk. Interestingly, results from functional analyses suggest that both of these variants have only partial functional activity. R1699Q was defective in foci formation in response to DNA damage and displayed intermediate transcriptional transactivation activity but showed no evidence for centrosome amplification. In contrast, A1708V displayed an intermediate transcriptional transactivation activity and a normal foci formation response in response to DNA damage but induced centrosome amplification. Conclusion

  8. Mesotrypsin Signature Mutation in a Chymotrypsin C (CTRC) Variant Associated with Chronic Pancreatitis.

    PubMed

    Szabó, András; Ludwig, Maren; Hegyi, Eszter; Szépeová, Renata; Witt, Heiko; Sahin-Tóth, Miklós

    2015-07-10

    Human chymotrypsin C (CTRC) protects against pancreatitis by degrading trypsinogen and thereby curtailing harmful intra-pancreatic trypsinogen activation. Loss-of-function mutations in CTRC increase the risk for chronic pancreatitis. Here we describe functional analysis of eight previously uncharacterized natural CTRC variants tested for potential defects in secretion, proteolytic stability, and catalytic activity. We found that all variants were secreted from transfected cells normally, and none suffered proteolytic degradation by trypsin. Five variants had normal enzymatic activity, whereas variant p.R29Q was catalytically inactive due to loss of activation by trypsin and variant p.S239C exhibited impaired activity possibly caused by disulfide mispairing. Surprisingly, variant p.G214R had increased activity on a small chromogenic peptide substrate but was markedly defective in cleaving bovine β-casein or the natural CTRC substrates human cationic trypsinogen and procarboxypeptidase A1. Mutation p.G214R is analogous to the evolutionary mutation in human mesotrypsin, which rendered this trypsin isoform resistant to proteinaceous inhibitors and conferred its ability to cleave these inhibitors. Similarly to the mesotrypsin phenotype, CTRC variant p.G214R was inhibited poorly by eglin C, ecotin, or a CTRC-specific variant of SGPI-2, and it readily cleaved the reactive-site peptide bonds in eglin C and ecotin. We conclude that CTRC variants p.R29Q, p.G214R, and p.S239C are risk factors for chronic pancreatitis. Furthermore, the mesotrypsin-like CTRC variant highlights how the same natural mutation in homologous pancreatic serine proteases can evolve a new physiological role or lead to pathology, determined by the biological context of protease function. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. A single R36Q mutation in the matrix protein of pigeon paramyxovirus type 1 reduces virus replication and shedding in pigeons.

    PubMed

    Xu, Haixu; Song, Qingqing; Zhu, Jie; Liu, Jiajia; Cheng, Xin; Hu, Shunlin; Wu, Shuang; Wang, Xiaoquan; Liu, Xiaowen; Liu, Xiufan

    2016-07-01

    Pigeon paramyxovirus type 1 (PPMV-1) is considered an antigenic and variant of avian paramyxovirus type 1 (APMV-1) that has adapted to pigeons as hosts. However, how this host-specific adaption of PPMV-1 is related to its biological characteristics is unknown. In this study, seven unique amino acids in PPMV-1 that are not present in other APMV-1 strains (n = 39 versus n = 106) were identified. R36 of the M protein was found to be not only a unique amino acid but also a positive-selection site. To investigate the role of R36 in host adaptation, a recombinant PPMV-1 with R36Q mutation was constructed. Our results indicated that the an R36Q mutation significantly attenuates pathogenicity in chickens, viral growth in both chicken embryo fibroblasts (CEFs) and pigeon embryo fibroblasts (PEFs), and virus replication and shedding in pigeons in comparison with the wild-type virus, suggesting that R36 is a key residue that evolved during the adaptation of PPMV-1 in pigeons.

  10. 7 CFR 28.462 - Leaf Grade 2.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 2 2012-01-01 2012-01-01 false Leaf Grade 2. 28.462 Section 28.462 Agriculture..., TESTING, AND STANDARDS Standards Official Cotton Standards of the United States for the Leaf Grade of American Upland Cotton § 28.462 Leaf Grade 2. Leaf Grade 2 is leaf which is within the range represented by...

  11. 7 CFR 28.462 - Leaf Grade 2.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 2 2011-01-01 2011-01-01 false Leaf Grade 2. 28.462 Section 28.462 Agriculture..., TESTING, AND STANDARDS Standards Official Cotton Standards of the United States for the Leaf Grade of American Upland Cotton § 28.462 Leaf Grade 2. Leaf Grade 2 is leaf which is within the range represented by...

  12. 7 CFR 28.462 - Leaf Grade 2.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false Leaf Grade 2. 28.462 Section 28.462 Agriculture..., TESTING, AND STANDARDS Standards Official Cotton Standards of the United States for the Leaf Grade of American Upland Cotton § 28.462 Leaf Grade 2. Leaf Grade 2 is leaf which is within the range represented by...

  13. 7 CFR 28.462 - Leaf Grade 2.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 2 2013-01-01 2013-01-01 false Leaf Grade 2. 28.462 Section 28.462 Agriculture..., TESTING, AND STANDARDS Standards Official Cotton Standards of the United States for the Leaf Grade of American Upland Cotton § 28.462 Leaf Grade 2. Leaf Grade 2 is leaf which is within the range represented by...

  14. 7 CFR 28.462 - Leaf Grade 2.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 2 2014-01-01 2014-01-01 false Leaf Grade 2. 28.462 Section 28.462 Agriculture..., TESTING, AND STANDARDS Standards Official Cotton Standards of the United States for the Leaf Grade of American Upland Cotton § 28.462 Leaf Grade 2. Leaf Grade 2 is leaf which is within the range represented by...

  15. Clinical evaluation of R202Q alteration of MEFV genes in Turkish children.

    PubMed

    Comak, Elif; Akman, Sema; Koyun, Mustafa; Dogan, Cagla Serpil; Gokceoglu, Arife Uslu; Arikan, Yunus; Keser, Ibrahim

    2014-12-01

    To date, over 200 alterations have been reported in Mediterranean fever (MEFV) genes, but it is not clear whether all these alterations are disease-causing mutations. This study aims to evaluate the clinical features of the children with R202Q alteration. The medical records of children with R202Q alteration were reviewed retrospectively. A total of 225 children, with 113 males, were included. Fifty-five patients were heterozygous, 30 patients were homozygous for R202Q, and 140 patients were compound heterozygous. Classical familial Mediterranean fever (FMF) phenotype was present in 113 patients: 2 heterozygous and 7 homozygous R202Q, 46 double homozygous R202Q and M694V, and 58 compound heterozygous. The main clinical characteristics of the patients were abdominal pain in 71.5 %, fever in 37.7 %, arthralgia/myalgia in 30.2 %, arthritis in 10.2 %, chest pain in 14.6 % and erysipelas-like erythema in 13.3 %. The frequency of abdominal pain was significantly lower in patients with homozygous R202Q alteration (p = 0.021), whereas patients with heterozygous R202Q mutations, though not statistically significant, had a higher frequency of arthralgia/myalgia (40.0 %, p = 0.05). R202Q alteration of the MEFV gene leads to symptoms consistent with FMF in some cases. This alteration may be associated with a mild phenotype and shows phenotypic differences other than the common MEFV mutations.

  16. Complementation of the Function of Glycoprotein H of Human Herpesvirus 6 Variant A by Glycoprotein H of Variant B in the Virus Life Cycle

    PubMed Central

    Oyaizu, Hiroko; Tang, Huamin; Ota, Megumi; Takenaka, Nobuyuki; Ozono, Keiichi; Yamanishi, Koichi

    2012-01-01

    Human herpesvirus 6 (HHV-6) is a T-cell-tropic betaherpesvirus. HHV-6 can be classified into two variants, HHV-6 variant A (HHV-6A) and HHV-6B, based on genetic, antigenic, and cell tropisms, although the homology of their entire genomic sequences is nearly 90%. The HHV-6A glycoprotein complex gH/gL/gQ1/gQ2 is a viral ligand that binds to the cellular receptor human CD46. Because gH has 94.3% amino acid identity between the variants, here we examined whether gH from one variant could complement its loss in the other. Recently, we successfully reconstituted HHV-6A from its cloned genome in a bacterial artificial chromosome (BAC) (rHHV-6ABAC). Using this system, we constructed HHV-6ABAC DNA containing the HHV-6B gH (BgH) gene instead of the HHV-6A gH (AgH) gene in Escherichia coli. Recombinant HHV-6ABAC expressing BgH (rHHV-6ABAC-BgH) was successfully reconstituted. In addition, a monoclonal antibody that blocks HHV-6B but not HHV-6A infection neutralized rHHV-6ABAC-BgH but not rHHV-6ABAC. These results indicate that HHV-6B gH can complement the function of HHV-6A gH in the viral infectious cycle. PMID:22647694

  17. Paraoxonase-1 gene Q192R polymorphism and reactive oxygen metabolites.

    PubMed

    Kotani, K; Tsuzaki, K; Sakane, N

    2012-01-01

    Paraoxonase-1 (PON1) is a high-density lipoprotein-associated antioxidant enzyme. The Q192R polymorphism of the PON1 gene can protect against oxidative conditions, but the relationship between Q192R polymorphism and oxidative stress-related markers remains controversial. In this study, the diacron reactive oxygen metabolites (d-ROMs) test was used to investigate the relationship between Q192R polymorphism and oxidative stress-related markers in Japanese subjects. Patients without a history of overt cardiovascular disease who were not receiving antioxidant medication were enrolled in a cross-sectional clinic-based study. An allele-specific polymerase chain reaction method was used to assess the PON1 Q192R polymorphism and compare the level of d-ROMs between genotypes. A total of 103 subjects were analysed. The RR genotype was associated with a significantly lower level of d-ROMs than the RQ and QQ genotypes. After multivariate analysis the relationship between the genotypes and level of d-ROMs remained independently significant. The RR genotype may be protective against oxidative stress in cardiovascular diseasefree Japanese subjects. In addition, the d-ROMs test can be useful for examining the role of the PON1 Q192R polymorphism under oxidative conditions.

  18. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants

    PubMed Central

    Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Casey, Graham; Chang-Claude, Jenny; Conti, David V.; Curtis, Keith R.; Duggan, David; Gallinger, Steven; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jenkins, Mark A.; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M.; Newcomb, Polly A.; Nickerson, Deborah A.; Potter, John D.; Schoen, Robert E.; Schumacher, Fredrick R.; Seminara, Daniela; Slattery, Martha L.; Hsu, Li; Chan, Andrew T.; White, Emily; Berndt, Sonja I.; Peters, Ulrike

    2016-01-01

    Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). PMID:27379672

  19. Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex.

    PubMed

    Palmer, Bradley M; Wang, Yuan; Teekakirikul, Polakit; Hinson, J Travis; Fatkin, Diane; Strouse, Stacy; Vanburen, Peter; Seidman, Christine E; Seidman, J G; Maughan, David W

    2008-04-01

    Male but not female mice carrying a single R403Q missense allele for cardiac alpha-myosin heavy chain (M-alphaMHC(R403Q/+) and F-alphaMHC(R403Q/+), respectively) develop significant hypertrophic cardiomyopathy (HCM) compared with male and female wild-type mice (M-alphaMHC(+/+) and F-alphaMHC(+/+), respectively) after approximately 30 wk of age. We tested the hypothesis that myofilament mechanical performance differs between M-alphaMHC(R403Q/+) and F-alphaMHC(R403Q/+) at younger ages (10-20 wk) and could account for sex differences in HCM development. The sensitivity of chemically skinned myocardial strips to Ca(2+) activation (pCa(50)) was significantly (P < 0.05) enhanced in male mice independent of genotype (M-alphaMHC(R403Q/+): 5.70 +/- 0.06, M-alphaMHC(+/+): 5.63 +/- 0.05, F-alphaMHC(R403Q/+): 5.57 +/- 0.03, F-alphaMHC(+/+): 5.54 +/- 0.04) by two-way ANOVA, whereas maximum developed tension was significantly enhanced in alpha-MHC(R403Q/+) independent of sex (M-alphaMHC(R403Q/+): 29.3 +/- 2.3, M-alphaMHC(+/+): 26.0 +/- 1.4, F-alphaMHC(R403Q/+): 30.2 +/- 2.1, F-alphaMHC(+/+): 26.2 +/- 1.2 mN/mm(2)). The frequency of maximum work generated by sinusoidal length perturbation was significantly higher in alphaMHC(R403Q/+) mice than in sex-matched controls (M-alphaMHC(R403Q/+): 2.26 +/- 0.47, M-alphaMHC(+/+): 1.29 +/- 0.18, F-alphaMHC(R403Q/+): 3.21 +/- 0.33, F-alphaMHC(+/+): 2.52 +/- 0.36 Hz). Unloaded shortening velocity was significantly enhanced in alphaMHC(R403Q/+) and in female mice (M-alphaMHC(R403Q/+): 2.26 +/- 0.47, M-alphaMHC(+/+): 1.29 +/- 0.18, F-alphaMHC(R403Q/+): 3.21 +/- 0.33, F-alphaMHC(+/+): 2.52 +/- 0.36 muscle lengths/s), and normalized mechanical power, calculated from the tension-velocity relationship, was significantly enhanced in alphaMHC(R403Q/+) independent of sex (M-alphaMHC(R403Q/+): 60 +/- 2 10(-3), M-alphaMHC(+/+): 37 +/- 3 10(-3), F-alphaMHC(R403Q/+): 57 +/- 3 10(-3), F-alphaMHC(+/+) 25 +/- 3 10(-3) muscle lengths/s x normalized tension

  20. 19 CFR 4.62 - Accounting for inward cargo.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Accounting for inward cargo. 4.62 Section 4.62 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY VESSELS IN FOREIGN AND DOMESTIC TRADES Foreign Clearances § 4.62 Accounting for inward cargo...

  1. Genetic and Pharmacological Strategies to Refunctionalize the von Hippel Lindau R167Q Mutant Protein

    PubMed Central

    Ding, Zhiyong; German, Peter; Bai, Shanshan; Reddy, A. Srinivas; Liu, Xian-De; Sun, Mianen; Zhou, Lijun; Chen, Xiaohua; Zhao, Xiaobei; Wu, Chengbiao; Zhang, Shuxing; Mills, Gordon B.; Jonasch, Eric

    2014-01-01

    Aberrant von Hippel Lindau (VHL) protein function is the underlying driver of VHL-related diseases, including both sporadic and inherited clear cell renal cell carcinoma (ccRCC). About one third of VHL mutations are missense point mutations, with R167Q being the most common VHL point mutation in hereditary VHL disease. Although it has been studied extensively, the ability of VHL-R167Q to downregulate hypoxia inducible factor 2α (HIF2α) is still controversial. In addition, the manner in which the mutation contributes to tumorigenesis is not fully understood. No therapeutic approach is available to target VHL-R167Q and similar missense point mutations. We analyzed VHL-R167Q proteostasis and function at normoxia, at hypoxia with different oxygen pressure, and in a xenograft mouse model. We showed that the protein levels of VHL-R167Q dictate its ability to downregulate HIF2α and suppress tumor growth. Strikingly, the proteasome inhibitors bortezomib and carfilzomib, which are currently in clinical use, stabilize VHL-R167Q and increase its ability to downregulate HIF2α. VHL-R167Q binds elongin C and elongin B with considerably less avidity than wild-type VHL does but retains residual capacity to generate a VHL-elongin C-elongin B complex, downregulate HIF2α, and suppress tumorigenesis, which could be rescued by increase VHL-R167Q levels. Finally, we used in silico approaches and identified other missense VHL mutants in addition to VHL-R167Q that might be rescued by similar strategies. Thus, our studies revealed detailed information describing how VHL-R167Q contributes to tumorigenesis and identified a potential targeted therapy for ccRCC and other VHL-related disease in patients carrying VHL-R167Q or similar missense mutations. PMID:24755468

  2. Effect of Q211 and K222 PRNP Polymorphic Variants in the Susceptibility of Goats to Oral Infection With Goat Bovine Spongiform Encephalopathy.

    PubMed

    Aguilar-Calvo, Patricia; Fast, Christine; Tauscher, Kerstin; Espinosa, Juan-Carlos; Groschup, Martin H; Nadeem, Muhammad; Goldmann, Wilfred; Langeveld, Jan; Bossers, Alex; Andreoletti, Olivier; Torres, Juan-María

    2015-08-15

    The prion protein-encoding gene (PRNP) is one of the major determinants for scrapie occurrence in sheep and goats. However, its effect on bovine spongiform encephalopathy (BSE) transmission to goats is not clear. Goats harboring wild-type, R/Q211 or Q/K222 PRNP genotypes were orally inoculated with a goat-BSE isolate to assess their relative susceptibility to BSE infection. Goats were killed at different time points during the incubation period and after the onset of clinical signs, and their brains as well as several peripheral tissues were analyzed for the accumulation of pathological prion protein (PrP(Sc)) and prion infectivity by mouse bioassay. R/Q211 goats displayed delayed clinical signs compared with wild-type goats. Deposits of PrP(Sc) were detected only in brain, whereas infectivity was present in peripheral tissues too. In contrast, none of the Q/K222 goats showed any evidence of clinical prion disease. No PrP(Sc) accumulation was observed in their brains or peripheral tissues, but very low infectivity was detected in some tissues very long after inoculation (44-45 months). These results demonstrate that transmission of goat BSE is genotype dependent, and they highlight the pivotal protective effect of the K222 PRNP variant in the oral susceptibility of goats to BSE. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25.

    PubMed

    Fejerman, Laura; Ahmadiyeh, Nasim; Hu, Donglei; Huntsman, Scott; Beckman, Kenneth B; Caswell, Jennifer L; Tsung, Karen; John, Esther M; Torres-Mejia, Gabriela; Carvajal-Carmona, Luis; Echeverry, María Magdalena; Tuazon, Anna Marie D; Ramirez, Carolina; Gignoux, Christopher R; Eng, Celeste; Gonzalez-Burchard, Esteban; Henderson, Brian; Le Marchand, Loic; Kooperberg, Charles; Hou, Lifang; Agalliu, Ilir; Kraft, Peter; Lindström, Sara; Perez-Stable, Eliseo J; Haiman, Christopher A; Ziv, Elad

    2014-10-20

    The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5' of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53-0.67, P=9 × 10(-18)), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21-0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49-0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.

  4. Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25

    PubMed Central

    Fejerman, Laura; Ahmadiyeh, Nasim; Hu, Donglei; Huntsman, Scott; Beckman, Kenneth B.; Caswell, Jennifer L.; Tsung, Karen; John, Esther M.; Torres-Mejia, Gabriela; Carvajal-Carmona, Luis; Echeverry, María Magdalena; Tuazon, Anna Marie D.; Ramirez, Carolina; Carvajal-Carmona, Luis; Echeverry, María Magdalena; Bohórquez, Mabel Elena; Prieto, Rodrigo; Criollo, Ángel; Ramírez, Carolina; Estrada, Ana Patricia; Suáres, John Jairo; Mateus, Gilbert; Castro, Jorge Mario; Sánchez, Yesid; Murillo, Raúl; Lucia Serrano, Martha; Sanabria, Carolina; Olaya, Justo Germán; Bolaños, Fernando; Vélez, Alejandro; Carmona, Jenny Andrea; Vélez, Alejandro; Rodríguez, Nancy Guerrero; Serón Sousa, Cristina; Mendez, Cesar Eduardo Alvarez; Galviz, Ana Isabel Orduz; Gignoux, Christopher R.; Eng, Celeste; Gonzalez-Burchard, Esteban; Henderson, Brian; Marchand, Loic Le; Kooperberg, Charles; Hou, Lifang; Agalliu, Ilir; Kraft, Peter; Lindström, Sara; Perez-Stable, Eliseo J.; Haiman, Christopher A.; Ziv, Elad

    2014-01-01

    The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5′ of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53–0.67, P=9 × 10−18), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21–0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49–0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations. PMID:25327703

  5. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer

    PubMed Central

    Kiemeney, Lambertus A.; Thorlacius, Steinunn; Sulem, Patrick; Geller, Frank; Aben, Katja K.H.; Stacey, Simon N.; Gudmundsson, Julius; Jakobsdottir, Margret; Bergthorsson, Jon T.; Sigurdsson, Asgeir; Blondal, Thorarinn; Witjes, J. Alfred; Vermeulen, Sita H.; Hulsbergen-van de Kaa, Christina A.; Swinkels, Dorine W.; Ploeg, Martine; Cornel, Erik B.; Vergunst, Henk; Thorgeirsson, Thorgeir E.; Gudbjartsson, Daniel; Gudjonsson, Sigurjon A.; Thorleifsson, Gudmar; Kristinsson, Kari T.; Mouy, Magali; Snorradottir, Steinunn; Placidi, Donatella; Campagna, Marcello; Arici, Cecilia; Koppova, Kvetoslava; Gurzau, Eugene; Rudnai, Peter; Kellen, Eliane; Polidoro, Silvia; Guarrera, Simonetta; Sacerdote, Carlotta; Sanchez, Manuel; Saez, Berta; Valdivia, Gabriel; Ryk, Charlotta; de Verdier, Petra; Lindblom, Annika; Golka, Klaus; Bishop, D. Timothy; Knowles, Margaret A.; Nikulasson, Sigfus; Petursdottir, Vigdis; Jonsson, Eirikur; Geirsson, Gudmundur; Kristjansson, Baldvin; Mayordomo, Jose I.; Steineck, Gunnar; Porru, Stefano; Buntinx, Frank; Zeegers, Maurice P.; Fletcher, Tony; Kumar, Rajiv; Matullo, Giuseppe; Vineis, Paolo; Kiltie, Anne E.; Gulcher, Jeffrey R.; Thorsteinsdottir, Unnur; Kong, Augustine; Rafnar, Thorunn; Stefansson, Kari

    2015-01-01

    We conducted a genome wide SNP association study on 1,803 Urinary Bladder Cancer (UBC) cases and 34,336 controls from Iceland and the Netherlands and follow up studies in seven additional case control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30kb upstream of the c-Myc gene (allele specific OR=1.22; P=9.34×10−12). Approximately 20% of individuals of European ancestry are homozygous for rs9642880 (T) and their estimated risk of developing UBC is 1.49 times that of non-carriers with population attributable risk (PAR) of 17%. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome wide significance, was captured by rs710521 (A) located near the TP63 gene on chromosome 3q28 (allele specific OR=1.19; P=1. 15× 10−7). PMID:18794855

  6. Coagulation factor VII variants resistant to inhibitory antibodies.

    PubMed

    Branchini, Alessio; Baroni, Marcello; Pfeiffer, Caroline; Batorova, Angelika; Giansily-Blaizot, Muriel; Schved, Jean F; Mariani, Guglielmo; Bernardi, Francesco; Pinotti, Mirko

    2014-11-01

    Replacement therapy is currently used to prevent and treat bleeding episodes in coagulation factor deficiencies. However, structural differences between the endogenous and therapeutic proteins might increase the risk for immune complications. This study was aimed at identifying factor (F)VII variants resistant to inhibitory antibodies developed after treatment with recombinant activated factor VII (rFVIIa) in a FVII-deficient patient homozygous for the p.A354V-p.P464Hfs mutation, which predicts trace levels of an elongated FVII variant in plasma. We performed fluorescent bead-based binding, ELISA-based competition as well as fluorogenic functional (activated FX and thrombin generation) assays in plasma and with recombinant proteins. We found that antibodies displayed higher affinity for the active than for the zymogen FVII (half-maximal binding at 0.54 ± 0.04 and 0.78 ± 0.07 BU/ml, respectively), and inhibited the coagulation initiation phase with a second-order kinetics. Isotypic analysis showed a polyclonal response with a large predominance of IgG1. We hypothesised that structural differences in the carboxyl-terminus between the inherited FVII and the therapeutic molecules contributed to the immune response. Intriguingly, a naturally-occurring, poorly secreted and 5-residue truncated FVII (FVII-462X) escaped inhibition. Among a series of truncated rFVII molecules, we identified a well-secreted and catalytically competent variant (rFVII-464X) with reduced binding to antibodies (half-maximal binding at 0.198 ± 0.003 BU/ml) as compared to the rFVII-wt (0.032 ± 0.002 BU/ml), which led to a 40-time reduced inhibition in activated FX generation assays. Taken together our results provide a paradigmatic example of mutation-related inhibitory antibodies, strongly support the FVII carboxyl-terminus as their main target and identify inhibitor-resistant FVII variants.

  7. gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes.

    PubMed

    Braun, L; Ghebrehiwet, B; Cossart, P

    2000-04-03

    InlB is a Listeria monocytogenes protein that promotes entry of the bacterium into mammalian cells by stimulating tyrosine phosphorylation of the adaptor proteins Gab1, Cbl and Shc, and activation of phosphatidyl- inositol (PI) 3-kinase. Using affinity chromatography and enzyme-linked immunosorbent assay, we demonstrate a direct interaction between InlB and the mammalian protein gC1q-R, the receptor of the globular part of the complement component C1q. Soluble C1q or anti-gC1q-R antibodies impair InlB-mediated entry. Transient transfection of GPC16 cells, which are non-permissive to InlB-mediated entry, with a plasmid-expressing human gC1q-R promotes entry of InlB-coated beads. Furthermore, several experiments indicate that membrane recruitment and activation of PI 3-kinase involve an InlB-gC1q-R interaction and that gC1q-R associates with Gab1 upon stimulation of Vero cells with InlB. Thus, gC1q-R constitutes a cellular receptor involved in InlB-mediated activation of PI 3-kinase and tyrosine phosphorylation of the adaptor protein Gab1. After E-cadherin, the receptor for internalin, gC1q-R is the second identified mammalian receptor promoting entry of L. monocytogenes into mammalian cells.

  8. Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome.

    PubMed

    Mlynarski, Elisabeth E; Xie, Michael; Taylor, Deanne; Sheridan, Molly B; Guo, Tingwei; Racedo, Silvia E; McDonald-McGinn, Donna M; Chow, Eva W C; Vorstman, Jacob; Swillen, Ann; Devriendt, Koen; Breckpot, Jeroen; Digilio, Maria Cristina; Marino, Bruno; Dallapiccola, Bruno; Philip, Nicole; Simon, Tony J; Roberts, Amy E; Piotrowicz, Małgorzata; Bearden, Carrie E; Eliez, Stephan; Gothelf, Doron; Coleman, Karlene; Kates, Wendy R; Devoto, Marcella; Zackai, Elaine; Heine-Suñer, Damian; Goldmuntz, Elizabeth; Bassett, Anne S; Morrow, Bernice E; Emanuel, Beverly S

    2016-03-01

    The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS; MIM #192430; 188400) is the most common microdeletion syndrome. The phenotypic presentation of 22q11DS is highly variable; approximately 60-75 % of 22q11DS patients have been reported to have a congenital heart defect (CHD), mostly of the conotruncal type, and/or aortic arch defect. The etiology of the cardiac phenotypic variability is not currently known for the majority of patients. We hypothesized that rare copy number variants (CNVs) outside the 22q11.2 deleted region may modify the risk of being born with a CHD in this sensitized population. Rare CNV analysis was performed using Affymetrix SNP Array 6.0 data from 946 22q11DS subjects with CHDs (n = 607) or with normal cardiac anatomy (n = 339). Although there was no significant difference in the overall burden of rare CNVs, an overabundance of CNVs affecting cardiac-related genes was detected in 22q11DS individuals with CHDs. When the rare CNVs were examined with regard to gene interactions, specific cardiac networks, such as Wnt signaling, appear to be overrepresented in 22q11DS CHD cases but not 22q11DS controls with a normal heart. Collectively, these data suggest that CNVs outside the 22q11.2 region may contain genes that modify risk for CHDs in some 22q11DS patients.

  9. Case history and genome-wide scans for copy number variants in a family with patient having 15q11.1-q11.2 duplication and 22q11.2 deletion, and schizophrenia.

    PubMed

    Takahashi, Sakae; Suzuki, Takahiro; Nakamura-Tomizuka, Sakura; Osaki, Koichi; Sotome, Yuta; Sagawa, Tomoaki; Uchiyama, Makoto

    2015-06-01

    Many studies have indicated that chromosomes 15q11 and 22q11 may be associated with the genetic etiologies of schizophrenia. We have followed an adult schizophrenia case with 15q11.1-q11.2 duplication and 22q11.2 deletion. Here we report his clinical history, and copy number variants (CNVs) identified by microarray and real-time PCR in the patient and his parents. This is the first report describing a detailed phenotype of an adult schizophrenic case with both 15q11 and 22q11 CNVs as revealed by novel and trustworthy technologies. Subjects were a 33-year-old male patient with 15q11 and 22q11 CNVs, and his normal parents. He fulfilled the DSM-IV criteria for schizophrenia at age 18 years. He was also diagnosed with 22q11.2 deletion syndrome by fluorescence in situ hybridization (FISH) at age 18 years. To search for CNVs in more detail, whole-genome array-CGH analyses including ∼ 420,000 probes were carried out in the patient and his parents. For validations of the CNVs detected by array-CGH, real-time PCR analyses of these CNVs were performed. The patient had two disease-specific CNVs, 15q11.1-q11.2 duplication (∼ 2.7 Mb) and 22q11.21 deletion (∼ 2.9 Mb). These two regions are important for the development of schizophrenia, and this patient had shown symptoms of schizophrenia. Thus, the two areas may contain causal genes for schizophrenia. © 2015 Wiley Periodicals, Inc.

  10. Ultradeep Sequencing for Detection of Quasispecies Variants in the Major Hydrophilic Region of Hepatitis B Virus in Indonesian Patients

    PubMed Central

    Yamani, Laura Navika; Utsumi, Takako; Juniastuti; Wandono, Hadi; Widjanarko, Doddy; Triantanoe, Ari; Wasityastuti, Widya; Liang, Yujiao; Okada, Rina; Tanahashi, Toshihito; Murakami, Yoshiki; Azuma, Takeshi; Soetjipto; Lusida, Maria Inge; Hayashi, Yoshitake

    2015-01-01

    Quasispecies of hepatitis B virus (HBV) with variations in the major hydrophilic region (MHR) of the HBV surface antigen (HBsAg) can evolve during infection, allowing HBV to evade neutralizing antibodies. These escape variants may contribute to chronic infections. In this study, we looked for MHR variants in HBV quasispecies using ultradeep sequencing and evaluated the relationship between these variants and clinical manifestations in infected patients. We enrolled 30 Indonesian patients with hepatitis B infection (11 with chronic hepatitis and 19 with advanced liver disease). The most common subgenotype/subtype of HBV was B3/adw (97%). The HBsAg titer was lower in patients with advanced liver disease than that in patients with chronic hepatitis. The MHR variants were grouped based on the percentage of the viral population affected: major, ≥20% of the total population; intermediate, 5% to <20%; and minor, 1% to <5%. The rates of MHR variation that were present in the major and intermediate viral population were significantly greater in patients with advanced liver disease than those in chronic patients. The most frequent MHR variants related to immune evasion in the major and intermediate populations were P120Q/T, T123A, P127T, Q129H/R, M133L/T, and G145R. The major population of MHR variants causing impaired of HBsAg secretion (e.g., G119R, Q129R, T140I, and G145R) was detected only in advanced liver disease patients. This is the first study to use ultradeep sequencing for the detection of MHR variants of HBV quasispecies in Indonesian patients. We found that a greater number of MHR variations was related to disease severity and reduced likelihood of HBsAg titer. PMID:26202119

  11. Interstitial deletion of 8q21-->22 associated with minor anomalies, congenital heart defect, and Dandy-Walker variant.

    PubMed

    Donahue, M L; Ryan, R M

    1995-03-13

    We describe an infant with a deletion of 8q21-->22 who had distinct clinical manifestations including minor facial anomalies, a congenital heart defect, a Dandy-Walker variant, and mild to moderate developmental delay. Her facial characteristics included small, wide-spaced eyes, asymmetric bilateral epicanthal folds, a broad nasal bridge, a "carp-shaped" mouth, micrognathia, and prominent, apparently low-set ears. Three other reports describe children with larger proximal deletions of 8q that include 8q21 and q22. These four children all have similar facial appearance. Of the others reported, one had a congenital heart defect and one had craniosynostosis. This case, in addition to the previously noted three cases, helps in delineating a recognizable syndrome.

  12. 34 CFR 462.2 - What regulations apply?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 3 2011-07-01 2011-07-01 false What regulations apply? 462.2 Section 462.2 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION MEASURING EDUCATIONAL GAIN IN THE NATIONAL REPORTING SYSTEM FOR ADULT EDUCATION...

  13. 34 CFR 462.2 - What regulations apply?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 3 2010-07-01 2010-07-01 false What regulations apply? 462.2 Section 462.2 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF VOCATIONAL AND ADULT EDUCATION, DEPARTMENT OF EDUCATION MEASURING EDUCATIONAL GAIN IN THE NATIONAL REPORTING SYSTEM FOR ADULT EDUCATION...

  14. 27 CFR 46.2 - Meaning of terms.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2011-04-01 2011-04-01 false Meaning of terms. 46.2 Section 46.2 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT... have the meaning ascribed in this section. Administrator. The Administrator, Alcohol and Tobacco Tax...

  15. 27 CFR 46.2 - Meaning of terms.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2013-04-01 2013-04-01 false Meaning of terms. 46.2 Section 46.2 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT... have the meaning ascribed in this section. Administrator. The Administrator, Alcohol and Tobacco Tax...

  16. 27 CFR 46.2 - Meaning of terms.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Meaning of terms. 46.2 Section 46.2 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT... have the meaning ascribed in this section. Administrator. The Administrator, Alcohol and Tobacco Tax...

  17. 27 CFR 46.2 - Meaning of terms.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2012-04-01 2011-04-01 true Meaning of terms. 46.2 Section 46.2 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT... have the meaning ascribed in this section. Administrator. The Administrator, Alcohol and Tobacco Tax...

  18. 27 CFR 46.2 - Meaning of terms.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2014-04-01 2014-04-01 false Meaning of terms. 46.2 Section 46.2 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT... have the meaning ascribed in this section. Administrator. The Administrator, Alcohol and Tobacco Tax...

  19. Non-ventricular, Clinical, and Functional Features of the RyR2(R420Q) Mutation Causing Catecholaminergic Polymorphic Ventricular Tachycardia.

    PubMed

    Domingo, Diana; Neco, Patricia; Fernández-Pons, Elena; Zissimopoulos, Spyros; Molina, Pilar; Olagüe, José; Suárez-Mier, M Paz; Lai, F Anthony; Gómez, Ana M; Zorio, Esther

    2015-05-01

    Catecholaminergic polymorphic ventricular tachycardia is a malignant disease, due to mutations in proteins controlling Ca(2+) homeostasis. While the phenotype is characterized by polymorphic ventricular arrhythmias under stress, supraventricular arrhythmias may occur and are not fully characterized. Twenty-five relatives from a Spanish family with several sudden deaths were evaluated with electrocardiogram, exercise testing, and optional epinephrine challenge. Selective RyR2 sequencing in an affected individual and cascade screening in the rest of the family was offered. The RyR2(R420Q) mutation was generated in HEK-293 cells using site-directed mutagenesis to conduct in vitro functional studies. The exercise testing unmasked catecholaminergic polymorphic ventricular tachycardia in 8 relatives (sensitivity = 89%; positive predictive value = 100%; negative predictive value = 93%), all of them carrying the heterozygous RyR2(R420Q) mutation, which was also present in the proband and a young girl without exercise testing, a 91% penetrance at the end of the follow-up. Remarkably, sinus bradycardia, atrial and junctional arrhythmias, and/or giant post-effort U-waves were identified in patients. Upon permeabilization and in intact cells, the RyR2(R420Q) expressing cells showed a smaller peak of Ca(2+) release than RyR2 wild-type cells. However, at physiologic intracellular Ca(2+) concentration, equivalent to the diastolic cytosolic concentration, the RyR2(R420Q) released more Ca(2+) and oscillated faster than RyR2 wild-type cells. The missense RyR2(R420Q) mutation was identified in the N-terminus of the RyR2 gene in this highly symptomatic family. Remarkably, this mutation is associated with sinus bradycardia, atrial and junctional arrhythmias, and giant U-waves. Collectively, functional heterologous expression studies suggest that the RyR2(R420Q) behaves as an aberrant channel, as a loss- or gain-of-function mutation depending on cytosolic intracellular Ca(2

  20. Effects of a 17q21 chromosome gene variant, tobacco smoke and furred pets on infant wheeze.

    PubMed

    Bräuner, E V; Loft, S; Raaschou-Nielsen, O; Vogel, U; Andersen, P S; Sørensen, M

    2012-01-01

    The first common genetic factor identified for pediatric asthma by genome-wide association is the chromosome 17q21 locus, harbouring the ORMDL3 gene. ORMDL3 is involved in facilitation of endoplasmic reticulum-mediated inflammatory responses, believed to underlie its asthma association. We investigated associations between the rs7216389 polymorphism in the 17q21 locus affecting ORMDL3 expression and the risk for recurrent wheeze and interactions with exposure to tobacco smoke and furred pets during pregnancy and infancy using a birth cohort of 101,042 infants. Rs7216389 was significantly associated with recurrent wheeze risk among 18-month-old infants. There was a 1.35-fold higher risk of recurrent wheeze among homozygous variant allele carriers compared with homozygous wild-type allele carriers. There was significant interaction between rs7216389 and domestic furred pets, with a positive association between pets and wheeze among homozygous wild-type carriers and a negative association among homozygous variant allele carriers. There was no interaction between rs7216389 and tobacco smoke exposure.

  1. Analysis of Shared Haplotypes amongst Palauans Maps Loci for Psychotic Disorders to 4q28 and 5q23-q31.

    PubMed

    Bodea, Corneliu A; Middleton, Frank A; Melhem, Nadine M; Klei, Lambertus; Song, Youeun; Tiobech, Josepha; Marumoto, Pearl; Yano, Victor; Faraone, Stephen V; Roeder, Kathryn; Myles-Worsley, Marina; Devlin, Bernie; Byerley, William

    2017-02-01

    To localize genetic variation affecting risk for psychotic disorders in the population of Palau, we genotyped DNA samples from 203 Palauan individuals diagnosed with psychotic disorders, broadly defined, and 125 control subjects using a genome-wide single nucleotide polymorphism array. Palau has unique features advantageous for this study: due to its population history, Palauans are substantially interrelated; affected individuals often, but not always, cluster in families; and we have essentially complete ascertainment of affected individuals. To localize risk variants to genomic regions, we evaluated long-shared haplotypes, ≥10 Mb, identifying clusters of affected individuals who share such haplotypes. This extensive sharing, typically identical by descent, was significantly greater in cases than population controls, even after controlling for relatedness. Several regions of the genome exhibited substantial excess of shared haplotypes for affected individuals, including 3p21, 3p12, 4q28, and 5q23-q31. Two of these regions, 4q28 and 5q23-q31, showed significant linkage by traditional LOD score analysis and could harbor variants of more sizeable risk for psychosis or a multiplicity of risk variants. The pattern of haplotype sharing in 4q28 highlights PCDH10 , encoding a cadherin-related neuronal receptor, as possibly involved in risk.

  2. Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria

    PubMed Central

    Magallón-Tejada, Ariel; Machevo, Sónia; Cisteró, Pau; Lavstsen, Thomas; Aide, Pedro; Jiménez, Alfons; Turner, Louise; Gupta, Himanshu; De Las Salas, Briegel; Mandomando, Inacio; Wang, Christian W.; Petersen, Jens E. V.; Muñoz, Jose; Gascón, Joaquim; Macete, Eusebio; Alonso, Pedro L.; Chitnis, Chetan E.

    2016-01-01

    Cytoadhesion of Plasmodium falciparum infected erythrocytes to gC1qR has been associated with severe malaria, but the parasite ligand involved is currently unknown. To assess if binding to gC1qR is mediated through the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, we analyzed by static binding assays and qPCR the cytoadhesion and var gene transcriptional profile of 86 P. falciparum isolates from Mozambican children with severe and uncomplicated malaria, as well as of a P. falciparum 3D7 line selected for binding to gC1qR (Pf3D7gC1qR). Transcript levels of DC8 correlated positively with cytoadhesion to gC1qR (rho = 0.287, P = 0.007), were higher in isolates from children with severe anemia than with uncomplicated malaria, as well as in isolates from Europeans presenting a first episode of malaria (n = 21) than Mozambican adults (n = 25), and were associated with an increased IgG recognition of infected erythrocytes by flow cytometry. Pf3D7gC1qR overexpressed the DC8 type PFD0020c (5.3-fold transcript levels relative to Seryl-tRNA-synthetase gene) compared to the unselected line (0.001-fold). DBLβ12 from PFD0020c bound to gC1qR in ELISA-based binding assays and polyclonal antibodies against this domain were able to inhibit binding to gC1qR of Pf3D7gC1qR and four Mozambican P. falciparum isolates by 50%. Our results show that DC8-type PfEMP1s mediate binding to gC1qR through conserved surface epitopes in DBLβ12 domain which can be inhibited by strain-transcending functional antibodies. This study supports a key role for gC1qR in malaria-associated endovascular pathogenesis and suggests the feasibility of designing interventions against severe malaria targeting this specific interaction. PMID:27835682

  3. VaDiR: an integrated approach to Variant Detection in RNA.

    PubMed

    Neums, Lisa; Suenaga, Seiji; Beyerlein, Peter; Anders, Sara; Koestler, Devin; Mariani, Andrea; Chien, Jeremy

    2018-02-01

    Advances in next-generation DNA sequencing technologies are now enabling detailed characterization of sequence variations in cancer genomes. With whole-genome sequencing, variations in coding and non-coding sequences can be discovered. But the cost associated with it is currently limiting its general use in research. Whole-exome sequencing is used to characterize sequence variations in coding regions, but the cost associated with capture reagents and biases in capture rate limit its full use in research. Additional limitations include uncertainty in assigning the functional significance of the mutations when these mutations are observed in the non-coding region or in genes that are not expressed in cancer tissue. We investigated the feasibility of uncovering mutations from expressed genes using RNA sequencing datasets with a method called Variant Detection in RNA(VaDiR) that integrates 3 variant callers, namely: SNPiR, RVBoost, and MuTect2. The combination of all 3 methods, which we called Tier 1 variants, produced the highest precision with true positive mutations from RNA-seq that could be validated at the DNA level. We also found that the integration of Tier 1 variants with those called by MuTect2 and SNPiR produced the highest recall with acceptable precision. Finally, we observed a higher rate of mutation discovery in genes that are expressed at higher levels. Our method, VaDiR, provides a possibility of uncovering mutations from RNA sequencing datasets that could be useful in further functional analysis. In addition, our approach allows orthogonal validation of DNA-based mutation discovery by providing complementary sequence variation analysis from paired RNA/DNA sequencing datasets.

  4. Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression.

    PubMed

    Sirkis, Daniel W; Bonham, Luke W; Aparicio, Renan E; Geier, Ethan G; Ramos, Eliana Marisa; Wang, Qing; Karydas, Anna; Miller, Zachary A; Miller, Bruce L; Coppola, Giovanni; Yokoyama, Jennifer S

    2016-09-02

    Rare variation in TREM2 has been associated with greater risk for Alzheimer's disease (AD). TREM2 encodes a cell surface receptor expressed on microglia and related cells, and the R47H variant associated with AD appears to affect the ability of TREM2 to bind extracellular ligands. In addition, other rare TREM2 mutations causing early-onset neurodegeneration are thought to impair cell surface expression. Using a sequence kernel association (SKAT) analysis in two independent AD cohorts, we found significant enrichment of rare TREM2 variants not previously characterized at the protein level. Heterologous expression of the identified variants showed that novel variants S31F and R47C displayed significantly reduced cell surface expression. In addition, we identified rare variant R136Q in a patient with language-predominant AD that also showed impaired surface expression. The results suggest rare TREM2 variants enriched in AD may be associated with altered TREM2 function and that AD risk may be conferred, in part, from altered TREM2 surface expression.

  5. Relationship between the melanocortin-1 receptor (MC1R) variant R306ter and physiological responses to mechanical or thermal stimuli in Labrador Retriever dogs.

    PubMed

    Perez, Tania E; Mealey, Katrina L; Burke, Neal S; Grubb, Tamara L; Court, Michael H; Greene, Stephen A

    2017-03-01

    Variants in the MC1R gene have been associated with red hair color and sensitivity to pain in humans. The study objective was to determine if a relationship exists between MC1R genotype and physiological thermal or mechanical nociceptive thresholds in Labrador Retriever dogs. Prospective experimental study. Thirty-four Labrador Retriever dogs were included in the study following public requests for volunteers. Owner consent was obtained and owners verified that their dog was apparently not experiencing pain and had not been treated for pain during the previous 14 days. The study was approved by the Institutional Animal Care and Use Committee. Nociceptive thresholds were determined from a mean of three thermal and five mechanical replications using commercially available algometers. Each dog was genotyped for the previously described MC1R variant (R306ter). Data were analyzed using one-way anova with post hoc comparisons using Tukey's test (p < 0.05). Thirteen dogs were homozygous wild-type (WT/WT), nine were heterozygous (WT/R306ter), and eight were homozygous variant (R306ter/R306ter) genotype. Four dogs could not be genotyped. A significant difference (p = 0.04) in mechanical nociceptive thresholds was identified between dogs with the WT/WT genotype (12.1±2.1 N) and those with the WT/R306ter genotype (9.2±2.4 N). A difference in mechanical, but not thermal, nociceptive threshold was observed between wild-type and heterozygous MC1R variants. Differences in nociceptive thresholds between homozygous R306ter variants and other genotypes for MC1R were not observed. Compared with the wild-type MC1R genotype, nociceptive sensitivity to mechanical force in dogs with a single variant R306ter allele may be greater. However, in contrast to the reported association between homozygous MC1R variants (associated with red hair color) and nociception in humans, we found no evidence of a similar relationship in dogs with the homozygous variant genotype. Copyright © 2017

  6. BigQ: a NoSQL based framework to handle genomic variants in i2b2.

    PubMed

    Gabetta, Matteo; Limongelli, Ivan; Rizzo, Ettore; Riva, Alberto; Segagni, Daniele; Bellazzi, Riccardo

    2015-12-29

    Precision medicine requires the tight integration of clinical and molecular data. To this end, it is mandatory to define proper technological solutions able to manage the overwhelming amount of high throughput genomic data needed to test associations between genomic signatures and human phenotypes. The i2b2 Center (Informatics for Integrating Biology and the Bedside) has developed a widely internationally adopted framework to use existing clinical data for discovery research that can help the definition of precision medicine interventions when coupled with genetic data. i2b2 can be significantly advanced by designing efficient management solutions of Next Generation Sequencing data. We developed BigQ, an extension of the i2b2 framework, which integrates patient clinical phenotypes with genomic variant profiles generated by Next Generation Sequencing. A visual programming i2b2 plugin allows retrieving variants belonging to the patients in a cohort by applying filters on genomic variant annotations. We report an evaluation of the query performance of our system on more than 11 million variants, showing that the implemented solution scales linearly in terms of query time and disk space with the number of variants. In this paper we describe a new i2b2 web service composed of an efficient and scalable document-based database that manages annotations of genomic variants and of a visual programming plug-in designed to dynamically perform queries on clinical and genetic data. The system therefore allows managing the fast growing volume of genomic variants and can be used to integrate heterogeneous genomic annotations.

  7. Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H.

    PubMed

    Mulkey, Sarah B; Ben-Zeev, Bruria; Nicolai, Joost; Carroll, John L; Grønborg, Sabine; Jiang, Yong-Hui; Joshi, Nishtha; Kelly, Megan; Koolen, David A; Mikati, Mohamad A; Park, Kristen; Pearl, Phillip L; Scheffer, Ingrid E; Spillmann, Rebecca C; Taglialatela, Maurizio; Vieker, Silvia; Weckhuysen, Sarah; Cooper, Edward C; Cilio, Maria Roberta

    2017-03-01

    To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome. Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course. Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism. Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted therapeutic approaches. Wiley Periodicals

  8. Mechanism and prognostic role of qR in V1 in patients with pulmonary arterial hypertension.

    PubMed

    Waligóra, Marcin; Kopeć, Grzegorz; Jonas, Kamil; Tyrka, Anna; Sarnecka, Agnieszka; Miszalski-Jamka, Tomasz; Urbańczyk-Zawadzka, Małgorzata; Podolec, Piotr

    The presence of qR pattern in lead V 1 of the 12-lead surface ECG has been proposed as a risk marker of death in patients with pulmonary arterial hypertension (PAH). We aimed to validate these findings in the modern era of PAH treatment and additionally to assess the relation of qR in V 1 to PAH severity. We also investigated the possible mechanisms underlying this ECG sign. Consecutive patients with PAH excluding patients with congenital heart defect were recruited between February 2008 and January 2016. A 12-lead standard ECG was acquired and analyzed for the presence of qR in V 1 and other potential prognostic patterns. Cardiac magnetic resonance and echocardiography were used for structural (masses and volumes) and functional (ejection fraction, eccentricity index) characterization of left (LV) and right (RV) ventricles. Standard markers of PAH severity were also assessed. We enrolled 66 patients (19 males), aged 50.0±15.7years with idiopathic PAH (n=52) and PAH associated with connective tissue disease (n=14). qR in V 1 was present in 26(39.4%) patients and was associated with worse functional capacity, hemodynamics and RV function. The main structural determinants of qR in V 1 were RV to LV volume ratio (OR: 3.99; 95% CI: 1.47-10.8, p=0.007) and diastolic eccentricity index (OR: 15.0; 95% CI: 1.29-175.5, p=0.03). During observation time of 30.5±19.4months, 20 (30.3%) patient died, 13 (50%) patients with qR and 7 (17.5%) patients without qR pattern. Electrocardiographic determinants of survival were qR (HR: 3.06, 95% CI: 1.21-7.4; p=0.02) and QRS duration (HR: 1.02, 95% CI: 1.01-1.04; p=0.01). Presence of qR in V 1 reflects RV dilation and diastolic interventricular septum flattening. It is a sign of advanced PAH and predicts the risk of death in this population. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Novel variants of the 5S rRNA genes in Eruca sativa.

    PubMed

    Singh, K; Bhatia, S; Lakshmikumaran, M

    1994-02-01

    The 5S ribosomal RNA (rRNA) genes of Eruca sativa were cloned and characterized. They are organized into clusters of tandemly repeated units. Each repeat unit consists of a 119-bp coding region followed by a noncoding spacer region that separates it from the coding region of the next repeat unit. Our study reports novel gene variants of the 5S rRNA genes in plants. Two families of the 5S rDNA, the 0.5-kb size family and the 1-kb size family, coexist in the E. sativa genome. The 0.5-kb size family consists of the 5S rRNA genes (S4) that have coding regions similar to those of other reported plant 5S rDNA sequences, whereas the 1-kb size family consists of the 5S rRNA gene variants (S1) that exist as 1-kb BamHI tandem repeats. S1 is made up of two variant units (V1 and V2) of 5S rDNA where the BamHI site between the two units is mutated. Sequence heterogeneity among S4, V1, and V2 units exists throughout the sequence and is not limited to the noncoding spacer region only. The coding regions of V1 and V2 show approximately 20% dissimilarity to the coding regions of S4 and other reported plant 5S rDNA sequences. Such a large variation in the coding regions of the 5S rDNA units within the same plant species has been observed for the first time. Restriction site variation is observed between the two size classes of 5S rDNA in E. sativa.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Interstitial deletion of 8q21{yields}22 associated with minor anomalies, congenital heart defect, and Dandy-Walker variant

    SciTech Connect

    Donahue, M.L.; Ryan, R.M.

    1995-03-13

    We describe an infant with a deletion of 8q21{yields}22 who had distinct clinical manifestations including minor facial anomalies, a congenital heart defect, a Dandy-Walker variant, and mild to moderate developmental delay. Her facial characteristics included small, wide-spaced eyes, asymmetric bilateral epicanthal folds, a broad nasal bridge, a {open_quotes}carp-shaped{close_quotes} mouth, micrognathia, and prominent, apparently low-set ears. Three other reports describe children with larger proximal deletions of 8q that include 8q21 and q22. These four children all have similar facial appearance. Of the others reported, one had a congenital heart defect and one had craniosynostosis. This case, in addition to the previouslymore » noted three cases, helps in delineating a recognizable syndrome. 12 refs., 3 figs., 1 tab.« less

  11. 42 CFR 441.462 - Statewideness, comparability and limitations on number served.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... number served. 441.462 Section 441.462 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT....462 Statewideness, comparability and limitations on number served. A State may do the following: (a) Provide self-directed PAS without regard to the requirements of statewideness. (b) Limit the population...

  12. 42 CFR 441.462 - Statewideness, comparability and limitations on number served.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... number served. 441.462 Section 441.462 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT....462 Statewideness, comparability and limitations on number served. A State may do the following: (a) Provide self-directed PAS without regard to the requirements of statewideness. (b) Limit the population...

  13. 42 CFR 441.462 - Statewideness, comparability and limitations on number served.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... number served. 441.462 Section 441.462 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT....462 Statewideness, comparability and limitations on number served. A State may do the following: (a) Provide self-directed PAS without regard to the requirements of statewideness. (b) Limit the population...

  14. 42 CFR 441.462 - Statewideness, comparability and limitations on number served.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... number served. 441.462 Section 441.462 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT....462 Statewideness, comparability and limitations on number served. A State may do the following: (a) Provide self-directed PAS without regard to the requirements of statewideness. (b) Limit the population...

  15. Solving the scalability issue in quantum-based refinement: Q|R#1.

    PubMed

    Zheng, Min; Moriarty, Nigel W; Xu, Yanting; Reimers, Jeffrey R; Afonine, Pavel V; Waller, Mark P

    2017-12-01

    Accurately refining biomacromolecules using a quantum-chemical method is challenging because the cost of a quantum-chemical calculation scales approximately as n m , where n is the number of atoms and m (≥3) is based on the quantum method of choice. This fundamental problem means that quantum-chemical calculations become intractable when the size of the system requires more computational resources than are available. In the development of the software package called Q|R, this issue is referred to as Q|R#1. A divide-and-conquer approach has been developed that fragments the atomic model into small manageable pieces in order to solve Q|R#1. Firstly, the atomic model of a crystal structure is analyzed to detect noncovalent interactions between residues, and the results of the analysis are represented as an interaction graph. Secondly, a graph-clustering algorithm is used to partition the interaction graph into a set of clusters in such a way as to minimize disruption to the noncovalent interaction network. Thirdly, the environment surrounding each individual cluster is analyzed and any residue that is interacting with a particular cluster is assigned to the buffer region of that particular cluster. A fragment is defined as a cluster plus its buffer region. The gradients for all atoms from each of the fragments are computed, and only the gradients from each cluster are combined to create the total gradients. A quantum-based refinement is carried out using the total gradients as chemical restraints. In order to validate this interaction graph-based fragmentation approach in Q|R, the entire atomic model of an amyloid cross-β spine crystal structure (PDB entry 2oNA) was refined.

  16. Methods for measuring serum activity levels of the 192 Q and R isoenzymes of paraoxonase 1 in QR heterozygous individuals.

    PubMed

    Teiber, John F; Kramer, Gerald L; Haley, Robert W

    2013-08-01

    Paraoxonase 1 (PON1), an esterase that hydrolyzes toxic organophosphates and has antioxidative and antiatherogenic properties, contains a common polymorphism at position 192: glutamine (Q) or arginine (R). The Q and R isoenzymes exhibit different physical and protective properties. We describe 2 methods for quantifying their serum activity levels. We measured serum hydrolytic activity with paraoxon [paraoxonase (PXN) activity], phenylacetate [arylesterase (AE) activity], and diazoxon [diazoxonase (DZN) activity] with standard automated assays. We determined PON1 Q192R genotypes with PCR and Q192R phenotypes using the PXN/AE and PXN/DZN ratios. Interpolation equations were empirically derived to predict the percentage of total PON1 hydrolytic activity due to the Q isoenzyme (%Q) from the PXN/AE and PXN/DZN ratios; %R is 100 - %Q. We estimated Q and R isoenzyme activity levels in sera from 2095 veterans by multiplying AE activity, a measure of total PON1 hydrolytic activity, by %Q and %R. In all 2095 samples, the PXN/AE and PXN/DZN ratios predicted Q192R phenotypes with nearly identical accuracy (κ = 0.997). In the 925 QR heterozygotes, the 2 interpolation methods predicted Q and R isoenzyme activity levels with excellent agreement (intraclass correlation 0.94). After excluding a few genotype/phenotype-discordant samples, the percentage of total PON1 activity due to the Q isoenzyme ranged from 22% to 70%. These new interpolation methods allow accurate estimation of PON1 192 Q and R isoenzyme activity levels, increasing specificity and power for studying susceptibility to disease.

  17. Zinc induces exposure of hydrophobic sites in the C-terminal domain of gC1q-R/p33.

    PubMed

    Kumar, Rajeev; Peerschke, Ellinor I B; Ghebrehiwet, Berhane

    2002-09-01

    Endothelial cells and platelets are known to express gC1q-R on their surface. In addition to C1q, endothelial cell gC1q-R has been shown to bind high molecular weight kininogen (HK) and factor XII (FXII). However, unlike C1q, whose interaction with gC1q-R does not require divalent ions, the binding of HK to gC1q-R is absolutely dependent on the presence of zinc. However, the mechanism by which zinc modulates this interaction is not fully understood. To investigate the role of zinc, binding studies were done using the hydrophobic dye, bis-ANS. The fluorescence intensity of bis-ANS, greatly increases and the emission maximum is blue-shifted from 525 to 485nm upon binding to hydrophobic sites on proteins. In this report, we show that a blue-shift in emission maximum is also observed when bis-ANS binds to gC1q-R in the presence but not in the absence of zinc suggesting that zinc induces exposure of hydrophobic sites in the molecule. The binding of bis-ANS to gC1q-R is specific, dose-dependent, and reversible. In the presence of zinc, this binding is abrogated by monoclonal antibody 74.5.2 directed against gC1q-R residues 204-218. This segment of gC1q-R, which corresponds to the beta6 strand in the crystal structure, has been shown previously to be the binding site for HK. A similar trend in zinc-induced gC1q-R binding was also observed using the hydrophobic matrix octyl-Sepharose. Taken together, our data suggest that zinc can induce the exposure of hydrophobic sites in the C-terminal domain of gC1q-R involved in binding to HK/FXII.

  18. RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells

    PubMed Central

    Dayal, Shubham; Zhou, Jun; Manivannan, Praveen; Siddiqui, Mohammad Adnan; Ahmad, Omaima Farid; Clark, Matthew; Awadia, Sahezeel; Garcia-Mata, Rafael; Shemshedini, Lirim; Malathi, Krishnamurthy

    2017-01-01

    The interferon antiviral pathways and prostate cancer genetics converge on a regulated endoribonuclease, RNase L. Positional cloning and linkage studies mapped Hereditary Prostate Cancer 1 (HPC1) to RNASEL. To date, there is no correlation of viral infections with prostate cancer, suggesting that RNase L may play additional roles in tumor suppression. Here, we demonstrate a role of RNase L as a suppressor of androgen receptor (AR) signaling, cell migration and matrix metalloproteinase activity. Using RNase L mutants, we show that its nucleolytic activity is dispensable for both AR signaling and migration. The most prevalent HPC1-associated mutations in RNase L, R462Q and E265X, enhance AR signaling and cell migration. RNase L negatively regulates cell migration and attachment on various extracellular matrices. We demonstrate that RNase L knockdown cells promote increased cell surface expression of integrin β1 which activates Focal Adhesion Kinase-Sarcoma (FAK-Src) pathway and Ras-related C3 botulinum toxin substrate 1-guanosine triphosphatase (Rac1-GTPase) activity to increase cell migration. Activity of matrix metalloproteinase (MMP)-2 and -9 is significantly increased in cells where RNase L levels are ablated. We show that mutations in RNase L found in HPC patients may promote prostate cancer by increasing expression of AR-responsive genes and cell motility and identify novel roles of RNase L as a prostate cancer susceptibility gene. PMID:28257035

  19. Functional paraoxonase 1 variants modify the risk of Parkinson's disease due to organophosphate exposure.

    PubMed

    Lee, Pei-Chen; Rhodes, Shannon L; Sinsheimer, Janet S; Bronstein, Jeff; Ritz, Beate

    2013-06-01

    We previously demonstrated that carriers of the "slower metabolizer" MM genotype of paraoxonase (PON1) who were also exposed to ambient organophosphate (OP) pesticides at their residences were at increased risk of developing Parkinson's disease (PD). Here, with a larger sample size, we extend our previous investigation to consider additional sources of ambient exposure and examined two additional functional PON1 variants. From 2001 to 2011, we enrolled incident cases of idiopathic PD and population controls living in central California. We genotyped three well-known functional PON1 SNPs: two exonic polymorphisms (PON1L55M and PON1Q192R) and the promoter region variant (PON1C-108T). Ambient exposures to diazinon, chlorpyrifos, and parathion at residential and workplace addresses were assessed using a validated geographic information system-based model incorporating records of agricultural pesticide applications in California. The odds ratio (OR) for Caucasians exposed to OPs at either residential or workplace addresses varied by PON1 genotype; for exposed carriers of the "faster" metabolizer genotypes, ML or LL, we estimated lower odds ratios (range, 1.20-1.39) than for exposed carriers of the "slower" metabolizer genotype MM (range, 1.78-2.45) relative to unexposed carriers of the faster genotypes. We observed similarly increased ORs for exposure across PON1Q192R genotypes, but no differences across PON1C-108T genotypes. The largest ORs were estimated for exposed carriers of both PON1192QQ and PON155MM (OR range, 2.84-3.57). Several functional PON1 variants may act together to modify PD risk for ambient OP exposures. While either PON1L55M or PON1Q192R may be sufficient to identify increased susceptibility, carriers of both slow metabolizer variants seem most susceptible to OP exposures. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study.

    PubMed

    Criado-García, Juan; Fuentes, Francisco; Cruz-Teno, Cristina; García-Rios, Antonio; Jiménez-Morales, Anabel; Delgado-Lista, Javier; Mata, Pedro; Alonso, Rodrigo; López-Miranda, José; Pérez-Jiménez, Francisco

    2011-04-09

    Heterozygous Familial Hypercholesterolemia (FH) is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH. This case-control study comprised 720 patients (546 with FH and 174 controls). We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag) and whether they could be predictive factors for cardiovascular risk. 75% (410) of the patients with FH were RR, 23% (127) RQ and 1.6% (9) QQ; in the control group 75.3% (131) were RR, 21.3% (37) RQ and 3.4% (6) QQ (p = 0.32). No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH) and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease), either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96). In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97). Our study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels.

  1. Fusion of Huntingtin interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2).

    PubMed

    Ross, T S; Bernard, O A; Berger, R; Gilliland, D G

    1998-06-15

    We report the fusion of the Huntingtin interactin protein 1 (HIP1) gene to the platelet-derived growth factor betareceptor (PDGFbetaR) gene in a patient with chronic myelomonocytic leukemia (CMML) with a t(5;7)(q33;q11.2) translocation. Southern blot analysis of patient bone marrow cells with a PDGFbetaR gene probe demonstrated rearrangement of the PDGFbetaR gene. Anchored polymerase chain reaction using PDGFbetaR primers identified a chimeric transcript containing the HIP1 gene located at 7q11.2 fused to the PDGFbetaR gene on 5q33. HIP1 is a 116-kD protein recently cloned by yeast two-hybrid screening for proteins that interact with Huntingtin, the mutated protein in Huntington's disease. The consequence of t(5;7)(q33;q11.2) is an HIP1/PDGFbetaR fusion gene that encodes amino acids 1 to 950 of HIP1 joined in-frame to the transmembrane and tyrosine kinase domains of the PDGFbetaR. The reciprocal PDGFbetaR/HIP1 transcript is not expressed. HIP1/PDGFbetaR is a 180-kD protein when expressed in the murine hematopoietic cell line, Ba/F3, and is constitutively tyrosine phosphorylated. Furthermore, HIP1/PDGFbetaR transforms the Ba/F3 cells to interleukin-3-independent growth. These data are consistent with an alternative mechanism for activation of PDGFbetaR tyrosine kinase activity by fusion with HIP1, leading to transformation of hematopoietic cells, and may implicate Huntingtin or HIP1 in the pathogenesis of hematopoietic malignancies.

  2. Structural analysis of two length variants of the rDNA intergenic spacer from Eruca sativa.

    PubMed

    Lakshmikumaran, M; Negi, M S

    1994-03-01

    Restriction enzyme analysis of the rRNA genes of Eruca sativa indicated the presence of many length variants within a single plant and also between different cultivars which is unusual for most crucifers studied so far. Two length variants of the rDNA intergenic spacer (IGS) from a single individual E. sativa (cv. Itsa) plant were cloned and characterized. The complete nucleotide sequences of both the variants (3 kb and 4 kb) were determined. The intergenic spacer contains three families of tandemly repeated DNA sequences denoted as A, B and C. However, the long (4 kb) variant shows the presence of an additional repeat, denoted as D, which is a duplication of a 224 bp sequence just upstream of the putative transcription initiation site. Repeat units belonging to the three different families (A, B and C) were in the size range of 22 to 30 bp. Such short repeat elements are present in the IGS of most of the crucifers analysed so far. Sequence analysis of the variants (3 kb and 4 kb) revealed that the length heterogeneity of the spacer is located at three different regions and is due to the varying copy numbers of repeat units belonging to families A and B. Length variation of the spacer is also due to the presence of a large duplication (D repeats) in the 4 kb variant which is absent in the 3 kb variant. The putative transcription initiation site was identified by comparisons with the rDNA sequences from other plant species.

  3. 12 CFR 4.62 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... AND RELEASE OF INFORMATION, CONTRACTING OUTREACH PROGRAM, POST-EMPLOYMENT RESTRICTIONS FOR SENIOR EXAMINERS Minority- , Women- , and Individuals With Disabilities-Owned Business Contracting Outreach Program; Contracting for Goods and Services § 4.62 Definitions. (a) Minority- and/or women-owned (small and large...

  4. 25 CFR 46.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... formal secondary or post-secondary educational program. Adult Basic Education (ABE) means instruction... AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION ADULT EDUCATION PROGRAM General Provisions § 46.2... Education means services or instruction below the college level for adults who: (1) Lack sufficient mastery...

  5. 25 CFR 46.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... formal secondary or post-secondary educational program. Adult Basic Education (ABE) means instruction... AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION ADULT EDUCATION PROGRAM General Provisions § 46.2... Education means services or instruction below the college level for adults who: (1) Lack sufficient mastery...

  6. 25 CFR 46.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... formal secondary or post-secondary educational program. Adult Basic Education (ABE) means instruction... AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION ADULT EDUCATION PROGRAM General Provisions § 46.2... Education means services or instruction below the college level for adults who: (1) Lack sufficient mastery...

  7. 25 CFR 46.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... formal secondary or post-secondary educational program. Adult Basic Education (ABE) means instruction... AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION ADULT EDUCATION PROGRAM General Provisions § 46.2... Education means services or instruction below the college level for adults who: (1) Lack sufficient mastery...

  8. 25 CFR 46.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... formal secondary or post-secondary educational program. Adult Basic Education (ABE) means instruction... AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION ADULT EDUCATION PROGRAM General Provisions § 46.2... Education means services or instruction below the college level for adults who: (1) Lack sufficient mastery...

  9. Association of MC4R variants with obesity-related traits in Hispanic children

    USDA-ARS?s Scientific Manuscript database

    Melanocortin 4 receptor (MC4R) has been implicated in the regulation of appetite and energy expenditure. In children, MC4R mutations have been associated with severe obesity. The main objective of this study was to investigate the potential functional effects of variants in MC4R gene on the variatio...

  10. 30 CFR 250.462 - What are the requirements for well-control drills?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... drills? 250.462 Section 250.462 Mineral Resources BUREAU OF SAFETY AND ENVIRONMENTAL ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Other Drilling Requirements § 250.462 What are the requirements for well...

  11. 30 CFR 250.462 - What are the requirements for well-control drills?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... drills? 250.462 Section 250.462 Mineral Resources BUREAU OF SAFETY AND ENVIRONMENTAL ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Other Drilling Requirements § 250.462 What are the requirements for well...

  12. 30 CFR 250.462 - What are the requirements for well-control drills?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... drills? 250.462 Section 250.462 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, REGULATION, AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Other Drilling Requirements § 250.462 What are the requirements...

  13. 30 CFR 250.462 - What are the requirements for well-control drills?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... drills? 250.462 Section 250.462 Mineral Resources BUREAU OF SAFETY AND ENVIRONMENTAL ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Other Drilling Requirements § 250.462 What are the requirements for well...

  14. Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies.

    PubMed

    Abnet, Christian C; Wang, Zhaoming; Song, Xin; Hu, Nan; Zhou, Fu-You; Freedman, Neal D; Li, Xue-Min; Yu, Kai; Shu, Xiao-Ou; Yuan, Jian-Min; Zheng, Wei; Dawsey, Sanford M; Liao, Linda M; Lee, Maxwell P; Ding, Ti; Qiao, You-Lin; Gao, Yu-Tang; Koh, Woon-Puay; Xiang, Yong-Bing; Tang, Ze-Zhong; Fan, Jin-Hu; Chung, Charles C; Wang, Chaoyu; Wheeler, William; Yeager, Meredith; Yuenger, Jeff; Hutchinson, Amy; Jacobs, Kevin B; Giffen, Carol A; Burdett, Laurie; Fraumeni, Joseph F; Tucker, Margaret A; Chow, Wong-Ho; Zhao, Xue-Ke; Li, Jiang-Man; Li, Ai-Li; Sun, Liang-Dan; Wei, Wu; Li, Ji-Lin; Zhang, Peng; Li, Hong-Lei; Cui, Wen-Yan; Wang, Wei-Peng; Liu, Zhi-Cai; Yang, Xia; Fu, Wen-Jing; Cui, Ji-Li; Lin, Hong-Li; Zhu, Wen-Liang; Liu, Min; Chen, Xi; Chen, Jie; Guo, Li; Han, Jing-Jing; Zhou, Sheng-Li; Huang, Jia; Wu, Yue; Yuan, Chao; Huang, Jing; Ji, Ai-Fang; Kul, Jian-Wei; Fan, Zhong-Min; Wang, Jian-Po; Zhang, Dong-Yun; Zhang, Lian-Qun; Zhang, Wei; Chen, Yuan-Fang; Ren, Jing-Li; Li, Xiu-Min; Dong, Jin-Cheng; Xing, Guo-Lan; Guo, Zhi-Gang; Yang, Jian-Xue; Mao, Yi-Ming; Yuan, Yuan; Guo, Er-Tao; Zhang, Wei; Hou, Zhi-Chao; Liu, Jing; Li, Yan; Tang, Sa; Chang, Jia; Peng, Xiu-Qin; Han, Min; Yin, Wan-Li; Liu, Ya-Li; Hu, Yan-Long; Liu, Yu; Yang, Liu-Qin; Zhu, Fu-Guo; Yang, Xiu-Feng; Feng, Xiao-Shan; Wang, Zhou; Li, Yin; Gao, She-Gan; Liu, Hai-Lin; Yuan, Ling; Jin, Yan; Zhang, Yan-Rui; Sheyhidin, Ilyar; Li, Feng; Chen, Bao-Ping; Ren, Shu-Wei; Liu, Bin; Li, Dan; Zhang, Gao-Fu; Yue, Wen-Bin; Feng, Chang-Wei; Qige, Qirenwang; Zhao, Jian-Ting; Yang, Wen-Jun; Lei, Guang-Yan; Chen, Long-Qi; Li, En-Min; Xu, Li-Yan; Wu, Zhi-Yong; Bao, Zhi-Qin; Chen, Ji-Li; Li, Xian-Chang; Zhuang, Xiang; Zhou, Ying-Fa; Zuo, Xian-Bo; Dong, Zi-Ming; Wang, Lu-Wen; Fan, Xue-Pin; Wang, Jin; Zhou, Qi; Ma, Guo-Shun; Zhang, Qin-Xian; Liu, Hai; Jian, Xin-Ying; Lian, Sin-Yong; Wang, Jin-Sheng; Chang, Fu-Bao; Lu, Chang-Dong; Miao, Jian-Jun; Chen, Zhi-Guo; Wang, Ran; Guo, Ming; Fan, Zeng-Lin; Tao, Ping; Liu, Tai-Jing; Wei, Jin-Chang; Kong, Qing-Peng; Fan, Lei; Wang, Xian-Zeng; Gao, Fu-Sheng; Wang, Tian-Yun; Xie, Dong; Wang, Li; Chen, Shu-Qing; Yang, Wan-Cai; Hong, Jun-Yan; Wang, Liang; Qiu, Song-Liang; Goldstein, Alisa M; Yuan, Zhi-Qing; Chanock, Stephen J; Zhang, Xue-Jun; Taylor, Philip R; Wang, Li-Dong

    2012-05-01

    Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.

  15. 27 CFR 70.462 - Shipments from the United States.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... the United States. For regulations under 26 U.S.C. 7653, see 27 CFR part 28 relating to exportation of... 27 Alcohol, Tobacco Products and Firearms 2 2012-04-01 2011-04-01 true Shipments from the United States. 70.462 Section 70.462 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE...

  16. 27 CFR 70.462 - Shipments from the United States.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... the United States. For regulations under 26 U.S.C. 7653, see 27 CFR part 28 relating to exportation of... 27 Alcohol, Tobacco Products and Firearms 2 2013-04-01 2013-04-01 false Shipments from the United States. 70.462 Section 70.462 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE...

  17. 30 CFR 250.462 - What are the requirements for well-control drills?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... drills? 250.462 Section 250.462 Mineral Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Other Drilling Requirements § 250.462 What are the requirements for well-control drills? You must...

  18. 45. BUILDING NO. 462, CHEMISTRY LAB (FORMERLY TRACER LOADING BUILDING), ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    45. BUILDING NO. 462, CHEMISTRY LAB (FORMERLY TRACER LOADING BUILDING), VIEW LOOKING SOUTHEAST AT WEST SIDE. BUILDING NO. 462-B, GENERAL PURPOSE MAGAZINE, AT LEFT. - Picatinny Arsenal, 400 Area, Gun Bag Loading District, State Route 15 near I-80, Dover, Morris County, NJ

  19. Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk

    PubMed Central

    Permuth, Jennifer B.; Pirie, Ailith; Ann Chen, Y.; Lin, Hui-Yi; Reid, Brett M.; Chen, Zhihua; Monteiro, Alvaro; Dennis, Joe; Mendoza-Fandino, Gustavo; Anton-Culver, Hoda; Bandera, Elisa V.; Bisogna, Maria; Brinton, Louise; Brooks-Wilson, Angela; Carney, Michael E.; Chenevix-Trench, Georgia; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; D’Aloisio, Aimee A.; Anne Doherty, Jennifer; Earp, Madalene; Edwards, Robert P.; Fridley, Brooke L.; Gayther, Simon A.; Gentry-Maharaj, Aleksandra; Goodman, Marc T.; Gronwald, Jacek; Hogdall, Estrid; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Karlan, Beth Y.; Kelemen, Linda E.; Kjaer, Suzanne K.; Kraft, Peter; Le, Nhu D.; Levine, Douglas A.; Lissowska, Jolanta; Lubinski, Jan; Matsuo, Keitaro; Menon, Usha; Modugno, Rosemary; Moysich, Kirsten B.; Nakanishi, Toru; Ness, Roberta B.; Olson, Sara; Orlow, Irene; Pearce, Celeste L.; Pejovic, Tanja; Poole, Elizabeth M.; Ramus, Susan J.; Anne Rossing, Mary; Sandler, Dale P.; Shu, Xiao-Ou; Song, Honglin; Taylor, Jack A.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Tworoger, Shelley S.; Webb, Penelope M.; Wentzensen, Nicolas; Wilkens, Lynne R.; Winham, Stacey; Woo, Yin-Ling; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Phelan, Catherine M.; Schildkraut, Joellen M.; Berchuck, Andrew; Goode, Ellen L.; Pharoah, Paul D. P.; Sellers, Thomas A.

    2016-01-01

    Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 × 10 − 7). One of the most significant signals (Pall histologies = 1.01 × 10 − 13;Pserous = 3.54 × 10 − 14) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r2 = 0.90) with a previously identified ‘best hit’ (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 × 10 − 5 > P≥5.0 ×10 − 7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 − 5; PSKAT-o = 9.23 × 10 − 4) and KRT13 (PAML = 1.67 × 10 − 4; PSKAT-o = 1.07 × 10 − 5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained

  20. Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.

    PubMed

    Permuth, Jennifer B; Pirie, Ailith; Ann Chen, Y; Lin, Hui-Yi; Reid, Brett M; Chen, Zhihua; Monteiro, Alvaro; Dennis, Joe; Mendoza-Fandino, Gustavo; Anton-Culver, Hoda; Bandera, Elisa V; Bisogna, Maria; Brinton, Louise; Brooks-Wilson, Angela; Carney, Michael E; Chenevix-Trench, Georgia; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; D'Aloisio, Aimee A; Anne Doherty, Jennifer; Earp, Madalene; Edwards, Robert P; Fridley, Brooke L; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Goodman, Marc T; Gronwald, Jacek; Hogdall, Estrid; Iversen, Edwin S; Jakubowska, Anna; Jensen, Allan; Karlan, Beth Y; Kelemen, Linda E; Kjaer, Suzanne K; Kraft, Peter; Le, Nhu D; Levine, Douglas A; Lissowska, Jolanta; Lubinski, Jan; Matsuo, Keitaro; Menon, Usha; Modugno, Rosemary; Moysich, Kirsten B; Nakanishi, Toru; Ness, Roberta B; Olson, Sara; Orlow, Irene; Pearce, Celeste L; Pejovic, Tanja; Poole, Elizabeth M; Ramus, Susan J; Anne Rossing, Mary; Sandler, Dale P; Shu, Xiao-Ou; Song, Honglin; Taylor, Jack A; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Tworoger, Shelley S; Webb, Penelope M; Wentzensen, Nicolas; Wilkens, Lynne R; Winham, Stacey; Woo, Yin-Ling; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Phelan, Catherine M; Schildkraut, Joellen M; Berchuck, Andrew; Goode, Ellen L; Pharoah, Paul D P; Sellers, Thomas A

    2016-08-15

    Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 × 10  -   7 ). One of the most significant signals (P all histologies  =   1.01 × 10  -   13 ;P serous  =   3.54 × 10  -   14 ) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r 2  =   0.90) with a previously identified 'best hit' (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 × 10  -   5  >   P≥5.0 ×10  -   7 ) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (P AML  =   3.23 × 10  -   5 ; P SKAT-o  =   9.23 × 10  -   4 ) and KRT13 (P AML  =   1.67 × 10  -   4 ; P SKAT-o  =   1.07 × 10  -   5 ), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed

  1. Association analysis of calpain 10 gene variants/haplotypes with gestational diabetes mellitus among Mexican women.

    PubMed

    Castro-Martínez, Anna Gabriela; Sánchez-Corona, José; Vázquez-Vargas, Adriana Patricia; García-Zapién, Alejandra Guadalupe; López-Quintero, Andres; Villalpando-Velazco, Héctor Javier; Flores-Martínez, Silvia Esperanza

    2018-02-28

    Gestational diabetes mellitus (GDM) is a metabolically complex disease with major genetic determinants. GDM has been associated with insulin resistance and dysfunction of pancreatic beta cells, so the GDM candidate genes are those that encode proteins modulating the function and secretion of insulin, such as that for calpain 10 (CAPN10). This study aimed to assess whether single nucleotide polymorphism (SNP)-43, SNP-44, SNP-63, and the indel-19 variant, and specific haplotypes of the CAPN10 gene were associated with gestational diabetes mellitus. We studied 116 patients with gestational diabetes mellitus and 83 women with normal glucose tolerance. Measurements of anthropometric and biochemical parameters were performed. SNP-43, SNP-44, and SNP-63 were identified by polymerase chain reaction (PCR)-restriction fragment length polymorphisms, while the indel-19 variant was detected by TaqMan qPCR assays.  The allele, genotype, and haplotype frequencies of the four variants did not differ significantly between women with gestational diabetes mellitus and controls. However, in women with gestational diabetes mellitus, glucose levels were significantly higher bearing the 3R/3R genotype than in carriers of the 3R/2R genotype of the indel-19 variant (p = 0.006). In conclusion, the 3R/3R genotype of the indel-19 variant of the CAPN-10 gene influenced increased glucose levels in these Mexican women with gestational diabetes mellitus.

  2. Antibody neutralization of cell-surface gC1qR/HABP1/SF2-p32 prevents lamellipodia formation and tumorigenesis

    PubMed Central

    Kim, Beom-Chan; Hwang, Hyun-Jung; An, Hyoung-Tae; Lee, Hyun; Park, Jun-Sub; Hong, Jin; Ko, Jesang; Kim, Chungho; Lee, Jae-Seon; Ko, Young-Gyu

    2016-01-01

    We previously demonstrated that cell-surface gC1qR is a key regulator of lamellipodia formation and cancer metastasis. Here, we screened a monoclonal mouse antibody against gC1qR to prevent cell migration by neutralizing cell-surface gC1qR. The anti-gC1qR antibody prevented growth factor-stimulated lamellipodia formation, cell migration and focal adhesion kinase activation by inactivating receptor tyrosine kinases (RTKs) in various cancer cells such as A549, MDA-MB-231, MCF7 and HeLa cells. The antibody neutralization of cell-surface gC1qR also inhibited angiogenesis because the anti-gC1qR antibody prevented growth factor-stimulated RTK activation, lamellipodia formation, cell migration and tube formation in HUVEC. In addition, we found that A549 tumorigenesis was reduced in a xenograft mouse model by following the administration of the anti-gC1qR antibody. With these data, we can conclude that the antibody neutralization of cell-surface gC1qR could be a good therapeutic strategy for cancer treatment. PMID:27363031

  3. Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies

    PubMed Central

    Abnet, Christian C.; Wang, Zhaoming; Song, Xin; Hu, Nan; Zhou, Fu-You; Freedman, Neal D.; Li, Xue-Min; Yu, Kai; Shu, Xiao-Ou; Yuan, Jian-Min; Zheng, Wei; Dawsey, Sanford M.; Liao, Linda M.; Lee, Maxwell P.; Ding, Ti; Qiao, You-Lin; Gao, Yu-Tang; Koh, Woon-Puay; Xiang, Yong-Bing; Tang, Ze-Zhong; Fan, Jin-Hu; Chung, Charles C.; Wang, Chaoyu; Wheeler, William; Yeager, Meredith; Yuenger, Jeff; Hutchinson, Amy; Jacobs, Kevin B.; Giffen, Carol A.; Burdett, Laurie; Fraumeni, Joseph F.; Tucker, Margaret A.; Chow, Wong-Ho; Zhao, Xue-Ke; Li, Jiang-Man; Li, Ai-Li; Sun, Liang-Dan; Wei, Wu; Li, Ji-Lin; Zhang, Peng; Li, Hong-Lei; Cui, Wen-Yan; Wang, Wei-Peng; Liu, Zhi-Cai; Yang, Xia; Fu, Wen-Jing; Cui, Ji-Li; Lin, Hong-Li; Zhu, Wen-Liang; Liu, Min; Chen, Xi; Chen, Jie; Guo, Li; Han, Jing-Jing; Zhou, Sheng-Li; Huang, Jia; Wu, Yue; Yuan, Chao; Huang, Jing; Ji, Ai-Fang; Kul, Jian-Wei; Fan, Zhong-Min; Wang, Jian-Po; Zhang, Dong-Yun; Zhang, Lian-Qun; Zhang, Wei; Chen, Yuan-Fang; Ren, Jing-Li; Li, Xiu-Min; Dong, Jin-Cheng; Xing, Guo-Lan; Guo, Zhi-Gang; Yang, Jian-Xue; Mao, Yi-Ming; Yuan, Yuan; Guo, Er-Tao; Zhang, Wei; Hou, Zhi-Chao; Liu, Jing; Li, Yan; Tang, Sa; Chang, Jia; Peng, Xiu-Qin; Han, Min; Yin, Wan-Li; Liu, Ya-Li; Hu, Yan-Long; Liu, Yu; Yang, Liu-Qin; Zhu, Fu-Guo; Yang, Xiu-Feng; Feng, Xiao-Shan; Wang, Zhou; Li, Yin; Gao, She-Gan; Liu, Hai-Lin; Yuan, Ling; Jin, Yan; Zhang, Yan-Rui; Sheyhidin, Ilyar; Li, Feng; Chen, Bao-Ping; Ren, Shu-Wei; Liu, Bin; Li, Dan; Zhang, Gao-Fu; Yue, Wen-Bin; Feng, Chang-Wei; Qige, Qirenwang; Zhao, Jian-Ting; Yang, Wen-Jun; Lei, Guang-Yan; Chen, Long-Qi; Li, En-Min; Xu, Li-Yan; Wu, Zhi-Yong; Bao, Zhi-Qin; Chen, Ji-Li; Li, Xian-Chang; Zhuang, Xiang; Zhou, Ying-Fa; Zuo, Xian-Bo; Dong, Zi-Ming; Wang, Lu-Wen; Fan, Xue-Pin; Wang, Jin; Zhou, Qi; Ma, Guo-Shun; Zhang, Qin-Xian; Liu, Hai; Jian, Xin-Ying; Lian, Sin-Yong; Wang, Jin-Sheng; Chang, Fu-Bao; Lu, Chang-Dong; Miao, Jian-Jun; Chen, Zhi-Guo; Wang, Ran; Guo, Ming; Fan, Zeng-Lin; Tao, Ping; Liu, Tai-Jing; Wei, Jin-Chang; Kong, Qing-Peng; Fan, Lei; Wang, Xian-Zeng; Gao, Fu-Sheng; Wang, Tian-Yun; Xie, Dong; Wang, Li; Chen, Shu-Qing; Yang, Wan-Cai; Hong, Jun-Yan; Wang, Liang; Qiu, Song-Liang; Goldstein, Alisa M.; Yuan, Zhi-Qing; Chanock, Stephen J.; Zhang, Xue-Jun; Taylor, Philip R.; Wang, Li-Dong

    2012-01-01

    Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19–1.40) and P= 7.63 × 10−10. An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants. PMID:22323360

  4. Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers

    PubMed Central

    French, Juliet D.; Ghoussaini, Maya; Edwards, Stacey L.; Meyer, Kerstin B.; Michailidou, Kyriaki; Ahmed, Shahana; Khan, Sofia; Maranian, Mel J.; O’Reilly, Martin; Hillman, Kristine M.; Betts, Joshua A.; Carroll, Thomas; Bailey, Peter J.; Dicks, Ed; Beesley, Jonathan; Tyrer, Jonathan; Maia, Ana-Teresa; Beck, Andrew; Knoblauch, Nicholas W.; Chen, Constance; Kraft, Peter; Barnes, Daniel; González-Neira, Anna; Alonso, M. Rosario; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Conroy, Don; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Verhoef, Senno; Cornelissen, Sten; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A.; Loehberg, Christian R.; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; dos Santos Silva, Isabel; Johnson, Nichola; Aitken, Zoe; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Guénel, Pascal; Truong, Thérèse; Laurent-Puig, Pierre; Menegaux, Florence; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Milne, Roger L.; Zamora, M. Pilar; Arias Perez, Jose Ignacio; Benitez, Javier; Anton-Culver, Hoda; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Lichtner, Peter; Schmutzler, Rita K.; Engel, Christoph; Brauch, Hiltrud; Hamann, Ute; Justenhoven, Christina; Aaltonen, Kirsimari; Heikkilä, Päivi; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Sueta, Aiko; Bogdanova, Natalia V.; Antonenkova, Natalia N.; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Wu, Anna H.; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O.; Lambrechts, Diether; Peeters, Stephanie; Smeets, Ann; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Sardella, Domenico; Couch, Fergus J.; Wang, Xianshu; Pankratz, Vernon S.; Lee, Adam; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Teo, Soo Hwang; Yip, Cheng Har; Ng, Char-Hong; Vithana, Eranga Nishanthie; Kristensen, Vessela; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Devilee, Peter; Seynaeve, Caroline; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Czene, Kamila; Klevebring, Daniel; Schoof, Nils; Hooning, Maartje J.; Martens, John W.M.; Collée, J. Margriet; Tilanus-Linthorst, Madeleine; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Balasubramanian, Sabapathy P.; Blot, William; Signorello, Lisa B.; Cai, Qiuyin; Pharoah, Paul D.P.; Healey, Catherine S.; Shah, Mitul; Pooley, Karen A.; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Sng, Jen-Hwei; Sim, Xueling; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; McKay, James; Toland, Amanda E.; Ambrosone, Christine B.; Yannoukakos, Drakoulis; Godwin, Andrew K.; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Chen, Shou-Tung; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J.; Ponder, Bruce A.J.; Nevanlinna, Heli; Brown, Melissa A.; Chenevix-Trench, Georgia; Easton, Douglas F.; Dunning, Alison M.

    2013-01-01

    Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1. PMID:23540573

  5. 12 CFR 46.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY ANNUAL STRESS TEST § 46.2 Definitions. For... appropriate for use in the stress tests under this part, including, but not limited to, baseline, adverse, and severely adverse scenarios. Stress test means a process to assess the potential impact of scenarios on the...

  6. 12 CFR 46.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY ANNUAL STRESS TEST § 46.2 Definitions. For... appropriate for use in the stress tests under this part, including, but not limited to, baseline, adverse, and severely adverse scenarios. Stress test means a process to assess the potential impact of scenarios on the...

  7. Common 5S rRNA variants are likely to be accepted in many sequence contexts

    NASA Technical Reports Server (NTRS)

    Zhang, Zhengdong; D'Souza, Lisa M.; Lee, Youn-Hyung; Fox, George E.

    2003-01-01

    Over evolutionary time RNA sequences which are successfully fixed in a population are selected from among those that satisfy the structural and chemical requirements imposed by the function of the RNA. These sequences together comprise the structure space of the RNA. In principle, a comprehensive understanding of RNA structure and function would make it possible to enumerate which specific RNA sequences belong to a particular structure space and which do not. We are using bacterial 5S rRNA as a model system to attempt to identify principles that can be used to predict which sequences do or do not belong to the 5S rRNA structure space. One promising idea is the very intuitive notion that frequently seen sequence changes in an aligned data set of naturally occurring 5S rRNAs would be widely accepted in many other 5S rRNA sequence contexts. To test this hypothesis, we first developed well-defined operational definitions for a Vibrio region of the 5S rRNA structure space and what is meant by a highly variable position. Fourteen sequence variants (10 point changes and 4 base-pair changes) were identified in this way, which, by the hypothesis, would be expected to incorporate successfully in any of the known sequences in the Vibrio region. All 14 of these changes were constructed and separately introduced into the Vibrio proteolyticus 5S rRNA sequence where they are not normally found. Each variant was evaluated for its ability to function as a valid 5S rRNA in an E. coli cellular context. It was found that 93% (13/14) of the variants tested are likely valid 5S rRNAs in this context. In addition, seven variants were constructed that, although present in the Vibrio region, did not meet the stringent criteria for a highly variable position. In this case, 86% (6/7) are likely valid. As a control we also examined seven variants that are seldom or never seen in the Vibrio region of 5S rRNA sequence space. In this case only two of seven were found to be potentially valid. The

  8. Structure and Function of Interacting IcmR-IcmQ Domains from a Type IVb Secretion System in Legionella pneumophila

    SciTech Connect

    Raychaudhury, S.; Farelli, J; Montminy, T

    2009-01-01

    During infection, Legionella pneumophila creates a replication vacuole within eukaryotic cells and this requires a Type IVb secretion system (T4bSS). IcmQ plays a critical role in the translocase and associates with IcmR. In this paper, we show that the N-terminal domain of IcmQ (Qn) mediates self-dimerization, whereas the C-terminal domain with a basic linker promotes membrane association. In addition, the binding of IcmR to IcmQ prevents self-dimerization and also blocks membrane permeabilization. However, IcmR does not completely block membrane binding by IcmQ. We then determined crystal structures of Qn with the interacting region of IcmR. In this complex, each proteinmore » forms an ?-helical hairpin within a parallel four-helix bundle. The amphipathic nature of helices in Qn suggests two possible models for membrane permeabilization by IcmQ. The Rm-Qn structure also suggests how IcmR-like proteins in other L. pneumophila species may interact with their IcmQ partners.« less

  9. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma.

    PubMed

    Ferreira, Manuel A R; Matheson, Melanie C; Duffy, David L; Marks, Guy B; Hui, Jennie; Le Souëf, Peter; Danoy, Patrick; Baltic, Svetlana; Nyholt, Dale R; Jenkins, Mark; Hayden, Catherine; Willemsen, Gonneke; Ang, Wei; Kuokkanen, Mikko; Beilby, John; Cheah, Faang; de Geus, Eco J C; Ramasamy, Adaikalavan; Vedantam, Sailaja; Salomaa, Veikko; Madden, Pamela A; Heath, Andrew C; Hopper, John L; Visscher, Peter M; Musk, Bill; Leeder, Stephen R; Jarvelin, Marjo-Riitta; Pennell, Craig; Boomsma, Dorret I; Hirschhorn, Joel N; Walters, Haydn; Martin, Nicholas G; James, Alan; Jones, Graham; Abramson, Michael J; Robertson, Colin F; Dharmage, Shyamali C; Brown, Matthew A; Montgomery, Grant W; Thompson, Philip J

    2011-09-10

    We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR 1·09, combined p=2·4×10(-8)) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10(-8)) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10(-4)), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to

  10. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma

    PubMed Central

    Ferreira, Manuel A.R.; Matheson, Melanie C.; Duffy, David L.; Marks, Guy B.; Hui, Jennie; Le Souëf, Peter; Danoy, Patrick; Baltic, Svetlana; Nyholt, Dale R.; Jenkins, Mark; Hayden, Catherine; Willemsen, Gonneke; Ang, Wei; Kuokkanen, Mikko; Beilby, John; Cheah, Faang; de Geus, Eco J. C.; Ramasamy, Adaikalavan; Vedantam, Sailaja; Salomaa, Veikko; Madden, Pamela A.; Heath, Andrew C.; Hopper, John L.; Visscher, Peter M.; Musk, Bill; Leeder, Stephen R.; Jarvelin, Marjo-Riitta; Pennell, Craig; Boomsma, Dorret I.; Hirschhorn, Joel; Walters, Haydn; Martin, Nicholas G.; James, Alan; Jones, Graham; Abramson, Michael J.; Robertson, Colin F.; Dharmage, Shyamali C.; Brown, Matthew A.; Montgomery, Grant W.; Thompson, Philip J.

    2012-01-01

    Background We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying asthma. Methods We performed a genome-wide association study (GWAS) in 2,669 physician-diagnosed asthmatics and 4,528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-SNP scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Findings Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR=1.09, combined P=2.4×10−8) in the interleukin-6 receptor gene (IL6R) and rs7130588 (OR=1.09, P=1.8×10−8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR = 1.33, P = 7×10−4), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-SNP association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that may be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP and BACH2. Interpretation The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally

  11. 34 CFR 462.10 - How does the Secretary review tests?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... SYSTEM FOR ADULT EDUCATION What Process Does the Secretary Use To Review the Suitability of Tests for Use... 34 Education 3 2010-07-01 2010-07-01 false How does the Secretary review tests? 462.10 Section 462.10 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF...

  12. miR669a and miR669q prevent skeletal muscle differentiation in postnatal cardiac progenitors

    PubMed Central

    Crippa, Stefania; Cassano, Marco; Messina, Graziella; Galli, Daniela; Galvez, Beatriz G.; Curk, Tomaz; Altomare, Claudia; Ronzoni, Flavio; Toelen, Jaan; Gijsbers, Rik; Debyser, Zeger; Janssens, Stefan; Zupan, Blaz; Zaza, Antonio; Cossu, Giulio

    2011-01-01

    Postnatal heart stem and progenitor cells are a potential therapeutic tool for cardiomyopathies, but little is known about the mechanisms that control cardiac differentiation. Recent work has highlighted an important role for microribonucleic acids (miRNAs) as regulators of cardiac and skeletal myogenesis. In this paper, we isolated cardiac progenitors from neonatal β-sarcoglycan (Sgcb)–null mouse hearts affected by dilated cardiomyopathy. Unexpectedly, Sgcb-null cardiac progenitors spontaneously differentiated into skeletal muscle fibers both in vitro and when transplanted into regenerating muscles or infarcted hearts. Differentiation potential correlated with the absence of expression of a novel miRNA, miR669q, and with down-regulation of miR669a. Other miRNAs are known to promote myogenesis, but only miR669a and miR669q act upstream of myogenic regulatory factors to prevent myogenesis by directly targeting the MyoD 3′ untranslated region. This finding reveals an added level of complexity in the mechanism of the fate choice of mesoderm progenitors and suggests that using endogenous cardiac stem cells therapeutically will require specially tailored procedures for certain genetic diseases. PMID:21708977

  13. Faster cross-bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation.

    PubMed

    Witjas-Paalberends, E Rosalie; Ferrara, Claudia; Scellini, Beatrice; Piroddi, Nicoletta; Montag, Judith; Tesi, Chiara; Stienen, Ger J M; Michels, Michelle; Ho, Carolyn Y; Kraft, Theresia; Poggesi, Corrado; van der Velden, Jolanda

    2014-08-01

    The first mutation associated with hypertrophic cardiomyopathy (HCM) is the R403Q mutation in the gene encoding β-myosin heavy chain (β-MyHC). R403Q locates in the globular head of myosin (S1), responsible for interaction with actin, and thus motor function of myosin. Increased cross-bridge relaxation kinetics caused by the R403Q mutation might underlie increased energetic cost of tension generation; however, direct evidence is absent. Here we studied to what extent cross-bridge kinetics and energetics are related in single cardiac myofibrils and multicellular cardiac muscle strips of three HCM patients with the R403Q mutation and nine sarcomere mutation-negative HCM patients (HCMsmn). Expression of R403Q was on average 41 ± 4% of total MYH7 mRNA. Cross-bridge slow relaxation kinetics in single R403Q myofibrils was significantly higher (P < 0.0001) than in HCMsmn myofibrils (0.47 ± 0.02 and 0.30 ± 0.02 s(-1), respectively). Moreover, compared to HCMsmn, tension cost was significantly higher in the muscle strips of the three R403Q patients (2.93 ± 0.25 and 1.78 ± 0.10 μmol l(-1) s(-1) kN(-1) m(-2), respectively) which showed a positive linear correlation with relaxation kinetics in the corresponding myofibril preparations. This correlation suggests that faster cross-bridge relaxation kinetics results in an increase in energetic cost of tension generation in human HCM with the R403Q mutation compared to HCMsmn. Therefore, increased tension cost might contribute to HCM disease in patients carrying the R403Q mutation. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

  14. The protective effect of LRRK2 p.R1398H on risk of Parkinson’s disease is independent of MAPT and SNCA variants

    PubMed Central

    Heckman, Michael G.; Elbaz, Alexis; Soto-Ortolaza, Alexandra I.; Serie, Daniel J.; Aasly, Jan O.; Annesi, Grazia; Auburger, Georg; Bacon, Justin A.; Boczarska-Jedynak, Magdalena; Bozi, Maria; Brighina, Laura; Chartier-Harlin, Marie-Christine; Dardiotis, Efthimios; Destée, Alain; Ferrarese, Carlo; Ferraris, Alessandro; Fiske, Brian; Gispert, Suzana; Hadjigeorgiou, Georgios M.; Hattori, Nobutaka; Ioannidis, John P. A.; Jasinska-Myga, Barbara; Jeon, Beom S.; Kim, Yun Joong; Klein, Christine; Kruger, Rejko; Kyratzi, Elli; Lin, Chin-Hsien; Lohmann, Katja; Loriot, Marie-Anne; Lynch, Timothy; Mellick, George D.; Mutez, Eugénie; Opala, Grzegorz; Park, Sung Sup; Petrucci, Simona; Quattrone, Aldo; Sharma, Manu; Silburn, Peter A.; Sohn, Young Ho; Stefanis, Leonidas; Tadic, Vera; Tomiyama, Hiroyuki; Uitti, Ryan J.; Valente, Enza Maria; Vassilatis, Demetrios K.; Vilariño-Güell, Carles; White, Linda R.; Wirdefeldt, Karin; Wszolek, Zbigniew K.; Wu, Ruey-Meei; Xiromerisiou, Georgia; Maraganore, Demetrius M.; Farrer, Matthew J.; Ross, Owen A.

    2013-01-01

    The best validated susceptibility variants for Parkinson’s disease (PD) are located in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined four SNCA variants (rs181489, rs356219, rs11931074, rs2583988), the MAPT H1-haplotype defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (N=10,322) and Asian (N=2,289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all P≥0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with PD is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations. PMID:23962496

  15. Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.

    PubMed

    Ghorbanoghli, Z; Nieuwenhuis, M H; Houwing-Duistermaat, J J; Jagmohan-Changur, S; Hes, F J; Tops, C M; Wagner, A; Aalfs, C M; Verhoef, S; Gómez García, E B; Sijmons, R H; Menko, F H; Letteboer, T G; Hoogerbrugge, N; van Wezel, T; Vasen, H F A; Wijnen, J T

    2016-10-01

    Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.

  16. IGF2R Genetic Variants, Circulating IGF2 Concentrations and Colon Cancer Risk in African Americans and Whites

    PubMed Central

    Hoyo, Cathrine; Murphy, Susan K.; Schildkraut, Joellen M.; Vidal, Adriana C.; Skaar, David; Millikan, Robert C.; Galanko, Joseph; Sandler, Robert S.; Jirtle, Randy; Keku, Temitope

    2012-01-01

    The Mannose 6 Phosphate/Insulin-like Growth Factor Receptor-2 (IGF2R) encodes a type-1 membrane protein that modulates availability of the potent mitogen, IGF2. We evaluated the associations between IGF2R non-synonymous genetic variants (c.5002G>A, Gly1619Arg(rs629849), and c.901C>G, Leu252Val(rs8191754)), circulating IGF2 levels, and colon cancer (CC) risk among African American and White participants enrolled in the North Carolina Colon Cancer Study (NCCCS). Generalized linear models were used to compare circulating levels of IGF2 among 298 African American and 518 White controls. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of IGF2R genetic variants and CC risk. Women homozygous for the IGF2R c.5002 G>A allele, had higher mean levels of circulating IGF2, 828 (SD=321) ng/ml compared to non-carriers, 595 (SD=217) ng/ml (p-value=0.01). This pattern was not apparent in individuals homozygous for the IGF2R c.901 C>G variant. Whites homozygous for the IGF2R c.901 C>G variant trended towards a higher risk of CC, OR=2.2 [95% CI(0.9–5.4)], whereas carrying the IGF2R c.5002 G>A variant was not associated with CC risk. Our findings support the hypothesis that being homozygous for the IGF2R c.5002 G>A modulates IGF2 circulating levels in a sex-specific manner, and while carrying the IGF2R c.901 C>G may increase cancer risk, the mechanism may not involve modulation of circulating IGF2. PMID:22377707

  17. IGF2R genetic variants, circulating IGF2 concentrations and colon cancer risk in African Americans and Whites.

    PubMed

    Hoyo, Cathrine; Murphy, Susan K; Schildkraut, Joellen M; Vidal, Adriana C; Skaar, David; Millikan, Robert C; Galanko, Joseph; Sandler, Robert S; Jirtle, Randy; Keku, Temitope

    2012-01-01

    The Mannose 6 Phosphate/Insulin-like Growth Factor Receptor-2 (IGF2R) encodes a type-1 membrane protein that modulates availability of the potent mitogen, IGF2. We evaluated the associations between IGF2R non-synonymous genetic variants (c.5002G>A, Gly1619Arg(rs629849), and c.901C>G, Leu252Val(rs8191754)), circulating IGF2 levels, and colon cancer (CC) risk among African American and White participants enrolled in the North Carolina Colon Cancer Study (NCCCS). Generalized linear models were used to compare circulating levels of IGF2 among 298 African American and 518 White controls. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of IGF2R genetic variants and CC risk. Women homozygous for the IGF2R c.5002 G>A allele, had higher mean levels of circulating IGF2, 828 (SD=321) ng/ml compared to non-carriers, 595 (SD=217) ng/ml (p-value=0.01). This pattern was not apparent in individuals homozygous for the IGF2R c.901 C>G variant. Whites homozygous for the IGF2R c.901 C>G variant trended towards a higher risk of CC, OR=2.2 [95% CI(0.9-5.4)], whereas carrying the IGF2R c.5002 G>A variant was not associated with CC risk. Our findings support the hypothesis that being homozygous for the IGF2R c.5002 G>A modulates IGF2 circulating levels in a sex-specific manner, and while carrying the IGF2R c.901 C>G may increase cancer risk, the mechanism may not involve modulation of circulating IGF2.

  18. R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study

    PubMed Central

    2011-01-01

    Background Heterozygous Familial Hypercholesterolemia (FH) is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH. Results This case-control study comprised 720 patients (546 with FH and 174 controls). We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag) and whether they could be predictive factors for cardiovascular risk. 75% (410) of the patients with FH were RR, 23% (127) RQ and 1.6% (9) QQ; in the control group 75.3% (131) were RR, 21.3% (37) RQ and 3.4% (6) QQ (p = 0.32). No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH) and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease), either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96). In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97). Conclusions Our study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels. PMID:21477332

  19. A Common Variant in the Von Willebrand Factor Gene is Associated With Multiple Functional Consequences

    PubMed Central

    Vaidya, Dhananjay; Yanek, Lisa R.; Herrera-Galeano, J. Enrique; Mathias, Rasika A.; Moy, Taryn F.; Faraday, Nauder; Becker, Lewis C.; Becker, Diane M.

    2010-01-01

    Von Willebrand Factor (vWF) is a plasma protein involved in thrombosis and hemostasis [1]. We examined whether common single nucleotide polymorphisms (SNPs) in the vWF gene were associated with vWF levels and platelet aggregation-related functional consequences in1230 Whites and 837 African Americans in a cross-sectional family based genetic study of platelet function. From a high-density scan, 28 SNPs with a minor allele frequency > 5% in both races were tested for association using age and sex adjusted variance components analysis in MERLIN. SNP rs216321, with the strongest association with vWF levels in biracial metaanalysis (p=9.5×10−6, Whites–p=8.1×10−4, African Americans–p=3.6×10−3), encoding a R852Q substitution in the D’D3 protein domain, demonstrated negative association with plasma vWF. The R852Q variant was recessively associated with 15.5% lower collagen-induced platelet aggregation adjusting for dose-response relationship (p=0.010, vWF-level adjusted p=0.003). Each copy of the R852Q variant was additively associated with 31% higher FVIII levels (p=0.039, vWF-adjusted p=0.033). In conclusion, this common missense polymorphism appears to have pleiotropic functional consequences. PMID:20941784

  20. Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis

    PubMed Central

    Lewis, Michele D.; Park, Hyun Woo; Brand, Randall E.; Gelrud, Andres; Anderson, Michelle A.; Banks, Peter A.; Conwell, Darwin; Lawrence, Christopher; Romagnuolo, Joseph; Baillie, John; Alkaade, Samer; Cote, Gregory; Gardner, Timothy B.; Amann, Stephen T.; Slivka, Adam; Sandhu, Bimaljit; Aloe, Amy; Kienholz, Michelle L.; Yadav, Dhiraj; Barmada, M. Michael; Bahar, Ivet; Lee, Min Goo; Whitcomb, David C.

    2014-01-01

    CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<<0.0001). WNK1-SPAK pathway-activated increases in CFTR

  1. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis.

    PubMed

    LaRusch, Jessica; Jung, Jinsei; General, Ignacio J; Lewis, Michele D; Park, Hyun Woo; Brand, Randall E; Gelrud, Andres; Anderson, Michelle A; Banks, Peter A; Conwell, Darwin; Lawrence, Christopher; Romagnuolo, Joseph; Baillie, John; Alkaade, Samer; Cote, Gregory; Gardner, Timothy B; Amann, Stephen T; Slivka, Adam; Sandhu, Bimaljit; Aloe, Amy; Kienholz, Michelle L; Yadav, Dhiraj; Barmada, M Michael; Bahar, Ivet; Lee, Min Goo; Whitcomb, David C

    2014-07-01

    CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<0.0001). WNK1-SPAK pathway-activated increases in CFTR

  2. Characterization of the two intra-individual sequence variants in the 18S rRNA gene in the plant parasitic nematode, Rotylenchulus reniformis.

    PubMed

    Nyaku, Seloame T; Sripathi, Venkateswara R; Kantety, Ramesh V; Gu, Yong Q; Lawrence, Kathy; Sharma, Govind C

    2013-01-01

    The 18S rRNA gene is fundamental to cellular and organismal protein synthesis and because of its stable persistence through generations it is also used in phylogenetic analysis among taxa. Sequence variation in this gene within a single species is rare, but it has been observed in few metazoan organisms. More frequently it has mostly been reported in the non-transcribed spacer region. Here, we have identified two sequence variants within the near full coding region of 18S rRNA gene from a single reniform nematode (RN) Rotylenchulus reniformis labeled as reniform nematode variant 1 (RN_VAR1) and variant 2 (RN_VAR2). All sequences from three of the four isolates had both RN variants in their sequences; however, isolate 13B had only RN variant 2 sequence. Specific variable base sites (96 or 5.5%) were found within the 18S rRNA gene that can clearly distinguish the two 18S rDNA variants of RN, in 11 (25.0%) and 33 (75.0%) of the 44 RN clones, for RN_VAR1 and RN_VAR2, respectively. Neighbor-joining trees show that the RN_VAR1 is very similar to the previously existing R. reniformis sequence in GenBank, while the RN_VAR2 sequence is more divergent. This is the first report of the identification of two major variants of the 18S rRNA gene in the same single RN, and documents the specific base variation between the two variants, and hypothesizes on simultaneous co-existence of these two variants for this gene.

  3. Characterization of the Two Intra-Individual Sequence Variants in the 18S rRNA Gene in the Plant Parasitic Nematode, Rotylenchulus reniformis

    PubMed Central

    Nyaku, Seloame T.; Sripathi, Venkateswara R.; Kantety, Ramesh V.; Gu, Yong Q.; Lawrence, Kathy; Sharma, Govind C.

    2013-01-01

    The 18S rRNA gene is fundamental to cellular and organismal protein synthesis and because of its stable persistence through generations it is also used in phylogenetic analysis among taxa. Sequence variation in this gene within a single species is rare, but it has been observed in few metazoan organisms. More frequently it has mostly been reported in the non-transcribed spacer region. Here, we have identified two sequence variants within the near full coding region of 18S rRNA gene from a single reniform nematode (RN) Rotylenchulus reniformis labeled as reniform nematode variant 1 (RN_VAR1) and variant 2 (RN_VAR2). All sequences from three of the four isolates had both RN variants in their sequences; however, isolate 13B had only RN variant 2 sequence. Specific variable base sites (96 or 5.5%) were found within the 18S rRNA gene that can clearly distinguish the two 18S rDNA variants of RN, in 11 (25.0%) and 33 (75.0%) of the 44 RN clones, for RN_VAR1 and RN_VAR2, respectively. Neighbor-joining trees show that the RN_VAR1 is very similar to the previously existing R. reniformis sequence in GenBank, while the RN_VAR2 sequence is more divergent. This is the first report of the identification of two major variants of the 18S rRNA gene in the same single RN, and documents the specific base variation between the two variants, and hypothesizes on simultaneous co-existence of these two variants for this gene. PMID:23593343

  4. 32 CFR 644.462 - Performance of restoration work by district engineer-extension of time.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Performance of restoration work by district engineer-extension of time. 644.462 Section 644.462 National Defense Department of Defense (Continued... Leasehold Improvements § 644.462 Performance of restoration work by district engineer—extension of time...

  5. Copy number variants in attention-deficit hyperactive disorder: identification of the 15q13 deletion and its functional role.

    PubMed

    Valbonesi, Stefano; Magri, Chiara; Traversa, Michele; Faraone, Stephen V; Cattaneo, Annamaria; Milanesi, Elena; Valenti, Vera; Gennarelli, Massimo; Scassellati, Catia

    2015-04-01

    Evidence has supported a role for rare copy number variants in the etiology of attention-deficit hyperactivity disorder (ADHD), in particular, the region 15q13, which is also a hot spot for several neuropsychiatric disorders. This region spans several genes, but their role and the biological implications remain unclear. We carried out, for the first time, an analysis of the 15q13 region in an Italian cohort of 117 ADHD patients and 77 controls using the MLPA method, confirmed by a genome single-nucleotide polymorphism array. In addition, we probed for downstream effects of the 15q13 deletions on gene expression by carrying out a transcriptomic analysis in blood. We found 15q13 deletions in two ADHD patients and identified 129 genes as significantly dysregulated in the blood of the two ADHD patients carrying 15q13 deletions compared with ADHD patients without 15q13 deletions. As expected, genes in the deleted region (KLF13, MTMR10) were downregulated in the two patients with deletions. Moreover, a pathway analysis identified apoptosis, oxidation reduction, and immune response as the mechanisms that were altered most significantly in the ADHD patients with 15q13 deletions. Interestingly, we showed that deletions in KLF13 and CHRNA7 influenced the expression of genes belonging to the same immune/inflammatory and oxidative stress signaling pathways. Our findings are consistent with the presence of 15q13 deletions in Italian ADHD patients. More interestingly, we show that pathways related to immune/inflammatory response and oxidative stress signaling are affected by the deletion of KFL13 and CHRNA7. Because the phenotypic effects of 15q13 are pleiotropic, our findings suggest that there are shared biologic pathways among multiple neuropsychiatric conditions.

  6. 34 CFR 462.1 - What is the scope of this part?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... ADULT EDUCATION, DEPARTMENT OF EDUCATION MEASURING EDUCATIONAL GAIN IN THE NATIONAL REPORTING SYSTEM FOR... the National Reporting System for Adult Education (NRS) to measure educational gain of participants in... 34 Education 3 2010-07-01 2010-07-01 false What is the scope of this part? 462.1 Section 462.1...

  7. 9 CFR 381.462 - Nutrient content claims for fat, fatty acids, and cholesterol content.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... acids, and cholesterol content. 381.462 Section 381.462 Animals and Animal Products FOOD SAFETY AND... Nutrition Labeling § 381.462 Nutrient content claims for fat, fatty acids, and cholesterol content. (a) General requirements. A claim about the level of fat, fatty acid, and cholesterol in a product may only be...

  8. 9 CFR 381.462 - Nutrient content claims for fat, fatty acids, and cholesterol content.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... acids, and cholesterol content. 381.462 Section 381.462 Animals and Animal Products FOOD SAFETY AND... Nutrition Labeling § 381.462 Nutrient content claims for fat, fatty acids, and cholesterol content. (a) General requirements. A claim about the level of fat, fatty acid, and cholesterol in a product may only be...

  9. Light resonances and the low-q2 bin of RK*$$ {R}_{K^{*}} $$

    SciTech Connect

    Altmannshofer, Wolfgang; Baker, Michael J.; Gori, Stefania

    LHCb has reported hints of lepton-flavor universality violation in the rare decaysmore » $$B \\to K^{(*)} \\ell^+\\ell^-$$, both in high- and low-$q^2$ bins. Although the high-$q^2$ hint may be explained by new short-ranged interactions, the low-$q^2$ one cannot. We thus explore the possibility that the latter is explained by a new light resonance. We find that LHCb's central value of $$R_{K^*}$$ in the low-$q^2$ bin is achievable in a restricted parameter space of new-physics scenarios in which the new, light resonance decays preferentially to electrons and has a mass within approximately $10$ MeV of the di-muon threshold. Interestingly, such an explanation can have a kinematic origin and does not require a source of lepton-flavor universality violation. A model-independent prediction is a narrow peak in the differential $$B \\to K^* e^+e^-$$ rate close to the di-muon threshold. If such a peak is observed, other observables, such as the differential $$B \\to K e^+e^-$$ rate and $$R_K$$, may be employed to distinguish between models. However, if a low-mass resonance is not observed and the low-$q^2$ anomaly increases in significance, then the case for an experimental origin of the lepton-flavor universality violating anomalies would be strengthened. Finally, to further explore this, we also point out that, in analogy to $$J/\\psi$$ decays, $e^+e^-$ and $$\\mu^+\\mu^-$$ decays of $$\\phi$$ mesons can be used as a cross check of lepton-flavor universality by LHCb with $5$ fb$$^{-1}$$ of integrated luminosity.« less

  10. Light resonances and the low-q2 bin of RK*$$ {R}_{K^{*}} $$

    DOE PAGES

    Altmannshofer, Wolfgang; Baker, Michael J.; Gori, Stefania; ...

    2018-03-29

    LHCb has reported hints of lepton-flavor universality violation in the rare decaysmore » $$B \\to K^{(*)} \\ell^+\\ell^-$$, both in high- and low-$q^2$ bins. Although the high-$q^2$ hint may be explained by new short-ranged interactions, the low-$q^2$ one cannot. We thus explore the possibility that the latter is explained by a new light resonance. We find that LHCb's central value of $$R_{K^*}$$ in the low-$q^2$ bin is achievable in a restricted parameter space of new-physics scenarios in which the new, light resonance decays preferentially to electrons and has a mass within approximately $10$ MeV of the di-muon threshold. Interestingly, such an explanation can have a kinematic origin and does not require a source of lepton-flavor universality violation. A model-independent prediction is a narrow peak in the differential $$B \\to K^* e^+e^-$$ rate close to the di-muon threshold. If such a peak is observed, other observables, such as the differential $$B \\to K e^+e^-$$ rate and $$R_K$$, may be employed to distinguish between models. However, if a low-mass resonance is not observed and the low-$q^2$ anomaly increases in significance, then the case for an experimental origin of the lepton-flavor universality violating anomalies would be strengthened. Finally, to further explore this, we also point out that, in analogy to $$J/\\psi$$ decays, $e^+e^-$ and $$\\mu^+\\mu^-$$ decays of $$\\phi$$ mesons can be used as a cross check of lepton-flavor universality by LHCb with $5$ fb$$^{-1}$$ of integrated luminosity.« less

  11. 9 CFR 381.462 - Nutrient content claims for fat, fatty acids, and cholesterol content.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... acids, and cholesterol content. 381.462 Section 381.462 Animals and Animal Products FOOD SAFETY AND... Nutrition Labeling § 381.462 Nutrient content claims for fat, fatty acids, and cholesterol content. Link to..., and cholesterol in a product may only be made on the label or in labeling of products if: (1) The...

  12. [Construction of thr461 --> Asn461 and Ile462 --> Val462 mutation vector of P4501A1 gene].

    PubMed

    Wei, Qing; Liu, Yi-Min; Wang, Hui; Zhao, Xiao-Lin; Ren, Tie-ling; Xiao, Yong-mei

    2006-09-01

    To construct Thr461 --> Asn461 and Ile462 --> Val462 mutation vector of P4501A1 gene and to provide scientific base for deeply researching on the function of cytochrome 1A1 gene (CYP1A1) and the mechanism of carcinogenesis. According to cDNA sequence of human CYP1A1 gene, universal primers (Pm3/Pm4) and mutant primers (Pt15/Pt16 and Pt17/Pt18) containing restriction enzyme site and mutation site were designed. The first set of primers involving Pm3/Pt16 and Pm3/Pt18 amplified a forward 1.5kb fragment from pGEM-T-CYP1A1 plasmid. The second set of primers involving Pt15/Pm4 and Pt17/Pm4 amplified a reverse 177-bp fragment from 10ng pGEM-T-CYP1A1 plasmid. The third set of primers involving Pm3/Pm4 amplified a 1.5kb fragment from the fomer PCR amplifications. The third PCR products were separated, purified and recovered from 1% agarose gel, then inserted into pMD-T vector. Subsequently the conjunct products were transformed into E. coil strain DH-5alpha., then the single clone was screened out and plasmids were extracted from such clone finally verified by restriction endonuclease analysis and sequencing. A 1.5kb fragment of tricycle PCR amplifications were digested by restriction endonucleases (BamHI and SailI) and sequenced bidirectionally by universal primers(T7p and SP6). The results verified that the cloned fragment including Asn461 and Val462 mutant site had 99.9% homology with the human cDNA of CYP1A1 gene in Genebank. The objective fragment containing Asn461 and Va462 mutant site with cDNA of the CYP1A1 gene has been successfully constructed in this experiment.

  13. p.Q192R SNP of PON1 seems not to be Associated with Carotid Atherosclerosis Risk Factors in an Asymptomatic and Normolipidemic Brazilian Population Sample.

    PubMed

    Scherrer, Daniel Zanetti; Zago, Vanessa Helena de Souza; Vieira, Isabela Calanca; Parra, Eliane Soler; Panzoldo, Natália Baratella; Alexandre, Fernanda; Secolin, Rodrigo; Baracat, Jamal; Quintão, Eder Carlos Rocha; Faria, Eliana Cotta de

    2015-07-01

    Evidences suggest that paraoxonase 1 (PON1) confers important antioxidant and anti-inflammatory properties when associated with high-density lipoprotein (HDL). To investigate the relationships between p.Q192R SNP of PON1, biochemical parameters and carotid atherosclerosis in an asymptomatic, normolipidemic Brazilian population sample. We studied 584 volunteers (females n = 326, males n = 258; 19-75 years of age). Total genomic DNA was extracted and SNP was detected in the TaqMan® SNP OpenArray® genotyping platform (Applied Biosystems, Foster City, CA). Plasma lipoproteins and apolipoproteins were determined and PON1 activity was measured using paraoxon as a substrate. High-resolution β-mode ultrasonography was used to measure cIMT and the presence of carotid atherosclerotic plaques in a subgroup of individuals (n = 317). The presence of p.192Q was associated with a significant increase in PON1 activity (RR = 12.30 (11.38); RQ = 46.96 (22.35); QQ = 85.35 (24.83) μmol/min; p < 0.0001), HDL-C (RR= 45 (37); RQ = 62 (39); QQ = 69 (29) mg/dL; p < 0.001) and apo A-I (RR = 140.76 ± 36.39; RQ = 147.62 ± 36.92; QQ = 147.49 ± 36.65 mg/dL; p = 0.019). Stepwise regression analysis revealed that heterozygous and p.192Q carriers influenced by 58% PON1 activity towards paraoxon. The univariate linear regression analysis demonstrated that p.Q192R SNP was not associated with mean cIMT; as a result, in the multiple regression analysis, no variables were selected with 5% significance. In logistic regression analysis, the studied parameters were not associated with the presence of carotid plaques. In low-risk individuals, the presence of the p.192Q variant of PON1 is associated with a beneficial plasma lipid profile but not with carotid atherosclerosis.

  14. High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.

    PubMed

    Kelleher, Raymond J; Geigenmüller, Ute; Hovhannisyan, Hayk; Trautman, Edwin; Pinard, Robert; Rathmell, Barbara; Carpenter, Randall; Margulies, David

    2012-01-01

    Identification of common molecular pathways affected by genetic variation in autism is important for understanding disease pathogenesis and devising effective therapies. Here, we test the hypothesis that rare genetic variation in the metabotropic glutamate-receptor (mGluR) signaling pathway contributes to autism susceptibility. Single-nucleotide variants in genes encoding components of the mGluR signaling pathway were identified by high-throughput multiplex sequencing of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched controls on two independent next-generation platforms. This analysis revealed significant enrichment of rare functional variants in the mGluR pathway in autism cases. Higher burdens of rare, potentially deleterious variants were identified in autism cases for three pathway genes previously implicated in syndromic autism spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in these genes also contributes to risk for non-syndromic autism. In addition, our analysis identified HOMER1, which encodes a postsynaptic density-localized scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a novel autism-risk gene. Rare, potentially deleterious HOMER1 variants identified uniquely in the autism population affected functionally important protein regions or regulatory sequences and co-segregated closely with autism among children of affected families. We also identified rare ASD-associated coding variants predicted to have damaging effects on components of the Ras/MAPK cascade. Collectively, these findings suggest that altered signaling downstream of mGluRs contributes to the pathogenesis of non-syndromic autism.

  15. High-Throughput Sequencing of mGluR Signaling Pathway Genes Reveals Enrichment of Rare Variants in Autism

    PubMed Central

    Hovhannisyan, Hayk; Trautman, Edwin; Pinard, Robert; Rathmell, Barbara; Carpenter, Randall; Margulies, David

    2012-01-01

    Identification of common molecular pathways affected by genetic variation in autism is important for understanding disease pathogenesis and devising effective therapies. Here, we test the hypothesis that rare genetic variation in the metabotropic glutamate-receptor (mGluR) signaling pathway contributes to autism susceptibility. Single-nucleotide variants in genes encoding components of the mGluR signaling pathway were identified by high-throughput multiplex sequencing of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched controls on two independent next-generation platforms. This analysis revealed significant enrichment of rare functional variants in the mGluR pathway in autism cases. Higher burdens of rare, potentially deleterious variants were identified in autism cases for three pathway genes previously implicated in syndromic autism spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in these genes also contributes to risk for non-syndromic autism. In addition, our analysis identified HOMER1, which encodes a postsynaptic density-localized scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a novel autism-risk gene. Rare, potentially deleterious HOMER1 variants identified uniquely in the autism population affected functionally important protein regions or regulatory sequences and co-segregated closely with autism among children of affected families. We also identified rare ASD-associated coding variants predicted to have damaging effects on components of the Ras/MAPK cascade. Collectively, these findings suggest that altered signaling downstream of mGluRs contributes to the pathogenesis of non-syndromic autism. PMID:22558107

  16. 9 CFR 381.462 - Nutrient content claims for fat, fatty acids, and cholesterol content.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... acids, and cholesterol content. 381.462 Section 381.462 Animals and Animal Products FOOD SAFETY AND... Nutrition Labeling § 381.462 Nutrient content claims for fat, fatty acids, and cholesterol content. Link to... level of fat, fatty acid, and cholesterol in a product may only be made on the label or in labeling of...

  17. Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3

    PubMed Central

    Wittmann, Thomas; Frixel, Sabrina; Höppner, Stefanie; Schindlbeck, Ulrike; Schams, Andrea; Kappler, Matthias; Hegermann, Jan; Wrede, Christoph; Liebisch, Gerhard; Vierzig, Anne; Zacharasiewicz, Angela; Kopp, Matthias Volkmar; Poets, Christian F; Baden, Winfried; Hartl, Dominik; van Kaam, Anton H; Lohse, Peter; Aslanidis, Charalampos; Zarbock, Ralf; Griese, Matthias

    2016-01-01

    The ABCA3 gene encodes a lipid transporter in type II pneumocytes critical for survival and normal respiratory function. The frequent ABCA3 variant R288K increases the risk for neonatal respiratory distress syndrome among term and late preterm neonates, but its role in children’s interstitial lung disease has not been studied in detail. In a retrospective cohort study of 228 children with interstitial lung disease related to the alveolar surfactant system, the frequency of R288K was assessed and the phenotype of patients carrying a single R288K variant further characterized by clinical course, lung histology, computed tomography and bronchoalveolar lavage phosphatidylcholine PC 32:0. Cell lines stably transfected with ABCA3-R288K were analyzed for intracellular transcription, processing and targeting of the protein. ABCA3 function was assessed by detoxification assay of doxorubicin, and the induction and volume of lamellar bodies. We found nine children with interstitial lung disease carrying a heterozygous R288K variant, a frequency significantly higher than in the general Caucasian population. All identified patients had neonatal respiratory insufficiency, recovered and developed chronic interstitial lung disease with intermittent exacerbations during early childhood. In vitro analysis showed normal transcription, processing, and targeting of ABCA3-R288K, but impaired detoxification function and smaller lamellar bodies. We propose that the R288K variant can underlie interstitial lung disease in childhood due to reduced function of ABCA3, demonstrated by decelerated detoxification of doxorubicin, reduced PC 32:0 content and decreased lamellar body volume. PMID:26928390

  18. De novo partial duplication 7(q11.2{r_arrow}q21.2) in a dysmorphic, developmentally retarded boy

    SciTech Connect

    Ross, M.; Pinsky, L.; Teebi, A.

    Chromosomal abnormalities involving chromosome 7q are rare; we report a case of partial duplication 7q. The propositus was born at 34 weeks by cesarian section, decided because of oligohydramnios, severe intrauterine growth retardation and fetal immobility. At birth, the baby was under the 5th percentile for height, weight and head circumference and had dysmorphic features, including slight asymmetry of the face, bilateral epicanthus, hypoplastic nasal bridge, short globular nose, asymmetrical dysplastic ears, fifth finger clinodactyly, short second and fifth toe. Ultrasound examination showed atrial and ventricular septal defects. At 18 months, the child had a fracture of the femur, secondarymore » to a minor trauma; skeletal X-rays showed generalized osteoporosis and normal healing. The karyotype with GTG-banding showed a de novo partial duplication of the long arm of chromosome 7 (46,XX,dup(7)(q11.23{r_arrow}q21.2)). Fluorescence in situ hybridization with a painting probe specific for chromosome 7 confirmed the intra-chromosomal rearrangement. The patient`s phenotype and his chromosomal abnormality do not match the previously reported cases of partial trisomy 7q. This case confirms the importance of FISH for the delineation of the chromosomal inbalance in structural chromosomal aberrations.« less

  19. Human SLC26A1 gene variants: a pilot study.

    PubMed

    Dawson, Paul A; Sim, Pearl; Mudge, David W; Cowley, David

    2013-01-01

    Kidney stones are a global health problem, incurring massive health costs annually. Why stones recur in many patients remains unknown but likely involves environmental, physiological, and genetic factors. The solute linked carrier (SLC) 26A1 gene has previously been linked to kidney stones in mice. SLC26A1 encodes the sulfate anion transporter 1 (SAT1) protein, and its loss in mice leads to hyperoxaluria and calcium oxalate renal stones. To investigate the possible involvement of SAT1 in human urolithiasis, we screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis, which is the commonest type. DNA sequence analyses showed missense mutations in seven patients: one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The M132 amino acid in human SAT1 is conserved with 15 other species and is located within the third transmembrane domain of the predicted SAT1 protein structure, suggesting that this amino acid may be important for SAT1 function. These initial findings demonstrate genetic variants in SLC26A1 of recurrent stone formers and warrant wider independent studies of SLC26A1 in humans with recurrent calcium oxalate stones.

  20. Calculation of k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}} for several small detectors and for two linear accelerators using Monte Carlo simulations

    SciTech Connect

    Francescon, P.; Cora, S.; Satariano, N.

    2011-12-15

    Purpose: The scope of this study was to determine a complete set of correction factors for several detectors in static small photon fields for two linear accelerators (linacs) and for several detectors. Methods: Measurements for Monte Carlo (MC) commissioning were performed for two linacs, Siemens Primus and Elekta Synergy. After having determined the source parameters that best fit the measurements of field specific output factors, profiles, and tissue-phantom ratio, the generalized version of the classical beam quality correction factor for static small fields, k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}},more » were determined for several types of detectors by using the egs{sub c}hamber Monte Carlo user code which can accurately reproduce the geometry and the material composition of the detector. The influence of many parameters (energy and radial FWHM of the electron beam source, field dimensions, type of accelerator) on the value of k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}} was evaluated. Moreover, a MC analysis of the parameters that influence the change of k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}} as a function of field dimension was performed. A detailed analysis of uncertainties related to the measurements of the field specific output factor and to the Monte Carlo calculation of k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}} was done. Results: The simulations demonstrated that the correction factor k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}} can be considered independent from the quality beam factor Q in the range 0.68 {+-} 0.01 for all the detectors analyzed. The k{sub Q{sub c{sub l{sub i

  1. The fibrous form of intracellular inclusion bodies in recombinant variant fibrinogen-producing cells is specific to the hepatic fibrinogen storage disease-inducible variant fibrinogen.

    PubMed

    Arai, Shinpei; Ogiwara, Naoko; Mukai, Saki; Takezawa, Yuka; Sugano, Mitsutoshi; Honda, Takayuki; Okumura, Nobuo

    2017-06-01

    Fibrinogen storage disease (FSD) is a rare disorder that is characterized by the accumulation of fibrinogen in hepatocytes and induces liver injury. Six mutations in the γC domain (γG284R, γT314P, γD316N, the deletion of γG346-Q350, γG366S, and γR375W) have been identified for FSD. Our group previously established γ375W fibrinogen-producing Chinese hamster ovary (CHO) cells and observed aberrant large granular and fibrous forms of intracellular inclusion bodies. The aim of this study was to investigate whether fibrous intracellular inclusion bodies are specific to FSD-inducible variant fibrinogen. Thirteen expression vectors encoding the variant γ-chain were stably or transiently transfected into CHO cells expressing normal fibrinogen Aα- and Bβ-chains or HuH-7 cells, which were then immunofluorescently stained. Six CHO and HuH-7 cell lines that transiently produced FSD-inducible variant fibrinogen presented the fibrous (3.2-22.7 and 2.1-24.5%, respectively) and large granular (5.4-25.5 and 7.7-23.9%) forms of intracellular inclusion bodies. Seven CHO and HuH-7 cell lines that transiently produced FSD-non-inducible variant fibrinogen only exhibit the large granular form. These results demonstrate that transiently transfected variant fibrinogen-producing CHO cells and inclusion bodies of the fibrous form may be useful in non-invasive screening for FSD risk factors for FSD before its onset.

  2. Structures of the G85R Variant of SOD1 in Familial Amyotrophic Lateral Sclerosis

    SciTech Connect

    Cao, Xiaohang; Antonyuk, Svetlana V.; Seetharaman, Sai V.

    2008-07-21

    Mutations in the gene encoding human copper-zinc superoxide dismutase (SOD1) cause a dominant form of the progressive neurodegenerative disease amyotrophic lateral sclerosis. Transgenic mice expressing the human G85R SOD1 variant develop paralytic symptoms concomitant with the appearance of SOD1-enriched proteinaceous inclusions in their neural tissues. The process(es) through which misfolding or aggregation of G85R SOD1 induces motor neuron toxicity is not understood. Here we present structures of the human G85R SOD1 variant determined by single crystal x-ray diffraction. Alterations in structure of the metal-binding loop elements relative to the wild type enzyme suggest a molecular basis for the metal ionmore » deficiency of the G85R SOD1 protein observed in the central nervous system of transgenic mice and in purified recombinant G85R SOD1. These findings support the notion that metal-deficient and/or disulfide-reduced mutant SOD1 species contribute to toxicity in SOD1-linked amyotrophic lateral sclerosis.« less

  3. Mosaic isochromosome 15q and maternal uniparental isodisomy for chromosome 15 in a patient with morbid obesity and variant PWS-like phenotype.

    PubMed

    Wang, Jia-Chi; Vaccarello-Cruz, Mary; Ross, Leslie; Owen, Renius; Pratt, Victoria M; Lightman, Katherine; Liu, Yan; Hafezi, Katayoun; Cherif, Dhia; Sahoo, Trilochan

    2013-07-01

    Angelman and Prader-Willi syndromes are reciprocal imprinting disorders caused by loss of maternally or paternally expressed genes, respectively, within 15q11.2-q13. Angelman syndrome (AS; OMIM 105830) is a neurodevelopmental disorder and is due to the loss of maternally expressed UBE3A gene. Prader-Willi syndrome (PWS; OMIM 176270) is a clinically distinct disorder caused by the loss of paternally expressed genes in the human chromosome region 15q11.2-q13. Recently published data strongly suggest a role for the paternally expressed small nucleolar RNA (snoRNA) cluster, SNORD116, in PWS etiology. Uniparental disomy (UPD) 15 is one of the important causes of PWS and AS. Interestingly, balanced and unbalanced chromosomal aberrations in the form of Robertsonian translocation, isochromosomes, supernumerary marker chromosomes and copy number variations have been strongly linked with the occurrence of UPD. Here we report on a very unique case with a mosaic isochromosome for the entire long arm of 15, that is, i(15)(q10), resulting in mosaic uniparental isodisomy for 15q and with no copy number alterations. This is the first report of UPD15 constituted by a mosaic, but copy number neutral chromosomal rearrangement in a patient with a variant PWS-like phenotype. Copyright © 2013 Wiley Periodicals, Inc.

  4. Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

    PubMed Central

    Glubb, Dylan M.; Maranian, Mel J.; Michailidou, Kyriaki; Pooley, Karen A.; Meyer, Kerstin B.; Kar, Siddhartha; Carlebur, Saskia; O’Reilly, Martin; Betts, Joshua A.; Hillman, Kristine M.; Kaufmann, Susanne; Beesley, Jonathan; Canisius, Sander; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel; Schmidt, Marjanka K.; Broeks, Annegien; Hogervorst, Frans B.; van der Schoot, C. Ellen; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A.; Ruebner, Matthias; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Pharoah, Paul D.P.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; González-Neira, Anna; Benitez, Javier; Zamora, M. Pilar; Arias Perez, Jose Ignacio; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Ko, Yon-Dschun; Brüning, Thomas; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tanaka, Hideo; Dörk, Thilo; Bogdanova, Natalia V.; Helbig, Sonja; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Wu, Anna H.; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O.; Lambrechts, Diether; Zhao, Hui; Weltens, Caroline; van Limbergen, Erik; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Seibold, Petra; Radice, Paolo; Peterlongo, Paolo; Barile, Monica; Capra, Fabio; Couch, Fergus J.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Teo, Soo Hwang; Yip, Cheng Har; See, Mee-Hoong; Cornes, Belinda; Cheng, Ching-Yu; Ikram, M. Kamran; Kristensen, Vessela; Zheng, Wei; Halverson, Sandra L.; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Van Asperen, Christi J.; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Czene, Kamila; Klevebring, Daniel; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W.M.; Collée, J. Margriet; Hall, Per; Li, Jingmei; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S.; Reed, Malcolm W.R.; Blot, William; Signorello, Lisa B.; Cai, Qiuyin; Shah, Mitul; Ghoussaini, Maya; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Tang, Anthony; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Olswold, Curtis; Slager, Susan; Toland, Amanda E.; Yannoukakos, Drakoulis; Shen, Chen-Yang; Wu, Pei-Ei; Yu, Jyh-Cherng; Hou, Ming-Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Pita, Guillermo; Alonso, M. Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S.; Brown, Melissa A.; Ponder, Bruce A.J.; Chenevix-Trench, Georgia; Thompson, Deborah J.; Edwards, Stacey L.; Easton, Douglas F.; Dunning, Alison M.; French, Juliet D.

    2015-01-01

    Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER+: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21–1.27, ptrend = 5.7 × 10−44) and estrogen-receptor-negative (ER−: OR = 1.10, 95% CI = 1.05–1.15, ptrend = 3.0 × 10−4) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10−5]) and five variants composing iCHAV3 (lead rs11949391; ER+: OR = 0.90, 95% CI = 0.87–0.93, pcond = 1.4 × 10−4). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival. PMID:25529635

  5. Gain of function AMP-activated protein kinase γ3 mutation (AMPKγ3R200Q) in pig muscle increases glycogen storage regardless of AMPK activation.

    PubMed

    Scheffler, Tracy L; Park, Sungkwon; Roach, Peter J; Gerrard, David E

    2016-06-01

    Chronic activation of AMP-activated protein kinase (AMPK) increases glycogen content in skeletal muscle. Previously, we demonstrated that a mutation in the ryanodine receptor (RyR1(R615C)) blunts AMPK phosphorylation in longissimus muscle of pigs with a gain of function mutation in the AMPKγ3 subunit (AMPKγ3(R200Q)); this may decrease the glycogen storage capacity of AMPKγ3(R200Q) + RyR1(R615C) muscle. Therefore, our aim in this study was to utilize our pig model to understand how AMPKγ3(R200Q) and AMPK activation contribute to glycogen storage and metabolism in muscle. We selected and bred pigs in order to generate offspring with naturally occurring AMPKγ3(R200Q), RyR1(R615C), and AMPKγ3(R200Q) + RyR1(R615C) mutations, and also retained wild-type littermates (control). We assessed glycogen content and parameters of glycogen metabolism in longissimus muscle. Regardless of RyR1(R615C), AMPKγ3(R200Q) increased the glycogen content by approximately 70%. Activity of glycogen synthase (GS) without the allosteric activator glucose 6-phosphate (G6P) was decreased in AMPKγ3(R200Q) relative to all other genotypes, whereas both AMPKγ3(R200Q) and AMPKγ3(R200Q) + RyR1(R615C) muscle exhibited increased GS activity with G6P. Increased activity of GS with G6P was not associated with increased abundance of GS or hexokinase 2. However, AMPKγ3(R200Q) enhanced UDP-glucose pyrophosphorylase 2 (UGP2) expression approximately threefold. Although UGP2 is not generally considered a rate-limiting enzyme for glycogen synthesis, our model suggests that UGP2 plays an important role in increasing flux to glycogen synthase. Moreover, we have shown that the capacity for glycogen storage is more closely related to the AMPKγ3(R200Q) mutation than activity. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  6. 38 CFR 1.462 - Confidentiality restrictions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... with the HIV, or sickle cell anemia. (2) Any answer to a request for a disclosure of patient records... Sickle Cell Anemia § 1.462 Confidentiality restrictions. (a) General. The patient records to which §§ 1.460 through 1.499 of this part apply may be disclosed or used only as permitted by these regulations...

  7. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

    PubMed Central

    Schwerd, T.; Bryant, R. V.; Pandey, S.; Capitani, M.; Meran, L.; Cazier, J.-B.; Jung, J.; Mondal, K.; Parkes, M.; Mathew, CG; Fiedler, K.; McCarthy, D. J.; Sullivan, PB; Rodrigues, A.; Travis, SPL; Moore, C.; Sambrook, J.; Ouwehand, W. H.; Roberts, D. J.; Danesh, J.; Russell, R. K.; Wilson, D. C.; Kelsen, J. R.; Cornall, R.; Denson, L. A.; Kugathasan, S.; Knaus, U. G.; Goncalves Serra, E.; Anderson, C. A.; Duerr, R. H.; McGovern, D. P. B.; Cho, J.; Powrie, F.; Li, V. S. W.; Muise, A. M.; Uhlig, H. H.

    2017-01-01

    Genetic defects that affect intestinal epithelial barrier function can present with very early onset inflammatory bowel disease (VEOIBD). Using whole genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 paediatric patients identified further seven male IBD patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex-vivo colonic explants and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes. PMID:29091079

  8. NUDT15 R139C Variants Increase the Risk of Azathioprine-Induced Leukopenia in Chinese Autoimmune Patients

    PubMed Central

    Fei, Xiang; Shu, Qing; Zhu, Huaijun; Hua, Bingzhu; Wang, Shiying; Guo, Ling; Fang, Yun; Ge, Weihong

    2018-01-01

    The aim of this study was to investigate the influence of NUDT15 R139C, thiopurine S-methyltransferase (TPMT), and 6-TGN on azathioprine (AZA) induced leukopenia in Chinese autoimmune patients. Among 87 enrolled patients, 23 (26.4%) had leukopenia. The NUDT15 R139C variant was associated with leukopenia (p = 1.86 × 10−7; OR: 7.59; 95% CI: 3.16–18.21). However, TPMT genotype was not shown to be correlated with the incidence of leukopenia (p = 0.95). There was no significant difference of 6-TGN concentration between patients with or without leukopenia (p = 0.15) and no association was found in patients with NUDT15 R139C variants alleles (p = 0.62). Finally, we found that the range of 6-TGN concentrations in autoimmune diseases was much lower than the established 6-TGN monitoring range for inflammatory bowel diseases. Therefore, the variant of NUDT15 R139C is strongly associated with AZA-induced leukopenia in Chinese patients with various autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, etc. PMID:29867468

  9. Identification of Rare Variants in TNNI3 with Atrial Fibrillation in a Chinese GeneID Population

    PubMed Central

    Wang, Chuchu; Wu, Manman; Qian, Jin; Li, Bin; Tu, Xin; Xu, Chengqi; Li, Sisi; Chen, Shanshan; Zhao, Yuanyuan; Huang, Yufeng; Shi, Lisong; Cheng, Xiang; Liao, Yuhua; Chen, Qiuyun; Xia, Yunlong; Yao, Wei; Wu, Gang; Cheng, Mian; Wang, Qing K.

    2015-01-01

    Despite advances by genome-wide association studies (GWAS), much of heritability of common human diseases remains missing, a phenomenon referred to as ‘missing heritability’. One potential cause for ‘missing heritability’ is the rare susceptibility variants overlooked by GWAS. Atrial fibrillation (AF) is the most common arrhythmia seen at hospitals and increases risk of stroke by 5-fold and doubles risk of heart failure and sudden death. Here we studied one large Chinese family with AF and hypertrophic cardiomyopathy (HCM). Whole-exome sequencing analysis identified a mutation in TNNI3, R186Q, that co-segregated with the disease in the family, but did not exist in >1,583 controls, suggesting that R186Q causes AF and HCM. High-resolution melting curve analysis and direct DNA sequence analysis were then used to screen mutations in all exons and exon-intron boundaries of TNNI3 in a panel of 1,127 unrelated AF patients and 1,583 non-AF subjects. Four novel missense variants were identified in TNNI3, including E64G, M154L, E187G and D196G in four independent AF patients, but no variant was found in 1,583 non-AF subjects. All variants were not found in public databases, including the ExAC Browser database with 60,706 exomes. These data suggests that rare TNNI3 variants are associated with AF (P=0.03). TNNI3 encodes troponin I, a key regulator of the contraction-relaxation function of cardiac muscle and was not previously implicated in AF. Thus, this study may identify a new biological pathway for the pathogenesis of AF and provides evidence to support the rare variant hypothesis for missing heritability. PMID:26169204

  10. Rare autism-associated variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter (hDAT R51W) in dopamine neurotransmission and behaviors.

    PubMed

    Cartier, Etienne; Hamilton, Peter J; Belovich, Andrea N; Shekar, Aparna; Campbell, Nicholas G; Saunders, Christine; Andreassen, Thorvald F; Gether, Ulrik; Veenstra-Vanderweele, Jeremy; Sutcliffe, James S; Ulery-Reynolds, Paula G; Erreger, Kevin; Matthies, Heinrich J G; Galli, Aurelio

    2015-02-01

    Syntaxin 1 (STX1) is a presynaptic plasma membrane protein that coordinates synaptic vesicle fusion. STX1 also regulates the function of neurotransmitter transporters, including the dopamine (DA) transporter (DAT). The DAT is a membrane protein that controls DA homeostasis through the high-affinity re-uptake of synaptically released DA. We adopt newly developed animal models and state-of-the-art biophysical techniques to determine the contribution of the identified gene variants to impairments in DA neurotransmission observed in autism spectrum disorder (ASD). Here, we characterize two independent autism-associated variants in the genes that encode STX1 and the DAT. We demonstrate that each variant dramatically alters DAT function. We identify molecular mechanisms that converge to inhibit reverse transport of DA and DA-associated behaviors. These mechanisms involve decreased phosphorylation of STX1 at Ser14 mediated by casein kinase 2 as well as a reduction in STX1/DAT interaction. These findings point to STX1/DAT interactions and STX1 phosphorylation as key regulators of DA homeostasis. We determine the molecular identity and the impact of these variants with the intent of defining DA dysfunction and associated behaviors as possible complications of ASD.

  11. Q-mode versus R-mode principal component analysis for linear discriminant analysis (LDA)

    NASA Astrophysics Data System (ADS)

    Lee, Loong Chuen; Liong, Choong-Yeun; Jemain, Abdul Aziz

    2017-05-01

    Many literature apply Principal Component Analysis (PCA) as either preliminary visualization or variable con-struction methods or both. Focus of PCA can be on the samples (R-mode PCA) or variables (Q-mode PCA). Traditionally, R-mode PCA has been the usual approach to reduce high-dimensionality data before the application of Linear Discriminant Analysis (LDA), to solve classification problems. Output from PCA composed of two new matrices known as loadings and scores matrices. Each matrix can then be used to produce a plot, i.e. loadings plot aids identification of important variables whereas scores plot presents spatial distribution of samples on new axes that are also known as Principal Components (PCs). Fundamentally, the scores matrix always be the input variables for building classification model. A recent paper uses Q-mode PCA but the focus of analysis was not on the variables but instead on the samples. As a result, the authors have exchanged the use of both loadings and scores plots in which clustering of samples was studied using loadings plot whereas scores plot has been used to identify important manifest variables. Therefore, the aim of this study is to statistically validate the proposed practice. Evaluation is based on performance of external error obtained from LDA models according to number of PCs. On top of that, bootstrapping was also conducted to evaluate the external error of each of the LDA models. Results show that LDA models produced by PCs from R-mode PCA give logical performance and the matched external error are also unbiased whereas the ones produced with Q-mode PCA show the opposites. With that, we concluded that PCs produced from Q-mode is not statistically stable and thus should not be applied to problems of classifying samples, but variables. We hope this paper will provide some insights on the disputable issues.

  12. Role of a Genetic Variant on the 15q25.1 Lung Cancer Susceptibility Locus in Smoking-Associated Nasopharyngeal Carcinoma

    PubMed Central

    Ji, Xuemei; Zhang, Weidong; Gui, Jiang; Fan, Xia; Zhang, Weiwei; Li, Yafang; An, Guangyu; Zhu, Dakai; Hu, Qiang

    2014-01-01

    Background The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC). Methods In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and alcohol consumption. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI). Results We found that individuals with CHRNA5 rs3841324 combined variant genotypes (ins/del+del/del) had a >1.5-fold elevated risk for NPC than those with the ins/ins genotype (adjusted OR = 1.52; 95% CI, 1.16–2.00), especially among ever smokers (adjusted OR = 2.07; 95% CI, 1.23–3.48). The combined variant genotypes acted jointly with cigarette smoking to contribute to a 4.35-fold increased NPC risk (adjusted OR = 4.35; 95% CI, 2.57–7.38). There was a dose-response relationship between deletion alleles and NPC susceptibility (trend test, P = 0.011). Conclusions Our results suggest that genetic variants on the 15q25.1 lung cancer susceptibility locus may influence susceptibility to NPC, particularly for smoking-associated NPC. Such work may be helpful to facilitate an understanding of the etiology of smoking-associated cancers and improve prevention efforts. PMID:25329654

  13. Preejection period can be calculated using R peak instead of Q.

    PubMed

    Seery, Mark D; Kondrak, Cheryl L; Streamer, Lindsey; Saltsman, Thomas; Lamarche, Veronica M

    2016-08-01

    Preejection period (PEP) is a common measure of sympathetic nervous system activation in psychophysiological research, which makes it important to measure reliably for as many participants as possible. PEP is typically calculated as the interval between the onset or peak of the electrocardiogram Q wave and the impedance cardiography B point, but the Q wave can lack clear definition and even its peak is not visible for all participants. We thus investigated the feasibility of using the electrocardiogram R wave peak (Rpeak ) instead of Q because it can be consistently identified with ease and precision. Across four samples (total N = 408), young adult participants completed a variety of minimally metabolically demanding laboratory tasks after a resting baseline. Results consistently supported a close relationship between absolute levels of the Rpeak -B interval and PEP (accounting for approximately 90% of the variance at baseline and 89% during task performance, on average), but for reactivity values, Rpeak -B was practically indistinguishable from PEP (accounting for over 98% of the variance, on average). Given that using Rpeak rather than the onset or peak of Q saves time, eliminates potential subjectivity, and can be applied to more participants (i.e., those without a visible Q wave), findings suggest that Rpeak -B likely provides an adequate estimate of PEP when absolute levels are of interest and clearly does so for within-person changes. © 2016 Society for Psychophysiological Research.

  14. Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism

    SciTech Connect

    Cole, Toby B.; Walter, Betsy J.; Shih, Diana M.

    2005-08-01

    The Q192R polymorphism of paraoxonase (PON1) has been shown to affect hydrolysis of organophosphorus compounds. The Q192 and R192 alloforms exhibit equivalent catalytic efficiencies of hydrolysis for diazoxon, the oxon form of the pesticide (DZ). However, the R192 alloform has a higher catalytic efficiency of hydrolysis than does the Q192 alloform for chlorpyrifos oxon (CPO), the oxon form of the pesticide chlorpyrifos (CPS). The current study examined the relevance of these observations for in-vivo exposures to chlorpyrifos and chlorpyrifos oxon. Methods Using a transgenic mouse model we examined the relevance of the Q192R polymorphism for exposure to CPS and CPOmore » in vivo. Transgenic mice were generated that expressed either human PON1Q192 or PON1R192 at equivalent levels, in the absence of endogenous mouse PON1. Dose-response and time course experiments were performed on adult mice exposed dermally to CPS or CPO. Morbidity and acetylcholinesterase (AChE) activity in the brain and diaphragm were determined in the first 24 h following exposure. Results Mice expressing PON1Q192 were significantly more sensitive to CPO, and to a lesser extent CPS, than were mice expressing PON1R192. The time course of inhibition following exposure to 1.2 mg/kg CPO revealed maximum inhibition of brain AChE at 6?12 h, with PON1R192, PON1Q192, and PON1? /? mice exhibiting 40, 70 and 85% inhibition, respectively, relative to control mice. The effect of PON1 removal on the dose?response curve for CPS exposure was remarkably consistent with a PBPK/PD model of CPS exposure. Conclusion These results indicate that individuals expressing only the PON1Q192 allele would be more sensitive to the adverse effects of CPO or CPS exposure, especially if they are expressing a low level of plasma PON1Q192.« less

  15. Tourette's syndrome is not associated with interleukin-10 receptor 1 variants on chromosome 11q23.3.

    PubMed

    Kindler, Jochen; Schosser, Alexandra; Stamenkovic, Mara; Schloegelhofer, Monika; Leisch, Friedrich; Hornik, Kurt; Aschauer, Harald; Gasche, Christoph

    2008-01-15

    Interleukin-10 receptor 1 (IL-10R1) single nucleotide polymorphisms, located on chromosome 11q23 - a strong candidate for linkage with Tourette's syndrome (TS) - have been investigated for association with TS. DNA of 77 patients with a DSM-IV (Diagnostic and Statistical Manual IV) diagnosis of TS and 250 healthy controls was genotyped. IL-10R1 was not associated with TS.

  16. The TREM2 variant p.R47H is a risk factor for sporadic amyotrophic lateral sclerosis

    PubMed Central

    Cady, Janet; Koval, Erica D.; Benitez, Bruno A.; Zaidman, Craig; Jockel-Balsarotti, Jennifer; Allred, Peggy; Baloh, Robert H.; Ravits, John; Simpson, Ericka; Appel, Stanley H.; Pestronk, Alan; Goate, Alison M.; Miller, Timothy M.; Cruchaga, Carlos; Harms, Matthew B.

    2014-01-01

    Importance Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which microglia play a significant and active role. Recently, a rare missense variant (p.R47H) in the microglial activating gene TREM2 was found to increase the risk of several neurodegenerative diseases, including Alzheimer’s disease. Whether the p.R47H variant is a risk factor for ALS is not currently known. Objective To determine if p.R47H (rs75932628) in TREM2 is a risk factor for ALS and assess whether TREM2 expression is dysregulated in disease. Design, setting, and participants 923 sporadic ALS subjects and 1854 normal controls self-reported as non-Hispanic white were collected from ALS clinics in the United States and genotyped for the p.R47H variant in TREM2. Clinical data was obtained on ALS subjects for genotype/phenotype correlations. Expression of TREM2 was measured by quantitative PCR and compared in spinal cord from 18 ALS subjects, 12 neurologically normal controls, as well as from wildtype and transgenic SOD1G93A mice. Main outcome measures Minor allele frequency of rs75932628 and relative expression of TREM2. Results The TREM2 variant p. R47H was more common in subject with ALS than in controls and is therefore a significant risk factor for ALS (OR=2.40; 95%CI=1.29-4.15; p=4.1×10-3). Furthermore, TREM2 expression was increased in spinal cords from ALS patients and SOD1G93A mice (p=2.8×10-4, p=2.8×10-9 respectively), confirming dysregulated TREM2 in disease. TREM2 expression in human spinal cord was negatively correlated with survival (p=0.04), but not other phenotypic aspects of disease. Conclusion and relevance This study demonstrates that the TREM2 p.R47H variant is a potent risk factor for sporadic amyotrophic lateral sclerosis. These findings identify the first genetic influence on neuro-inflammation in ALS and highlight the TREM2 signaling pathway as a therapeutic target in ALS and other neurodegenerative diseases. PMID:24535663

  17. A Novel Tau Mutation in Exon 12, p.Q336H, Causes Hereditary Pick Disease

    PubMed Central

    Tacik, Pawel; DeTure, Michael; Hinkle, Kelly M.; Lin, Wen-Lang; Sanchez-Contreras, Monica; Carlomagno, Yari; Pedraza, Otto; Rademakers, Rosa; Ross, Owen A.; Wszolek, Zbigniew K.; Dickson, Dennis W.

    2015-01-01

    Pick disease (PiD) is a frontotemporal lobar degeneration with distinctive neuronal inclusions (Pick bodies) that are enriched in 3-repeat (3R) tau. Although mostly sporadic, mutations in the tau gene (MAPT) have been reported. We screened 24 cases of neuropathologically confirmed PiD for MAPT mutations and found a novel mutation (c.1008G>C, p.Q336H) in one patient. Pathogenicity was confirmed on microtubule assembly and tau filament formation assays. The patient was compared to sporadic PiD and PiD associated with MAPT mutations from a review of the literature. The patient had behavioral changes at 55 years of age, followed by reduced verbal fluency, parkinsonism and death at 63 years of age. His mother and maternal uncle had similar symptoms. Recombinant tau with p.Q336H mutation formed filaments faster than wild type tau, especially with 3R tau. It also promoted more microtubule assembly than wild type tau. We conclude that mutations in MAPT, including p.Q336H, can be associated with clinical, pathologic, and biochemical features that are similar to those in sporadic PiD. The pathomechanism of p.Q336H, and another previously reported variant at the same codon (p.Q336R), appears to be unique to MAPT mutations in that they not only predispose to abnormal tau filament formation but also facilitate microtubule assembly in a 3R tau-dependent manner. PMID:26426266

  18. Rare Autism-Associated Variants Implicate Syntaxin 1 (STX1 R26Q) Phosphorylation and the Dopamine Transporter (hDAT R51W) in Dopamine Neurotransmission and Behaviors

    PubMed Central

    Cartier, Etienne; Hamilton, Peter J.; Belovich, Andrea N.; Shekar, Aparna; Campbell, Nicholas G.; Saunders, Christine; Andreassen, Thorvald F.; Gether, Ulrik; Veenstra-Vanderweele, Jeremy; Sutcliffe, James S.; Ulery-Reynolds, Paula G.; Erreger, Kevin; Matthies, Heinrich J.G.; Galli, Aurelio

    2015-01-01

    Background Syntaxin 1 (STX1) is a presynaptic plasma membrane protein that coordinates synaptic vesicle fusion. STX1 also regulates the function of neurotransmitter transporters, including the dopamine (DA) transporter (DAT). The DAT is a membrane protein that controls DA homeostasis through the high-affinity re-uptake of synaptically released DA. Methods We adopt newly developed animal models and state-of-the-art biophysical techniques to determine the contribution of the identified gene variants to impairments in DA neurotransmission observed in autism spectrum disorder (ASD). Outcomes Here, we characterize two independent autism-associated variants in the genes that encode STX1 and the DAT. We demonstrate that each variant dramatically alters DAT function. We identify molecular mechanisms that converge to inhibit reverse transport of DA and DA-associated behaviors. These mechanisms involve decreased phosphorylation of STX1 at Ser14 mediated by casein kinase 2 as well as a reduction in STX1/DAT interaction. These findings point to STX1/DAT interactions and STX1 phosphorylation as key regulators of DA homeostasis. Interpretation We determine the molecular identity and the impact of these variants with the intent of defining DA dysfunction and associated behaviors as possible complications of ASD. PMID:25774383

  19. A hantavirus causing hemorrhagic fever with renal syndrome requires gC1qR/p32 for efficient cell binding and infection

    SciTech Connect

    Choi, Yun; Kwon, Young-Chan; Kim, Soo-In

    Hantaan virus (HTNV) is a pathogenic hantavirus that causes hemorrhagic fever with renal syndrome (HFRS). HTNV infection is mediated by {alpha}v{beta}3 integrin. We used protein blots of Vero E6 cell homogenates to demonstrate that radiolabeled HTNV virions bind to gC1qR/p32, the acidic 32-kDa protein known as the receptor for the globular head domain of complement C1q. RNAi-mediated suppression of gC1qR/p32 markedly reduced HTNV binding and infection in human lung epithelial A549 cells. Conversely, transient expression of either simian or human gC1qR/p32 rendered non-permissive CHO cells susceptible to HTNV infection. These results suggest an important role for gC1qR/p32 in HTNV infectionmore » and pathogenesis.« less

  20. Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.

    PubMed

    Hardt, Karin; Heick, Sven Boris; Betz, Beate; Goecke, Timm; Yazdanparast, Haniyeh; Küppers, Robin; Servan, Kati; Steinke, Verena; Rahner, Nils; Morak, Monika; Holinski-Feder, Elke; Engel, Christoph; Möslein, Gabriela; Schackert, Hans-Konrad; von Knebel Doeberitz, Magnus; Pox, Christian; Hegemann, Johannes H; Royer-Pokora, Brigitte

    2011-06-01

    Missense mutations of the DNA mismatch repair gene MLH1 are found in a significant fraction of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) and their pathogenicity often remains unclear. We report here all 88 MLH1 missense variants identified in families from the German HNPCC consortium with clinical details of these patients/families. We investigated 23 MLH1 missense variants by two functional in vivo assays in yeast; seven map to the ATPase and 16 to the protein interaction domain. In the yeast-2-hybrid (Y2H) assay three variants in the ATPase and twelve variants in the interaction domain showed no or a reduced interaction with PMS2; seven showed a normal and one a significantly higher interaction. Using the Lys2A (14) reporter system to study the dominant negative mutator effect (DNE), 16 variants showed no or a low mutator effect, suggesting that these are nonfunctional, three were intermediate and four wild type in this assay. The DNE and Y2H results were concordant for all variants in the interaction domain, whereas slightly divergent results were obtained for variants in the ATPase domain. Analysis of the stability of the missense proteins in yeast and human embryonic kidney cells (293T) revealed a very low expression for seven of the variants in yeast and for nine in human cells. In total 15 variants were classified as deleterious, five were classified as variants of unclassified significance (VUS) and three were basically normal in the functional assays, P603R, K618R, Q689R, suggesting that these are neutral.

  1. R47H TREM2 variant increases risk of typical early-onset Alzheimer’s disease but not of prion or frontotemporal dementia

    PubMed Central

    CF, Slattery; J, Beck; L, Harper; G, Adamson; Z, Abdi; J, Uphill; T, Campbell; R, Druyeh; CJ, Mahoney; JD, Rohrer; J, Kenny; J, Lowe; KK, Leung; J, Barnes; SL, Clegg; M, Blair; JM, Nicholas; RJ, Guerreiro; JB, Rowe; C, Ponto; I, Zerr; H, Kretzschmar; P, Gambetti; SJ, Crutch; JD, Warren; MN, Rossor; NC, Fox; J, Collinge; JM, Schott; S, Mead

    2015-01-01

    Background Rare TREM2 variants are significant risk factors for Alzheimer’s disease. Methods We used next generation sequencing of the whole gene (n=700), exon 2 Sanger sequencing (n=2634), p.R47H genotyping (n=3518) and genome wide association study imputation (n=13048) to determine whether TREM2 variants are risk factors or phenotypic modifiers in patients with Alzheimer’s disease (n=1002), frontotemporal dementia (n=358), sporadic (n=2500) and variant (n=115) Creutzfeldt-Jakob disease. Results We confirm only p.R47H as a risk factor for Alzheimer’s disease (OR=2.19; 95%CI=1.04-4.51; P=0.03). p.R47H does not significantly alter risk for frontotemporal dementia (OR=0.81), variant or sporadic Creutzfeldt-Jakob disease (OR=1.06 95%CI=0.66-1.69) in our cohorts. Individuals with p.R47H associated Alzheimer’s (n=12) had significantly earlier symptom onset than individuals with no TREM2 variants (n=551) (55.2years vs. 61.7years, P=0.02). We note that heterozygous p.R47H Alzheimer’s disease is memory led and otherwise indistinguishable from “typical” sporadic Alzheimer’s. Conclusion We find p.R47H is a risk factor for Alzheimer’s disease, but not frontotemporal dementia or prion disease. PMID:25160042

  2. Neuroblastoma in a boy with MCA/MR syndrome, deletion 11q, and duplication 12q

    SciTech Connect

    Koiffmann, C.P.; Vianna-Morgante, A.M.; Wajntal, A.

    Deletion 11q23{r_arrow}qter and duplication 12q23{r_arrow}qter are described in a boy with neuroblastoma, multiple congenital anomalies, and mental retardation. The patient has clinical manifestations of 11q deletion and 12q duplication syndromes. The possible involvement of the segment 11q23{r_arrow}24 in the cause of the neuroblastoma is discussed. 18 refs., 2 figs., 1 tab.

  3. Common variants in the obesity-associated genes FTO and MC4R are not associated with risk of colorectal cancer.

    PubMed

    Yang, Baiyu; Thrift, Aaron P; Figueiredo, Jane C; Jenkins, Mark A; Schumacher, Fredrick R; Conti, David V; Lin, Yi; Win, Aung Ko; Limburg, Paul J; Berndt, Sonja I; Brenner, Hermann; Chan, Andrew T; Chang-Claude, Jenny; Hoffmeister, Michael; Hudson, Thomas J; Marchand, Loïc Le; Newcomb, Polly A; Slattery, Martha L; White, Emily; Peters, Ulrike; Casey, Graham; Campbell, Peter T

    2016-10-01

    Obesity is a convincing risk factor for colorectal cancer. Genetic variants in or near FTO and MC4R are consistently associated with body mass index and other body size measures, but whether they are also associated with colorectal cancer risk is unclear. In the discovery stage, we tested associations of 677 FTO and 323 MC4R single nucleotide polymorphisms (SNPs) 100kb upstream and 300kb downstream from each respective locus with risk of colorectal cancer in data from the Colon Cancer Family Registry (CCFR: 1960 cases; 1777 controls). Next, all SNPs that were nominally statistically significant (p<0.05) in the discovery stage were included in replication analyses in data from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO: 9716 cases; 9844 controls). In the discovery stage, 43 FTO variants and 18 MC4R variants were associated with colorectal cancer risk (p<0.05). No SNPs remained statistically significant in the replication analysis after accounting for multiple comparisons. We found no evidence that individual variants in or near the obesity-related genes FTO and MC4R are associated with risk of colorectal cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. The R403Q Myosin Mutation Implicated in Familial Hypertrophic Cardiomyopathy Causes Disorder at the Actomyosin Interface

    PubMed Central

    Volkmann, Niels; Lui, HongJun; Hazelwood, Larnele; Trybus, Kathleen M.; Lowey, Susan; Hanein, Dorit

    2007-01-01

    Background Mutations in virtually all of the proteins comprising the cardiac muscle sarcomere have been implicated in causing Familial Hypertrophic Cardiomyopathy (FHC). Mutations in the β-myosin heavy chain (MHC) remain among the most common causes of FHC, with the widely studied R403Q mutation resulting in an especially severe clinical prognosis. In vitro functional studies of cardiac myosin containing the R403Q mutation have revealed significant changes in enzymatic and mechanical properties compared to wild-type myosin. It has been proposed that these molecular changes must trigger events that ultimately lead to the clinical phenotype. Principal Findings Here we examine the structural consequences of the R403Q mutation in a recombinant smooth muscle myosin subfragment (S1), whose kinetic features have much in common with slow β-MHC. We obtained three-dimensional reconstructions of wild-type and R403Q smooth muscle S1 bound to actin filaments in the presence (ADP) and absence (apo) of nucleotide by electron cryomicroscopy and image analysis. We observed that the mutant S1 was attached to actin at highly variable angles compared to wild-type reconstructions, suggesting a severe disruption of the actin-myosin interaction at the interface. Significance These results provide structural evidence that disarray at the molecular level may be linked to the histopathological myocyte disarray characteristic of the diseased state. PMID:17987111

  5. Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease.

    PubMed

    Morimoto, Takaaki; Mineharu, Yohei; Ono, Koh; Nakatochi, Masahiro; Ichihara, Sahoko; Kabata, Risako; Takagi, Yasushi; Cao, Yang; Zhao, Lanying; Kobayashi, Hatasu; Harada, Kouji H; Takenaka, Katsunobu; Funaki, Takeshi; Yokota, Mitsuhiro; Matsubara, Tatsuaki; Yamamoto, Ken; Izawa, Hideo; Kimura, Takeshi; Miyamoto, Susumu; Koizumi, Akio

    2017-01-01

    The genetic architecture of coronary artery disease has not been fully elucidated, especially in Asian countries. Moyamoya disease is a progressive cerebrovascular disease that is reported to be complicated by coronary artery disease. Because most Japanese patients with moyamoya disease carry the p.R4810K variant of the ring finger 213 gene (RNF213), this may also be a risk factor for coronary artery disease; however, this possibility has never been tested. We genotyped the RNF213 p.R4810K variant in 956 coronary artery disease patients and 716 controls and tested the association between p.R4810K and coronary artery disease. We also validated the association in an independent population of 311 coronary artery disease patients and 494 controls. In the replication study, the p.R4810K genotypes were imputed from genome-wide genotyping data based on the 1000 Genomes Project. We used multivariate logistic regression analyses to adjust for well-known risk factors such as dyslipidemia and smoking habits. In the primary study population, the frequency of the minor variant allele was significantly higher in patients with coronary artery disease than in controls (2.04% vs. 0.98%), with an odds ratio of 2.11 (p = 0.017). Under a dominant model, after adjustment for risk factors, the association remained significant, with an odds ratio of 2.90 (95% confidence interval: 1.37-6.61; p = 0.005). In the replication study, the association was significant after adjustment for age and sex (odds ratio = 4.99; 95% confidence interval: 1.16-21.53; p = 0.031), although it did not reach statistical significance when further adjusted for risk factors (odds ratio = 3.82; 95% confidence interval: 0.87-16.77; p = 0.076). The RNF213 p.R4810K variant appears to be significantly associated with coronary artery disease in the Japanese population.

  6. Significance of common variants on human chromosome 8q24 in relation to the risk of prostate cancer in native Japanese men

    PubMed Central

    Liu, Miao; Kurosaki, Takayuki; Suzuki, Motofumi; Enomoto, Yutaka; Nishimatsu, Hiroaki; Arai, Tomio; Sawabe, Motoji; Hosoi, Takayuki; Homma, Yukio; Kitamura, Tadaichi

    2009-01-01

    Background Common variants on human chromosome 8q24, rs1447295 (C/A) and rs6983267 (T/G), have been recently linked to the prevalence of prostate cancer in European and American populations. Here, we evaluated whether the single-nucleotide polymorphisms rs1447295 and rs6983267 were associated with the risk of sporadic prostate cancer as well as latent prostate cancer in a native Japanese population. Results We analyzed genomic DNA samples from 391 sporadic prostate cancer patients, 323 controls who had died from causes unrelated to cancer and 112 Japanese men who were diagnosed as having latent prostate cancer based on autopsy results. The polymorphisms were determined by allelic discrimination using a fluorescent-based TaqMan assay. The A allele of rs1447295 was significantly associated with the risk of sporadic prostate cancer (p = 0.04; age-adjusted OR, 1.34), while the G allele of rs6983267 showed a trend towards being a high-risk allele (p = 0.06; age-adjusted OR, 1.27). No significant difference between these two polymorphisms and the risk of latent prostate cancer was observed in the present Japanese population. Conclusion Known variants on human chromosome 8q24 may be risk factors for sporadic prostate cancer in native Japanese men. PMID:19602258

  7. p.Q192R SNP of PON1 seems not to be Associated with Carotid Atherosclerosis Risk Factors in an Asymptomatic and Normolipidemic Brazilian Population Sample

    PubMed Central

    Scherrer, Daniel Zanetti; Zago, Vanessa Helena de Souza; Vieira, Isabela Calanca; Parra, Eliane Soler; Panzoldo, Natália Baratella; Alexandre, Fernanda; Secolin, Rodrigo; Baracat, Jamal; Quintão, Eder Carlos Rocha; de Faria, Eliana Cotta

    2015-01-01

    Background Evidences suggest that paraoxonase 1 (PON1) confers important antioxidant and anti-inflammatory properties when associated with high-density lipoprotein (HDL). Objective To investigate the relationships between p.Q192R SNP of PON1, biochemical parameters and carotid atherosclerosis in an asymptomatic, normolipidemic Brazilian population sample. Methods We studied 584 volunteers (females n = 326, males n = 258; 19-75 years of age). Total genomic DNA was extracted and SNP was detected in the TaqMan® SNP OpenArray® genotyping platform (Applied Biosystems, Foster City, CA). Plasma lipoproteins and apolipoproteins were determined and PON1 activity was measured using paraoxon as a substrate. High-resolution β-mode ultrasonography was used to measure cIMT and the presence of carotid atherosclerotic plaques in a subgroup of individuals (n = 317). Results The presence of p.192Q was associated with a significant increase in PON1 activity (RR = 12.30 (11.38); RQ = 46.96 (22.35); QQ = 85.35 (24.83) μmol/min; p < 0.0001), HDL-C (RR= 45 (37); RQ = 62 (39); QQ = 69 (29) mg/dL; p < 0.001) and apo A-I (RR = 140.76 ± 36.39; RQ = 147.62 ± 36.92; QQ = 147.49 ± 36.65 mg/dL; p = 0.019). Stepwise regression analysis revealed that heterozygous and p.192Q carriers influenced by 58% PON1 activity towards paraoxon. The univariate linear regression analysis demonstrated that p.Q192R SNP was not associated with mean cIMT; as a result, in the multiple regression analysis, no variables were selected with 5% significance. In logistic regression analysis, the studied parameters were not associated with the presence of carotid plaques. Conclusion In low-risk individuals, the presence of the p.192Q variant of PON1 is associated with a beneficial plasma lipid profile but not with carotid atherosclerosis. PMID:26039660

  8. Paraoxonase 1 (PON1)-L55M among common variants in the coding region of the paraoxonase gene family may contribute to the glycemic control in type 2 diabetes.

    PubMed

    Mahrooz, Abdolkarim; Hashemi-Soteh, Mohammad Bagher; Heydari, Masoud; Boorank, Ruzbeh; Ramazani, Fatemeh; Mahmoudi, Ali; Kianmehr, Anvarsadat; Alizadeh, Ahad

    2018-05-19

    Genome studies have shown that the genes encoding paraoxonase 1 (PON1) and PON2 are associated with glucose metabolism. The goal of this study was to simultaneously evaluate the association between functional variants in PON1 and PON2 genes and susceptibility for type 2 diabetes (T2D) and determine whether they can affect glycemic control. We performed a case-control study with 145 newly diagnosed patients with T2D and 148 controls. The common variants including PON1-Q192R, PON1-L55M and PON2-S311C were genotyped by PCR-based RFLP. A mismatch-PCR/RFLP was applied for genotyping the PON2-A148G variant. The variant PON1-Q192R in males (OR = 2.55, 95%CI 1.16-5.69, p = 0.023) and PON2-A148G in females (OR = 1.56, 95%CI 1.00-2.44, p = 0.059) were associated with T2D. Compared with the LL genotypes of PON1-L55M, HbA1c levels were significantly lower in the LM genotypes (p = 0.01) and MM genotypes (p = 0.032) in patients. Multiple linear regression analyses showed that among the study variants only the PON1-L55M variant as an independent variable significantly associated with glycemic control. This variant significantly influenced glycemic control in patients with poor glycemic control so that it was better with the following order: LL < LM < MM. Based on gamma correlation, there was a significant inverse association between the number of M alleles of the PON1-L55M and HbA1c levels (r = -0.261, p = 0.001). Sex should be considered a confounding variable in association studies on the variants PON1-Q192R and PON2-A148G in T2D. Patients sharing the 55 M allele were prone to having good glycemic control. Our findings provide genetic evidence that the PON1-L55M variant may be a factor contributing to glycemic control. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains.

    PubMed

    Haddick, Patrick C G; Larson, Jessica L; Rathore, Nisha; Bhangale, Tushar R; Phung, Qui T; Srinivasan, Karpagam; Hansen, David V; Lill, Jennie R; Pericak-Vance, Margaret A; Haines, Jonathan; Farrer, Lindsay A; Kauwe, John S; Schellenberg, Gerard D; Cruchaga, Carlos; Goate, Alison M; Behrens, Timothy W; Watts, Ryan J; Graham, Robert R; Kaminker, Joshua S; van der Brug, Marcel

    2017-01-01

    The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer's disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated with the age of onset of Alzheimer's disease in APOE ɛ4 carriers. Across five datasets, p.D358A had a meta P = 3 ×10-4 and an odds ratio = 1.3, 95% confidence interval 1.12 -1.48. Our study suggests that a common coding region variant of the IL-6 receptor results in neuroinflammatory changes that may influence the age of onset of Alzheimer's disease in APOE ɛ4 carriers.

  10. Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1.

    PubMed

    Glubb, Dylan M; Maranian, Mel J; Michailidou, Kyriaki; Pooley, Karen A; Meyer, Kerstin B; Kar, Siddhartha; Carlebur, Saskia; O'Reilly, Martin; Betts, Joshua A; Hillman, Kristine M; Kaufmann, Susanne; Beesley, Jonathan; Canisius, Sander; Hopper, John L; Southey, Melissa C; Tsimiklis, Helen; Apicella, Carmel; Schmidt, Marjanka K; Broeks, Annegien; Hogervorst, Frans B; van der Schoot, C Ellen; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A; Ruebner, Matthias; Ekici, Arif B; Beckmann, Matthias W; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Pharoah, Paul D P; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; González-Neira, Anna; Benitez, Javier; Zamora, M Pilar; Arias Perez, Jose Ignacio; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Ko, Yon-Dschun; Brüning, Thomas; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tanaka, Hideo; Dörk, Thilo; Bogdanova, Natalia V; Helbig, Sonja; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Wu, Anna H; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O; Lambrechts, Diether; Zhao, Hui; Weltens, Caroline; van Limbergen, Erik; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Seibold, Petra; Radice, Paolo; Peterlongo, Paolo; Barile, Monica; Capra, Fabio; Couch, Fergus J; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Giles, Graham G; Milne, Roger L; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Teo, Soo Hwang; Yip, Cheng Har; See, Mee-Hoong; Cornes, Belinda; Cheng, Ching-Yu; Ikram, M Kamran; Kristensen, Vessela; Zheng, Wei; Halverson, Sandra L; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Van Asperen, Christi J; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Klevebring, Daniel; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; Collée, J Margriet; Hall, Per; Li, Jingmei; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Blot, William; Signorello, Lisa B; Cai, Qiuyin; Shah, Mitul; Ghoussaini, Maya; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Tang, Anthony; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Olswold, Curtis; Slager, Susan; Toland, Amanda E; Yannoukakos, Drakoulis; Shen, Chen-Yang; Wu, Pei-Ei; Yu, Jyh-Cherng; Hou, Ming-Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S; Brown, Melissa A; Ponder, Bruce A J; Chenevix-Trench, Georgia; Thompson, Deborah J; Edwards, Stacey L; Easton, Douglas F; Dunning, Alison M; French, Juliet D

    2015-01-08

    Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All

  11. Where is the exact origin of narrow premature ventricular contractions manifesting qR in inferior wall leads?

    PubMed

    Zheng, Cheng; Li, Jin; Lin, Jia-Xuan; Wang, Lu-Ping; Lin, Jia-Feng

    2016-04-04

    In recent years, radiofrequency catheter ablation(RFCA) has been established as an effective therapy for idiopathic premature ventricular contractions (PVCs), however, its effect on the narrow PVCs (QRS duration < 130 msec) with qR pattern in inferior leads, may not been fully concluded. Characteristics of 12-lead electrocardiogram (ECG) and electrophysiologic recordings were analyzed in 40 patients with symptomatic PVCs manifesting narrow QRS complex with qR pattern in inferior leads. The procedure of RFCA was performed based on pace mapping and activation mapping. Among the 40 patients with narrow PVCs, complete elimination of PVCs was achieved by RFCA in 35 patients during a median follow-up period of 23 months. Successful ablation was achieved on 19 patients at the sites where earliest Purkinje potentials were recorded in left ventricular anterosuperior septum, thus PVCs arising from left anterior fascicle (LAF) were confirmed, for these PVCs, the QRS morphology were right bundle branch and left posterior fascicle block (RBBB + LPFB) with rightward axis, the average QRS duration 116.07 ± 7.96 ms, R or rsR'in lead V1,with transition zone ahead of lead V1 in precordial leads. Another 16 successful RFCA were achieved by energy delivery at interleaflet triangle(ILT) between right coronary cusp(RCC) and left coronary cusp(LCC) where no Purkinje potentials were recorded, for narrow PVCs arising from the L-RCC ILT, the QRS morphology were similar to the PVCs arising from LAF but much narrower in QRS duration (100.44 ± 3.49 vs. 116.07 ± 7.96 ms, p < 0.05), they were also R or Rs in lead V1 with the transition zone ahead of lead V1. For 5 symptomatic narrow PVCs failed to the procedure of RFCA, their electrocardiographic characteristics showed that the narrowest QRS duration (91.80 ± 6.94 vs. 100.44 ± 3.49, 116.07 ± 7.96 ms, p < 0.05), rs or rS (r/s or r/S≦1) morphology in lead V1 with the precordial transition zone behind lead V3. Most of idiopathic PVCs of

  12. 34 CFR 462.12 - What procedures does the Secretary use to review the suitability of tests?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... regarding the suitability of a test, the Secretary publishes in the Federal Register and posts on the... suitability of tests? 462.12 Section 462.12 Education Regulations of the Offices of the Department of... Review the Suitability of Tests for Use in the NRS? § 462.12 What procedures does the Secretary use to...

  13. 34 CFR 462.12 - What procedures does the Secretary use to review the suitability of tests?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... regarding the suitability of a test, the Secretary publishes in the Federal Register and posts on the... suitability of tests? 462.12 Section 462.12 Education Regulations of the Offices of the Department of... Review the Suitability of Tests for Use in the NRS? § 462.12 What procedures does the Secretary use to...

  14. 34 CFR 462.12 - What procedures does the Secretary use to review the suitability of tests?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... regarding the suitability of a test, the Secretary publishes in the Federal Register and posts on the... suitability of tests? 462.12 Section 462.12 Education Regulations of the Offices of the Department of... Review the Suitability of Tests for Use in the NRS? § 462.12 What procedures does the Secretary use to...

  15. 34 CFR 462.12 - What procedures does the Secretary use to review the suitability of tests?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... regarding the suitability of a test, the Secretary publishes in the Federal Register and posts on the... suitability of tests? 462.12 Section 462.12 Education Regulations of the Offices of the Department of... Review the Suitability of Tests for Use in the NRS? § 462.12 What procedures does the Secretary use to...

  16. KISS1R signals independently of Gαq/11 and triggers LH secretion via the β-arrestin pathway in the male mouse.

    PubMed

    Ahow, Maryse; Min, Le; Pampillo, Macarena; Nash, Connor; Wen, Junping; Soltis, Kathleen; Carroll, Rona S; Glidewell-Kenney, Christine A; Mellon, Pamela L; Bhattacharya, Moshmi; Tobet, Stuart A; Kaiser, Ursula B; Babwah, Andy V

    2014-11-01

    Hypothalamic GnRH is the master regulator of the neuroendocrine reproductive axis, and its secretion is regulated by many factors. Among these is kisspeptin (Kp), a potent trigger of GnRH secretion. Kp signals via the Kp receptor (KISS1R), a Gαq/11-coupled 7-transmembrane-spanning receptor. Until this study, it was understood that KISS1R mediates GnRH secretion via the Gαq/11-coupled pathway in an ERK1/2-dependent manner. We recently demonstrated that KISS1R also signals independently of Gαq/11 via β-arrestin and that this pathway also mediates ERK1/2 activation. Because GnRH secretion is ERK1/2-dependent, we hypothesized that KISS1R regulates GnRH secretion via both the Gαq/11- and β-arrestin-coupled pathways. To test this hypothesis, we measured LH secretion, a surrogate marker of GnRH secretion, in mice lacking either β-arrestin-1 or β-arrestin-2. Results revealed that Kp-dependent LH secretion was significantly diminished relative to wild-type mice (P < .001), thus supporting that β-arrestin mediates Kp-induced GnRH secretion. Based on this, we hypothesized that Gαq/11-uncoupled KISS1R mutants, like L148S, will display Gαq/11-independent signaling. To test this hypothesis, L148S was expressed in HEK 293 cells. and results confirmed that, although strongly uncoupled from Gαq/11, L148S retained the ability to trigger significant Kp-dependent ERK1/2 phosphorylation (P < .05). Furthermore, using mouse embryonic fibroblasts lacking β-arrestin-1 and -2, we demonstrated that L148S-mediated ERK1/2 phosphorylation is β-arrestin-dependent. Overall, we conclude that KISS1R signals via Gαq/11 and β-arrestin to regulate GnRH secretion. This novel and important finding could explain why patients bearing some types of Gαq/11-uncoupled KISS1R mutants display partial gonadotropic deficiency and even a reversal of the condition, idiopathic hypogonadotropic hypogonadism.

  17. RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

    PubMed Central

    Wang, Yue Yi; Mesirca, Pietro; Marqués-Sulé, Elena; Villejoubert, Olivier; D’Ocon, Pilar; Ruiz, Cristina; Domingo, Diana; Zorio, Esther; Mangoni, Matteo E.; Benitah, Jean-Pierre; Gómez, Ana María

    2017-01-01

    Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal genetic arrhythmia that manifests syncope or sudden death in children and young adults under stress conditions. CPVT patients often present bradycardia and sino-atrial node (SAN) dysfunction. However, the mechanism remains unclear. We analyzed SAN function in two CPVT families and in a novel knock-in (KI) mouse model carrying the RyR2R420Q mutation. Humans and KI mice presented slower resting heart rate. Accordingly, the rate of spontaneous intracellular Ca2+ ([Ca2+]i) transients was slower in KI mouse SAN preparations than in WT, without any significant alteration in the “funny” current (If ). The L-type Ca2+ current was reduced in KI SAN cells in a [Ca2+]i-dependent way, suggesting that bradycardia was due to disrupted crosstalk between the “voltage” and “Ca2+” clock, and the mechanisms of pacemaking was induced by aberrant spontaneous RyR2- dependent Ca2+ release. This finding was consistent with a higher Ca2+ leak during diastolic periods produced by long-lasting Ca2+ sparks in KI SAN cells. Our results uncover a mechanism for the CPVT-causing RyR2 N-terminal mutation R420Q, and they highlight the fact that enhancing the Ca2+ clock may slow the heart rhythm by disturbing the coupling between Ca2+ and voltage clocks. PMID:28422759

  18. Thalamic miR-338-3p mediates auditory thalamocortical disruption and its late onset in 22q11.2 microdeletion models

    PubMed Central

    Chun, Sungkun; Du, Fei; Westmoreland, Joby J.; Han, Seung Baek; Wang, Yong-Dong; Eddins, Donnie; Bayazitov, Ildar T.; Devaraju, Prakash; Yu, Jing; Mellado Lagarde, Marcia M.; Anderson, Kara; Zakharenko, Stanislav S.

    2016-01-01

    Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical projections recently emerged as a neural circuit specifically disrupted in 22q11DS mouse models, in which haploinsufficiency of the microRNA-processing gene Dgcr8 resulted in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory thalamocortical phenotypes have a delayed onset in 22q11DS mouse models and are associated with an age-dependent reduction of the microRNA miR-338-3p, which targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the thalamocortical abnormalities, and miR-338-3p deletion/knockdown mimicked thalamocortical and behavioral deficits and eliminated their age dependence. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory thalamocortical signaling in 22q11DS mouse models and may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset. PMID:27892953

  19. Predicting the Functional Impact of KCNQ1 Variants of Unknown Significance.

    PubMed

    Li, Bian; Mendenhall, Jeffrey L; Kroncke, Brett M; Taylor, Keenan C; Huang, Hui; Smith, Derek K; Vanoye, Carlos G; Blume, Jeffrey D; George, Alfred L; Sanders, Charles R; Meiler, Jens

    2017-10-01

    An emerging standard-of-care for long-QT syndrome uses clinical genetic testing to identify genetic variants of the KCNQ1 potassium channel. However, interpreting results from genetic testing is confounded by the presence of variants of unknown significance for which there is inadequate evidence of pathogenicity. In this study, we curated from the literature a high-quality set of 107 functionally characterized KCNQ1 variants. Based on this data set, we completed a detailed quantitative analysis on the sequence conservation patterns of subdomains of KCNQ1 and the distribution of pathogenic variants therein. We found that conserved subdomains generally are critical for channel function and are enriched with dysfunctional variants. Using this experimentally validated data set, we trained a neural network, designated Q1VarPred, specifically for predicting the functional impact of KCNQ1 variants of unknown significance. The estimated predictive performance of Q1VarPred in terms of Matthew's correlation coefficient and area under the receiver operating characteristic curve were 0.581 and 0.884, respectively, superior to the performance of 8 previous methods tested in parallel. Q1VarPred is publicly available as a web server at http://meilerlab.org/q1varpred. Although a plethora of tools are available for making pathogenicity predictions over a genome-wide scale, previous tools fail to perform in a robust manner when applied to KCNQ1. The contrasting and favorable results for Q1VarPred suggest a promising approach, where a machine-learning algorithm is tailored to a specific protein target and trained with a functionally validated data set to calibrate informatics tools. © 2017 American Heart Association, Inc.

  20. Non-syndromic hearing loss caused by the dominant cis mutation R75Q with the recessive mutation V37I of the GJB2 (Connexin 26) gene.

    PubMed

    Kim, Juwon; Jung, Jinsei; Lee, Min Goo; Choi, Jae Young; Lee, Kyung-A

    2015-06-19

    GJB2 alleles containing two cis mutations have been rarely found in non-syndromic hearing loss. Herein, we present a Korean patient with non-syndromic hearing loss caused by the R75Q cis mutation with V37I, which arose de novo in the father and was inherited by the patient. Biochemical coupling and hemichannel permeability assays were performed after molecular cloning and transfection of HEK293T cells. Student's t-tests or analysis of variance followed by Tukey's multiple comparison test was used as statistical analysis. Biochemical coupling was significantly reduced in connexin 26 (Cx26)-R75Q- and Cx26-V37I-transfected cells, with greater extent in Cx26-R75Q and Cx26-R75Q+V37I cells. Interestingly, our patient and his father with the mutations had more residual hearing compared with patients with the dominant mutation alone. Although the difference in hemichannel activity between R75Q alone and R75Q in combination with V37I failed to reach significance, it is of note that there is a possibility that V37I located upstream of R75Q might have the ability to ameliorate R75Q expression. Our study emphasizes the importance of cis mutations with R75Q, as the gene effect of R75Q can be modulated depending on the type of additional mutation.

  1. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes.

    PubMed

    Lal, Dennis; Reinthaler, Eva M; Dejanovic, Borislav; May, Patrick; Thiele, Holger; Lehesjoki, Anna-Elina; Schwarz, Günter; Riesch, Erik; Ikram, M Arfan; van Duijn, Cornelia M; Uitterlinden, Andre G; Hofman, Albert; Steinböck, Hannelore; Gruber-Sedlmayr, Ursula; Neophytou, Birgit; Zara, Federico; Hahn, Andreas; Gormley, Padhraig; Becker, Felicitas; Weber, Yvonne G; Cilio, Maria Roberta; Kunz, Wolfram S; Krause, Roland; Zimprich, Fritz; Lemke, Johannes R; Nürnberg, Peter; Sander, Thomas; Lerche, Holger; Neubauer, Bernd A

    2016-01-01

    The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10-4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.

  2. Non-Coding Keratin Variants Associate with Liver Fibrosis Progression in Patients with Hemochromatosis

    PubMed Central

    Lunova, Mariia; Guldiken, Nurdan; Lienau, Tim C.; Stickel, Felix; Omary, M. Bishr

    2012-01-01

    Background Keratins 8 and 18 (K8/K18) are intermediate filament proteins that protect the liver from various forms of injury. Exonic K8/K18 variants associate with adverse outcome in acute liver failure and with liver fibrosis progression in patients with chronic hepatitis C infection or primary biliary cirrhosis. Given the association of K8/K18 variants with end-stage liver disease and progression in several chronic liver disorders, we studied the importance of keratin variants in patients with hemochromatosis. Methods The entire K8/K18 exonic regions were analyzed in 162 hemochromatosis patients carrying homozygous C282Y HFE (hemochromatosis gene) mutations. 234 liver-healthy subjects were used as controls. Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Previously-generated transgenic mice overexpressing K8 G62C were studied for their susceptibility to iron overload. Susceptibility to iron toxicity of primary hepatocytes that express K8 wild-type and G62C was also assessed. Results We identified amino-acid-altering keratin heterozygous variants in 10 of 162 hemochromatosis patients (6.2%) and non-coding heterozygous variants in 6 additional patients (3.7%). Two novel K8 variants (Q169E/R275W) were found. K8 R341H was the most common amino-acid altering variant (4 patients), and exclusively associated with an intronic KRT8 IVS7+10delC deletion. Intronic, but not amino-acid-altering variants associated with the development of liver fibrosis. In mice, or ex vivo, the K8 G62C variant did not affect iron-accumulation in response to iron-rich diet or the extent of iron-induced hepatocellular injury. Conclusion In patients with hemochromatosis, intronic but not exonic K8/K18 variants associate with liver fibrosis development. PMID:22412904

  3. [Correlation of chromosome 1p and 19q status and expression of R132H mutant IDH1 protein in oligodendroglial tumors].

    PubMed

    Yao, Kun; Duan, Zejun; Hu, Zeliang; Bian, Yu; Qi, Xueling

    2014-10-01

    To correlate the presence of chromosome 1p/19q deletion with the expression of R132H mutant IDH1 status in oligodendroglial tumors, and to explore molecular markers for predicting chemosensitivity of oligodendroglial tumors. The study included 75 oligodendroglial tumors (38 oligodendrogliomas and 37 oligoastrocytomas). Immunohistochemistry was used to detect the expression of R132H mutant IDH1 protein, and fluorescence in situ hybridization (FISH) was employed to detect 1p/19q deletion. Deletion of chromosome 1p and/or 19q was detected in 37 cases (37/75, 49.3%), among which co-deletion of 1p and 19q was seen in 34 cases (closely correlated, P < 0.01). Oligodendrogliomas WHOIIhad a slightly higher deletion rate than oligodendrogliomas WHO III, although without statistical significance. Oligodendrogliomas WHO IIand WHO III had a significantly higher deletion rate of chromosome 1p/19q than oligoastrocytomas WHO II and WHO III (P < 0.05). While combined loss of 1p/19q was always detected in oligodendrogliomas when FISH was positive, isolated 1p or 19q deletion was only found in oligoastrocytomas. The expression of R132H mutant IDH1 was detected in 51 of 75 cases (68.0%), in which oligodendrogliomas had a higher positive rate than oligoastrocytomas. Statistical analysis demonstrated a significant correlation between the expression of R132H mutant IDH1 protein and the presence of combined 1p/19q deletion in oligodendrogliomas (P < 0.05). A significant correlation was observed between the expression of R132H mutant protein and 1p/19q LOH.Expression of 132H mutant IDH1 protein is the potential biomarker for predicating the presence of 1p/19q deletion in oligodendrogliomas.

  4. Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children

    USDA-ARS?s Scientific Manuscript database

    Melanocortin-4-receptor (MC4R) haploinsufficiency is the most common form of monogenic obesity; however, the frequency of MC4R variants and their functional effects in general populations remain uncertain. The aim of this study was to identify and characterize the effects of MC4R variants in Hispani...

  5. Common variants in the obesity-associated genes FTO and MC4R are not associated with risk of colorectal cancer

    PubMed Central

    Yang, Baiyu; Thrift, Aaron P.; Figueiredo, Jane C.; Jenkins, Mark A.; Schumacher, Fredrick R.; Conti, David V.; Lin, Yi; Win, Aung Ko; Limburg, Paul J.; Berndt, Sonja I.; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hoffmeister, Michael; Hudson, Thomas J.; Marchand, Loïc Le; Newcomb, Polly A.; Slattery, Martha L.; White, Emily; Peters, Ulrike; Casey, Graham; Campbell, Peter T.

    2016-01-01

    Background Obesity is a convincing risk factor for colorectal cancer. Genetic variants in or near FTO and MC4R are consistently associated with body mass index and other body size measures, but whether they are also associated with colorectal cancer risk is unclear. Methods In the discovery stage, we tested associations of 677 FTO and 323 MC4R single nucleotide polymorphisms (SNPs) 100kb upstream and 300kb downstream from each respective locus with risk of colorectal cancer in data from the Colon Cancer Family Registry (CCFR: 1,960 cases; 1,777 controls). Next, all SNPs that were nominally statistically signif icant (p<0.05) in the discovery stage were included in replication analyses in data from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO: 9,716 cases; 9,844 controls). Results In the discovery stage, 43 FTO variants and 18 MC4R variants were associated with colorectal cancer risk (p<0.05). No SNPs remained statistically significant in the replication analysis after accounting for multiple comparisons. Conclusion We found no evidence that individual variants in or near the obesity-related genes FTO and MC4R are associated with risk of colorectal cancer. PMID:27449576

  6. Chromosome 17q12 variants contribute to risk of early-onset prostate cancer

    PubMed Central

    Levin, Albert M.; Machiela, Mitchell J.; Zuhlke, Kimberly A.; Ray, Anna M.; Cooney, Kathleen A.; Douglas, Julie A.

    2008-01-01

    In a recent genome-wide association study by Gudmundsson et al. (2007), two prostate cancer susceptibility loci were identified on chromosome 17q. The first locus, at 17q12, was distinguished by two intronic single nucleotide polymorphisms (SNPs) in the TCF2 gene (rs4430796 and rs7501939). The second locus was in a gene-poor region of 17q24, where the strongest evidence of association was for SNP rs1859962. To determine if these loci were also associated with hereditary prostate cancer, we genotyped them in a family-based association sample of 403 non-Hispanic white families, including 1,015 men with and without prostate cancer. SNPs rs4430796 and rs7501939, which were in strong linkage disequilibrium (r2=0.68), showed the strongest evidence of prostate cancer association. Using a family-based association test, the “A” allele of SNP rs4430796 was over-transmitted to affected men (p=0.006), with an odds ratio of 1.40 (95%CI=1.09–1.81) under an additive genetic model. Notably, rs4430796 was significantly associated with prostate cancer among men diagnosed at an early (<50 years) but not later age (p=0.006 versus p=0.118). Our results confirm the prostate cancer association with SNPs on chromosome 17q12 initially reported by Gudmundsson et al. In addition, our results suggest that the increased risk associated with these SNPs is approximately doubled in individuals predisposed to develop early onset disease. Importantly, these SNPs do not account for a significant portion of our prior prostate cancer linkage evidence on chromosome 17. Thus, there likely exist one or more additional independent prostate cancer susceptibility loci in this region. PMID:18701471

  7. Genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

    PubMed Central

    Scott, Robert A.; Freitag, Daniel F.; Li, Li; Chu, Audrey Y.; Surendran, Praveen; Young, Robin; Grarup, Niels; Stancáková, Alena; Chen, Yuning; V.Varga, Tibor; Yaghootkar, Hanieh; Luan, Jian'an; Zhao, Jing Hua; Willems, Sara M.; Wessel, Jennifer; Wang, Shuai; Maruthur, Nisa; Michailidou, Kyriaki; Pirie, Ailith; van der Lee, Sven J.; Gillson, Christopher; Olama, Ali Amin Al; Amouyel, Philippe; Arriola, Larraitz; Arveiler, Dominique; Aviles-Olmos, Iciar; Balkau, Beverley; Barricarte, Aurelio; Barroso, Inês; Garcia, Sara Benlloch; Bis, Joshua C.; Blankenberg, Stefan; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Borecki, Ingrid B.; Bork-Jensen, Jette; Bowden, Sarah; Caldas, Carlos; Caslake, Muriel; Cupples, L. Adrienne; Cruchaga, Carlos; Czajkowski, Jacek; den Hoed, Marcel; Dunn, Janet A.; Earl, Helena M.; Ehret, Georg B.; Ferrannini, Ele; Ferrieres, Jean; Foltynie, Thomas; Ford, Ian; Forouhi, Nita G.; Gianfagna, Francesco; Gonzalez, Carlos; Grioni, Sara; Hiller, Louise; Jansson, Jan-Håkan; Jørgensen, Marit E.; Jukema, J. Wouter; Kaaks, Rudolf; Kee, Frank; Kerrison, Nicola D.; Key, Timothy J.; Kontto, Jukka; Kote-Jarai, Zsofia; Kraja, Aldi T.; Kuulasmaa, Kari; Kuusisto, Johanna; Linneberg, Allan; Liu, Chunyu; Marenne, Gaëlle; Mohlke, Karen L.; Morris, Andrew P.; Muir, Kenneth; Müller-Nurasyid, Martina; Munroe, Patricia B.; Navarro, Carmen; Nielsen, Sune F.; Nilsson, Peter M.; Nordestgaard, Børge G.; Packard, Chris J.; Palli, Domenico; Panico, Salvatore; Peloso, Gina M.; Perola, Markus; Peters, Annette; Poole, Christopher J.; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Salomaa, Veikko; Sánchez, María-José; Sattar, Naveed; Sharp, Stephen J.; Sims, Rebecca; Slimani, Nadia; Smith, Jennifer A.; Thompson, Deborah J.; Trompet, Stella; Tumino, Rosario; van der A, Daphne L.; van der Schouw, Yvonne T.; Virtamo, Jarmo; Walker, Mark; Walter, Klaudia; Abraham, Jean E.; Amundadottir, Laufey T.; Aponte, Jennifer L.; Butterworth, Adam S.; Dupuis, Josée; Easton, Douglas F.; Eeles, Rosalind A.; Erdmann, Jeanette; Franks, Paul W.; Frayling, Timothy M.; Hansen, Torben; Howson, Joanna M. M.; Jørgensen, Torben; Kooner, Jaspal; Laakso, Markku; Langenberg, Claudia; McCarthy, Mark I.; Pankow, James S.; Pedersen, Oluf; Riboli, Elio; Rotter, Jerome I.; Saleheen, Danish; Samani, Nilesh J.; Schunkert, Heribert; Vollenweider, Peter; O'Rahilly, Stephen; Deloukas, Panos; Danesh, John; Goodarzi, Mark O.; Kathiresan, Sekar; Meigs, James B.; Ehm, Margaret G.; Wareham, Nicholas J.; Waterworth, Dawn M.

    2016-01-01

    Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to inform development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in 6 genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing, and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr;rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and lower T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomised controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process. PMID:27252175

  8. gC1qR expression in chimpanzees with resolved and chronic infection: Potential role of HCV core/gC1qR-mediated T cell suppression in the outcome of HCV infection

    SciTech Connect

    Yao Zhiqang; Shata, Mohamed Tarek; Tricoche, Nancy

    2006-03-15

    Chimpanzee is a unique animal model for HCV infection, in which about 50% of infections resolve spontaneously. It has been reported that the magnitude of T cell responses to HCV core in recovered chimpanzees is greater than that in chronically infected ones. However, the mechanism(s) by which the chimpanzees with resolved infection overcome core-mediated immunosuppression remains unknown. In this study, we examined the effect of HCV core on T cell responsiveness in chimpanzees with resolved and chronic HCV infection. We found that core protein strongly inhibited T cell activation and proliferation in chimpanzees with chronic infection, while this inhibition wasmore » limited in chimpanzees with resolved infection. Notably, the level of gC1qR, as well as the binding of core protein, on the surface of T cells was lower in recovered chimpanzees when compared to chimpanzees with chronic HCV infection. Intriguingly, the observed differences in gC1qR expression levels and susceptibility to core-induced suppression amongst HCV-chronically infected and recovered chimpanzees were observed prior to HCV challenge, suggesting a possible genetic determination of the outcome of infection. These findings suggest that gC1qR expression on the surface of T cells is crucial for HCV core-mediated T cell suppression and viral clearance, and that represents a novel mechanism by which a virus usurps host machinery for persistence.« less

  9. 22 CFR 46.2 - Authority of departure-control officer to prevent alien's departure from the United States.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Authority of departure-control officer to prevent alien's departure from the United States. 46.2 Section 46.2 Foreign Relations DEPARTMENT OF STATE VISAS CONTROL OF ALIENS DEPARTING FROM THE UNITED STATES § 46.2 Authority of departure-control officer...

  10. 22 CFR 46.2 - Authority of departure-control officer to prevent alien's departure from the United States.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Authority of departure-control officer to prevent alien's departure from the United States. 46.2 Section 46.2 Foreign Relations DEPARTMENT OF STATE VISAS CONTROL OF ALIENS DEPARTING FROM THE UNITED STATES § 46.2 Authority of departure-control officer...

  11. 22 CFR 46.2 - Authority of departure-control officer to prevent alien's departure from the United States.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Authority of departure-control officer to prevent alien's departure from the United States. 46.2 Section 46.2 Foreign Relations DEPARTMENT OF STATE VISAS CONTROL OF ALIENS DEPARTING FROM THE UNITED STATES § 46.2 Authority of departure-control officer...

  12. 22 CFR 46.2 - Authority of departure-control officer to prevent alien's departure from the United States.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Authority of departure-control officer to prevent alien's departure from the United States. 46.2 Section 46.2 Foreign Relations DEPARTMENT OF STATE VISAS CONTROL OF ALIENS DEPARTING FROM THE UNITED STATES § 46.2 Authority of departure-control officer...

  13. Genome-Wide Analysis of Copy Number Variants in Attention Deficit Hyperactivity Disorder: The Role of Rare Variants and Duplications at 15q13.3

    PubMed Central

    Franke, Barbara; Mick, Eric; Anney, Richard J.L.; Freitag, Christine M.; Gill, Michael; Thapar, Anita; O'Donovan, Michael C.; Owen, Michael J.; Holmans, Peter; Kent, Lindsey; Middleton, Frank; Zhang-James, Yanli; Liu, Lu; Meyer, Jobst; Nguyen, Thuy Trang; Romanos, Jasmin; Romanos, Marcel; Seitz, Christiane; Renner, Tobias J.; Walitza, Susanne; Warnke, Andreas; Palmason, Haukur; Buitelaar, Jan; Rommelse, Nanda; Vasquez, Alejandro Arias; Hawi, Ziarih; Langley, Kate; Sergeant, Joseph; Steinhausen, Hans-Christoph; Roeyers, Herbert; Biederman, Joseph; Zaharieva, Irina; Hakonarson, Hakon; Elia, Josephine; Lionel, Anath C.; Crosbie, Jennifer; Marshall, Christian R.; Schachar, Russell; Scherer, Stephen W.; Todorov, Alexandre; Smalley, Susan L.; Loo, Sandra; Nelson, Stanley; Shtir, Corina; Asherson, Philip; Reif, Andreas; Lesch, Klaus-Peter

    2012-01-01

    Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. Method: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. Results: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. Conclusions: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology. PMID:22420048

  14. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3.

    PubMed

    Williams, Nigel M; Franke, Barbara; Mick, Eric; Anney, Richard J L; Freitag, Christine M; Gill, Michael; Thapar, Anita; O'Donovan, Michael C; Owen, Michael J; Holmans, Peter; Kent, Lindsey; Middleton, Frank; Zhang-James, Yanli; Liu, Lu; Meyer, Jobst; Nguyen, Thuy Trang; Romanos, Jasmin; Romanos, Marcel; Seitz, Christiane; Renner, Tobias J; Walitza, Susanne; Warnke, Andreas; Palmason, Haukur; Buitelaar, Jan; Rommelse, Nanda; Vasquez, Alejandro Arias; Hawi, Ziarih; Langley, Kate; Sergeant, Joseph; Steinhausen, Hans-Christoph; Roeyers, Herbert; Biederman, Joseph; Zaharieva, Irina; Hakonarson, Hakon; Elia, Josephine; Lionel, Anath C; Crosbie, Jennifer; Marshall, Christian R; Schachar, Russell; Scherer, Stephen W; Todorov, Alexandre; Smalley, Susan L; Loo, Sandra; Nelson, Stanley; Shtir, Corina; Asherson, Philip; Reif, Andreas; Lesch, Klaus-Peter; Faraone, Stephen V

    2012-02-01

    Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

  15. Association analysis of bitter receptor genes in five isolated populations identifies a significant correlation between TAS2R43 variants and coffee liking.

    PubMed

    Pirastu, Nicola; Kooyman, Maarten; Traglia, Michela; Robino, Antonietta; Willems, Sara M; Pistis, Giorgio; d'Adamo, Pio; Amin, Najaf; d'Eustacchio, Angela; Navarini, Luciano; Sala, Cinzia; Karssen, Lennart C; van Duijn, Cornelia; Toniolo, Daniela; Gasparini, Paolo

    2014-01-01

    Coffee, one of the most popular beverages in the world, contains many different physiologically active compounds with a potential impact on people's health. Despite the recent attention given to the genetic basis of its consumption, very little has been done in understanding genes influencing coffee preference among different individuals. Given its markedly bitter taste, we decided to verify if bitter receptor genes (TAS2Rs) variants affect coffee liking. In this light, 4066 people from different parts of Europe and Central Asia filled in a field questionnaire on coffee liking. They have been consequently recruited and included in the study. Eighty-eight SNPs covering the 25 TAS2R genes were selected from the available imputed ones and used to run association analysis for coffee liking. A significant association was detected with three SNP: one synonymous and two functional variants (W35S and H212R) on the TAS2R43 gene. Both variants have been shown to greatly reduce in vitro protein activity. Surprisingly the wild type allele, which corresponds to the functional form of the protein, is associated to higher liking of coffee. Since the hTAS2R43 receptor is sensible to caffeine, we verified if the detected variants produced differences in caffeine bitter perception on a subsample of people coming from the FVG cohort. We found a significant association between differences in caffeine perception and the H212R variant but not with the W35S, which suggests that the effect of the TAS2R43 gene on coffee liking is mediated by caffeine and in particular by the H212R variant. No other significant association was found with other TAS2R genes. In conclusion, the present study opens new perspectives in the understanding of coffee liking. Further studies are needed to clarify the role of the TAS2R43 gene in coffee hedonics and to identify which other genes and pathways are involved in its genetics.

  16. Association Analysis of Bitter Receptor Genes in Five Isolated Populations Identifies a Significant Correlation between TAS2R43 Variants and Coffee Liking

    PubMed Central

    Pirastu, Nicola; Kooyman, Maarten; Traglia, Michela; Robino, Antonietta; Willems, Sara M.; Pistis, Giorgio; d’Adamo, Pio; Amin, Najaf; d’Eustacchio, Angela; Navarini, Luciano; Sala, Cinzia; Karssen, Lennart C.; van Duijn, Cornelia; Toniolo, Daniela; Gasparini, Paolo

    2014-01-01

    Coffee, one of the most popular beverages in the world, contains many different physiologically active compounds with a potential impact on people’s health. Despite the recent attention given to the genetic basis of its consumption, very little has been done in understanding genes influencing coffee preference among different individuals. Given its markedly bitter taste, we decided to verify if bitter receptor genes (TAS2Rs) variants affect coffee liking. In this light, 4066 people from different parts of Europe and Central Asia filled in a field questionnaire on coffee liking. They have been consequently recruited and included in the study. Eighty-eight SNPs covering the 25 TAS2R genes were selected from the available imputed ones and used to run association analysis for coffee liking. A significant association was detected with three SNP: one synonymous and two functional variants (W35S and H212R) on the TAS2R43 gene. Both variants have been shown to greatly reduce in vitro protein activity. Surprisingly the wild type allele, which corresponds to the functional form of the protein, is associated to higher liking of coffee. Since the hTAS2R43 receptor is sensible to caffeine, we verified if the detected variants produced differences in caffeine bitter perception on a subsample of people coming from the FVG cohort. We found a significant association between differences in caffeine perception and the H212R variant but not with the W35S, which suggests that the effect of the TAS2R43 gene on coffee liking is mediated by caffeine and in particular by the H212R variant. No other significant association was found with other TAS2R genes. In conclusion, the present study opens new perspectives in the understanding of coffee liking. Further studies are needed to clarify the role of the TAS2R43 gene in coffee hedonics and to identify which other genes and pathways are involved in its genetics. PMID:24647340

  17. R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family

    PubMed Central

    Korvatska, Olena; Leverenz, James B.; Jayadev, Suman; McMillan, Pamela; Kurtz, Irina; Guo, Xindi; Rumbaugh, Malia; Matsushita, Mark; Girirajan, Santhosh; Dorschner, Michael O.; Kiianitsa, Kostantin; Yu, Chang-En; Brkanac, Zoran; Garden, Gwenn A.; Raskind, Wendy H.; Bird, Thomas D.

    2016-01-01

    Importance The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders. Objective To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases. Design, Setting, and Participants This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014. A total of 131 families with LOAD (751 individuals) were included from the University of Washington Alzheimer Disease Research Center. To identify LOAD genes/risk factors in the LOAD123 family with 21 affected members and 12 autopsies, we sequenced 4 exomes. Candidate variants were tested for cosegregation with the disease. TREM2 R47H was genotyped in an additional 130 families with LOAD. We performed clinical and neuropathological assessments of patients with and without R47H and evaluated the variant's effect on brain pathology, cellular morphology, and expression of microglial markers. Main Outcomes and Measures We assessed the effect of TREM2 genotype on age at onset and disease duration. We compared Braak and Consortium to Establish a Registry for Alzheimer's Disease scores, presence of α-synuclein and TAR DNA-binding protein 43 aggregates, and additional vascular or Parkinson pathology in TREM2 R47H carriers vs noncarriers. Microglial activation was assessed by quantitative immunohistochemistry and morphometry. Results Twelve of 16 patients with AD in the LOAD123 family carried R47H. Eleven patients with dementia had apolipoprotein E 4 (ApoE4) and R47H genotypes. We also found a rare missense variant, D353N, in a nominated AD risk gene, unc-5 homolog C (UNC5C), in 5 affected individuals in the LOAD123 family. R47H carriers demonstrated a shortened disease duration (mean [SD], 6.7 [2.8] vs 11.1 [6.6] years; 2-tailed t test; P = .04) and more frequent α-synucleinopathy. The

  18. TREM2 R47H variant and risk of essential tremor: A cross-sectional international multicenter study

    PubMed Central

    Ortega-Cubero, Sara; Lorenzo-Betancor, Oswaldo; Lorenzo, Elena; Agúndez, José A.G.; Jiménez-Jiménez, Félix J.; Ross, Owen A.; Wurster, Isabel; Mielke, Carina; Lin, Juei-Jueng; Coria, Francisco; Clarimon, Jordi; Ezquerra, Mario; Brighina, Laura; Annesi, Grazia; Alonso-Navarro, Hortensia; García-Martin, Elena; Gironell, Alex; Marti, Maria J.; Yueh, Kuo-Chu; Wszolek, Zbigniew K.; Sharma, Manu; Berg, Daniela; Krüger, Rejko; Pastor, Maria A.; Pastor, Pau

    2015-01-01

    Introduction Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET. Methods This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency. Results There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203–29.626; p = 0.042), but it was not replicated in other populations. Conclusions These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed. PMID:25585992

  19. TREM2 R47H variant and risk of essential tremor: a cross-sectional international multicenter study.

    PubMed

    Ortega-Cubero, Sara; Lorenzo-Betancor, Oswaldo; Lorenzo, Elena; Agúndez, José A G; Jiménez-Jiménez, Félix J; Ross, Owen A; Wurster, Isabel; Mielke, Carina; Lin, Juei-Jueng; Coria, Francisco; Clarimon, Jordi; Ezquerra, Mario; Brighina, Laura; Annesi, Grazia; Alonso-Navarro, Hortensia; García-Martin, Elena; Gironell, Alex; Marti, Maria J; Yueh, Kuo-Chu; Wszolek, Zbigniew K; Sharma, Manu; Berg, Daniela; Krüger, Rejko; Pastor, Maria A; Pastor, Pau

    2015-03-01

    Essential tremor (ET) is the most frequent movement disorder in adults. Its pathophysiology is not clearly understood, however there is growing evidence showing common etiologic factors with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (AD, PD). Recently, a rare p.R47H substitution (rs75932628) in the TREM2 protein (triggering receptor expressed on myeloid cells 2; OMIM: *605086) has been proposed as a risk factor for AD, PD and amyotrophic lateral sclerosis (ALS). The objective of the study was to determine whether TREM2 p.R47H allele is also a risk factor for developing ET. This was a cross-sectional multicenter international study. An initial case-control cohort from Spain (n = 456 ET, n = 2715 controls) was genotyped. In a replication phase, a case-control series (n = 897 ET, n = 1449 controls) from different populations (Italy, Germany, North-America and Taiwan) was studied. Owed to the rarity of the variant, published results on p.R47H allele frequency from 14777 healthy controls from European, North American or Chinese descent were additionally considered. The main outcome measure was p.R47H (rs75932628) allelic frequency. There was a significant association between TREM2 p.R47H variant and ET in the Spanish cohort (odds ratio [OR], 5.97; 95% CI, 1.203-29.626; p = 0.042), but it was not replicated in other populations. These results argue in favor of population-specific differences in the allelic distribution and suggest that p.R47H (rs75932628) variant may contribute to the susceptibility of ET in Spanish population. However, taking into account the very low frequency of p.R47H, further confirmatory analyses of larger ET series are needed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Association of Paraoxonase-1 Q192R (rs662) Single Nucleotide Variation with Cardiovascular Risk in Coffee Harvesters of Central Colombia

    PubMed Central

    Garzón-Castaño, Sandra; Ramos-Márquez, Martha E.; Hernández-Cañaveral, Iván

    2017-01-01

    Paraoxonase 1 (PON1), a high-density lipoprotein-associated antioxidant enzyme, hydrolyzes several organophosphate pesticides and oxidized lipids. The PON1 Q192R polymorphism affects the catalytic efficiency and is considered a risk factor for pesticide intoxication and cardiovascular disease (CVD) but the association is not consistent between individuals or populations. We aimed to study the association of PON1 Q192R polymorphism with CVD risk in coffee harvesters of central Colombia. Demographics were collected from 205 subjects via standardized questionnaires. Lipid profiles and serum butyrylcholinesterase (BChE) were measured by standard procedures. The calculated 10-year atherosclerotic CVD (ASCVD) risk was used as the cardiovascular risk estimate. Q192R genotype was determined by real-time PCR. Prevalence of hypertension, hypercholesterolemia, and the 10-year ASCVD risk was 33%, 62%, and 22%, respectively. BChE levels were no indicative of recent pesticide exposure, although a positive correlation was observed with BChE and hypercholesterolemia. The Q192R genotype frequencies were 38% (QQ), 44% (QR), and 18% (RR). We found an association of the 192Q genotype with hypertension. The results of this study signal the importance to evaluate the influence and potential interactions of BChE and PON1 192Q allele with known genetic and environmental factors implicated in the pathogenesis of CVD. PMID:29430251

  1. Association between Q192R paraoxonase 1 polymorphism and serumadipocyte-fatty acid binding protein (FABP4) levels in Mexican women.

    PubMed

    Ochoa-Martínez, Ángeles C; Ruíz-Vera, Tania; Orta-García, Sandra T; Domínguez-Cortinas, Gabriela; Jiménez-Avalos, Jorge A; Pérez-Maldonado, Iván N

    2017-06-01

    This study aimed to evaluate the genetic effects of PON1 Q192R polymorphism on serum FABP4 levels in Mexican women. PON1 Q192R polymorphism was genotyped using a TaqMan allelic discrimination assay and serum FABP4 concentration was measured using an enzyme-linked immunosorbent assay. The distribution of genotype frequencies in the assessed women (PON1 Q192R polymorphism) was QQ = 20%, QR = 48% and RR = 32%. Significantly higher serum FABP4 levels were found in women with genotype QR/RR (20.6 ± 2.20 ng/mL), when compared with the levels found in the QQ group (12.8 ± 1.70 ng/mL) (p = .004). After, the odds ratio (OR) was calculated by binomial logistic regression analysis and a significantly higher OR was found in the QR/RR group when compared with the QQ group (OR = 3.45; 95% CI = 1.80-16.50; p < .05). The results support an association between 192R-allele of the PON1 polymorphism (Q192R) and increased serum FABP4 levels (suggested as an early biomarker of CVDs risk) in assessed Mexican women.

  2. Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma.

    PubMed

    McDaniel, Lee D; Conkrite, Karina L; Chang, Xiao; Capasso, Mario; Vaksman, Zalman; Oldridge, Derek A; Zachariou, Anna; Horn, Millicent; Diamond, Maura; Hou, Cuiping; Iolascon, Achille; Hakonarson, Hakon; Rahman, Nazneen; Devoto, Marcella; Diskin, Sharon J

    2017-05-01

    Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly presents in young children and accounts for approximately 12% of pediatric oncology deaths. Here, we report on a genome-wide association study (GWAS) in a discovery cohort or 2,101 cases and 4,202 controls of European ancestry. We identify two new association signals at 3q25 and 4p16 that replicated robustly in multiple independent cohorts comprising 1,163 cases and 4,396 controls (3q25: rs6441201 combined P = 1.2x10-11, Odds Ratio 1.23, 95% CI:1.16-1.31; 4p16: rs3796727 combined P = 1.26x10-12, Odds Ratio 1.30, 95% CI: 1.21-1.40). The 4p16 signal maps within the carboxypeptidase Z (CPZ) gene. The 3q25 signal resides within the arginine/serine-rich coiled-coil 1 (RSRC1) gene and upstream of the myeloid leukemia factor 1 (MLF1) gene. Increased expression of MLF1 was observed in neuroblastoma cells homozygous for the rs6441201 risk allele (P = 0.02), and significant growth inhibition was observed upon depletion of MLF1 (P < 0.0001) in neuroblastoma cells. Taken together, we show that common DNA variants within CPZ at 4p16 and upstream of MLF1 at 3q25 influence neuroblastoma susceptibility and MLF1 likely plays an important role in neuroblastoma tumorigenesis.

  3. Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma

    PubMed Central

    Capasso, Mario; Vaksman, Zalman; Zachariou, Anna; Horn, Millicent; Diamond, Maura; Hou, Cuiping; Iolascon, Achille; Hakonarson, Hakon; Rahman, Nazneen

    2017-01-01

    Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly presents in young children and accounts for approximately 12% of pediatric oncology deaths. Here, we report on a genome-wide association study (GWAS) in a discovery cohort or 2,101 cases and 4,202 controls of European ancestry. We identify two new association signals at 3q25 and 4p16 that replicated robustly in multiple independent cohorts comprising 1,163 cases and 4,396 controls (3q25: rs6441201 combined P = 1.2x10-11, Odds Ratio 1.23, 95% CI:1.16–1.31; 4p16: rs3796727 combined P = 1.26x10-12, Odds Ratio 1.30, 95% CI: 1.21–1.40). The 4p16 signal maps within the carboxypeptidase Z (CPZ) gene. The 3q25 signal resides within the arginine/serine-rich coiled-coil 1 (RSRC1) gene and upstream of the myeloid leukemia factor 1 (MLF1) gene. Increased expression of MLF1 was observed in neuroblastoma cells homozygous for the rs6441201 risk allele (P = 0.02), and significant growth inhibition was observed upon depletion of MLF1 (P < 0.0001) in neuroblastoma cells. Taken together, we show that common DNA variants within CPZ at 4p16 and upstream of MLF1 at 3q25 influence neuroblastoma susceptibility and MLF1 likely plays an important role in neuroblastoma tumorigenesis. PMID:28545128

  4. Disease-associated variants in different categories of disease located in distinct regulatory elements.

    PubMed

    Ma, Meng; Ru, Ying; Chuang, Ling-Shiang; Hsu, Nai-Yun; Shi, Li-Song; Hakenberg, Jörg; Cheng, Wei-Yi; Uzilov, Andrew; Ding, Wei; Glicksberg, Benjamin S; Chen, Rong

    2015-01-01

    The invention of high throughput sequencing technologies has led to the discoveries of hundreds of thousands of genetic variants associated with thousands of human diseases. Many of these genetic variants are located outside the protein coding regions, and as such, it is challenging to interpret the function of these genetic variants by traditional genetic approaches. Recent genome-wide functional genomics studies, such as FANTOM5 and ENCODE have uncovered a large number of regulatory elements across hundreds of different tissues or cell lines in the human genome. These findings provide an opportunity to study the interaction between regulatory elements and disease-associated genetic variants. Identifying these diseased-related regulatory elements will shed light on understanding the mechanisms of how these variants regulate gene expression and ultimately result in disease formation and progression. In this study, we curated and categorized 27,558 Mendelian disease variants, 20,964 complex disease variants, 5,809 cancer predisposing germline variants, and 43,364 recurrent cancer somatic mutations. Compared against nine different types of regulatory regions from FANTOM5 and ENCODE projects, we found that different types of disease variants show distinctive propensity for particular regulatory elements. Mendelian disease variants and recurrent cancer somatic mutations are 22-fold and 10- fold significantly enriched in promoter regions respectively (q<0.001), compared with allele-frequency-matched genomic background. Separate from these two categories, cancer predisposing germline variants are 27-fold enriched in histone modification regions (q<0.001), 10-fold enriched in chromatin physical interaction regions (q<0.001), and 6-fold enriched in transcription promoters (q<0.001). Furthermore, Mendelian disease variants and recurrent cancer somatic mutations share very similar distribution across types of functional effects. We further found that regulatory regions are

  5. Disease-associated variants in different categories of disease located in distinct regulatory elements

    PubMed Central

    2015-01-01

    Background The invention of high throughput sequencing technologies has led to the discoveries of hundreds of thousands of genetic variants associated with thousands of human diseases. Many of these genetic variants are located outside the protein coding regions, and as such, it is challenging to interpret the function of these genetic variants by traditional genetic approaches. Recent genome-wide functional genomics studies, such as FANTOM5 and ENCODE have uncovered a large number of regulatory elements across hundreds of different tissues or cell lines in the human genome. These findings provide an opportunity to study the interaction between regulatory elements and disease-associated genetic variants. Identifying these diseased-related regulatory elements will shed light on understanding the mechanisms of how these variants regulate gene expression and ultimately result in disease formation and progression. Results In this study, we curated and categorized 27,558 Mendelian disease variants, 20,964 complex disease variants, 5,809 cancer predisposing germline variants, and 43,364 recurrent cancer somatic mutations. Compared against nine different types of regulatory regions from FANTOM5 and ENCODE projects, we found that different types of disease variants show distinctive propensity for particular regulatory elements. Mendelian disease variants and recurrent cancer somatic mutations are 22-fold and 10- fold significantly enriched in promoter regions respectively (q<0.001), compared with allele-frequency-matched genomic background. Separate from these two categories, cancer predisposing germline variants are 27-fold enriched in histone modification regions (q<0.001), 10-fold enriched in chromatin physical interaction regions (q<0.001), and 6-fold enriched in transcription promoters (q<0.001). Furthermore, Mendelian disease variants and recurrent cancer somatic mutations share very similar distribution across types of functional effects. We further found that

  6. Effects of common hemoglobin variants on HbA1c measurements in China: results for α- and β-globin variants measured by six methods.

    PubMed

    Xu, Anping; Chen, Weidong; Xia, Yong; Zhou, Yu; Ji, Ling

    2018-04-07

    HbA1c is a widely used biomarker for diabetes mellitus management. Here, we evaluated the accuracy of six methods for determining HbA1c values in Chinese patients with common α- and β-globin chains variants in China. Blood samples from normal subjects and individuals exhibiting hemoglobin variants were analyzed for HbA1c, using Sebia Capillarys 2 Flex Piercing (C2FP), Bio-Rad Variant II Turbo 2.0, Tosoh HLC-723 G8 (ver. 5.24), Arkray ADAMS A1c HA-8180V fast mode, Cobas c501 and Trinity Ultra2 systems. DNA sequencing revealed five common β-globin chain variants and three common α-globin chain variants. The most common variant was Hb E, followed by Hb New York, Hb J-Bangkok, Hb G-Coushatta, Hb Q-Thailand, Hb G-Honolulu, Hb Ube-2 and Hb G-Taipei. Variant II Turbo 2.0, Ultra2 and Cobas c501 showed good agreement with C2FP for most samples with variants. HLC-723 G8 yielded no HbA1c values for Hb J-Bangkok, Hb Q-Thailand and Hb G-Honolulu. Samples with Hb E, Hb G-Coushatta, Hb G-Taipei and Hb Ube-2 produced significant negative biases for HLC-723 G8. HA-8180V showed statistically significant differences for Hb E, Hb G-Coushatta, Hb G-Taipei, Hb Q-Thailand and Hb G-Honolulu. HA-8180V yielded no HbA1c values for Hb J-Bangkok. All methods showed good agreement for samples with Hb New York. Some common hemoglobin variants can interfere with HbA1c determination by the most popular methods in China.

  7. Detrimental effects of melanocortin-1 receptor (MC1R) variants on the clinical outcomes of BRAF V600 metastatic melanoma patients treated with BRAF inhibitors.

    PubMed

    Guida, Michele; Strippoli, Sabino; Ferretta, Anna; Bartolomeo, Nicola; Porcelli, Letizia; Maida, Immacolata; Azzariti, Amalia; Tommasi, Stefania; Grieco, Claudia; Guida, Stefania; Albano, Anna; Lorusso, Vito; Guida, Gabriella

    2016-11-01

    Melanocortin-1 receptor (MC1R) plays a key role in skin pigmentation, and its variants are linked with a higher melanoma risk. The influence of MC1R variants on the outcomes of patients with metastatic melanoma (MM) treated with BRAF inhibitors (BRAFi) is unknown. We studied the MC1R status in a cohort of 53 consecutive BRAF-mutated patients with MM treated with BRAFi. We also evaluated the effect of vemurafenib in four V600 BRAF melanoma cell lines with/without MC1R variants. We found a significant correlation between the presence of MC1R variants and worse outcomes in terms of both overall response rate (ORR; 59% versus 95%, P = 0.011 univariate, P = 0.028 multivariate analysis) and progression-free survival (PFS) shorter than 6 months (72% versus 33%, P = 0.012 univariate, P = 0.027 multivariate analysis). No difference in overall survival (OS) was reported, probably due to subsequent treatments. Data in vitro showed a significant different phosphorylation of Erk1/2 and p38 MAPK during treatment, associated with a greater increase in vemurafenib IC50 in MC1R variant cell lines. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children1234

    PubMed Central

    Cole, Shelley A; Voruganti, V Saroja; Cai, Guowen; Haack, Karin; Kent, Jack W; Blangero, John; Comuzzie, Anthony G; McPherson, John D; Gibbs, Richard A

    2010-01-01

    Background: Melanocortin-4-receptor (MC4R) haploinsufficiency is the most common form of monogenic obesity; however, the frequency of MC4R variants and their functional effects in general populations remain uncertain. Objective: The aim was to identify and characterize the effects of MC4R variants in Hispanic children. Design: MC4R was resequenced in 376 parents, and the identified single nucleotide polymorphisms (SNPs) were genotyped in 613 parents and 1016 children from the Viva la Familia cohort. Measured genotype analysis (MGA) tested associations between SNPs and phenotypes. Bayesian quantitative trait nucleotide (BQTN) analysis was used to infer the most likely functional polymorphisms influencing obesity-related traits. Results: Seven rare SNPs in coding and 18 SNPs in flanking regions of MC4R were identified. MGA showed suggestive associations between MC4R variants and body size, adiposity, glucose, insulin, leptin, ghrelin, energy expenditure, physical activity, and food intake. BQTN analysis identified SNP 1704 in a predicted micro-RNA target sequence in the downstream flanking region of MC4R as a strong, probable functional variant influencing total, sedentary, and moderate activities with posterior probabilities of 1.0. SNP 2132 was identified as a variant with a high probability (1.0) of exerting a functional effect on total energy expenditure and sleeping metabolic rate. SNP rs34114122 was selected as having likely functional effects on the appetite hormone ghrelin, with a posterior probability of 0.81. Conclusion: This comprehensive investigation provides strong evidence that MC4R genetic variants are likely to play a functional role in the regulation of weight, not only through energy intake but through energy expenditure. PMID:19889825

  9. Role of ptsP, orfT, and sss recombinase genes in root colonization by Pseudomonas fluorescens Q8r1-96.

    PubMed

    Mavrodi, Olga V; Mavrodi, Dmitri V; Weller, David M; Thomashow, Linda S

    2006-11-01

    Pseudomonas fluorescens Q8r1-96 produces 2,4-diacetylphloroglucinol (2,4-DAPG), a polyketide antibiotic that suppresses a wide variety of soilborne fungal pathogens, including Gaeumannomyces graminis var. tritici, which causes take-all disease of wheat. Strain Q8r1-96 is representative of the D-genotype of 2,4-DAPG producers, which are exceptional because of their ability to aggressively colonize and maintain large populations on the roots of host plants, including wheat, pea, and sugar beet. In this study, three genes, an sss recombinase gene, ptsP, and orfT, which are important in the interaction of Pseudomonas spp. with various hosts, were investigated to determine their contributions to the unusual colonization properties of strain Q8r1-96. The sss recombinase and ptsP genes influence global processes, including phenotypic plasticity and organic nitrogen utilization, respectively. The orfT gene contributes to the pathogenicity of Pseudomonas aeruginosa in plants and animals and is conserved among saprophytic rhizosphere pseudomonads, but its function is unknown. Clones containing these genes were identified in a Q8r1-96 genomic library, sequenced, and used to construct gene replacement mutants of Q8r1-96. Mutants were characterized to determine their 2,4-DAPG production, motility, fluorescence, colony morphology, exoprotease and hydrogen cyanide (HCN) production, carbon and nitrogen utilization, and ability to colonize the rhizosphere of wheat grown in natural soil. The ptsP mutant was impaired in wheat root colonization, whereas mutants with mutations in the sss recombinase gene and orfT were not. However, all three mutants were less competitive than wild-type P. fluorescens Q8r1-96 in the wheat rhizosphere when they were introduced into the soil by paired inoculation with the parental strain.

  10. A rare case of a three way complex variant positive Philadelphia translocation involving chromosome (9;11;22)(q34;p15;q11) in chronic myeloid leukemia: A case report

    PubMed Central

    Asif, Muhammad; Hussain, Abrar; Rasool, Mahmood

    2016-01-01

    The t(9;22)(q34;q11) translocation is present in 90–95% of patients with chronic myeloid leukemia (CML). Variant complex translocations have been observed in 5–8% of CML patients, in which a third chromosome other than (9;22) is involved. Imatinib mesylate is the first line breakpoint cluster region-Abelson gene (BCR/ABL)-targeted oral therapy for CML, and may produce a complete response in 70–80% of CML patients in the chronic phase. In the present study, a bone marrow sample was used for conventional cytogenetic analysis, and the fluorescence in situ hybridization (FISH) test was used for BCR/ABL gene detection. A hematological analysis was also performed to determine the white blood cell (WBC) count, red blood cell count, hemoglobin levels, packed and mean cell volumes, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and platelet values of the patient. The hematological analysis of the patient indicated the increased WBC of 186.5×103 cells/µl, and decreased hemoglobin levels of 11.1 g/dl. The FISH test revealed that 67% cells demonstrated BCR/ABL gene translocation. The patient was treated with 400 mg imatinib mesylate daily, and was monitored at various intervals over a 6-month period. The present study reports the rare case of a patient that demonstrates a three-way Philadelphia chromosome-positive translocation involving 46XY,t(9;11;22)(q34;p15;q11)[10], alongside CML in the chronic phase. The translocation was analyzed using cytogenetic and FISH tests. PMID:27602125

  11. Recipient’s Genetic R702W NOD2 Variant Is Associated with an Increased Risk of Bacterial Infections after Orthotopic Liver Transplantation

    PubMed Central

    van Hoek, Bart; van den Berg, Arie P.; Porte, Robert J.; Blokzijl, Hans; Coenraad, Minneke J.; Hepkema, Bouke G.; Schaapherder, Alexander F.; Ringers, Jan; Weersma, Rinse K.; Verspaget, Hein W.

    2013-01-01

    Introduction Orthotopic liver transplantation (OLT) is accompanied by a significant postoperative infection risk. Immunosuppression to prevent rejection increases the susceptibility to infections, mainly by impairing the adaptive immune system. Genetic polymorphisms in the lectin complement pathway of the donor have recently been identified as important risk determinants of clinically significant bacterial infection (CSI) after OLT. Another genetic factor involved in innate immunity is NOD2, which was reported to be associated with increased risk of spontaneous bacterial peritonitis in cirrhotic patients. Methods We assessed association of three genetic NOD2 variants (R702W, G908R and 3020insC) with increased risk of CSI after OLT. 288 OLT recipient-donor pairs from two tertiary referral centers were genotyped for the three NOD2 variants. The probability of CSI in relation to NOD2 gene variants was determined with cumulative incidence curves and log-rank analysis. Results The R702W NOD2 variant in the recipient was associated with CSI after OLT. Eight out of 15 (53.3%) individuals with a mutated genotype compared to 80/273 (29.3%) with wild type genotype developed CSI (p=0.027, univariate cox regression), illustrated by a higher frequency of CSI after OLT over time (p=0.0003, log rank analysis). Multivariate analysis (including the donor lectin complement pathway profile) showed independence of this R702W NOD2 association from other risk factors (HR 2.0; p=0.04). The other NOD2 variants, G908R and 3020insC, in the recipient were not associated with CSI. There was no association with CSI after OLT for any of the NOD2 variants in the donor. Conclusion The mutated NOD2 R702W genotype in the recipient is independently associated with an increased risk of bacterial infections after liver transplantation, indicating a predisposing role for this genetic factor impairing the recipient’s innate immune system. PMID:23977330

  12. 34 CFR 462.13 - What criteria and requirements does the Secretary use for determining the suitability of tests?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... must ensure negligible overlap in items across pre- and post-testing. Scores associated with these... for determining the suitability of tests? 462.13 Section 462.13 Education Regulations of the Offices... the Secretary Use To Review the Suitability of Tests for Use in the NRS? § 462.13 What criteria and...

  13. Constacyclic codes over the ring F_q+v{F}_q+v2F_q and their applications of constructing new non-binary quantum codes

    NASA Astrophysics Data System (ADS)

    Ma, Fanghui; Gao, Jian; Fu, Fang-Wei

    2018-06-01

    Let R={F}_q+v{F}_q+v2{F}_q be a finite non-chain ring, where q is an odd prime power and v^3=v. In this paper, we propose two methods of constructing quantum codes from (α +β v+γ v2)-constacyclic codes over R. The first one is obtained via the Gray map and the Calderbank-Shor-Steane construction from Euclidean dual-containing (α +β v+γ v2)-constacyclic codes over R. The second one is obtained via the Gray map and the Hermitian construction from Hermitian dual-containing (α +β v+γ v2)-constacyclic codes over R. As an application, some new non-binary quantum codes are obtained.

  14. Anaplasma phagocytophilum in questing Ixodes ricinus ticks: comparison of prevalences and partial 16S rRNA gene variants in urban, pasture, and natural habitats.

    PubMed

    Overzier, Evelyn; Pfister, Kurt; Thiel, Claudia; Herb, Ingrid; Mahling, Monia; Silaghi, Cornelia

    2013-03-01

    Urban, natural, and pasture areas were investigated for prevalences and 16S rRNA gene variants of Anaplasma phagocytophilum in questing Ixodes ricinus ticks. The prevalences differed significantly between habitat types, and year-to-year variations in prevalence and habitat-dependent occurrence of 16S rRNA gene variants were detected.

  15. 34 CFR 462.13 - What criteria and requirements does the Secretary use for determining the suitability of tests?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... for determining the suitability of tests? 462.13 Section 462.13 Education Regulations of the Offices... the Secretary Use To Review the Suitability of Tests for Use in the NRS? § 462.13 What criteria and requirements does the Secretary use for determining the suitability of tests? In order for the Secretary to...

  16. 34 CFR 462.13 - What criteria and requirements does the Secretary use for determining the suitability of tests?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... for determining the suitability of tests? 462.13 Section 462.13 Education Regulations of the Offices... the Secretary Use To Review the Suitability of Tests for Use in the NRS? § 462.13 What criteria and requirements does the Secretary use for determining the suitability of tests? In order for the Secretary to...

  17. 34 CFR 462.13 - What criteria and requirements does the Secretary use for determining the suitability of tests?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... for determining the suitability of tests? 462.13 Section 462.13 Education Regulations of the Offices... the Secretary Use To Review the Suitability of Tests for Use in the NRS? § 462.13 What criteria and requirements does the Secretary use for determining the suitability of tests? In order for the Secretary to...

  18. 34 CFR 462.13 - What criteria and requirements does the Secretary use for determining the suitability of tests?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... for determining the suitability of tests? 462.13 Section 462.13 Education Regulations of the Offices... the Secretary Use To Review the Suitability of Tests for Use in the NRS? § 462.13 What criteria and requirements does the Secretary use for determining the suitability of tests? In order for the Secretary to...

  19. Meta-q-plate for complex beam shaping

    PubMed Central

    Ji, Wei; Lee, Chun-Hong; Chen, Peng; Hu, Wei; Ming, Yang; Zhang, Lijian; Lin, Tsung-Hsien; Chigrinov, Vladimir; Lu, Yan-Qing

    2016-01-01

    Optical beam shaping plays a key role in optics and photonics. In this work, meta-q-plate featured by arbitrarily space-variant optical axes is proposed and demonstrated via liquid crystal photoalignment based on a polarization-sensitive alignment agent and a dynamic micro-lithography system. Meta-q-plates with multiple-, azimuthally/radially variant topological charges and initial azimuthal angles are fabricated. Accordingly, complex beams with elliptical, asymmetrical, multi-ringed and hurricane transverse profiles are generated, making the manipulation of optical vortex up to an unprecedented flexibility. The evolution, handedness and Michelson interferogram of the hurricane one are theoretically analysed and experimentally verified. The design facilitates the manipulation of polarization and spatial degrees of freedom of light in a point-to-point manner. The realization of meta-q-plate drastically enhances the capability of beam shaping and may pave a bright way towards optical manipulations, OAM based informatics, quantum optics and other fields. PMID:27149897

  20. Meta-q-plate for complex beam shaping.

    PubMed

    Ji, Wei; Lee, Chun-Hong; Chen, Peng; Hu, Wei; Ming, Yang; Zhang, Lijian; Lin, Tsung-Hsien; Chigrinov, Vladimir; Lu, Yan-Qing

    2016-05-06

    Optical beam shaping plays a key role in optics and photonics. In this work, meta-q-plate featured by arbitrarily space-variant optical axes is proposed and demonstrated via liquid crystal photoalignment based on a polarization-sensitive alignment agent and a dynamic micro-lithography system. Meta-q-plates with multiple-, azimuthally/radially variant topological charges and initial azimuthal angles are fabricated. Accordingly, complex beams with elliptical, asymmetrical, multi-ringed and hurricane transverse profiles are generated, making the manipulation of optical vortex up to an unprecedented flexibility. The evolution, handedness and Michelson interferogram of the hurricane one are theoretically analysed and experimentally verified. The design facilitates the manipulation of polarization and spatial degrees of freedom of light in a point-to-point manner. The realization of meta-q-plate drastically enhances the capability of beam shaping and may pave a bright way towards optical manipulations, OAM based informatics, quantum optics and other fields.

  1. rDNA Copy Number Variants Are Frequent Passenger Mutations in Saccharomyces cerevisiae Deletion Collections and de Novo Transformants

    PubMed Central

    Kwan, Elizabeth X.; Wang, Xiaobin S.; Amemiya, Haley M.; Brewer, Bonita J.; Raghuraman, M. K.

    2016-01-01

    The Saccharomyces cerevisiae ribosomal DNA (rDNA) locus is known to exhibit greater instability relative to the rest of the genome. However, wild-type cells preferentially maintain a stable number of rDNA copies, suggesting underlying genetic control of the size of this locus. We performed a screen of a subset of the Yeast Knock-Out (YKO) single gene deletion collection to identify genetic regulators of this locus and to determine if rDNA copy number correlates with yeast replicative lifespan. While we found no correlation between replicative lifespan and rDNA size, we identified 64 candidate strains with significant rDNA copy number differences. However, in the process of validating candidate rDNA variants, we observed that independent isolates of our de novo gene deletion strains had unsolicited but significant changes in rDNA copy number. Moreover, we were not able to recapitulate rDNA phenotypes from the YKO yeast deletion collection. Instead, we found that the standard lithium acetate transformation protocol is a significant source of rDNA copy number variation, with lithium acetate exposure being the treatment causing variable rDNA copy number events after transformation. As the effects of variable rDNA copy number are being increasingly reported, our finding that rDNA is affected by lithium acetate exposure suggested that rDNA copy number variants may be influential passenger mutations in standard strain construction in S. cerevisiae. PMID:27449518

  2. rDNA Copy Number Variants Are Frequent Passenger Mutations in Saccharomyces cerevisiae Deletion Collections and de Novo Transformants.

    PubMed

    Kwan, Elizabeth X; Wang, Xiaobin S; Amemiya, Haley M; Brewer, Bonita J; Raghuraman, M K

    2016-09-08

    The Saccharomyces cerevisiae ribosomal DNA (rDNA) locus is known to exhibit greater instability relative to the rest of the genome. However, wild-type cells preferentially maintain a stable number of rDNA copies, suggesting underlying genetic control of the size of this locus. We performed a screen of a subset of the Yeast Knock-Out (YKO) single gene deletion collection to identify genetic regulators of this locus and to determine if rDNA copy number correlates with yeast replicative lifespan. While we found no correlation between replicative lifespan and rDNA size, we identified 64 candidate strains with significant rDNA copy number differences. However, in the process of validating candidate rDNA variants, we observed that independent isolates of our de novo gene deletion strains had unsolicited but significant changes in rDNA copy number. Moreover, we were not able to recapitulate rDNA phenotypes from the YKO yeast deletion collection. Instead, we found that the standard lithium acetate transformation protocol is a significant source of rDNA copy number variation, with lithium acetate exposure being the treatment causing variable rDNA copy number events after transformation. As the effects of variable rDNA copy number are being increasingly reported, our finding that rDNA is affected by lithium acetate exposure suggested that rDNA copy number variants may be influential passenger mutations in standard strain construction in S. cerevisiae. Copyright © 2016 Kwan et al.

  3. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

    PubMed Central

    May, Patrick; Thiele, Holger; Lehesjoki, Anna-Elina; Schwarz, Günter; Riesch, Erik; Ikram, M. Arfan; van Duijn, Cornelia M.; Uitterlinden, Andre G.; Hofman, Albert; Steinböck, Hannelore; Gruber-Sedlmayr, Ursula; Neophytou, Birgit; Zara, Federico; Hahn, Andreas; Gormley, Padhraig; Becker, Felicitas; Weber, Yvonne G.; Cilio, Maria Roberta; Kunz, Wolfram S.; Krause, Roland; Zimprich, Fritz; Lemke, Johannes R.; Nürnberg, Peter; Sander, Thomas; Lerche, Holger; Neubauer, Bernd A.

    2016-01-01

    Objective The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10−4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions. PMID:26990884

  4. Functional non-synonymous variants of ABCG2 and gout risk.

    PubMed

    Stiburkova, Blanka; Pavelcova, Katerina; Zavada, Jakub; Petru, Lenka; Simek, Pavel; Cepek, Pavel; Pavlikova, Marketa; Matsuo, Hirotaka; Merriman, Tony R; Pavelka, Karel

    2017-11-01

    Common dysfunctional variants of ATP binding cassette subfamily G member 2 (Junior blood group) (ABCG2), a high-capacity urate transporter gene, that result in decreased urate excretion are major causes of hyperuricemia and gout. In the present study, our objective was to determine the frequency and effect on gout of common and rare non-synonymous and other functional allelic variants in the ABCG2 gene. The main cohort recruited from the Czech Republic consisted of 145 gout patients; 115 normouricaemic controls were used for comparison. We amplified, directly sequenced and analysed 15 ABCG2 exons. The associations between genetic variants and clinical phenotype were analysed using the t-test, Fisher's exact test and a logistic and linear regression approach. Data from a New Zealand Polynesian sample set and the UK Biobank were included for the p.V12M analysis. In the ABCG2 gene, 18 intronic (one dysfunctional splicing) and 11 exonic variants were detected: 9 were non-synonymous (2 common, 7 rare including 1 novel), namely p.V12M, p.Q141K, p.R147W, p.T153M, p.F373C, p.T434M, p.S476P, p.D620N and p.K360del. The p.Q141K (rs2231142) variant had a significantly higher minor allele frequency (0.23) in the gout patients compared with the European-origin population (0.09) and was significantly more common among gout patients than among normouricaemic controls (odds ratio = 3.26, P < 0.0001). Patients with non-synonymous allelic variants had an earlier onset of gout (42 vs 48 years, P = 0.0143) and a greater likelihood of a familial history of gout (41% vs 27%, odds ratio = 1.96, P = 0.053). In a meta-analysis p.V12M exerted a protective effect from gout (P < 0.0001). Genetic variants of ABCG2, common and rare, increased the risk of gout. Non-synonymous allelic variants of ABCG2 had a significant effect on earlier onset of gout and the presence of a familial gout history. ABCG2 should thus be considered a common and significant risk factor for gout. © The Author 2017

  5. Influence of serum leptin levels and Q223R leptin receptor polymorphism on clinical characteristic of patients with rheumatoid arthritis from Western Mexico.

    PubMed

    Angel-Chávez, Luis I; Ruelas-Cinco, Elizabeth; Hernández-Bello, Jorge; Castro, Elena; Vázquez-Villamar, Mirna; Parra-Rojas, Isela; Brennan-Bourdon, L Michele; Muñoz-Barrios, Salvador; Guerrero-Velázquez, Celia; Muñoz-Valle, José Francisco

    2018-04-01

    The aim of the present study was to evaluate the possible association between the Q223R Leptin receptor (LEPR) polymorphism (A>G; rs1137101) and leptin levels in patients with rheumatoid arthritis (RA) from Western Mexico. A cross-sectional study was performed with 70 RA patients and 74 controls subject (CS). Disease activity was evaluated using DAS28 score, the Q223R LEPR polymorphism was determined by the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and serum leptin levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and rheumatoid factor (RF) were quantified. RA patients had significant high serum leptin levels compared with CS; leptin levels correlated strongly with body composition measures, but not with inflammatory markers, disease evolution, and activity. The genotype and allele frequencies of the Q223R LEPR polymorphism were not associated with RA. Similarly, leptin levels did not differ between Q223R LEPR genotypes. The LEPR Q223R polymorphism was not associated with RA risk in patients from Mexican population, even though high levels of serum leptin were present and these could explain the low weight observed in RA patients when they were compared to control subjects. However, the serum leptin levels did not correlate with inflammatory markers, severity and disease evolution.

  6. ReadqPCR and NormqPCR: R packages for the reading, quality checking and normalisation of RT-qPCR quantification cycle (Cq) data.

    PubMed

    Perkins, James R; Dawes, John M; McMahon, Steve B; Bennett, David L H; Orengo, Christine; Kohl, Matthias

    2012-07-02

    Measuring gene transcription using real-time reverse transcription polymerase chain reaction (RT-qPCR) technology is a mainstay of molecular biology. Technologies now exist to measure the abundance of many transcripts in parallel. The selection of the optimal reference gene for the normalisation of this data is a recurring problem, and several algorithms have been developed in order to solve it. So far nothing in R exists to unite these methods, together with other functions to read in and normalise the data using the chosen reference gene(s). We have developed two R/Bioconductor packages, ReadqPCR and NormqPCR, intended for a user with some experience with high-throughput data analysis using R, who wishes to use R to analyse RT-qPCR data. We illustrate their potential use in a workflow analysing a generic RT-qPCR experiment, and apply this to a real dataset. Packages are available from http://www.bioconductor.org/packages/release/bioc/html/ReadqPCR.htmland http://www.bioconductor.org/packages/release/bioc/html/NormqPCR.html These packages increase the repetoire of RT-qPCR analysis tools available to the R user and allow them to (amongst other things) read their data into R, hold it in an ExpressionSet compatible R object, choose appropriate reference genes, normalise the data and look for differential expression between samples.

  7. ReadqPCR and NormqPCR: R packages for the reading, quality checking and normalisation of RT-qPCR quantification cycle (Cq) data

    PubMed Central

    2012-01-01

    Background Measuring gene transcription using real-time reverse transcription polymerase chain reaction (RT-qPCR) technology is a mainstay of molecular biology. Technologies now exist to measure the abundance of many transcripts in parallel. The selection of the optimal reference gene for the normalisation of this data is a recurring problem, and several algorithms have been developed in order to solve it. So far nothing in R exists to unite these methods, together with other functions to read in and normalise the data using the chosen reference gene(s). Results We have developed two R/Bioconductor packages, ReadqPCR and NormqPCR, intended for a user with some experience with high-throughput data analysis using R, who wishes to use R to analyse RT-qPCR data. We illustrate their potential use in a workflow analysing a generic RT-qPCR experiment, and apply this to a real dataset. Packages are available from http://www.bioconductor.org/packages/release/bioc/html/ReadqPCR.htmland http://www.bioconductor.org/packages/release/bioc/html/NormqPCR.html Conclusions These packages increase the repetoire of RT-qPCR analysis tools available to the R user and allow them to (amongst other things) read their data into R, hold it in an ExpressionSet compatible R object, choose appropriate reference genes, normalise the data and look for differential expression between samples. PMID:22748112

  8. pcr: an R package for quality assessment, analysis and testing of qPCR data

    PubMed Central

    Ahmed, Mahmoud

    2018-01-01

    Background Real-time quantitative PCR (qPCR) is a broadly used technique in the biomedical research. Currently, few different analysis models are used to determine the quality of data and to quantify the mRNA level across the experimental conditions. Methods We developed an R package to implement methods for quality assessment, analysis and testing qPCR data for statistical significance. Double Delta CT and standard curve models were implemented to quantify the relative expression of target genes from CT in standard qPCR control-group experiments. In addition, calculation of amplification efficiency and curves from serial dilution qPCR experiments are used to assess the quality of the data. Finally, two-group testing and linear models were used to test for significance of the difference in expression control groups and conditions of interest. Results Using two datasets from qPCR experiments, we applied different quality assessment, analysis and statistical testing in the pcr package and compared the results to the original published articles. The final relative expression values from the different models, as well as the intermediary outputs, were checked against the expected results in the original papers and were found to be accurate and reliable. Conclusion The pcr package provides an intuitive and unified interface for its main functions to allow biologist to perform all necessary steps of qPCR analysis and produce graphs in a uniform way. PMID:29576953

  9. Follicular variant of papillary thyroid carcinoma: genome-wide appraisal of a controversial entity.

    PubMed

    Wreesmann, Volkert B; Ghossein, Ronald A; Hezel, Michael; Banerjee, Debenranrath; Shaha, Ashok R; Tuttle, R Michael; Shah, Jatin P; Rao, Pulivarthi H; Singh, Bhuvanesh

    2004-08-01

    The majority of thyroid tumors are classified as papillary (papillary thyroid carcinomas; PTCs) or follicular neoplasms (follicular thyroid adenomas and carcinomas; FTA/FTC) based on nuclear features and the cellular growth pattern. However, classification of the follicular variant of papillary thyroid carcinoma (FVPTC) remains an issue of debate. These tumors contain a predominantly follicular growth pattern but display nuclear features and overall clinical behavior consistent with PTC. In this study, we used comparative genomic hybridization (CGH) to compare the global chromosomal aberrations in FVPTC to the PTC of classical variant (classical PTC) and FTA/FTC. In addition, we assessed the presence of peroxisome proliferator-activated receptor-gamma (PPARG) alteration, a genetic event specific to FTA/FTC, using Southern blot and immunohistochemistry analyses. In sharp contrast to the findings in classical PTC (4% of cases), CGH analysis demonstrated that both FVPTC (59% of cases) and FTA/FTC (36% of cases) were commonly characterized by aneuploidy (P = 0.0002). Moreover, the pattern of chromosomal aberrations (gains at chromosome arms 2q, 4q, 5q, 6q, 8q, and 13q and deletions at 1p, 9q, 16q, 17q, 19q, and 22q) in the follicular variant of PTC closely resembled that of FTA/FTC. Aberrations in PPARG were uniquely detected in FVPTC and FTA/FTC. Our findings suggest a stronger relationship between the FVPTC and FTA/FTC than previously appreciated and support further consideration of the current classification of thyroid neoplasms. Copyright 2004 Wiley-Liss, Inc.

  10. Role of ptsP, orfT, and sss Recombinase Genes in Root Colonization by Pseudomonas fluorescens Q8r1-96▿

    PubMed Central

    Mavrodi, Olga V.; Mavrodi, Dmitri V.; Weller, David M.; Thomashow, Linda S.

    2006-01-01

    Pseudomonas fluorescens Q8r1-96 produces 2,4-diacetylphloroglucinol (2,4-DAPG), a polyketide antibiotic that suppresses a wide variety of soilborne fungal pathogens, including Gaeumannomyces graminis var. tritici, which causes take-all disease of wheat. Strain Q8r1-96 is representative of the D-genotype of 2,4-DAPG producers, which are exceptional because of their ability to aggressively colonize and maintain large populations on the roots of host plants, including wheat, pea, and sugar beet. In this study, three genes, an sss recombinase gene, ptsP, and orfT, which are important in the interaction of Pseudomonas spp. with various hosts, were investigated to determine their contributions to the unusual colonization properties of strain Q8r1-96. The sss recombinase and ptsP genes influence global processes, including phenotypic plasticity and organic nitrogen utilization, respectively. The orfT gene contributes to the pathogenicity of Pseudomonas aeruginosa in plants and animals and is conserved among saprophytic rhizosphere pseudomonads, but its function is unknown. Clones containing these genes were identified in a Q8r1-96 genomic library, sequenced, and used to construct gene replacement mutants of Q8r1-96. Mutants were characterized to determine their 2,4-DAPG production, motility, fluorescence, colony morphology, exoprotease and hydrogen cyanide (HCN) production, carbon and nitrogen utilization, and ability to colonize the rhizosphere of wheat grown in natural soil. The ptsP mutant was impaired in wheat root colonization, whereas mutants with mutations in the sss recombinase gene and orfT were not. However, all three mutants were less competitive than wild-type P. fluorescens Q8r1-96 in the wheat rhizosphere when they were introduced into the soil by paired inoculation with the parental strain. PMID:16936061

  11. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

    PubMed Central

    Zhang, Mingfeng; Wang, Zhaoming; Obazee, Ofure; Jia, Jinping; Childs, Erica J.; Hoskins, Jason; Figlioli, Gisella; Mocci, Evelina; Collins, Irene; Chung, Charles C.; Hautman, Christopher; Arslan, Alan A.; Beane-Freeman, Laura; Bracci, Paige M.; Buring, Julie; Duell, Eric J.; Gallinger, Steven; Giles, Graham G.; Goodman, Gary E.; Goodman, Phyllis J.; Kamineni, Aruna; Kolonel, Laurence N.; Kulke, Matthew H.; Malats, Núria; Olson, Sara H.; Sesso, Howard D.; Visvanathan, Kala; White, Emily; Zheng, Wei; Abnet, Christian C.; Albanes, Demetrius; Andreotti, Gabriella; Brais, Lauren; Bueno-de-Mesquita, H. Bas; Basso, Daniela; Berndt, Sonja I.; Boutron-Ruault, Marie-Christine; Bijlsma, Maarten F.; Brenner, Hermann; Burdette, Laurie; Campa, Daniele; Caporaso, Neil E.; Capurso, Gabriele; Cavestro, Giulia Martina; Cotterchio, Michelle; Costello, Eithne; Elena, Joanne; Boggi, Ugo; Gaziano, J. Michael; Gazouli, Maria; Giovannucci, Edward L.; Goggins, Michael; Gross, Myron; Haiman, Christopher A.; Hassan, Manal; Helzlsouer, Kathy J.; Hu, Nan; Hunter, David J.; Iskierka-Jazdzewska, Elzbieta; Jenab, Mazda; Kaaks, Rudolf; Key, Timothy J.; Khaw, Kay-Tee; Klein, Eric A.; Kogevinas, Manolis; Krogh, Vittorio; Kupcinskas, Juozas; Kurtz, Robert C.; Landi, Maria T.; Landi, Stefano; Marchand, Le Loic; Mambrini, Andrea; Mannisto, Satu; Milne, Roger L.; Neale, Rachel E.; Oberg, Ann L.; Panico, Salvatore; Patel, Alpa V.; Peeters, Petra H. M.; Peters, Ulrike; Pezzilli, Raffaele; Porta, Miquel; Purdue, Mark; Quiros, J. Ramón; Riboli, Elio; Rothman, Nathaniel; Scarpa, Aldo; Scelo, Ghislaine; Shu, Xiao-Ou; Silverman, Debra T.; Soucek, Pavel; Strobel, Oliver; Sund, Malin; Małecka-Panas, Ewa; Taylor, Philip R.; Tavano, Francesca; Travis, Ruth C.; Thornquist, Mark; Tjønneland, Anne; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Vashist, Yogesh; Vodicka, Pavel; Wactawski-Wende, Jean; Wentzensen, Nicolas; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Kooperberg, Charles; Risch, Harvey A.; Jacobs, Eric J.; Li, Donghui; Fuchs, Charles; Hoover, Robert; Hartge, Patricia; Chanock, Stephen J.; Petersen, Gloria M.; Stolzenberg-Solomon, Rachael S.; Wolpin, Brian M.; Kraft, Peter; Klein, Alison P.; Canzian, Federico; Amundadottir, Laufey T.

    2016-01-01

    Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88×10−15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22×10−9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70×10−8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7×10−8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5×10−4-2.0×10−3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology. PMID:27579533

  12. Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech

    PubMed Central

    Wijsman, Ellen M.; Nato, Alejandro Q.; Matsushita, Mark M.; Chapman, Kathy L.; Stanaway, Ian B.; Wolff, John; Oda, Kaori; Gabo, Virginia B.; Raskind, Wendy H.

    2016-01-01

    Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS. Complementary genomic methods included Markov chain Monte Carlo linkage analysis, copy-number analysis, identity-by-descent sharing, and exome sequencing with variant filtering. No overlaps in regions with positive evidence of linkage between the two families were found. In one family, linkage analysis detected two chromosomal regions of interest, 5p15.1-p14.1, and 17p13.1-q11.1, inherited separately from the two founders. Single-point linkage analysis of selected variants identified CDH18 as a primary gene of interest and additionally, MYO10, NIPBL, GLP2R, NCOR1, FLCN, SMCR8, NEK8, and ANKRD12, possibly with additive effects. Linkage analysis in the second family detected five regions with LOD scores approaching the highest values possible in the family. A gene of interest was C4orf21 (ZGRF1) on 4q25-q28.2. Evidence for previously described causal copy-number variations and validated or suspected genes was not found. Results are consistent with a heterogeneous CAS etiology, as is expected in many neurogenic disorders. Future studies will investigate genome variants in these and other families with CAS. PMID:27120335

  13. [The molecular-cytogenetic characterization and tyrosine kinase inhibitors efficacy in newly diagnosed chronic phase CML patients with variant Philadelphia chromosomes].

    PubMed

    Zhao, J J; Zhang, Y L; Zhang, S J; Zhou, J; Yu, F K; Zu, Y L; Zhao, H F; Li, Z; Song, Y P

    2018-03-14

    Objective: To investigate the molecular-cytogenetic characterization and impact on tyrosine kinase inhibitors (TKIs) therapy in chronic phase of chronic myeloid leukemia (CML-CP) patients with variant Ph chromosome (vPh). Methods: The clinical data of 32 patients with vPh chromosomes were collected and compared with 703 patients with typical Ph chromosome in newly diagnosed CML-CP who were on first-line imatinib (IM) and with BCR-ABL transcript of P210. Results: There was no significant difference in demographic and hematological characteristics between vPh and classic Ph patients. 3(9.4%) of the 32 vPh cases were simple variant translocations. Among the remaining 29 cases with complex variant translocations, 28 cases (87.5%) involved 3 chromosomes, and only 1 (3.1%) involved 4 chromosomes. Except for 8, 15, 18, X, and Y chromosomes, the other chromosomes were involved. The frequency of chromosome 12q(15.5%) and 1p (12.1%) were higher involved. The most common FISH signal pattern was 2G2R1Y (74.1%), followed by 1G1R2F (14.8%), 2G1R1Y (3.7%), 1G2R1Y (3.7%), 1G1R1Y (3.7%). The comparison of complete cytogenetic response (CCyR) ( P =0.269), major molecular response (MMR) ( P =0.391) were carried out between simple and complex mechanisms, without difference. Compared with the classic Ph, the patients with vPh had higher IM primary resistance rate ( χ 2 =3.978, P =0.046), especially primary hematological resistance ( χ 2 =7.870, P =0.005), but the difference of CCyR ( χ 2 =0.192, P =0.661), MMR ( χ 2 =0.822, P =0.365), EFS ( χ 2 =0.509, P =0.476), OS ( χ 2 =3.485, P =0.062) were not statistically significant, and multivariate analysis showed that the presence of vPh did not affect OS ( RR =0.692, 95% CI 0.393-1.765, P =0.658)、EFS ( RR =0.893, 95% CI 0.347-2.132, P =0.126) and PFS ( RR =1.176, 95% CI 0.643-2.682, P =0.703). Conclusion: CML-CP patients with vPh and classic Ph had similar demographic and hematological characteristics. Except for 22q11, 9q34, the

  14. Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status

    PubMed Central

    Luedeke, Manuel; Rinckleb, Antje E.; FitzGerald, Liesel M.; Geybels, Milan S.; Schleutker, Johanna; Eeles, Rosalind A.; Teixeira, Manuel R.; Cannon-Albright, Lisa; Ostrander, Elaine A.; Weikert, Steffen; Herkommer, Kathleen; Wahlfors, Tiina; Visakorpi, Tapio; Leinonen, Katri A.; Tammela, Teuvo L.J.; Cooper, Colin S.; Kote-Jarai, Zsofia; Edwards, Sandra; Goh, Chee L.; McCarthy, Frank; Parker, Chris; Flohr, Penny; Paulo, Paula; Jerónimo, Carmen; Henrique, Rui; Krause, Hans; Wach, Sven; Lieb, Verena; Rau, Tilman T.; Vogel, Walther; Kuefer, Rainer; Hofer, Matthias D.; Perner, Sven; Rubin, Mark A.; Agarwal, Archana M.; Easton, Doug F.; Al Olama, Ali Amin; Benlloch, Sara; Hoegel, Josef; Stanford, Janet L.

    2016-01-01

    Abstract Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (P < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, P = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, P = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa. PMID:27798103

  15. ZBTB16-RARα variant of acute promyelocytic leukemia with tuberculosis: a case report and review of literature.

    PubMed

    Palta, Anshu; Dhiman, Pratibha; Cruz, Sanjay D

    2012-09-01

    A 23-year-old male presented with pulmonary tuberculosis and swelling of both lower limbs. He was put on antitubercular treatment. Hemogram showed mild anemia and Pseudo Pelger-huet cells. The bone marrow (BM) examination showed 52% promyelocytes with regular round to oval nuclei, few granules and were positive for CD13 and CD33, and negative for HLA-DR. Cytogenetic analysis of the BM aspirate revealed an apparently balanced t(11;17)(q23;q21). Final diagnosis rendered was acute promyelocytic leukemia (APL) with t(11;17)(q23;q21); ZBTB16/RARA. APL is a distinct subtype of acute myeloid leukemia. The variant APL with t(11;17)(q23;q21) cases that are associated with the ZBTB16/RARA fusion gene have been reported as being resistant to all-trans-retinoic acid (ATRA). Therefore, differential diagnosis of variant APL with t(11;17)(q23;q12) from classical APL with t(15;17)(q22;q12); PML-RARA is very important. Here we have discussed the importance of distinct morphology of variant APL and also significance of rare presentation with tuberculosis.

  16. 34 CFR 462.4 - What are the transition rules for using tests to measure educational gain for the National...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... measure educational gain for the National Reporting System for Adult Education (NRS)? 462.4 Section 462.4... ADULT EDUCATION, DEPARTMENT OF EDUCATION MEASURING EDUCATIONAL GAIN IN THE NATIONAL REPORTING SYSTEM FOR ADULT EDUCATION General § 462.4 What are the transition rules for using tests to measure educational...

  17. 34 CFR 462.4 - What are the transition rules for using tests to measure educational gain for the National...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... measure educational gain for the National Reporting System for Adult Education (NRS)? 462.4 Section 462.4... ADULT EDUCATION, DEPARTMENT OF EDUCATION MEASURING EDUCATIONAL GAIN IN THE NATIONAL REPORTING SYSTEM FOR ADULT EDUCATION General § 462.4 What are the transition rules for using tests to measure educational...

  18. 34 CFR 462.4 - What are the transition rules for using tests to measure educational gain for the National...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... measure educational gain for the National Reporting System for Adult Education (NRS)? 462.4 Section 462.4... ADULT EDUCATION, DEPARTMENT OF EDUCATION MEASURING EDUCATIONAL GAIN IN THE NATIONAL REPORTING SYSTEM FOR ADULT EDUCATION General § 462.4 What are the transition rules for using tests to measure educational...

  19. 34 CFR 462.4 - What are the transition rules for using tests to measure educational gain for the National...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... measure educational gain for the National Reporting System for Adult Education (NRS)? 462.4 Section 462.4... ADULT EDUCATION, DEPARTMENT OF EDUCATION MEASURING EDUCATIONAL GAIN IN THE NATIONAL REPORTING SYSTEM FOR ADULT EDUCATION General § 462.4 What are the transition rules for using tests to measure educational...

  20. Autonomic control network active in Aplysia during locomotion includes neurons that express splice variants of R15-neuropeptides.

    PubMed

    Romanova, Elena V; McKay, Natasha; Weiss, Klaudiusz R; Sweedler, Jonathan V; Koester, John

    2007-01-01

    Splice-variant products of the R15 neuropeptide gene are differentially expressed within the CNS of Aplysia. The goal of this study was to test whether the neurons in the abdominal ganglion that express the peptides encoded by this gene are part of a common circuit. Expression of R15 peptides had been demonstrated previously in neuron R15. Using a combination of immunocytochemical and analytical methods, this study demonstrated that R15 peptides are also expressed in heart exciter neuron RB(HE), the two L9(G) gill motoneurons, and L40--a newly identified interneuron. Mass spectrometric profiling of individual neurons that exhibit R15 peptide-like immunoreactivity confirmed the mutually exclusive expression of two splice-variant forms of R15 peptides in different neurons. The L9(G) cells were found to co-express pedal peptide in addition to the R15 peptides. The R15 peptide-expressing neurons examined here were shown to be part of an autonomic control circuit that is active during fictive locomotion. Activity in this circuit contributes to implementing a central command that may help to coordinate autonomic activity with escape locomotion. Chronic extracellular nerve recording was used to determine the activity patterns of a subset of neurons of this circuit in vivo. These results demonstrate the potential utility of using shared patterns of neuropeptide expression as a guide for neural circuit identification.

  1. Nogo Receptor 1 (RTN4R) as a Candidate Gene for Schizophrenia: Analysis Using Human and Mouse Genetic Approaches

    PubMed Central

    Hsu, Ruby; Woodroffe, Abigail; Lai, Wen-Sung; Cook, Melloni N.; Mukai, Jun; Dunning, Jonathan P.; Swanson, Douglas J.; Roos, J. Louw; Abecasis, Gonçalo R.; Karayiorgou, Maria; Gogos, Joseph A.

    2007-01-01

    Background NOGO Receptor 1 (RTN4R) regulates axonal growth, as well as axon regeneration after injury. The gene maps to the 22q11.2 schizophrenia susceptibility locus and is thus a strong functional and positional candidate gene. Methodology/Principal Findings We evaluate evidence for genetic association between common RTN4R polymorphisms and schizophrenia in a large family sample of Afrikaner origin and screen the exonic sequence of RTN4R for rare variants in an independent sample from the U.S. We also employ animal model studies to assay a panel of schizophrenia-related behavioral tasks in an Rtn4r-deficient mouse model. We found weak sex-specific evidence for association between common RTN4R polymorphisms and schizophrenia in the Afrikaner patients. In the U.S. sample, we identified two novel non-conservative RTN4R coding variants in two patients with schizophrenia that were absent in 600 control chromosomes. In our complementary mouse model studies, we identified a haploinsufficient effect of Rtn4r on locomotor activity, but normal performance in schizophrenia-related behavioral tasks. We also provide evidence that Rtn4r deficiency can modulate the long-term behavioral effects of transient postnatal N-methyl-D-aspartate (NMDA) receptor hypofunction. Conclusions Our results do not support a major role of RTN4R in susceptibility to schizophrenia or the cognitive and behavioral deficits observed in individuals with 22q11 microdeletions. However, they suggest that RTN4R may modulate the genetic risk or clinical expression of schizophrenia in a subset of patients and identify additional studies that will be necessary to clarify the role of RTN4R in psychiatric phenotypes. In addition, our results raise interesting issues about evaluating the significance of rare genetic variants in disease and their role in causation. PMID:18043741

  2. Nogo Receptor 1 (RTN4R) as a candidate gene for schizophrenia: analysis using human and mouse genetic approaches.

    PubMed

    Hsu, Ruby; Woodroffe, Abigail; Lai, Wen-Sung; Cook, Melloni N; Mukai, Jun; Dunning, Jonathan P; Swanson, Douglas J; Roos, J Louw; Abecasis, Gonçalo R; Karayiorgou, Maria; Gogos, Joseph A

    2007-11-28

    NOGO Receptor 1 (RTN4R) regulates axonal growth, as well as axon regeneration after injury. The gene maps to the 22q11.2 schizophrenia susceptibility locus and is thus a strong functional and positional candidate gene. We evaluate evidence for genetic association between common RTN4R polymorphisms and schizophrenia in a large family sample of Afrikaner origin and screen the exonic sequence of RTN4R for rare variants in an independent sample from the U.S. We also employ animal model studies to assay a panel of schizophrenia-related behavioral tasks in an Rtn4r-deficient mouse model. We found weak sex-specific evidence for association between common RTN4R polymorphisms and schizophrenia in the Afrikaner patients. In the U.S. sample, we identified two novel non-conservative RTN4R coding variants in two patients with schizophrenia that were absent in 600 control chromosomes. In our complementary mouse model studies, we identified a haploinsufficient effect of Rtn4r on locomotor activity, but normal performance in schizophrenia-related behavioral tasks. We also provide evidence that Rtn4r deficiency can modulate the long-term behavioral effects of transient postnatal N-methyl-D-aspartate (NMDA) receptor hypofunction. Our results do not support a major role of RTN4R in susceptibility to schizophrenia or the cognitive and behavioral deficits observed in individuals with 22q11 microdeletions. However, they suggest that RTN4R may modulate the genetic risk or clinical expression of schizophrenia in a subset of patients and identify additional studies that will be necessary to clarify the role of RTN4R in psychiatric phenotypes. In addition, our results raise interesting issues about evaluating the significance of rare genetic variants in disease and their role in causation.

  3. The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants.

    PubMed

    Zhang, J; Kuehl, P; Green, E D; Touchman, J W; Watkins, P B; Daly, A; Hall, S D; Maurel, P; Relling, M; Brimer, C; Yasuda, K; Wrighton, S A; Hancock, M; Kim, R B; Strom, S; Thummel, K; Russell, C G; Hudson, J R; Schuetz, E G; Boguski, M S

    2001-10-01

    The pregnane X receptor (PXR)/steroid and xenobiotic receptor (SXR) transcriptionally activates cytochrome P4503A4 (CYP3A4) when ligand activated by endobiotics and xenobiotics. We cloned the human PXR gene and analysed the sequence in DNAs of individuals whose CYP3A phenotype was known. The PXR gene spans 35 kb, contains nine exons, and mapped to chromosome 13q11-13. Thirty-eight single nucleotide polymorphisms (SNPs) were identified including six SNPs in the coding region. Three of the coding SNPs are non-synonymous creating new PXR alleles [PXR*2, P27S (79C to T); PXR*3, G36R (106G to A); and PXR*4, R122Q (4321G to A)]. The frequency of PXR*2 was 0.20 in African Americans and was never found in Caucasians. Hepatic expression of CYP3A4 protein was not significantly different between African Americans homozygous for PXR*1 compared to those with one PXR*2 allele. PXR*4 was a rare variant found in only one Caucasian person. Homology modelling suggested that R122Q, (PXR*4) is a direct DNA contact site variation in the third alpha-helix in the DNA binding domain. Compared with PXR*1, and variants PXR*2 and PXR*3, only the variant PXR*4 protein had significantly decreased affinity for the PXR binding sequence in electromobility shift assays and attenuated ligand activation of the CYP3A4 reporter plasmids in transient transfection assays. However, the person heterozygous for PXR*4 is normal for CYP3A4 metabolism phenotype. The relevance of each of the 38 PXR SNPs identified in DNA of individuals whose CYP3A basal and rifampin-inducible CYP3A4 expression was determined in vivo and/or in vitro was demonstrated by univariate statistical analysis. Because ligand activation of PXR and upregulation of a system of drug detoxification genes are major determinants of drug interactions, it will now be useful to extend this work to determine the association of these common PXR SNPs to human variation in induction of other drug detoxification gene targets.

  4. Differential modulation of late sodium current by protein kinase A in R1623Q mutant of LQT3

    PubMed Central

    Tsurugi, Takuo; Nagatomo, Toshihisa; Abe, Haruhiko; Oginosawa, Yasushi; Takemasa, Hiroko; Kohno, Ritsuko; Makita, Naomasa; Makielski, Jonathan C.; Otsuji, Yutaka

    2009-01-01

    Aims In the type 3 long QT syndrome (LQT3), shortening of the QT interval by overdrive pacing is used to prevent life-threatening arrhythmias. However, it is unclear whether accelerated heart rate induced by β-adrenergic agents produces similar effects on the late sodium current (INa) to those by overdrive pacing therapy. We analyzed the β-adrenergic-like effects of protein kinase A and fluoride on INa in R1623Q mutant channels. Main methods cDNA encoding either wild-type (WT) or R1623Q mutant of hNav1.5 was stably transfected into HEK293 cells. INa was recorded using a whole-cell patch-clamp technique at 23 °C. Key findings In R1623Q channels, 2 mM pCPT-AMP and 120 mM fluoride significantly delayed macroscopic current decay and increased relative amplitude of the late INa in a time-dependent manner. Modulations of peak INa gating kinetics (activation, inactivation, recovery from inactivation) by fluoride were similar in WT and R1623Q channels. The effects of fluoride were almost completely abolished by concomitant dialysis with a protein kinase inhibitor. We also compared the effect of pacing with that of β-adrenergic stimulation by analyzing the frequency-dependence of the late INa. Fluoride augmented frequency-dependent reduction of the late INa, which was due to preferential delay of recovery of late INa. However, the increase in late INa by fluoride at steady-state was more potent than the frequency-dependent reduction of late INa. Significance Different basic mechanisms participate in the QT interval shortening by pacing and β-adrenergic stimulation in the LQT3. PMID:19167409

  5. Supersymmetric Q-balls: A numerical study

    SciTech Connect

    Campanelli, L.; INFN--Sezione di Ferrara, I-44100 Ferrara; Ruggieri, M.

    2008-02-15

    We study numerically a class of nontopological solitons, the Q-balls, arising in a supersymmetric extension of the standard model with low-energy, gauge-mediated symmetry breaking. Taking into account the exact form of the supersymmetric potential giving rise to Q-balls, we find that there is a lower limit on the value of the charge Q in order to make them classically stable: Q > or approx. 5x10{sup 2}Q{sub cr}, where Q{sub cr} is constant depending on the parameters defining the potential and can be in the range 1 < or approx. Q{sub cr} < or approx. 10{sup 8} {sup divide} {sup 16}.more » If Q is the baryon number, stability with respect to the decay into protons requires Q > or approx. 10{sup 17}Q{sub cr}, while if the gravitino mass is greater then m{sub 3/2} > or approx. 61 MeV, no stable gauge-mediation supersymmetric Q-balls exist. Finally, we find that energy and radius of Q-balls can be parametrized as E{approx}{xi}{sub E}Q{sup 3/4} and R{approx}{xi}{sub R}Q{sup 1/4}, where {xi}{sub E} and {xi}{sub R} are slowly varying functions of the charge.« less

  6. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

    PubMed Central

    Lawrenson, Kate; Iversen, Edwin S.; Tyrer, Jonathan; Weber, Rachel Palmieri; Concannon, Patrick; Hazelett, Dennis J.; Li, Qiyuan; Marks, Jeffrey R.; Berchuck, Andrew; Lee, Janet M.; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Ann; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Plisiecka-Halasa, Joanna; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Gronwald, Jacek; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Jakubowska, Anna; Paul, James; Jensen, Allan; Karlan, Beth Y.; Kjaer, Susanne Kruger; Kelemen, Linda E.; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Cannioto, Rikki; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; Nevanlinna, Heli; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Noor Azmi, Mat Adenan; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Phelan, Catherine M.; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Budzilowska, Agnieszka; Sellers, Thomas A.; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Timorek, Agnieszka; Tworoger, Shelley S.; Nieuwenhuysen, Els Van; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Coetzee, Gerhard A.; Freedman, Matthew L.; Monteiro, Alvaro N.A.; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta; Pharoah, Paul D.; Gayther, Simon A.; Schildkraut, Joellen M.

    2015-01-01

    Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10–7). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r 2 with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11–1.24, P = 1.1×10−7). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10−8). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r 2 = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10-8). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene. PMID:26424751

  7. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.

    PubMed

    Lawrenson, Kate; Iversen, Edwin S; Tyrer, Jonathan; Weber, Rachel Palmieri; Concannon, Patrick; Hazelett, Dennis J; Li, Qiyuan; Marks, Jeffrey R; Berchuck, Andrew; Lee, Janet M; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Bandera, Elisa V; Bean, Yukie; Beckmann, Matthias W; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Ann; Chen, Zhihua; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Plisiecka-Halasa, Joanna; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Eccles, Diana; Easton, Douglas T; Edwards, Robert P; Eilber, Ursula; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Gronwald, Jacek; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Jakubowska, Anna; Paul, James; Jensen, Allan; Karlan, Beth Y; Kjaer, Susanne Kruger; Kelemen, Linda E; Kellar, Melissa; Kelley, Joseph L; Kiemeney, Lambertus A; Krakstad, Camilla; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Cannioto, Rikki; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Nevanlinna, Heli; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Narod, Steven A; Nedergaard, Lotte; Ness, Roberta B; Noor Azmi, Mat Adenan; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jennifer; Phelan, Catherine M; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Budzilowska, Agnieszka; Sellers, Thomas A; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Sucheston, Lara; Tangen, Ingvild L; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Timorek, Agnieszka; Tworoger, Shelley S; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Coetzee, Gerhard A; Freedman, Matthew L; Monteiro, Alvaro N A; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta; Pharoah, Paul D; Gayther, Simon A; Schildkraut, Joellen M

    2015-11-01

    Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia

    PubMed Central

    Brenner, Darren R.; Amos, Christopher I.; Brhane, Yonathan; Timofeeva, Maria N.; Caporaso, Neil; Wang, Yufei; Christiani, David C.; Bickeböller, Heike; Yang, Ping; Albanes, Demetrius; Stevens, Victoria L.; Gapstur, Susan; McKay, James; Boffetta, Paolo; Zaridze, David; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Mates, Dana; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Krokan, Hans E.; Skorpen, Frank; Gabrielsen, Maiken E.; Vatten, Lars; Njølstad, Inger; Chen, Chu; Goodman, Gary; Lathrop, Mark; Vooder, Tõnu; Välk, Kristjan; Nelis, Mari; Metspalu, Andres; Broderick, Peter; Eisen, Timothy; Wu, Xifeng; Zhang, Di; Chen, Wei; Spitz, Margaret R.; Wei, Yongyue; Su, Li; Xie, Dong; She, Jun; Matsuo, Keitaro; Matsuda, Fumihiko; Ito, Hidemi; Risch, Angela; Heinrich, Joachim; Rosenberger, Albert; Muley, Thomas; Dienemann, Hendrik; Field, John K.; Raji, Olaide; Chen, Ying; Gosney, John; Liloglou, Triantafillos; Davies, Michael P.A.; Marcus, Michael; McLaughlin, John; Orlow, Irene; Han, Younghun; Li, Yafang; Zong, Xuchen; Johansson, Mattias; Liu, Geoffrey; Tworoger, Shelley S.; Le Marchand, Loic; Henderson, Brian E.; Wilkens, Lynne R.; Dai, Juncheng; Shen, Hongbing; Houlston, Richard S.; Landi, Maria T.; Brennan, Paul; Hung, Rayjean J.

    2015-01-01

    Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10−8) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10−7) and MTMR2 at 11q21 (rs10501831, P = 3.1×10−6) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10−7) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10−4 for KCNIP4, represented by rs9799795) and AC (P = 2.16×10−4 for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range. PMID:26363033

  9. 20 CFR 410.462 - Presumption relating to respirable disease.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Presumption relating to respirable disease... Pneumoconiosis § 410.462 Presumption relating to respirable disease. (a) Even though the existence of... was employed for 10 years or more in the Nation's coal mines and died from a respirable disease, it...

  10. 20 CFR 410.462 - Presumption relating to respirable disease.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 20 Employees' Benefits 2 2011-04-01 2011-04-01 false Presumption relating to respirable disease... Pneumoconiosis § 410.462 Presumption relating to respirable disease. (a) Even though the existence of... was employed for 10 years or more in the Nation's coal mines and died from a respirable disease, it...

  11. On the output factor measurements of the CyberKnife iris collimator small fields: Experimental determination of the k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}} correction factors for microchamber and diode detectors

    SciTech Connect

    Pantelis, E.; Moutsatsos, A.; Zourari, K.

    Purpose: To measure the output factors (OFs) of the small fields formed by the variable aperture collimator system (iris) of a CyberKnife (CK) robotic radiosurgery system, and determine the k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}} correction factors for a microchamber and four diode detectors. Methods: OF measurements were performed using a PTW PinPoint 31014 microchamber, four diode detectors (PTW-60017, -60012, -60008, and the SunNuclear EDGE detector), TLD-100 microcubes, alanine dosimeters, EBT films, and polymer gels for the 5 mm, 7.5 mm, 10 mm, 12.5 mm, and 15 mm irismore » collimators at 650 mm, 800 mm, and 1000 mm source to detector distance (SDD). The alanine OF measurements were corrected for volume averaging effects using the 3D dose distributions registered in polymer gel dosimeters. k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}} correction factors for the PinPoint microchamber and the diode dosimeters were calculated through comparison against corresponding polymer gel, EBT, alanine, and TLD results. Results: Experimental OF results are presented for the array of dosimetric systems used. The PinPoint microchamber was found to underestimate small field OFs, and a k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}} correction factor ranging from 1.127 {+-} 0.022 (for the 5 mm iris collimator) to 1.004 {+-} 0.010 (for the 15 mm iris collimator) was determined at the reference SDD of 800 mm. The PinPoint k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}} correction factor was also found to increase with decreasing SDD; k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}} values equal to 1.220 {+-} 0.028 and 1

  12. Intrathecal P/Q- and R-type calcium channel blockades on spinal substance P release and c-Fos expression

    PubMed Central

    Terashima, Tetsuji; Xu, Qinghao; Yamaguchi, Shigeki; Yaksh, Tony L.

    2013-01-01

    Intrathecal (IT) studies have shown that several voltage sensitive calcium channels (VSCCs), such as the L-, N- and T-type may play roles in nociception and that of these only the N-type regulates primary afferent substance P (SP) release. However, the actions of other VSCCs at the spinal level are not well known. We investigated the roles of spinal P/Q- and R-type VSCCs, by IT administration of R-type (SNX-482) and P/Q-type (ω-agatoxin IVA) VSCC blockers on intraplantar formalin-evoked flinching, SP release from primary afferents and c-Fos expression in spinal dorsal horn. Intraplantar injection of formalin (2.5%, 50 µL) produced an intense, characteristic biphasic paw flinching response. In rats with IT catheters, IT SNX-482 (0.5 µg) reduced formalin-evoked paw flinching in both phase 1 and 2 compared with vehicle. Intraplantar formalin caused robust neurokinin 1 receptor (NK1r) internalization (indicating SP release) and c-Fos expression in the ipsilateral dorsal horn, which were blocked by IT SNX-482. IT ω-agatoxin IVA (0.03, 0.125 and 0.5 µg) did not reduce formalin-evoked paw flinching or c-Fos expression at any doses, with higher doses resulting in motor dysfunction. Thus, we demonstrated that blockade of spinal R-type, but not P/Q type VSCCs attenuated formalin-induced pain behavior, NK1r internalization and c-Fos expression in the superficial dorsal horn. This study supports a role for Cav2.3 in presynaptic neurotransmitter release from peptidergic nociceptive afferents and pain behaviors. PMID:23810829

  13. 34 CFR 462.12 - What procedures does the Secretary use to review the suitability of tests?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... item selection must ensure negligible overlap in items across pre- and post-testing; (iv) Includes a... regarding the suitability of a test, the Secretary publishes in the Federal Register and posts on the... suitability of tests? 462.12 Section 462.12 Education Regulations of the Offices of the Department of...

  14. Construction of a DNA library representing 15q11-13 by subtraction of two flow sorted marker chromosome-specific libraries

    SciTech Connect

    Blennow, E.; Werelius, B.; Nordenskjoeld, M.

    Constitutional extra {open_quotes}marker chromosomes{close_quotes} are found in {approx}0.5/1000 of newborns. Of these, 50% are inverted duplications of the pericentromeric region of chromosome 15, including two variants; (1) inv dup(15)(pter{yields}q11:q11{yields}pter) and (2) inv dup(15) (pter{yields}q12-13::q12-13{yields}pter). Variant (1) is found in phenotypically normal individuals, whereas variant (2) will produce a typical clinical picture including mental retardation, autism, hyperactivity and discrete dysmorphic features. Fluorescence in situ hybridization (FISH) using single copy probes from the Prader-Willi region confirms these observations as well as chromosome painting using a flow-sorted marker chromosome-specific library from a variant (1) marker, hybridized to the chromosomes of a patient withmore » a variant (2) marker chromosome. Followingly, a flow-sorted biotinylated variant (1) library was subtracted from a non-labeled variant (2) library using magnetic beads and subsequent amplification by degenerate oligonucleotide-primed PCR (DOP-PCR). The successful result was demonstrated by using the amplified material for chromosome painting on chromosome slides from variant (1) and variant (2) patients. We have constructed a library from 15q11-13. This region contains genes producing a specific abnormal phenotype when found in a tri- or tetrasomic state. The region also contains the genes responsible for the Prader-Willi and Angelman syndromes when the paternal/maternal copy is missing, respectively. It is therefore a region where parental imprinting plays an important role. The isolated library may be used to isolate single copy clones which will allow further investigations of this region.« less

  15. Exome Sequencing Identifies Potential Risk Variants for Mendelian Disorders at High Prevalence in Qatar

    PubMed Central

    Rodriguez-Flores, Juan L.; Fakhro, Khalid; Hackett, Neil R.; Salit, Jacqueline; Fuller, Jennifer; Agosto-Perez, Francisco; Gharbiah, Maey; Malek, Joel A.; Zirie, Mahmoud; Jayyousi, Amin; Badii, Ramin; Al-Marri, Ajayeb Al-Nabet; Chouchane, Lotfi; Stadler, Dora J.; Hunter-Zinck, Haley; Mezey, Jason G.; Crystal, Ronald G.

    2013-01-01

    Exome sequencing of families of related individuals has been highly successful in identifying genetic polymorphisms responsible for Mendelian disorders. Here, we demonstrate the value of the reverse approach, where we use exome sequencing of a sample of unrelated individuals to analyze allele frequencies of known causal mutations for Mendelian diseases. We sequenced the exomes of 100 individuals representing the three major genetic subgroups of the Qatari population (Q1 Bedouin, Q2 Persian-South Asian, Q3 African) and identified 37 variants in 33 genes with effects on 36 clinically significant Mendelian diseases. These include variants not present in 1000 Genomes and variants at high frequency when compared to 1000 Genomes populations. Several of these Mendelian variants were only segregating in one Qatari subpopulation, where the observed subpopulation specificity trends were confirmed in an independent population of 386 Qataris. Pre-marital genetic screening in Qatar tests for only 4 out of the 37, such that this study provides a set of Mendelian disease variants with potential impact on the epidemiological profile of the population that could be incorporated into the testing program if further experimental and clinical characterization confirms high penetrance. PMID:24123366

  16. Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population.

    PubMed

    Vestmar, Marie A; Andersson, Ehm A; Christensen, Charlotte R; Hauge, Maria; Glümer, Charlotte; Linneberg, Allan; Witte, Daniel R; Jørgensen, Marit E; Christensen, Cramer; Brandslund, Ivan; Lauritzen, Torsten; Pedersen, Oluf; Holst, Birgitte; Grarup, Niels; Schwartz, Thue W; Hansen, Torben

    2016-09-01

    p.R270H (rs116454156) in the long chain fatty acid 7TM receptor FFAR4 (GPR120) which results in impaired Gαq (Gq) coupled signalling, has been associated with obesity. We aimed to extend the functional in vitro analyses of p.R270H and to investigate the association with obesity and glucose-related traits in the Danish population. Surface expression, Gq and Gi coupled signalling as well as β-arrestin recruitment were examined in vitro. p.R270H was genotyped using the exome chip array in 11 479 Danish adult individuals. Of these 4391 were obese and 4415 were normal weight. Association with quantitative metabolic traits comprised 8720 non-diabetic individuals. p.R270H showed reduced surface expression of FFAR4. Ligand-independent activity was eliminated and strongly impaired through the Gq and Gi signalling pathways, respectively. The ligand-induced maximal signalling efficacy of p.R270H was reduced only through the Gq pathway. The p.R270H variant did not affect β-arrestin recruitment. p.R270H was not associated with increased risk of obesity nor increased fasting plasma glucose levels in the Danish study populations. Nor was it associated with these two traits in the European Network for Genetic and Genomic Epidemiology consortium data (N=34 901-71 175; p>0.70). It was also not associated with waist-hip ratio, glucose metabolism during an oral glucose tolerance test, lipid levels or with markers of adiposity (leptin, adiponectin), inflammation (high-sensitive C reactive protein; hs-CRP) and liver function (alanine aminotransferase) in the Danish population (p>0.05). We demonstrate that p.R270H of FFAR4 impairs Gq and Gi signalling of FFAR4 in vitro; however, this impaired signalling for p.R270H does not translate into associations with human metabolic phenotypes in the investigated populations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  17. 34 CFR 462.43 - How is educational gain measured?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...(b), with the student's educational functioning level as measured by the post-test described in § 462... reading score on the pre-test with the reading score on the post-test. (2) A student is considered to have made an educational gain when the student's post-test indicates that the student has completed one or...

  18. 34 CFR 462.43 - How is educational gain measured?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...(b), with the student's educational functioning level as measured by the post-test described in § 462... reading score on the pre-test with the reading score on the post-test. (2) A student is considered to have made an educational gain when the student's post-test indicates that the student has completed one or...

  19. 34 CFR 462.43 - How is educational gain measured?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...(b), with the student's educational functioning level as measured by the post-test described in § 462... reading score on the pre-test with the reading score on the post-test. (2) A student is considered to have made an educational gain when the student's post-test indicates that the student has completed one or...

  20. 34 CFR 462.43 - How is educational gain measured?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...(b), with the student's educational functioning level as measured by the post-test described in § 462... reading score on the pre-test with the reading score on the post-test. (2) A student is considered to have made an educational gain when the student's post-test indicates that the student has completed one or...

  1. 34 CFR 462.43 - How is educational gain measured?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...(b), with the student's educational functioning level as measured by the post-test described in § 462... reading score on the pre-test with the reading score on the post-test. (2) A student is considered to have made an educational gain when the student's post-test indicates that the student has completed one or...

  2. An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

    PubMed Central

    Wyszynski, Asaf; Hong, Chi-Chen; Lam, Kristin; Michailidou, Kyriaki; Lytle, Christian; Yao, Song; Zhang, Yali; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Nordestgaard, Børge G.; González-Neira, Anna; Benitez, Javier; Neuhausen, Susan L.; Brenner, Hermann; Dieffenbach, Aida Karina; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Ito, Hidemi; Dörk, Thilo; Bogdanova, Natalia V.; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Wu, Anna H.; Van Den Berg, David; Lambrechts, Diether; Wildiers, Hans; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Peterlongo, Paolo; Couch, Fergus J.; Olson, Janet E.; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Henderson, Brian E.; Dumont, Martine; Teo, Soo Hwang; Wong, Tien Y.; Kristensen, Vessela; Zheng, Wei; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Andrulis, Irene L.; Knight, Julia A.; Devilee, Peter; Seynaeve, Caroline; García-Closas, Montserrat; Figueroa, Jonine; Klevebring, Daniel; Czene, Kamila; Hooning, Maartje J.; van den Ouweland, Ans M.W.; Darabi, Hatef; Shu, Xiao-Ou; Gao, Yu-Tang; Cox, Angela; Blot, William; Signorello, Lisa B.; Shah, Mitul; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Miao, Hui; Hamann, Ute; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; McKay, James; Toland, Amanda E.; Yannoukakos, Drakoulis; Shen, Chen-Yang; Wu, Pei-Ei; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Pharoah, Paul D.P.; Dunning, Alison M.; Chenevix-Trench, Georgia; Hall, Per; Bandera, Elisa; Amos, Chris; Ambrosone, Christine; Easton, Douglas F.; Cole, Michael D.

    2016-01-01

    Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55–0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10−19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10−15 − 5.6 × 10−17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5. PMID:27402876

  3. Unexpected dependence of RyR1 splice variant expression in human lower limb muscles on fiber-type composition.

    PubMed

    Willemse, Hermia; Theodoratos, Angelo; Smith, Paul N; Dulhunty, Angela F

    2016-02-01

    The skeletal muscle ryanodine receptor Ca(2+) release channel (RyR1), essential for excitation-contraction (EC) coupling, demonstrates a known developmentally regulated alternative splicing in the ASI region. We now find unexpectedly that the expression of the splice variants is closely related to fiber type in adult human lower limb muscles. We examined the distribution of myosin heavy chain isoforms and ASI splice variants in gluteus minimus, gluteus medius and vastus medialis from patients aged 45 to 85 years. There was a strong positive correlation between ASI(+)RyR1 and the percentage of type 2 fibers in the muscles (r = 0.725), and a correspondingly strong negative correlation between the percentages of ASI(+)RyR1 and percentage of type 1 fibers. When the type 2 fiber data were separated into type 2X and type 2A, the correlation with ASI(+)RyR1 was stronger in type 2X fibers (r = 0.781) than in type 2A fibers (r = 0.461). There was no significant correlation between age and either fiber-type composition or ASI(+)RyR1/ASI(-)RyR1 ratio. The results suggest that the reduced expression of ASI(-)RyR1 during development may reflect a reduction in type 1 fibers during development. Preferential expression of ASI(-) RyR1, having a higher gain of in Ca(2+) release during EC coupling than ASI(+)RyR1, may compensate for the reduced terminal cisternae volume, fewer junctional contacts and reduced charge movement in type 1 fibers.

  4. Associations between a common variant near the MC4R gene and serum triglyceride levels in an obese pediatric cohort.

    PubMed

    Fernandes, Ariana Ester; de Melo, Maria Edna; Fujiwara, Clarissa Tamie Hiwatashi; Pioltine, Marina Brosso; Matioli, Sergio Russo; Santos, Aritânia; Cercato, Cintia; Halpern, Alfredo; Mancini, Marcio C

    2015-08-01

    Polymorphisms near the MC4R gene may be related to an increased risk for obesity, but studies of variations in this gene and its relation to cardiometabolic profiles and food intake are scarce and controversial. The aim of this study is to evaluate the influence of the variants rs12970134 and rs17782313 near the MC4R gene in food intake, binge eating (BE) behavior, anthropometric parameters, body composition, metabolic profile, and cardiometabolic risk factors in obese children and adolescents. This is a cross-sectional study that included obese children and adolescents. We evaluated anthropometric, metabolic parameters and cardiometabolic risk factors, including hypertension, impaired fasting glucose, hypertriglyceridemia, and low HDL-cholesterol. BE was assessed through the BE scale, and a 24-h recall was used to evaluate total caloric intake and percentage of macronutrients and types of dietary fat. The MC4R variants rs12970134 and rs17782313 were genotyped using TaqMan assay. To assess the magnitude of risk, a logistic regression adjusted for Z-BMI, age, and gender was performed, adopting the significance level of 0.05. The study included 518 subjects (52.1 % girls, 12.7 ± 2.7 years old, Z-BMI = 3.24 ± 0.57). Carriers of the variant rs17782313 exhibit increased triglyceride levels (108 ± 48 vs. 119 ± 54, p = 0.034) and an increased risk of hypertriglyceridemia (OR 1.985, 95 % CI 1.288-3.057, p = 0.002). There was no association of the SNP rs12970134 with clinical, metabolic, or nutritional parameters. The variant rs12970134 and rs17782313 did not influence food intake or the presence of BE. The variant rs17782313 is associated with an increased risk of hypertriglyceridemia in obese children and adolescents.

  5. The Interstitial Duplication 15q11.2-q13 Syndrome Includes Autism, Mild Facial Anomalies and a Characteristic EEG Signature

    PubMed Central

    Urraca, Nora; Cleary, Julie; Brewer, Victoria; Pivnick, Eniko K; McVicar, Kathryn; Thibert, Ronald L; Schanen, N Carolyn; Esmer, Carmen; Lamport, Dustin; Reiter, Lawrence T

    2013-01-01

    Chromosomal copy number variants (CNV) are the most common genetic lesion found in autism. Many autism-associated CNVs are duplications of chromosome 15q. Although most cases of interstitial (int) dup(15) that present clinically are de novo and maternally derived or inherited, both pathogenic and unaffected paternal duplications of 15q have been identified. We performed a phenotype/genotype analysis of individuals with interstitial 15q duplications to broaden our understanding of the 15q syndrome and investigate the contribution of 15q duplication to increased autism risk. All subjects were recruited solely on the basis of interstitial duplication 15q11.2-q13 status. Comparative array genome hybridization was used to determine the duplication size and boundaries while the methylation status of the maternally methylated small nuclear ribonucleoprotein polypeptide N gene was used to determine the parent of origin of the duplication. We determined the duplication size and parental origin for 14 int dup(15) subjects: 10 maternal and 4 paternal cases. The majority of int dup(15) cases recruited were maternal in origin, most likely due to our finding that maternal duplication was coincident with autism spectrum disorder. The size of the duplication did not correlate with the severity of the phenotype as established by Autism Diagnostic Observation Scale calibrated severity score. We identified phenotypes not comprehensively described before in this cohort including mild facial dysmorphism, sleep problems and an unusual electroencephalogram variant. Our results are consistent with the hypothesis that the maternally expressed ubiquitin protein ligase E3A gene is primarily responsible for the autism phenotype in int dup(15) since all maternal cases tested presented on the autism spectrum. PMID:23495136

  6. Common variants at 12q14 and 12q24 are associated with hippocampal volume.

    PubMed

    Bis, Joshua C; DeCarli, Charles; Smith, Albert Vernon; van der Lijn, Fedde; Crivello, Fabrice; Fornage, Myriam; Debette, Stephanie; Shulman, Joshua M; Schmidt, Helena; Srikanth, Velandai; Schuur, Maaike; Yu, Lei; Choi, Seung-Hoan; Sigurdsson, Sigurdur; Verhaaren, Benjamin F J; DeStefano, Anita L; Lambert, Jean-Charles; Jack, Clifford R; Struchalin, Maksim; Stankovich, Jim; Ibrahim-Verbaas, Carla A; Fleischman, Debra; Zijdenbos, Alex; den Heijer, Tom; Mazoyer, Bernard; Coker, Laura H; Enzinger, Christian; Danoy, Patrick; Amin, Najaf; Arfanakis, Konstantinos; van Buchem, Mark A; de Bruijn, Renée F A G; Beiser, Alexa; Dufouil, Carole; Huang, Juebin; Cavalieri, Margherita; Thomson, Russell; Niessen, Wiro J; Chibnik, Lori B; Gislason, Gauti K; Hofman, Albert; Pikula, Aleksandra; Amouyel, Philippe; Freeman, Kevin B; Phan, Thanh G; Oostra, Ben A; Stein, Jason L; Medland, Sarah E; Vasquez, Alejandro Arias; Hibar, Derrek P; Wright, Margaret J; Franke, Barbara; Martin, Nicholas G; Thompson, Paul M; Nalls, Michael A; Uitterlinden, Andre G; Au, Rhoda; Elbaz, Alexis; Beare, Richard J; van Swieten, John C; Lopez, Oscar L; Harris, Tamara B; Chouraki, Vincent; Breteler, Monique M B; De Jager, Philip L; Becker, James T; Vernooij, Meike W; Knopman, David; Fazekas, Franz; Wolf, Philip A; van der Lugt, Aad; Gudnason, Vilmundur; Longstreth, W T; Brown, Matthew A; Bennett, David A; van Duijn, Cornelia M; Mosley, Thomas H; Schmidt, Reinhold; Tzourio, Christophe; Launer, Lenore J; Ikram, M Arfan; Seshadri, Sudha

    2012-04-15

    Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

  7. Coronary heart disease-associated variation in TCF21 disrupts a miR-224 binding site and miRNA-mediated regulation.

    PubMed

    Miller, Clint L; Haas, Ulrike; Diaz, Roxanne; Leeper, Nicholas J; Kundu, Ramendra K; Patlolla, Bhagat; Assimes, Themistocles L; Kaiser, Frank J; Perisic, Ljubica; Hedin, Ulf; Maegdefessel, Lars; Schunkert, Heribert; Erdmann, Jeanette; Quertermous, Thomas; Sczakiel, Georg

    2014-03-01

    Genome-wide association studies (GWAS) have identified chromosomal loci that affect risk of coronary heart disease (CHD) independent of classical risk factors. One such association signal has been identified at 6q23.2 in both Caucasians and East Asians. The lead CHD-associated polymorphism in this region, rs12190287, resides in the 3' untranslated region (3'-UTR) of TCF21, a basic-helix-loop-helix transcription factor, and is predicted to alter the seed binding sequence for miR-224. Allelic imbalance studies in circulating leukocytes and human coronary artery smooth muscle cells (HCASMC) showed significant imbalance of the TCF21 transcript that correlated with genotype at rs12190287, consistent with this variant contributing to allele-specific expression differences. 3' UTR reporter gene transfection studies in HCASMC showed that the disease-associated C allele has reduced expression compared to the protective G allele. Kinetic analyses in vitro revealed faster RNA-RNA complex formation and greater binding of miR-224 with the TCF21 C allelic transcript. In addition, in vitro probing with Pb2+ and RNase T1 revealed structural differences between the TCF21 variants in proximity of the rs12190287 variant, which are predicted to provide greater access to the C allele for miR-224 binding. miR-224 and TCF21 expression levels were anti-correlated in HCASMC, and miR-224 modulates the transcriptional response of TCF21 to transforming growth factor-β (TGF-β) and platelet derived growth factor (PDGF) signaling in an allele-specific manner. Lastly, miR-224 and TCF21 were localized in human coronary artery lesions and anti-correlated during atherosclerosis. Together, these data suggest that miR-224 interaction with the TCF21 transcript contributes to allelic imbalance of this gene, thus partly explaining the genetic risk for coronary heart disease associated at 6q23.2. These studies implicating rs12190287 in the miRNA-dependent regulation of TCF21, in conjunction with

  8. Screening of copy number variants in the 22q11.2 region of congenital heart disease patients from the São Miguel Island, Azores, revealed the second patient with a triplication.

    PubMed

    Pires, Renato; Pires, Luís M; Vaz, Sara O; Maciel, Paula; Anjos, Rui; Moniz, Raquel; Branco, Claudia C; Cabral, Rita; Carreira, Isabel M; Mota-Vieira, Luisa

    2014-11-07

    The rearrangements in the 22q11.2 chromosomal region, responsible for the 22q11.2 deletion and microduplication syndromes, are frequently associated with congenital heart disease (CHD). The present work aimed to identify the genetic basis of CHD in 87 patients from the São Miguel Island, Azores, through the detection of copy number variants (CNVs) in the 22q11.2 region. These structural variants were searched using multiplex ligation-dependent probe amplification (MLPA). In patients with CNVs, we additionally performed fluorescent in situ hybridization (FISH) for the assessment of the exact number of 22q11.2 copies among each chromosome, and array comparative genomic hybridization (array-CGH) for the determination of the exact length of CNVs. We found that four patients (4.6%; A to D) carried CNVs. Patients A and D, both affected with a ventricular septal defect, carried a de novo 2.5 Mb deletion of the 22q11.2 region, which was probably originated by inter-chromosomal (inter-chromatid) non-allelic homologous recombination (NAHR) events in the regions containing low-copy repeats (LCRs). Patient C, with an atrial septal defect, carried a de novo 2.5 Mb duplication of 22q11.2 region, which could have been probably generated during gametogenesis by NAHR or by unequal crossing-over; additionally, this patient presented a benign 288 Kb duplication, which included the TOP3B gene inherited from her healthy mother. Finally, patient B showed a 3 Mb triplication associated with dysmorphic facial features, cognitive deficit and heart defects, a clinical feature not reported in the only case described so far in the literature. The evaluation of patient B's parents revealed a 2.5 Mb duplication in her father, suggesting a paternal inheritance with an extra copy. This report allowed the identification of rare deletion and microduplication syndromes in Azorean CHD patients. Moreover, we report the second patient with a 22q11.2 triplication, and we suggest that patients with

  9. Type 2 diabetes susceptibility genes on chromosome 1q21-24.

    PubMed

    Hasstedt, S J; Chu, W S; Das, S K; Wang, H; Elbein, S C

    2008-03-01

    Type 2 diabetes (T2D) has been linked to chromosome 1q21-24 in multiple samples, including a Utah family sample. Variants in 13 of the numerous candidate genes in the 1q region were tested for association with T2D in a Utah case-control sample. The most promising, 19 variants in 6 candidates, were genotyped on the Utah family sample. Herein, we tested the 19 variants individually and in pairs for an effect on T2D risk in family members using a logistic regression model that accounted for gender, age, and BMI and attributed residual genetic effects to a polygenic component. Seven variants increased risk significantly through 5 pairs of interactions. The significant variant pairs were apolipoprotein A-II (APOA2) rs6413453 interacting with calsequestrin 1 (CASQ1) rs617698, dual specificity phosphatase 12 (DUSP12) rs1503814, and retinoid X receptor gamma (RXRG) rs10918169, a poly-T insertion-deletion polymorphism in liver pyruvate kinase (PKLR) interacting with APOA2 rs12143180, and DUSP12 rs1027702 interacting with RXRG rs10918169. Genotypes of these 5 variant pairs accounted for 25.8% of the genetic variance in T2D in these pedigrees.

  10. Whole-Genome Sequencing Suggests Schizophrenia Risk Mechanisms in Humans with 22q11.2 Deletion Syndrome

    PubMed Central

    Merico, Daniele; Zarrei, Mehdi; Costain, Gregory; Ogura, Lucas; Alipanahi, Babak; Gazzellone, Matthew J.; Butcher, Nancy J.; Thiruvahindrapuram, Bhooma; Nalpathamkalam, Thomas; Chow, Eva W. C.; Andrade, Danielle M.; Frey, Brendan J.; Marshall, Christian R.; Scherer, Stephen W.; Bassett, Anne S.

    2015-01-01

    Chromosome 22q11.2 microdeletions impart a high but incomplete risk for schizophrenia. Possible mechanisms include genome-wide effects of DGCR8 haploinsufficiency. In a proof-of-principle study to assess the power of this model, we used high-quality, whole-genome sequencing of nine individuals with 22q11.2 deletions and extreme phenotypes (schizophrenia, or no psychotic disorder at age >50 years). The schizophrenia group had a greater burden of rare, damaging variants impacting protein-coding neurofunctional genes, including genes involved in neuron projection (nominal P = 0.02, joint burden of three variant types). Variants in the intact 22q11.2 region were not major contributors. Restricting to genes affected by a DGCR8 mechanism tended to amplify between-group differences. Damaging variants in highly conserved long intergenic noncoding RNA genes also were enriched in the schizophrenia group (nominal P = 0.04). The findings support the 22q11.2 deletion model as a threshold-lowering first hit for schizophrenia risk. If applied to a larger and thus better-powered cohort, this appears to be a promising approach to identify genome-wide rare variants in coding and noncoding sequence that perturb gene networks relevant to idiopathic schizophrenia. Similarly designed studies exploiting genetic models may prove useful to help delineate the genetic architecture of other complex phenotypes. PMID:26384369

  11. Whole-Genome Sequencing Suggests Schizophrenia Risk Mechanisms in Humans with 22q11.2 Deletion Syndrome.

    PubMed

    Merico, Daniele; Zarrei, Mehdi; Costain, Gregory; Ogura, Lucas; Alipanahi, Babak; Gazzellone, Matthew J; Butcher, Nancy J; Thiruvahindrapuram, Bhooma; Nalpathamkalam, Thomas; Chow, Eva W C; Andrade, Danielle M; Frey, Brendan J; Marshall, Christian R; Scherer, Stephen W; Bassett, Anne S

    2015-09-16

    Chromosome 22q11.2 microdeletions impart a high but incomplete risk for schizophrenia. Possible mechanisms include genome-wide effects of DGCR8 haploinsufficiency. In a proof-of-principle study to assess the power of this model, we used high-quality, whole-genome sequencing of nine individuals with 22q11.2 deletions and extreme phenotypes (schizophrenia, or no psychotic disorder at age >50 years). The schizophrenia group had a greater burden of rare, damaging variants impacting protein-coding neurofunctional genes, including genes involved in neuron projection (nominal P = 0.02, joint burden of three variant types). Variants in the intact 22q11.2 region were not major contributors. Restricting to genes affected by a DGCR8 mechanism tended to amplify between-group differences. Damaging variants in highly conserved long intergenic noncoding RNA genes also were enriched in the schizophrenia group (nominal P = 0.04). The findings support the 22q11.2 deletion model as a threshold-lowering first hit for schizophrenia risk. If applied to a larger and thus better-powered cohort, this appears to be a promising approach to identify genome-wide rare variants in coding and noncoding sequence that perturb gene networks relevant to idiopathic schizophrenia. Similarly designed studies exploiting genetic models may prove useful to help delineate the genetic architecture of other complex phenotypes. Copyright © 2015 Merico et al.

  12. Interaction between GPR120 p.R270H loss-of-function variant and dietary fat intake on incident type 2 diabetes risk in the D.E.S.I.R. study.

    PubMed

    Lamri, A; Bonnefond, A; Meyre, D; Balkau, B; Roussel, R; Marre, M; Froguel, P; Fumeron, F

    2016-10-01

    GPR120 (encoded by FFAR4) is a lipid sensor that plays an important role in the control of energy balance. GPR120 is activated by long chain fatty acids (FAs) including omega-3 FAs. In humans, the loss of function p.R270H variant of the gene FFAR4 has been associated with a lower protein activity, an increased risk of obesity and higher fasting plasma glucose levels. The aim of this study was to investigate whether p.R270H interacts with dietary fat intake to modulate the risk of type 2 diabetes (T2D, 198 incident; 368 prevalent cases) and overweight (787 incident and 2891 prevalent cases) in the prospective D.E.S.I.R. study (n = 5,212, 9 years follow-up). The association of p.R270H with dietary fat and total calories was assessed by linear mixed models. The interaction between p.R270H and dietary fat on T2D and overweight was assessed by logistic regression analysis. The p.R270H variant had a minor allele frequency of 1.45% and was not significantly associated with total calories intake, fat intake or the total calories derived from fat (%). However, there was a significant interaction between p.R270H and dietary fat modulating the incidence of T2D (Pinteraction = 0.02) where the H-carriers had a higher risk of T2D than RR homozygotes in the low fat intake category only. The interaction between p.R270H and fat intake modulating the incidence and prevalence of overweight was not significant. The p.R270H variant of GPR120 modulates the risk of T2D in interaction with dietary fat intake in the D.E.S.I.R. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

  13. IL-23 Receptor (IL-23R) Gene Protects Against Pediatric Crohn’s Disease

    PubMed Central

    Dubinsky, Marla C.; Wang, Dai; Picornell, Yoana; Wrobel, Iwona; Katzir, Lirona; Quiros, Antonio; Dutridge, Debra; Wahbeh, Ghassan; Silber, Gary; Bahar, Ron; Mengesha, Emebet; Targan, Stephan R.; Taylor, Kent D.; Rotter, Jerome I.

    2007-01-01

    Background The IL-23 receptor (IL-23R) has been found to be associated with small bowel Crohn’s disease (CD) in a whole genome association study. Specifically, the rare allele of the R381Q single nucleotide polymorphism (SNP) conferred protection against CD. It is unknown whether IL-23R is associated with IBD in children. The aim was to examine the association of IL-23R with susceptibility to IBD in pediatric patients. Methods DNA was collected from 609 subjects (151 CD and 52 ulcerative colitis [UC] trios). Trios were genotyped for the R381Q SNP of the IL-23R gene and SNP8, SNP12, SNP13, of the CARD15 gene using Taqman. The transmission disequilibrium test (TDT) was used for association to disease using GENEHUNTER 2.0. Results The rare allele of R381Q SNP was present in 2.7% of CD and 2.9% UC probands. The CARD15 frequency was 31.5% (CD) and 18% (UC). The IL-23R allele was negatively associated with inflammatory bowel disease (IBD): the R381Q SNP was undertransmitted in children with IBD (8 transmitted [T] versus 27 untransmitted [UT]; P = 0.001). This association was significant for all CD patients (6 T versus 19 UT; P = 0.009), especially for non-Jewish CD patients (2 T versus 17 UT; P = 0.0006). TDT showed a borderline association for UC (2 T versus 8 UT; P = 0.06). As expected, CARD15 was associated with CD in children by the TDT (58 T versus 22 UT P = 0.00006), but not with UC. Conclusions The protective IL-23R R381Q variant was particularly associated with CD in non-Jewish children. Thus, the initial whole genome association study based on ileal CD in adults has been extended to the pediatric population and beyond small bowel CD. PMID:17309073

  14. Associations of variants in FTO and near MC4R with obesity traits in South Asian Indians.

    PubMed

    Vasan, Senthil K; Fall, Tove; Neville, Matthew J; Antonisamy, Belavendra; Fall, Caroline H; Geethanjali, Finney S; Gu, Harvest F; Raghupathy, Palany; Samuel, Prasanna; Thomas, Nihal; Brismar, Kerstin; Ingelsson, Erik; Karpe, Fredrik

    2012-11-01

    Recent genome-wide association studies show that loci in FTO and melanocortin 4 receptor (MC4R) associate with obesity-related traits. Outside Western populations the associations between these variants have not always been consistent and in Indians it has been suggested that FTO relates to diabetes without an obvious intermediary obesity phenotype. We investigated the association between genetic variants in FTO (rs9939609) and near MC4R (rs17782313) with obesity- and type 2 diabetes (T2DM)-related traits in a longitudinal birth cohort of 2,151 healthy individuals from the Vellore birth cohort in South India. The FTO locus displayed significant associations with several conventional obesity-related anthropometric traits. The per allele increase is about 1% for BMI, waist circumference (WC), hip circumference (HC), and waist-hip ratio. Consistent associations were observed for adipose tissue-specific measurements such as skinfold thickness reinforcing the association with obesity-related traits. Obesity associations for the MC4R locus were weak or nonsignificant but a signal for height (P < 0.001) was observed. The effect on obesity-related traits for FTO was seen in adulthood, but not at younger ages. The loci also showed nominal associations with increased blood glucose but these associations were lost on BMI adjustment. The effect of FTO on obesity-related traits was driven by an urban environmental influence. We conclude that rs9939609 variant in the FTO locus is associated with measures of adiposity and metabolic consequences in South Indians with an enhanced effect associated with urban living. The detection of these associations in Indians is challenging because conventional anthropometric obesity measures work poorly in the Indian "thin-fat" phenotype.

  15. GnRH Neuron-Specific Ablation of Gαq/11 Results in Only Partial Inactivation of the Neuroendocrine-Reproductive Axis in Both Male and Female Mice: In Vivo Evidence for Kiss1r-Coupled Gαq/11-Independent GnRH Secretion.

    PubMed

    Babwah, Andy V; Navarro, Víctor M; Ahow, Maryse; Pampillo, Macarena; Nash, Connor; Fayazi, Mehri; Calder, Michele; Elbert, Adrienne; Urbanski, Henryk F; Wettschureck, Nina; Offermanns, Stefan; Carroll, Rona S; Bhattacharya, Moshmi; Tobet, Stuart A; Kaiser, Ursula B

    2015-09-16

    The gonadotropin-releasing hormone (GnRH) is the master regulator of fertility and kisspeptin (KP) is a potent trigger of GnRH secretion from GnRH neurons. KP signals via KISS1R, a Gαq/11-coupled receptor, and mice bearing a global deletion of Kiss1r (Kiss1r(-/-)) or a GnRH neuron-specific deletion of Kiss1r (Kiss1r(d/d)) display hypogonadotropic hypogonadism and infertility. KISS1R also signals via β-arrestin, and in mice lacking β-arrestin-1 or -2, KP-triggered GnRH secretion is significantly diminished. Based on these findings, we hypothesized that ablation of Gαq/11 in GnRH neurons would diminish but not completely block KP-triggered GnRH secretion and that Gαq/11-independent GnRH secretion would be sufficient to maintain fertility. To test this, Gnaq (encodes Gαq) was selectively inactivated in the GnRH neurons of global Gna11 (encodes Gα11)-null mice by crossing Gnrh-Cre and Gnaq(fl/fl);Gna11(-/-) mice. Experimental Gnaq(fl/fl);Gna11(-/-);Gnrh-Cre (Gnaq(d/d)) and control Gnaq(fl/fl);Gna11(-/-) (Gnaq(fl/fl)) littermate mice were generated and subjected to reproductive profiling. This process revealed that testicular development and spermatogenesis, preputial separation, and anogenital distance in males and day of vaginal opening and of first estrus in females were significantly less affected in Gnaq(d/d) mice than in previously characterized Kiss1r(-/-) or Kiss1r(d/d) mice. Additionally, Gnaq(d/d) males were subfertile, and although Gnaq(d/d) females did not ovulate spontaneously, they responded efficiently to a single dose of gonadotropins. Finally, KP stimulation triggered a significant increase in gonadotropins and testosterone levels in Gnaq(d/d) mice. We therefore conclude that the milder reproductive phenotypes and maintained responsiveness to KP and gonadotropins reflect Gαq/11-independent GnRH secretion and activation of the neuroendocrine-reproductive axis in Gnaq(d/d) mice. The gonadotropin-releasing hormone (GnRH) is the master regulator of

  16. On the q-type distributions

    NASA Astrophysics Data System (ADS)

    Nadarajah, Saralees; Kotz, Samuel

    2007-04-01

    Various q-type distributions have appeared in the physics literature in the recent years, see e.g. L.C. Malacarne, R.S. Mendes, E. K. Lenzi, q-exponential distribution in urban agglomeration, Phys. Rev. E 65, (2002) 017106. S.M.D. Queiros, On a possible dynamical scenario leading to a generalised Gamma distribution, in xxx.lanl.gov-physics/0411111. U.M.S. Costa, V.N. Freire, L.C. Malacarne, R.S. Mendes, S. Picoli Jr., E.A. de Vasconcelos, E.F. da Silva Jr., An improved description of the dielectric breakdown in oxides based on a generalized Weibull distribution, Physica A 361, (2006) 215. S. Picoli, Jr., R.S. Mendes, L.C. Malacarne, q-exponential, Weibull, and q-Weibull distributions: an empirical analysis, Physica A 324 (2003) 678-688. A.M.C. de Souza, C. Tsallis, Student's t- and r- distributions: unified derivation from an entropic variational principle, Physica A 236 (1997) 52-57. It is pointed out in the paper that many of these are the same as or particular cases of what has been known in the statistics literature. Several of these statistical distributions are discussed and references provided. We feel that this paper could be of assistance for modeling problems of the type considered by L.C. Malacarne, R.S. Mendes, E. K. Lenzi, q-exponential distribution in urban agglomeration, Phys. Rev. E 65, (2002) 017106. S.M.D. Queiros, On a possible dynamical scenario leading to a generalised Gamma distribution, in xxx.lanl.gov-physics/0411111. U.M.S. Costa, V.N. Freire, L.C. Malacarne, R.S. Mendes, S. Picoli Jr., E.A. de Vasconcelos, E.F. da Silva Jr., An improved description of the dielectric breakdown in oxides based on a generalized Weibull distribution, Physica A 361, (2006) 215. S. Picoli, Jr., R.S. Mendes, L.C. Malacarne, q-exponential, Weibull, and q-Weibull distributions: an empirical analysis, Physica A 324 (2003) 678-688. A.M.C. de Souza, C. Tsallis, Student's t- and r- distributions: unified derivation from an entropic variational principle, Physica A 236

  17. Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia.

    PubMed

    Brenner, Darren R; Amos, Christopher I; Brhane, Yonathan; Timofeeva, Maria N; Caporaso, Neil; Wang, Yufei; Christiani, David C; Bickeböller, Heike; Yang, Ping; Albanes, Demetrius; Stevens, Victoria L; Gapstur, Susan; McKay, James; Boffetta, Paolo; Zaridze, David; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Mates, Dana; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Krokan, Hans E; Skorpen, Frank; Gabrielsen, Maiken E; Vatten, Lars; Njølstad, Inger; Chen, Chu; Goodman, Gary; Lathrop, Mark; Vooder, Tõnu; Välk, Kristjan; Nelis, Mari; Metspalu, Andres; Broderick, Peter; Eisen, Timothy; Wu, Xifeng; Zhang, Di; Chen, Wei; Spitz, Margaret R; Wei, Yongyue; Su, Li; Xie, Dong; She, Jun; Matsuo, Keitaro; Matsuda, Fumihiko; Ito, Hidemi; Risch, Angela; Heinrich, Joachim; Rosenberger, Albert; Muley, Thomas; Dienemann, Hendrik; Field, John K; Raji, Olaide; Chen, Ying; Gosney, John; Liloglou, Triantafillos; Davies, Michael P A; Marcus, Michael; McLaughlin, John; Orlow, Irene; Han, Younghun; Li, Yafang; Zong, Xuchen; Johansson, Mattias; Liu, Geoffrey; Tworoger, Shelley S; Le Marchand, Loic; Henderson, Brian E; Wilkens, Lynne R; Dai, Juncheng; Shen, Hongbing; Houlston, Richard S; Landi, Maria T; Brennan, Paul; Hung, Rayjean J

    2015-11-01

    Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1×10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16×10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Transgenic mouse α- and β-cardiac myosins containing the R403Q mutation show isoform-dependent transient kinetic differences.

    PubMed

    Lowey, Susan; Bretton, Vera; Gulick, James; Robbins, Jeffrey; Trybus, Kathleen M

    2013-05-24

    Familial hypertrophic cardiomyopathy (FHC) is a major cause of sudden cardiac death in young athletes. The discovery in 1990 that a point mutation at residue 403 (R403Q) in the β-myosin heavy chain (MHC) caused a severe form of FHC was the first of many demonstrations linking FHC to mutations in muscle proteins. A mouse model for FHC has been widely used to study the mechanochemical properties of mutated cardiac myosin, but mouse hearts express α-MHC, whereas the ventricles of larger mammals express predominantly β-MHC. To address the role of the isoform backbone on function, we generated a transgenic mouse in which the endogenous α-MHC was partially replaced with transgenically encoded β-MHC or α-MHC. A His6 tag was cloned at the N terminus, along with R403Q, to facilitate isolation of myosin subfragment 1 (S1). Stopped flow kinetics were used to measure the equilibrium constants and rates of nucleotide binding and release for the mouse S1 isoforms bound to actin. For the wild-type isoforms, we found that the affinity of MgADP for α-S1 (100 μM) is ~ 4-fold weaker than for β-S1 (25 μM). Correspondingly, the MgADP release rate for α-S1 (350 s(-1)) is ~3-fold greater than for β-S1 (120 s(-1)). Introducing the R403Q mutation caused only a minor reduction in kinetics for β-S1, but R403Q in α-S1 caused the ADP release rate to increase by 20% (430 s(-1)). These transient kinetic studies on mouse cardiac myosins provide strong evidence that the functional impact of an FHC mutation on myosin depends on the isoform backbone.

  19. De novo 14q24.2q24.3 microdeletion including IFT43 is associated with intellectual disability, skeletal anomalies, cardiac anomalies, and myopia.

    PubMed

    Stokman, Marijn F; Oud, Machteld M; van Binsbergen, Ellen; Slaats, Gisela G; Nicolaou, Nayia; Renkema, Kirsten Y; Nijman, Isaac J; Roepman, Ronald; Giles, Rachel H; Arts, Heleen H; Knoers, Nine V A M; van Haelst, Mieke M

    2016-06-01

    We report an 11-year-old girl with mild intellectual disability, skeletal anomalies, congenital heart defect, myopia, and facial dysmorphisms including an extra incisor, cup-shaped ears, and a preauricular skin tag. Array comparative genomic hybridization analysis identified a de novo 4.5-Mb microdeletion on chromosome 14q24.2q24.3. The deleted region and phenotype partially overlap with previously reported patients. Here, we provide an overview of the literature on 14q24 microdeletions and further delineate the associated phenotype. We performed exome sequencing to examine other causes for the phenotype and queried genes present in the 14q24.2q24.3 microdeletion that are associated with recessive disease for variants in the non-deleted allele. The deleted region contains 65 protein-coding genes, including the ciliary gene IFT43. Although Sanger and exome sequencing did not identify variants in the second IFT43 allele or in other IFT complex A-protein-encoding genes, immunocytochemistry showed increased accumulation of IFT-B proteins at the ciliary tip in patient-derived fibroblasts compared to control cells, demonstrating defective retrograde ciliary transport. This could suggest a ciliary defect in the pathogenesis of this disorder. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  20. Predominance of hepatitis C virus Q80K among NS3 baseline-resistance-associated amino acid variants in direct-antiviral-agent-naïve patients with chronic hepatitis: single-centre experience.

    PubMed

    Ruggiero, Tina; Proietti, Alex; Boglione, Lucio; Milia, Maria Grazia; Allice, Tiziano; Burdino, Elisa; Orofino, Giancarlo; Bonora, Stefano; Di Perri, Giovanni; Ghisetti, Valeria

    2015-11-01

    In the era of direct-acting antiviral agents (DAAs), hepatitis C virus (HCV) genotyping tests at baseline are controversial. The HCV NS3-Q80K polymorphism is associated with resistance to the recently approved NS3 inhibitor simeprevir (SMV) when combined with PEG-interferon and ribavirin (PEG-IFN/RBV) and alternative therapy should be considered for patients with baseline Q80K. The aim of this study was to provide an estimate of Q80K prevalence at baseline in a study group of 205 DAA-naïve patients (21% of them with HIV coinfection) using NS3 full-population direct sequencing to detect resistance-associated amino acid variants (RAVs). NS3 RAVs were identified in 56 patients (27.3%). Q80K was the most frequently reported one (41%), in both HIV/HCV-coinfected and HCV-monoinfected patients, but it was only detectable in cases of HCV-subtype 1a infection. Therefore, in clinical practice, an NS3-Q80K genotyping test prior to simeprevir plus PEG-IFN/RBV treatment is highly recommended.

  1. Early-life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice.

    PubMed

    Holland, Michelle L; Lowe, Robert; Caton, Paul W; Gemma, Carolina; Carbajosa, Guillermo; Danson, Amy F; Carpenter, Asha A M; Loche, Elena; Ozanne, Susan E; Rakyan, Vardhman K

    2016-07-29

    A suboptimal early-life environment, due to poor nutrition or stress during pregnancy, can influence lifelong phenotypes in the progeny. Epigenetic factors are thought to be key mediators of these effects. We show that protein restriction in mice from conception until weaning induces a linear correlation between growth restriction and DNA methylation at ribosomal DNA (rDNA). This epigenetic response remains into adulthood and is restricted to rDNA copies associated with a specific genetic variant within the promoter. Related effects are also found in models of maternal high-fat or obesogenic diets. Our work identifies environmentally induced epigenetic dynamics that are dependent on underlying genetic variation and establishes rDNA as a genomic target of nutritional insults. Copyright © 2016, American Association for the Advancement of Science.

  2. Early therapy-related myeloid sarcoma and deletion of 9q22.32 to q31.1.

    PubMed

    Brickler, Molly M; Basel, Donald G; Gheorghe, Gabriela; Margolis, David M; Kelly, Michael E; Ehrhardt, Matthew J

    2014-09-01

    Survival following childhood neuroblastoma is improving with low rates of secondary myeloid neoplasms. We describe a 13-month-old male with intermediate risk neuroblastoma who developed an isolated scalp therapy-related myeloid sarcoma (t-MS). Developmental delays and two distinct malignancies prompted constitutional evaluation. Chromosomal microarray identified a 7.3 Mb deletion of 9q22.32 to 9q31.1. He remains in remission 11 months following hematopoietic cell transplant. Unusual presentations of rare diseases necessitate a multidisciplinary approach and adaptation of standardized protocols to accommodate increased risks imposed by genetic variants. © 2014 Wiley Periodicals, Inc.

  3. SOCS1 and SOCS3 Are Targeted by Hepatitis C Virus Core/gC1qR Ligation To Inhibit T-Cell Function

    PubMed Central

    Yao, Zhi Qiang; Waggoner, Stephen N.; Cruise, Michael W.; Hall, Caroline; Xie, Xuefang; Oldach, David W.; Hahn, Young S.

    2005-01-01

    T cells play an important role in the control of hepatitis C virus (HCV) infection. We have previously demonstrated that the HCV core inhibits T-cell responses through interaction with gC1qR. We show here that core proteins from chronic and resolved HCV patients differ in sequence, gC1qR-binding ability, and T-cell inhibition. Specifically, chronic core isolates bind to gC1qR more efficiently and inhibit T-cell proliferation as well as gamma interferon (IFN-γ) production more profoundly than resolved core isolates. This inhibition is mediated by the disruption of STAT phosphorylation through the induction of SOCS molecules. Silencing either SOCS1 or SOCS3 by small interfering RNA dramatically augments the production of IFN-γ in T cells, thereby abrogating the inhibitory effect of core. Additionally, the ability of core proteins from patients with chronic infections to induce SOCS proteins and suppress STAT activation greatly exceeds that of core proteins from patients with resolved infections. These results suggest that the HCV core/gC1qR-induced T-cell dysfunction involves the induction of SOCS, a powerful inhibitor of cytokine signaling, which represents a novel mechanism by which a virus usurps the host machinery for persistence. PMID:16306613

  4. Interferon-related genetic markers of necroinflammatory activity in chronic hepatitis C.

    PubMed

    López-Rodríguez, Rosario; Hernández-Bartolomé, Ángel; Borque, María Jesús; Rodríguez-Muñoz, Yolanda; Martín-Vílchez, Samuel; García-Buey, Luisa; González-Moreno, Leticia; Real-Martínez, Yolanda; Muñoz de Rueda, Paloma; Salmerón, Javier; Vidal-Castiñeira, José Ramón; López-Larrea, Carlos; Rodrigo, Luis; Moreno-Otero, Ricardo; Sanz-Cameno, Paloma

    2017-01-01

    Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients. NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0-2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates. Seven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74). The identified genetic variants in interferon signaling

  5. Low fraction of the 222K PrP variant in the protease-resistant moiety of PrPres in heterozygous scrapie positive goats.

    PubMed

    Mazza, Maria; Guglielmetti, Chiara; Ingravalle, Francesco; Brusadore, Sonia; Langeveld, Jan P M; Ekateriniadou, Loukia V; Andréoletti, Olivier; Casalone, Cristina; Acutis, Pier Luigi

    2017-07-01

    The presence of lysine (K) at codon 222 has been associated with resistance to classical scrapie in goats, but few scrapie cases have been identified in 222Q/K animals. To investigate the contribution of the 222K variant to PrPres formation in natural and experimental Q/K scrapie cases, we applied an immunoblotting method based on the use of two different monoclonal antibodies, F99/97.6.1 and SAF84, chosen for their different affinities to 222K and 222Q PrP variants. Our finding that PrPres seems to be formed nearly totally by the 222Q variant provides evidence that the 222K PrP variant confers resistance to conversion to PrPres formation and reinforces the view that this mutation has a protective role against classical scrapie in goats.

  6. Low fraction of the 222K PrP variant in the protease-resistant moiety of PrPres in heterozygous scrapie positive goats

    PubMed Central

    Guglielmetti, Chiara; Ingravalle, Francesco; Brusadore, Sonia; Langeveld, Jan P. M.; Ekateriniadou, Loukia V.; Andréoletti, Olivier; Casalone, Cristina; Acutis, Pier Luigi

    2017-01-01

    The presence of lysine (K) at codon 222 has been associated with resistance to classical scrapie in goats, but few scrapie cases have been identified in 222Q/K animals. To investigate the contribution of the 222K variant to PrPres formation in natural and experimental Q/K scrapie cases, we applied an immunoblotting method based on the use of two different monoclonal antibodies, F99/97.6.1 and SAF84, chosen for their different affinities to 222K and 222Q PrP variants. Our finding that PrPres seems to be formed nearly totally by the 222Q variant provides evidence that the 222K PrP variant confers resistance to conversion to PrPres formation and reinforces the view that this mutation has a protective role against classical scrapie in goats. PMID:28691895

  7. The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder.

    PubMed

    Wenger, Tara L; Kao, Charlly; McDonald-McGinn, Donna M; Zackai, Elaine H; Bailey, Alice; Schultz, Robert T; Morrow, Bernice E; Emanuel, Beverly S; Hakonarson, Hakon

    2016-01-19

    While abnormal signaling mediated through metabotropic glutamate receptor 5 (mGluR5) is involved in the pathophysiology of Autism Spectrum Disorder (ASD), Fragile X Syndrome and Tuberous Sclerosis, the role of other mGluRs and their associated signaling network genes in syndromic ASD is unknown. This study sought to determine whether mGluR Copy Number Variants (CNV's) were overrepresented in children with syndromic ASD and if mGluR "second hit" confers additional risk for ASD in 22q11.2 Deletion Syndrome (22q11DS). To determine whether mGluR network CNV'S are enriched in syndromic ASD, we examined microarrays from children with ASD (n = 539). Patient categorization (syndromic vs nonsyndromic) was done via blinded medical chart review in mGluR positive and randomly selected mGluR negative cases. 11.5% of ASD had mGluR CNV's vs. 3.2% in controls (p < 0.001). Syndromic ASD was more prevalent in children with mGluR CNVs (74% vs 16%, p < 0.001). A comparison cohort with 22q11DS (n = 25 with ASD, n = 50 without ASD), all haploinsufficient for mGluR network gene RANBP1, were evaluated for "second mGluR hits". 20% with 22q11.2DS + ASD had "second hits" in mGluR network genes vs 2% in 22q11.2DS-ASD (p < 0.014). We propose that altered RANBP1 expression may provide a mechanistic link for several seemingly unrelated genetic and environmental forms of ASD.

  8. The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder

    PubMed Central

    Wenger, Tara L.; Kao, Charlly; McDonald-McGinn, Donna M.; Zackai, Elaine H.; Bailey, Alice; Schultz, Robert T.; Morrow, Bernice E.; Emanuel, Beverly S.; Hakonarson, Hakon

    2016-01-01

    While abnormal signaling mediated through metabotropic glutamate receptor 5 (mGluR5) is involved in the pathophysiology of Autism Spectrum Disorder (ASD), Fragile X Syndrome and Tuberous Sclerosis, the role of other mGluRs and their associated signaling network genes in syndromic ASD is unknown. This study sought to determine whether mGluR Copy Number Variants (CNV’s) were overrepresented in children with syndromic ASD and if mGluR “second hit” confers additional risk for ASD in 22q11.2 Deletion Syndrome (22q11DS). To determine whether mGluR network CNV’S are enriched in syndromic ASD, we examined microarrays from children with ASD (n = 539). Patient categorization (syndromic vs nonsyndromic) was done via blinded medical chart review in mGluR positive and randomly selected mGluR negative cases. 11.5% of ASD had mGluR CNV’s vs. 3.2% in controls (p < 0.001). Syndromic ASD was more prevalent in children with mGluR CNVs (74% vs 16%, p < 0.001). A comparison cohort with 22q11DS (n = 25 with ASD, n = 50 without ASD), all haploinsufficient for mGluR network gene RANBP1, were evaluated for “second mGluR hits”. 20% with 22q11.2DS + ASD had “second hits” in mGluR network genes vs 2% in 22q11.2DS-ASD (p < 0.014). We propose that altered RANBP1 expression may provide a mechanistic link for several seemingly unrelated genetic and environmental forms of ASD. PMID:26781481

  9. Genetic variants of 17q21 are associated with childhood-onset asthma and related phenotypes in a northeastern Han Chinese population: a case-control study.

    PubMed

    Yu, X; Yu, C; Ren, Z; Deng, Y; Song, J; Zhang, H; Zhou, H

    2014-05-01

    A genome-wide association study (GWAS) suggested that variants on chromosome 17q21 were associated with childhood-onset asthma in white populations. Two replication studies had been conducted in southern Han Chinese population in 2009 and 2012. However, these two Chinese replication results were inconsistent. To further confirm the role of 17q21 common variants, an association study of 17q21 single nucleotide polymorphisms (SNPs) with the risk of childhood-onset asthma was performed in a Han population from northeastern China. In this study, rs3894194, rs12603332 and rs11650680 were genotyped in 435 asthmatic children and 601 healthy controls by using a SNaPshot method. Our data showed that the allelic frequency of rs12603332 and rs11650680 showed significant differences between asthmatic cases and healthy controls, with an odds ratio (OR) of 1.36 [95% confidence interval (CI) 1.12-1.65, P=0.002] and an OR of 1.36 (95% CI 1.07-1.74, P=0.01). Genotype distribution analysis also showed the significant associations of the above two loci with childhood asthma under dominant, recessive and additive model (dominant OR=1.57, 95% CI 1.04-2.36, P=0.032; recessive OR=1.41, 95% CI 1.09-1.83, P=0.009; additive OR=1.97, 95% CI 1.24-3.14, P=0.004; recessive OR=1.50, 95% CI 1.13-1.98, P=0.005). Besides, linear regression analysis showed that rs3894194 and rs12603332 were also significantly associated with asthma phenotypes such as log10 -transformed immunoglobulin E (IgE) level (IU/ml) and log10 -transformed eosinophil percentage (dominant, P=0.04; additive, P=0.01; recessive, P=0.04; recessive, P=0.03; additive, P=0.02). Collectively, our findings suggest that orosomucoid 1-like 3 (ORMDL3) locus on chromosome 17q21 is a risk factor for childhood-onset asthma in northeastern Han Chinese population. Further studies will be needed to elucidate the pathogenesis that ORMDL3 locus predisposes to childhood-onset asthma. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. miR expression in MYC-negative DLBCL/BL with partial trisomy 11 is similar to classical Burkitt lymphoma and different from diffuse large B-cell lymphoma.

    PubMed

    Zajdel, Michalina; Rymkiewicz, Grzegorz; Chechlinska, Magdalena; Blachnio, Katarzyna; Pienkowska-Grela, Barbara; Grygalewicz, Beata; Goryca, Krzysztof; Cieslikowska, Maria; Bystydzienski, Zbigniew; Swoboda, Pawel; Walewski, Jan; Siwicki, Jan Konrad

    2015-07-01

    Fast and reliable differential diagnosis of Burkitt lymphoma (BL) vs. diffuse large B cell lymphoma (DLBCL) is of major importance for therapeutic decisions and patient outcome. Aggressive B cell non-Hodgkin lymphomas (B-NHLs) that do not belong to the abovementioned entities were categorized by the current WHO lymphoma classification as "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL" (DLBCL/BL). We have recently described a DLBCL/BL subgroup with recurrent chromosome 11q aberrations, resembling BL (B-NHLs[11q]). Here, we analyzed 102 prospectively collected fine needle aspirates from patients with aggressive B-NHLs in order to investigate the potential of microRNA (miR)-155, its precursor BIC, as well as miR-21 and miR-26a to differentiate BL from DLBCL, and from DLBCL/BL that include B-NHLs[11q]. Both BL and DLBCL/BL cases, including B-NHLs[11q], demonstrated significantly lower expression levels of miR-155/BIC, miR-21, and miR-26a compared to primary DLBCL. In conclusion, the miRs expression in B-NHLs[11q] provides a new suggestion, in addition to pathomorphological and clinical similarities between classical, i.e., MYC translocation-positive BL, and B-NHLs[11q], to recognize the B-NHLs[11q] subgroup of DLBCL/BL category as a MYC translocation-negative variant of BL in most cases, and points to the potential utility of miR-155/BIC/miR-21/miR-26a for the differential diagnosis of a heterogeneous category of DLBCL/BL.

  11. Short communication: Genetic variants of Sarcocystis cruzi in infected Malaysian cattle based on 18S rDNA.

    PubMed

    Ng, Yit Han; Fong, Mun Yik; Subramaniam, Vellayan; Shahari, Shahhaziq; Lau, Yee Ling

    2015-12-01

    Sarcocystis species are pathogenic parasites that infect a wide range of animals, including cattle. A high prevalence of cattle sarcocystosis has been reported worldwide, but its status is unknown in Malaysia. This study focused on utilizing 18S rDNA to identify Sarcocystis species in Malaysian cattle and to determine their genetic variants. In this study, only Sarcocystis cruzi was detected in Malaysian cattle. The intra-species S. cruzi phylogenetic tree analysis and principal coordinate analysis (PCoA), respectively displayed two minor groups among the parasite isolates. This finding was supported by high Wright FST value (FST=0.647). The definitive hosts (dogs) may play a fundamental role in the development of S. cruzi genetic variants. Additionally, the existence of microheterogeneity within the S. cruzi merozoites and/or distinct genetic variants arisen from independent merozoites in mature sarcocysts, possibly contributed to the existence of intra-species variations within the population. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Association of TAS2R38 variants with sweet food intake in children aged 1-6 years.

    PubMed

    Pawellek, Ingrid; Grote, Veit; Rzehak, Peter; Xhonneux, Annick; Verduci, Elvira; Stolarczyk, Anna; Closa-Monasterolo, Ricardo; Reischl, Eva; Koletzko, Berthold

    2016-12-01

    We aimed at studying whether genetic variants of the TAS2R38 gene are associated with energy intake from sweet tasting foods, total energy and macronutrient intake and body weight in children. Children (n = 691) from five European countries were genotyped for the first variant site rs713598 of the TAS2R38 bitter receptor gene. Three-day dietary records were obtained yearly from one to six years of age. Foods were categorized in sweet and non-sweet-tasting. Mixed models were used to describe group differences in food and nutrient intake and BMI z-score over time. TAS2R38 genotype was related to energy intake from sweet tasting foods: Children with PP and PA genotype consumed an average 83 kJ/d (95% CI 21 to 146; p = 0.009) more sweet tasting foods than children with AA genotype and a mean 56 kJ/d (95% CI 15 to 98; p = 0.007) more energy from energy dense sweet products. Intake of sweet tasting foods was lower in girls than boys and differed between countries. TAS2R38 genotype was not associated with the intake of energy, macronutrients, sugar, single food groups and BMI z-score. Despite many other factors influencing food preference and intake in children, actual intake of sweet food items is associated with TAS2R38 genotype. Children with PP or PA genotype consume more (energy dense) sweet tasting foods. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. PON1 L55M and Q192R gene polymorphisms and CAD risks in patients with hyperlipidemia : Clinical study of possible associations.

    PubMed

    Chen, H; Ding, S; Zhou, M; Wu, X; Liu, X; Liu, J; Wu, Y; Liu, D

    2017-08-23

    A decreased plasma high density lipoprotein (HDL) cholesterol level is a strong risk factor for coronary artery disease (CAD). Antioxidant activity of HDL mainly lies in the activity of paraoxonase (PON). This study aimed to investigate the relationships between PON1 L55M and Q192R polymorphisms, and the risks of CAD in patients with hyperlipidemia. From January 2014 to January 2016, 244 patients were divided into hyperlipidemia, hyperlipidemia + CAD, and control groups. The hyperlipidemia and hyperlipidemia + CAD groups were designated as the case group. Serum PON1 concentrations were measured using the enzyme-linked immunosorbent assay. After isolating genomic DNA, the PON1 L55M and Q192R genes were amplified by polymerase chain reaction and sequenced. In the case group, the genotypes LM and LL were detected significantly more often than in the control group, as were the alleles R (33.33%, 42.12%) and L (22.78%, 29.11%). The frequency of QR and RR genotypes was significantly higher in the hyperlipidemia + CAD group than in the hyperlipidemia group; the allele R in the hyperlipidemia + CAD group (42.77%) was more frequent than in the hyperlipidemia group (23.78%). The Q192R polymorphism was associated with low serum PON1 concentrations, and the lowest concentration was observed in the 192QR + 192RR genotype (P = 0.03). Logistic regression analysis showed a significant correlation between the 192R allele and smoking (P = 0.03), body mass index (P = 0.02), systolic blood pressure (P = 0.004), total cholesterol (P = 0.03), triglycerides (P = 0.01), HDL (P = 0.004), and low density lipoprotein (P = 0.02). The PON1 alleles 192R and 55L are associated with CAD, and the Q192R polymorphism may be a risk factor for CAD.

  14. A single amino acid change, Q114R, in the cleavage-site sequence of Newcastle disease virus fusion protein attenuates viral replication and pathogenicity.

    PubMed

    Samal, Sweety; Kumar, Sachin; Khattar, Sunil K; Samal, Siba K

    2011-10-01

    A key determinant of Newcastle disease virus (NDV) virulence is the amino acid sequence at the fusion (F) protein cleavage site. The NDV F protein is synthesized as an inactive precursor, F(0), and is activated by proteolytic cleavage between amino acids 116 and 117 to produce two disulfide-linked subunits, F(1) and F(2). The consensus sequence of the F protein cleavage site of virulent [(112)(R/K)-R-Q-(R/K)-R↓F-I(118)] and avirulent [(112)(G/E)-(K/R)-Q-(G/E)-R↓L-I(118)] strains contains a conserved glutamine residue at position 114. Recently, some NDV strains from Africa and Madagascar were isolated from healthy birds and have been reported to contain five basic residues (R-R-R-K-R↓F-I/V or R-R-R-R-R↓F-I/V) at the F protein cleavage site. In this study, we have evaluated the role of this conserved glutamine residue in the replication and pathogenicity of NDV by using the moderately pathogenic Beaudette C strain and by making Q114R, K115R and I118V mutants of the F protein in this strain. Our results showed that changing the glutamine to a basic arginine residue reduced viral replication and attenuated the pathogenicity of the virus in chickens. The pathogenicity was further reduced when the isoleucine at position 118 was substituted for valine.

  15. Development of atherosclerotic-moyamoya syndrome with genetic variant of RNF213 p.R4810K and p.T1727M: A case report.

    PubMed

    Liu, Ying; Wu, Xueying; Fan, Zhaoyang; Cheng, Jingdan; Zhong, Lele; Lin, Yongzhong; Qu, Xiaofeng

    2018-05-01

    We report a rare case of atherosclerotic-moyamoya syndrome (A-MMS) in an adult female with genetic variant of both ring finger 213 (RNF213) p.R4810K and p.T1727M. A 46-year-old previously healthy, right-handed woman displayed transient slurred speech, which started to worsen four years ago. Initial magnetic resonance angiography (MRA) revealed stenosis in left middle cerebral artery (MCA), bilateral anterior cerebral artery (ACA), and left posterior cerebral artery (PCA). The patient subsequently underwent catheter angiography, which confirmed the formation of moyamoya vessels, with Suzuki's angiographic staging of grade-3 on the left side. Although the patient had been on both anti-platelet and statin therapy at the time, a follow-up examination showed further exacerbation of left MCA stenosis, along with enhanced moyamoya vessel formation. On black-blood imaging using DANTE-SPACE, there were eccentric, evolving lesions in the left MCA. We next screened for potential genetic variants, using genomic DNA samples isolated from both the patient and her immediate family members. The results showed that the patient, along with her mother, sister, and brother, possessed the heterozygous variant of the RNF213 gene, including c.14429G > A (p.R4810K) and c.5180C > T (p.T1727M). The patient's daughter did not have the variant. Collectively, we present a unique case of A-MMS with genetic variant of RNF213 p.R4810K and p.T1727M, manifesting as progression. Based on the family tree, these two mutations are on the same RNF213 haplotype. Whether atherosclerosis is the cause of A-MMS or it further exacerbates the injury of MMD to the A-MMS patients with RNF213 gene variant is a question to be investigated. Copyright © 2018. Published by Elsevier B.V.

  16. 34 CFR 462.42 - How are tests used to place students at an NRS educational functioning level?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... functioning level. (b) A local eligible provider must use the results of the post-test described in § 462.41(c... 34 Education 3 2011-07-01 2011-07-01 false How are tests used to place students at an NRS... Eligible Providers Follow When Measuring Educational Gain? § 462.42 How are tests used to place students at...

  17. 34 CFR 462.42 - How are tests used to place students at an NRS educational functioning level?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... functioning level. (b) A local eligible provider must use the results of the post-test described in § 462.41(c... 34 Education 3 2013-07-01 2013-07-01 false How are tests used to place students at an NRS... Eligible Providers Follow When Measuring Educational Gain? § 462.42 How are tests used to place students at...

  18. 34 CFR 462.42 - How are tests used to place students at an NRS educational functioning level?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... functioning level. (b) A local eligible provider must use the results of the post-test described in § 462.41(c... 34 Education 3 2014-07-01 2014-07-01 false How are tests used to place students at an NRS... Eligible Providers Follow When Measuring Educational Gain? § 462.42 How are tests used to place students at...

  19. 34 CFR 462.42 - How are tests used to place students at an NRS educational functioning level?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... functioning level. (b) A local eligible provider must use the results of the post-test described in § 462.41(c... 34 Education 3 2010-07-01 2010-07-01 false How are tests used to place students at an NRS... Eligible Providers Follow When Measuring Educational Gain? § 462.42 How are tests used to place students at...

  20. 34 CFR 462.42 - How are tests used to place students at an NRS educational functioning level?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... functioning level. (b) A local eligible provider must use the results of the post-test described in § 462.41(c... 34 Education 3 2012-07-01 2012-07-01 false How are tests used to place students at an NRS... Eligible Providers Follow When Measuring Educational Gain? § 462.42 How are tests used to place students at...

  1. Preliminary spectrum of genetic variants in familial hypercholesterolemia in Argentina.

    PubMed

    Bañares, Virginia G; Corral, Pablo; Medeiros, Ana Margarida; Araujo, María Beatriz; Lozada, Alfredo; Bustamante, Juan; Cerretini, Roxana; López, Graciela; Bourbon, Mafalda; Schreier, Laura E

    Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol and early cardiovascular disease. As cardiovascular disease is a leading cause of mortality in Argentina, early identification of patients with FH is of great public health importance. The aim of our study was to identify families with FH and to approximate to the characterization of the genetic spectrum mutations of FH in Argentina. Thirty-three not related index cases were selected with clinical diagnosis of FH. Genetic analysis was performed by sequencing, multiplex ligation-dependent probe amplification, and bioinformatics tools. Twenty genetic variants were identified among 24 cases (73%), 95% on the low-density lipoprotein receptor gene. The only variant on APOB was the R3527Q. Four were novel variants: c.-135C>A, c.170A>C p.(Asp57Ala), c.684G>C p.(Glu228Asp), and c.1895A>T p.(Asn632Ile); the bioinformatics' analysis revealed clear destabilizing effects for 2 of them. The exon 14 presented the highest number of variants (32%). Four variants were observed in more than 1 case and the c.2043C>A p.(Cys681*) was carried by 18% of index cases. Two true homozygotes, 3 compound heterozygotes, and 1 double heterozygote were identified. This study characterizes for the first time in Argentina genetic variants associated with FH and suggest that the allelic heterogeneity of the FH in the country could have 1 relative common low-density lipoprotein receptor mutation. This knowledge is important for the genotype-phenotype correlation and for optimizing both cholesterol-lowering therapies and mutational analysis protocols. In addition, these data contribute to the understanding of the molecular basis of FH in Argentina. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  2. Clinical Significance of the Single Nucleotide Polymorphism TLR2 R753Q in Heart Transplant Recipients at Risk for Cytomegalovirus Disease

    PubMed Central

    Schneider, Martina; Matiqi, Teresa; Kundi, Michael; Rieder, Franz JJ; Andreas, Martin; Strassl, Robert; Zuckermann, Andreas; Jungbauer, Christof; Steininger, Christoph

    2017-01-01

    Background The Toll-like receptor 2 (TLR2) is a significant component of innate immunity against cytomegalovirus (CMV) infection but information on the clinical significance of the most common single nucleotide polymorphism (SNP) (R753Q) is conflicting. Objectives The inconsistent observations of the immunological and clinical significance of the TLR2 R753Q polymorphism for CMV infection indicates the influence of confounders. Study design The presence of the TLR2 polymorphism was determined by a genotyping assay of 175 HTX patients and 281 healthy blood donors and evaluated in relation to selected virological and clinical parameters. Results Relative frequency of TLR2 polymorphism was similar in HTX patients and blood donors (homozygous wild-type, 94.3% vs. 94.0%; heterozygous, 5.1% vs. 5.7%; homozygous mutated, <1%). CMV viremia was detectable in 108 (61.7%) of HTX patients. The TLR2 polymorphism was neither associated with occurrence or level of CMV infection nor with survival, graft failure or rejection, or CMV serostatus of patient before transplantation. Nevertheless, CMV viremia occurred in 83.1% of R+/D+, 77.1% of R+/D-, and 64.3% of R-/D+ patients. Time of first CMV viremia was in R-/D+ patients later than in CMV-seropositive patients (median, 182 days versus 23 days; P<0.001) corresponding to the duration of antiviral prophylaxis in R-/D+ patients. Conclusions The TLR2 R753Q polymorphism is extremely rare in the general population and HTX patients. Screening for this risk factor of CMV disease may not be cost-effective in contrast to testing for CMV viremia. PMID:27723526

  3. Variants of early-onset restrictive eating disturbances in middle childhood.

    PubMed

    Kurz, Susanne; van Dyck, Zoé; Dremmel, Daniela; Munsch, Simone; Hilbert, Anja

    2016-01-01

    This study sought to determine the factor structure of the newly developed self-report screening questionnaire Eating Disturbances in Youth-Questionnaire (EDY-Q) as well as to report the distribution of variants of early-onset restrictive eating disturbances characteristic of avoidant/restrictive food intake disorder (ARFID) in a middle childhood population sample. Using the EDY-Q, a total of 1,444 children aged 8-13 years were screened in elementary schools in Switzerland via self-report. The factor analysis of the 12 items covering ARFID related symptoms was performed using a principal component analysis (PCA). The PCA showed a four factor solution, with clear allocation to the scales covering three variants of early-onset restrictive eating disturbances and weight problems. Inadequate overall food intake was reported by 19.3% of the children, a limited accepted amount of food by 26.1%, and food avoidance based on a specific underlying fear by 5.0%. The postulated factor structure of the EDY-Q was confirmed, further supporting the existence of distinct variants of early-onset restrictive eating disturbances. Avoidant/restrictive eating behavior seems to be a common experience in middle childhood, but results have to be confirmed using validated interviews. © 2015 Wiley Periodicals, Inc.

  4. Evolution of simeprevir-resistant variants over time by ultra-deep sequencing in HCV genotype 1b.

    PubMed

    Akuta, Norio; Suzuki, Fumitaka; Sezaki, Hitomi; Suzuki, Yoshiyuki; Hosaka, Tetsuya; Kobayashi, Masahiro; Kobayashi, Mariko; Saitoh, Satoshi; Ikeda, Kenji; Kumada, Hiromitsu

    2014-08-01

    Using ultra-deep sequencing technology, the present study was designed to investigate the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time. In Toranomon Hospital, 18 Japanese patients infected with HCV genotype 1b, received triple therapy of simeprevir/PEG-IFN/ribavirin (DRAGON or CONCERT study). Sustained virological response rate was 67%, and that was significantly higher in patients with IL28B rs8099917 TT than in those with non-TT. Six patients, who did not achieve sustained virological response, were tested for resistant variants by ultra-deep sequencing, at the baseline, at the time of re-elevation of viral loads, and at 96 weeks after the completion of treatment. Twelve of 18 resistant variants, detected at re-elevation of viral load, were de novo resistant variants. Ten of 12 de novo resistant variants become undetectable over time, and that five of seven resistant variants, detected at baseline, persisted over time. In one patient, variants of Q80R at baseline (0.3%) increased at 96-week after the cessation of treatment (10.2%), and de novo resistant variants of D168E (0.3%) also increased at 96-week after the cessation of treatment (9.7%). In conclusion, the present study indicates that the emergence of simeprevir-resistant variants after the start of treatment could not be predicted at baseline, and the majority of de novo resistant variants become undetectable over time. Further large-scale prospective studies should be performed to investigate the clinical utility in detecting simeprevir-resistant variants. © 2014 Wiley Periodicals, Inc.

  5. Pathogenic copy number variants in patients with congenital hypopituitarism associated with complex phenotypes.

    PubMed

    Correa, Fernanda A; Jorge, Alexander Al; Nakaguma, Marilena; Canton, Ana Pm; Costa, Silvia S; Funari, Mariana F; Lerario, Antonio M; Franca, Marcela M; Carvalho, Luciani R; Krepischi, Ana Cv; Arnhold, Ivo Jp; Rosenberg, Carla; Mendonca, Berenice B

    2018-03-01

    The aetiology of congenital hypopituitarism (CH) is unknown in most patients. Rare copy number variants (CNVs) have been implicated as the cause of genetic syndromes with previously unknown aetiology. Our aim was to study the presence of CNVs and their pathogenicity in patients with idiopathic CH associated with complex phenotypes. We selected 39 patients with syndromic CH for array-based comparative genomic hybridization (aCGH). Patients with pathogenic CNVs were also evaluated by whole exome sequencing. Twenty rare CNVs were detected in 19 patients. Among the identified rare CNVs, six were classified as benign, eleven as variants of uncertain clinical significance (VUS) and four as pathogenic. The three patients with pathogenic CNVs had combined pituitary hormone deficiencies, and the associated complex phenotypes were intellectual disabilities: trichorhinophalangeal type I syndrome (TRPS1) and developmental delay/intellectual disability with cardiac malformation, respectively. Patient one has a de novo 1.6-Mb deletion located at chromosome 3q13.31q13.32, which overlaps with the region of the 3q13.31 deletion syndrome. Patient two has a 10.5-Mb de novo deletion at 8q23.1q24.11, encompassing the TRPS1 gene; his phenotype is compatible with TRPS1. Patient three carries a chromosome translocation t(2p24.3;4q35.1) resulting in two terminal alterations: a 2p25.3p24.3 duplication of 14.7 Mb and a 4-Mb deletion at 4q35.1q35.2. Copy number variants explained the phenotype in 8% of patients with hypopituitarism and additional complex phenotypes. This suggests that chromosomal alterations are an important contributor to syndromic hypopituitarism. © 2017 John Wiley & Sons Ltd.

  6. Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations.

    PubMed

    Van Montfrans, Joris M; Hartman, Esther A R; Braun, Kees P J; Hennekam, Eric A M; Hak, Elisabeth A; Nederkoorn, Paul J; Westendorp, Willeke F; Bredius, Robbert G M; Kollen, Wouter J W; Schölvinck, Elisabeth H; Legger, G Elizabeth; Meyts, Isabelle; Liston, Adrian; Lichtenbelt, Klaske D; Giltay, Jacques C; Van Haaften, Gijs; De Vries Simons, Gaby M; Leavis, Helen; Sanders, Cornelis J G; Bierings, Marc B; Nierkens, Stefan; Van Gijn, Marielle E

    2016-05-01

    To determine the genotype-phenotype association in patients with adenosine deaminase-2 (ADA2) deficiency due to identical homozygous R169Q mutations inCECR1 METHODS: We present a case series of nine ADA2-deficient patients with an identical homozygous R169Q mutation. Clinical and diagnostic data were collected and available MRI studies were reviewed. We performed genealogy and haplotype analyses and measured serum ADA2 activity. ADA2 activity values were correlated to clinical symptoms. Age of presentation differed widely between the nine presented patients (range: 0 months to 8 years). The main clinical manifestations were (hepato)splenomegaly (8/9), skin involvement (8/9) and neurological involvement (8/9, of whom 6 encountered stroke). Considerable variation was seen in type, frequency and intensity of other symptoms, which included aplastic anaemia, acute myeloid leukaemia and cutaneous ulcers. Common laboratory abnormalities included cytopenias and hypogammaglobulinaemia. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. Genealogical studies did not identify a common ancestor; however, based on allele frequency, a North-West European founder effect can be noted. Three patients underwent haematopoietic cell transplantation, after which ADA2 activity was restored and clinical symptoms resolved. This case series revealed large phenotypic variability in patients with ADA2 deficiency though they were homozygous for the same R169Q mutation inCECR1 Disease modifiers, including epigenetic and environmental factors, thus seem important in determining the phenotype. Furthermore, haematopoietic cell transplantation appears promising for those patients with a severe clinical phenotype. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions

  7. A Germline Variant on Chromosome 4q31.1 Associates with Susceptibility to Developing Colon Cancer Metastasis

    PubMed Central

    Schmit, Stephanie L.; Stadler, Zsofia K.; Joseph, Vijai; Zhang, Lu; Willis, Joseph E.; Scacheri, Peter; Veigl, Martina; Adams, Mark D.; Raskin, Leon; Sullivan, John F.; Stratton, Kelly; Shia, Jinru; Ellis, Nathan; Rennert, Hedy S.; Manschreck, Christopher; Li, Li; Offit, Kenneth; Elston, Robert C.; Rennert, Gadi; Gruber, Stephen B.

    2016-01-01

    We tested for germline variants showing association to colon cancer metastasis using a genome-wide association study that compared Ashkenazi Jewish individuals with stage IV metastatic colon cancers versus those with stage I or II non-metastatic colon cancers. In a two-stage study design, we demonstrated significant association to developing metastatic disease for rs60745952, that in Ashkenazi discovery and validation cohorts, respectively, showed an odds ratio (OR) = 2.3 (P = 2.73E-06) and OR = 1.89 (P = 8.05E-04) (exceeding validation threshold of 0.0044). Significant association to metastatic colon cancer was further confirmed by a meta-analysis of rs60745952 in these datasets plus an additional Ashkenazi validation cohort (OR = 1.92; 95% CI: 1.28–2.87), and by a permutation test that demonstrated a significantly longer haplotype surrounding rs60745952 in the stage IV samples. rs60745952, located in an intergenic region on chromosome 4q31.1, and not previously associated with cancer, is, thus, a germline genetic marker for susceptibility to developing colon cancer metastases among Ashkenazi Jews. PMID:26751797

  8. Interaction of HmC1q with leech microglial cells: involvement of C1qBP-related molecule in the induction of cell chemotaxis

    PubMed Central

    2012-01-01

    Background In invertebrates, the medicinal leech is considered to be an interesting and appropriate model to study neuroimmune mechanisms. Indeed, this non-vertebrate animal can restore normal function of its central nervous system (CNS) after injury. Microglia accumulation at the damage site has been shown to be required for axon sprouting and for efficient regeneration. We characterized HmC1q as a novel chemotactic factor for leech microglial cell recruitment. In mammals, a C1q-binding protein (C1qBP alias gC1qR), which interacts with the globular head of C1q, has been reported to participate in C1q-mediated chemotaxis of blood immune cells. In this study, we evaluated the chemotactic activities of a recombinant form of HmC1q and its interaction with a newly characterized leech C1qBP that acts as its potential ligand. Methods Recombinant HmC1q (rHmC1q) was produced in the yeast Pichia pastoris. Chemotaxis assays were performed to investigate rHmC1q-dependent microglia migration. The involvement of a C1qBP-related molecule in this chemotaxis mechanism was assessed by flow cytometry and with affinity purification experiments. The cellular localization of C1qBP mRNA and protein in leech was investigated using immunohistochemistry and in situ hybridization techniques. Results rHmC1q-stimulated microglia migrate in a dose-dependent manner. This rHmC1q-induced chemotaxis was reduced when cells were preincubated with either anti-HmC1q or anti-human C1qBP antibodies. A C1qBP-related molecule was characterized in leech microglia. Conclusions A previous study showed that recruitment of microglia is observed after HmC1q release at the cut end of axons. Here, we demonstrate that rHmC1q-dependent chemotaxis might be driven via a HmC1q-binding protein located on the microglial cell surface. Taken together, these results highlight the importance of the interaction between C1q and C1qBP in microglial activation leading to nerve repair in the medicinal leech. PMID:22356764

  9. Interaction of HmC1q with leech microglial cells: involvement of C1qBP-related molecule in the induction of cell chemotaxis.

    PubMed

    Tahtouh, Muriel; Garçon-Bocquet, Annelise; Croq, Françoise; Vizioli, Jacopo; Sautière, Pierre-Eric; Van Camp, Christelle; Salzet, Michel; Nagnan-le Meillour, Patricia; Pestel, Joël; Lefebvre, Christophe

    2012-02-22

    In invertebrates, the medicinal leech is considered to be an interesting and appropriate model to study neuroimmune mechanisms. Indeed, this non-vertebrate animal can restore normal function of its central nervous system (CNS) after injury. Microglia accumulation at the damage site has been shown to be required for axon sprouting and for efficient regeneration. We characterized HmC1q as a novel chemotactic factor for leech microglial cell recruitment. In mammals, a C1q-binding protein (C1qBP alias gC1qR), which interacts with the globular head of C1q, has been reported to participate in C1q-mediated chemotaxis of blood immune cells. In this study, we evaluated the chemotactic activities of a recombinant form of HmC1q and its interaction with a newly characterized leech C1qBP that acts as its potential ligand. Recombinant HmC1q (rHmC1q) was produced in the yeast Pichia pastoris. Chemotaxis assays were performed to investigate rHmC1q-dependent microglia migration. The involvement of a C1qBP-related molecule in this chemotaxis mechanism was assessed by flow cytometry and with affinity purification experiments. The cellular localization of C1qBP mRNA and protein in leech was investigated using immunohistochemistry and in situ hybridization techniques. rHmC1q-stimulated microglia migrate in a dose-dependent manner. This rHmC1q-induced chemotaxis was reduced when cells were preincubated with either anti-HmC1q or anti-human C1qBP antibodies. A C1qBP-related molecule was characterized in leech microglia. A previous study showed that recruitment of microglia is observed after HmC1q release at the cut end of axons. Here, we demonstrate that rHmC1q-dependent chemotaxis might be driven via a HmC1q-binding protein located on the microglial cell surface. Taken together, these results highlight the importance of the interaction between C1q and C1qBP in microglial activation leading to nerve repair in the medicinal leech.

  10. seawaveQ: an R package providing a model and utilities for analyzing trends in chemical concentrations in streams with a seasonal wave (seawave) and adjustment for streamflow (Q) and other ancillary variables

    USGS Publications Warehouse

    Ryberg, Karen R.; Vecchia, Aldo V.

    2013-01-01

    The seawaveQ R package fits a parametric regression model (seawaveQ) to pesticide concentration data from streamwater samples to assess variability and trends. The model incorporates the strong seasonality and high degree of censoring common in pesticide data and users can incorporate numerous ancillary variables, such as streamflow anomalies. The model is fitted to pesticide data using maximum likelihood methods for censored data and is robust in terms of pesticide, stream location, and degree of censoring of the concentration data. This R package standardizes this methodology for trend analysis, documents the code, and provides help and tutorial information, as well as providing additional utility functions for plotting pesticide and other chemical concentration data.

  11. Hypertrophic cardiomyopathy mutation R58Q in the myosin regulatory light chain perturbs thick filament-based regulation in cardiac muscle.

    PubMed

    Kampourakis, Thomas; Ponnam, Saraswathi; Irving, Malcolm

    2018-04-01

    Hypertrophic cardiomyopathy (HCM) is frequently linked to mutations in the protein components of the myosin-containing thick filaments leading to contractile dysfunction and ultimately heart failure. However, the molecular structure-function relationships that underlie these pathological effects remain largely obscure. Here we chose an example mutation (R58Q) in the myosin regulatory light chain (RLC) that is associated with a severe HCM phenotype and combined the results from a wide range of in vitro and in situ structural and functional studies on isolated protein components, myofibrils and ventricular trabeculae to create an extensive map of structure-function relationships. The results can be understood in terms of a unifying hypothesis that illuminates both the effects of the mutation and physiological signaling pathways. R58Q promotes an OFF state of the thick filaments that reduces the number of myosin head domains that are available for actin interaction and ATP utilization. Moreover this mutation uncouples two aspects of length-dependent activation (LDA), the cellular basis of the Frank-Starling relation that couples cardiac output to venous return; R58Q reduces maximum calcium-activated force with no significant effect on myofilament calcium sensitivity. Finally, phosphorylation of R58Q-RLC to levels that may be relevant both physiologically and pathologically restores the regulatory state of the thick filament and the effect of sarcomere length on maximum calcium-activated force and thick filament structure, as well as increasing calcium sensitivity. We conclude that perturbation of thick filament-based regulation may be a common mechanism in the etiology of missense mutation-associated HCM, and that this signaling pathway offers a promising target for the development of novel therapeutics. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. 42 CFR 441.462 - Statewideness, comparability and limitations on number served.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 4 2010-10-01 2010-10-01 false Statewideness, comparability and limitations on....462 Statewideness, comparability and limitations on number served. A State may do the following: (a... eligible to receive these services without regard to comparability of amount, duration, and scope of...

  13. RefCNV: Identification of Gene-Based Copy Number Variants Using Whole Exome Sequencing.

    PubMed

    Chang, Lun-Ching; Das, Biswajit; Lih, Chih-Jian; Si, Han; Camalier, Corinne E; McGregor, Paul M; Polley, Eric

    2016-01-01

    With rapid advances in DNA sequencing technologies, whole exome sequencing (WES) has become a popular approach for detecting somatic mutations in oncology studies. The initial intent of WES was to characterize single nucleotide variants, but it was observed that the number of sequencing reads that mapped to a genomic region correlated with the DNA copy number variants (CNVs). We propose a method RefCNV that uses a reference set to estimate the distribution of the coverage for each exon. The construction of the reference set includes an evaluation of the sources of variability in the coverage distribution. We observed that the processing steps had an impact on the coverage distribution. For each exon, we compared the observed coverage with the expected normal coverage. Thresholds for determining CNVs were selected to control the false-positive error rate. RefCNV prediction correlated significantly (r = 0.96-0.86) with CNV measured by digital polymerase chain reaction for MET (7q31), EGFR (7p12), or ERBB2 (17q12) in 13 tumor cell lines. The genome-wide CNV analysis showed a good overall correlation (Spearman's coefficient = 0.82) between RefCNV estimation and publicly available CNV data in Cancer Cell Line Encyclopedia. RefCNV also showed better performance than three other CNV estimation methods in genome-wide CNV analysis.

  14. SCRIB and PUF60 Are Primary Drivers of the Multisystemic Phenotypes of the 8q24.3 Copy-Number Variant

    PubMed Central

    Dauber, Andrew; Golzio, Christelle; Guenot, Cécile; Jodelka, Francine M.; Kibaek, Maria; Kjaergaard, Susanne; Leheup, Bruno; Martinet, Danielle; Nowaczyk, Malgorzata J.M.; Rosenfeld, Jill A.; Zeesman, Susan; Zunich, Janice; Beckmann, Jacques S.; Hirschhorn, Joel N.; Hastings, Michelle L.; Jacquemont, Sebastien; Katsanis, Nicholas

    2013-01-01

    Copy-number variants (CNVs) represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report on five individuals with coloboma, microcephaly, developmental delay, short stature, and craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q24.3. Fine mapping localized a commonly deleted 78 kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of the planar cell polarity effector SCRIB and the splicing factor PUF60 to the syndromic phenotype, and the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified an individual with microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C>T variant leading to a p.His169Tyr change in PUF60. Functional testing of this allele in vivo and in vitro showed that the mutation perturbs the relative dosage of two PUF60 isoforms and, subsequently, the splicing efficiency of downstream PUF60 targets. These data inform the functions of two genes not associated previously with human genetic disease and demonstrate how CNVs can exhibit complex genetic architecture, with the phenotype being the amalgam of both discrete dosage dysfunction of single transcripts and also of binary genetic interactions. PMID:24140112

  15. Does Q223R Polymorphism of Leptin Receptor Influence on Anthropometric Parameters and Bone Density in Childhood Cancer Survivors?

    PubMed Central

    Sawicka-Żukowska, Malgorzata; Krawczuk-Rybak, Maryna; Muszynska-Roslan, Katarzyna; Panasiuk, Anna; Latoch, Eryk; Konstantynowicz, Jerzy

    2013-01-01

    Childhood cancer survivors are in augmented risk for developing obesity. For many factors leptin and leptin receptor gene polymorphism play an important role in the development and metabolism not only of fat, but also, bone tissue. The aim of the analysis was to find the relationships between Q223R, leptin levels, and anthropometric parameters. Patients and Methods. In the study 74 cancer survivors participated (ALL n = 64, lymphomas n = 10), and the control group consisted of 51 healthy peers. Leptin blood concentration was determined by ELISA method. To estimate leptin receptor gene polymorphism, RFLP method was used. Bone mineral density (BMD) and content (BMC), fat, and lean tissue measurements were obtained by DXA. Results. We found no correlations between serum leptin concentrations and anthropometric parameters nor BMD. Serum leptin concentrations were significantly lower in the group of cancer survivors compared to controls; however, in those overweight from examined group we found leptin levels higher than those in nonoverweight. Genotype Q223R was not associated with higher leptin levels, BMI, BMD, body fat or lean tissue. Conclusion. To our knowledge, this is the first report describing the relationship between BMD and Q223R polymorphism in childhood cancer survivors. Further analysis, based on a larger group of patients, is needed to confirm these findings. PMID:24319457

  16. A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants.

    PubMed

    Nedeljkovic, Ivana; Terzikhan, Natalie; Vonk, Judith M; van der Plaat, Diana A; Lahousse, Lies; van Diemen, Cleo C; Hobbs, Brian D; Qiao, Dandi; Cho, Michael H; Brusselle, Guy G; Postma, Dirkje S; Boezen, H M; van Duijn, Cornelia M; Amin, Najaf

    2018-01-01

    Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare genetic variants underlying COPD through a genome-wide linkage scan. Affected-only analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a genetic isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak. The identified rare variants were then tested for association with COPD in a large meta-analysis of several cohorts. Significant evidence for linkage was observed on chromosomes 15q14-15q25 [logarithm of the odds (LOD) score = 5.52], 11p15.4-11q14.1 (LOD = 3.71) and 5q14.3-5q33.2 (LOD = 3.49). In the chromosome 15 peak, that harbors the known COPD locus for nicotinic receptors, and in the chromosome 5 peak we could not identify shared variants. In the chromosome 11 locus, we identified four rare (minor allele frequency (MAF) <0.02), predicted pathogenic, missense variants. These were shared among the affected family members. The identified variants localize to genes including neuroblast differentiation-associated protein ( AHNAK ), previously associated with blood biomarkers in COPD, phospholipase C Beta 3 ( PLCB3 ), shown to increase airway hyper-responsiveness, solute carrier family 22-A11 ( SLC22A11 ), involved in amino acid metabolism and ion transport, and metallothionein-like protein 5 ( MTL5 ), involved in nicotinate and nicotinamide metabolism. Association of SLC22A11 and MTL5 variants were confirmed in the meta-analysis of 9,888 cases and 27,060 controls. In conclusion, we have identified novel rare variants in plausible genes related to COPD. Further studies utilizing large sample

  17. ACTN3 R577X and ACE I/D gene variants influence performance in elite sprinters: a multi-cohort study.

    PubMed

    Papadimitriou, Ioannis D; Lucia, Alejandro; Pitsiladis, Yannis P; Pushkarev, Vladimir P; Dyatlov, Dmitry A; Orekhov, Evgeniy F; Artioli, Guilherme G; Guilherme, João Paulo L F; Lancha, Antonio H; Ginevičienė, Valentina; Cieszczyk, Pawel; Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Muniesa, Carlos A; Kouvatsi, Anastasia; Massidda, Myosotis; Calò, Carla Maria; Garton, Fleur; Houweling, Peter J; Wang, Guan; Austin, Krista; Druzhevskaya, Anastasiya M; Astratenkova, Irina V; Ahmetov, Ildus I; Bishop, David J; North, Kathryn N; Eynon, Nir

    2016-04-13

    To date, studies investigating the association between ACTN3 R577X and ACE I/D gene variants and elite sprint/power performance have been limited by small cohorts from mixed sport disciplines, without quantitative measures of performance. To examine the association between these variants and sprint time in elite athletes. We collected a total of 555 best personal 100-, 200-, and 400-m times of 346 elite sprinters in a large cohort of elite Caucasian or African origin sprinters from 10 different countries. Sprinters were genotyped for ACTN3 R577X and ACE ID variants. On average, male Caucasian sprinters with the ACTN3 577RR or the ACE DD genotype had faster best 200-m sprint time than their 577XX (21.19 ± 0.53 s vs. 21.86 ± 0.54 s, p = 0.016) and ACE II (21.33 ± 0.56 vs. 21.93 ± 0.67 sec, p = 0.004) counterparts and only one case of ACE II, and no cases of ACTN3 577XX, had a faster 200-m time than the 2012 London Olympics qualifying (vs. 12 qualified sprinters with 577RR or 577RX genotype). Caucasian sprinters with the ACE DD genotype had faster best 400-m sprint time than their ACE II counterparts (46.94 ± 1.19 s vs. 48.50 ± 1.07 s, p = 0.003). Using genetic models we found that the ACTN3 577R allele and ACE D allele dominant model account for 0.92 % and 1.48 % of sprint time variance, respectively. Despite sprint performance relying on many gene variants and environment, the % sprint time variance explained by ACE and ACTN3 is substantial at the elite level and might be the difference between a world record and only making the final.

  18. 20 CFR 404.462 - Nonpayment of hospital and medical insurance benefits of alien outside United States for more...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Nonpayment of hospital and medical insurance benefits of alien outside United States for more than 6 months. 404.462 Section 404.462 Employees' Benefits... alien outside United States for more than 6 months. No payments may be made under part A (hospital...

  19. Analysis of CHRNA7 rare variants in autism spectrum disorder susceptibility.

    PubMed

    Bacchelli, Elena; Battaglia, Agatino; Cameli, Cinzia; Lomartire, Silvia; Tancredi, Raffaella; Thomson, Susanne; Sutcliffe, James S; Maestrini, Elena

    2015-04-01

    Chromosome 15q13.3 recurrent microdeletions are causally associated with a wide range of phenotypes, including autism spectrum disorder (ASD), seizures, intellectual disability, and other psychiatric conditions. Whether the reciprocal microduplication is pathogenic is less certain. CHRNA7, encoding for the alpha7 subunit of the neuronal nicotinic acetylcholine receptor, is considered the likely culprit gene in mediating neurological phenotypes in 15q13.3 deletion cases. To assess if CHRNA7 rare variants confer risk to ASD, we performed copy number variant analysis and Sanger sequencing of the CHRNA7 coding sequence in a sample of 135 ASD cases. Sequence variation in this gene remains largely unexplored, given the existence of a fusion gene, CHRFAM7A, which includes a nearly identical partial duplication of CHRNA7. Hence, attempts to sequence coding exons must distinguish between CHRNA7 and CHRFAM7A, making next-generation sequencing approaches unreliable for this purpose. A CHRNA7 microduplication was detected in a patient with autism and moderate cognitive impairment; while no rare damaging variants were identified in the coding region, we detected rare variants in the promoter region, previously described to functionally reduce transcription. This study represents the first sequence variant analysis of CHRNA7 in a sample of idiopathic autism. © 2015 Wiley Periodicals, Inc.

  20. Multi-PAS domain-mediated protein oligomerization of PpsR from Rhodobacter sphaeroides

    SciTech Connect

    Heintz, Udo; Meinhart, Anton; Winkler, Andreas, E-mail: andreas.winkler@mpimf-heidelberg.mpg.de

    2014-03-01

    Crystal structures of two truncated variants of the transcription factor PpsR from R. sphaeroides are presented that enabled the phasing of a triple PAS domain construct. Together, these structures reveal the importance of α-helical PAS extensions for multi-PAS domain-mediated protein oligomerization and function. Per–ARNT–Sim (PAS) domains are essential modules of many multi-domain signalling proteins that mediate protein interaction and/or sense environmental stimuli. Frequently, multiple PAS domains are present within single polypeptide chains, where their interplay is required for protein function. Although many isolated PAS domain structures have been reported over the last decades, only a few structures of multi-PAS proteinsmore » are known. Therefore, the molecular mechanism of multi-PAS domain-mediated protein oligomerization and function is poorly understood. The transcription factor PpsR from Rhodobacter sphaeroides is such a multi-PAS domain protein that, in addition to its three PAS domains, contains a glutamine-rich linker and a C-terminal helix–turn–helix DNA-binding motif. Here, crystal structures of two N-terminally and C-terminally truncated PpsR variants that comprise a single (PpsR{sub Q-PAS1}) and two (PpsR{sub N-Q-PAS1}) PAS domains, respectively, are presented and the multi-step strategy required for the phasing of a triple PAS domain construct (PpsR{sub ΔHTH}) is illustrated. While parts of the biologically relevant dimerization interface can already be observed in the two shorter constructs, the PpsR{sub ΔHTH} structure reveals how three PAS domains enable the formation of multiple oligomeric states (dimer, tetramer and octamer), highlighting that not only the PAS cores but also their α-helical extensions are essential for protein oligomerization. The results demonstrate that the long helical glutamine-rich linker of PpsR results from a direct fusion of the N-cap of the PAS1 domain with the C-terminal extension of the N

  1. Japanese version of the ALS-FTD-Questionnaire (ALS-FTD-Q-J).

    PubMed

    Watanabe, Yasuhiro; Beeldman, Emma; Raaphorst, Joost; Izumi, Yuishin; Yoshino, Hiide; Masuda, Michihito; Atsuta, Naoki; Ito, Satoru; Adachi, Tadashi; Adachi, Yoshiki; Yokota, Osamu; Oda, Masaya; Hanashima, Ritsuko; Ogino, Mieko; Ichikawa, Hiroo; Hasegawa, Kazuko; Kimura, Hideki; Shimizu, Toshio; Aiba, Ikuko; Yabe, Hayato; Kanba, Makoto; Kusumi, Kimiyoshi; Aoki, Tetsuya; Hiroe, Yu; Watanabe, Hirohisa; Nishiyama, Kazutoshi; Nomoto, Masahiro; Sobue, Gen; Nakashima, Kenji

    2016-08-15

    Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share common clinical, genetic and neuropathological features. Some ALS patients have behavioral/personality changes, which could result in significant obstacles in the care provided by family members and caregivers. An easy screening tool would contribute greatly to the evaluation of these symptoms. We translated the ALS-FTD-Questionnaire, developed in the Netherlands, into Japanese (ALS-FTD-Q-J) and examined the clinimetric properties (internal consistency, construct and clinical validity). Patients with ALS and/or behavioral variant FTD (bvFTD) were evaluated alongside healthy controls in this multicenter study. All ALS patients, regardless of bvFTD status, were further evaluated by the frontal behavioral inventory (FBI) and for frontal/executive function, cognition, anxiety/depression, and motor functions. Data from 146 subjects were analyzed: ALS (92), ALS-bvFTD (6), bvFTD (16), and healthy controls (32). The internal consistency of the ALS-FTD-Q-J was good (Cronbach α=0.92). The ALS-FTD-Q-J showed construct validity as it exhibited a high correlation with the FBI (r=0.79). However, correlations were moderate with anxiety/depression and low with cognitive scales, in contrast to the original report, i.e. a moderate correlation with cognition and a low correlation with anxiety/depression. The ALS-FTD-Q-J discriminated ALS patients from (ALS-)bvFTD patients and controls. Thus, the ALS-FTD-Q-J is useful for evaluating Japanese ALS/FTD patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma

    PubMed Central

    Kubiak, Anna; Czetwertyńska, Małgorzata; Świerniak, Michał; Gierlikowski, Wojciech; Kolanowska, Monika; Bakuła-Zalewska, Elwira; Jhiang, Sissy M.; Jażdżewski, Krystian; Wójcicka, Anna

    2018-01-01

    Aberrant expression of the sodium-iodide symporter (NIS) and the resistance to post-operative radioactive iodide treatment is a crucial cause of higher mortality of some thyroid cancer patients. In this study, we analyzed the impact of miR-146a on the expression and function of NIS and on the overall survival of thyroid cancer patients. The study included 2441 patients (2163 women; 278 men); including 359 cases with follicular variant of papillary thyroid carcinoma (fvPTC). miR:NIS interactions were analyzed in cell lines using in vivo binding and inhibition assays and radioactive iodine uptake assays. Tumor/blood DNA was used for rs2910164 genotyping. Overall survival was assessed retrospectively. In the results, we showed that miR-146a-3p directly binds to and inhibits NIS. Inhibition of miR-146a-3p restores the expression and function of NIS, increasing radioactive iodine uptake. Rs2910164 functional variant within miR-146a-3p is associated with increased overall mortality among fvPTC female patients. The deaths per 1000 person-years were 29.7 in CC carriers vs. 5.08 in GG/GC-carriers (HR = 6.21, p = 0.006). Higher mortality of CC vs. GG/GC carriers was also observed in patients with lower clinical stage (HR = 22.72, p < 0.001), smaller tumor size (pT1/pT2) (HR = 25.05, p < 0.001), lack of extrathyroidal invasion (HR = 9.03, p = 0.02), lack of nodular invasion (HR = 7.84, p = 0.002), lack of metastases (HR = 6.5, p = 0.005) and older (age at diagnosis >50 years) (HR = 7.8, p = 0.002). MiR-146a-3p underwent somatic mutations in 16.1% of analyzed specimens, mainly towards the deleterious C allele. In this report we propose a novel molecular marker of the clinical outcome of fvPTC patients. Rs2910164 increases the overall mortality with inhibition of NIS and disruption of radioiodine uptake as a possible mechanism. PMID:29495389

  3. Saitohin Q7R polymorphism is associated with late-onset Alzheimer's disease susceptibility among caucasian populations: a meta-analysis.

    PubMed

    Huang, Rong; Tian, Sai; Cai, Rongrong; Sun, Jie; Xia, Wenqing; Dong, Xue; Shen, Yanjue; Wang, Shaohua

    2017-08-01

    Saitohin (STH) Q7R polymorphism has been reported to influence the individual's susceptibility to Alzheimer's disease (AD); however, conclusions remain controversial. Therefore, we performed this meta-analysis to explore the association between STH Q7R polymorphism and AD risk. Systematic literature searches were performed in the PubMed, Embase, Cochrane Library and Web of Science for studies published before 31 August 2016. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association using a fixed- or random-effects model. Subgroup analyses, Galbraith plot and sensitivity analyses were also performed. All statistical analyses were performed with STATA Version 12.0. A total of 19 case-control studies from 17 publications with 4387 cases and 3972 controls were included in our meta-analysis. The results showed that the Q7R polymorphism was significantly associated with an increased risk of AD in a recessive model (RR versus QQ+QR, OR = 1.27, 95% CI = 1.01-1.60, P = 0.040). After excluding the four studies not carried out in caucasians, the overall association was unchanged in all comparison models. Further subgroup analyses stratified by the time of AD onset, and the quality of included studies provided statistical evidence of significant increased risk of AD in RR versus QQ+QR model only in late-onset subjects (OR = 1.56, 95% CI = 1.07-2.26, P = 0.021) and in studies with high quality (OR = 1.37, 95% CI = 1.01-1.86, P = 0.043). This meta-analysis suggests that the RR genotype in saitohin Q7R polymorphism may be a human-specific risk factor for AD, especially among late-onset AD subjects and caucasian populations. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  4. An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.

    PubMed

    Wyszynski, Asaf; Hong, Chi-Chen; Lam, Kristin; Michailidou, Kyriaki; Lytle, Christian; Yao, Song; Zhang, Yali; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Beckmann, Matthias W; Peto, Julian; Dos-Santos-Silva, Isabel; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Nordestgaard, Børge G; González-Neira, Anna; Benitez, Javier; Neuhausen, Susan L; Brenner, Hermann; Dieffenbach, Aida Karina; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Ito, Hidemi; Dörk, Thilo; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Wu, Anna H; Van Den Berg, David; Lambrechts, Diether; Wildiers, Hans; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Peterlongo, Paolo; Couch, Fergus J; Olson, Janet E; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Henderson, Brian E; Dumont, Martine; Teo, Soo Hwang; Wong, Tien Y; Kristensen, Vessela; Zheng, Wei; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Seynaeve, Caroline; García-Closas, Montserrat; Figueroa, Jonine; Klevebring, Daniel; Czene, Kamila; Hooning, Maartje J; van den Ouweland, Ans M W; Darabi, Hatef; Shu, Xiao-Ou; Gao, Yu-Tang; Cox, Angela; Blot, William; Signorello, Lisa B; Shah, Mitul; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Miao, Hui; Hamann, Ute; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; McKay, James; Toland, Amanda E; Yannoukakos, Drakoulis; Shen, Chen-Yang; Wu, Pei-Ei; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Pharoah, Paul D P; Dunning, Alison M; Chenevix-Trench, Georgia; Hall, Per; Bandera, Elisa; Amos, Chris; Ambrosone, Christine; Easton, Douglas F; Cole, Michael D

    2016-09-01

    Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10 -19 ) and identify 13 additional linked variants (r 2  >   0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10 -15 - 5.6 × 10 -17 ). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. Sequence Variation in the Small-Subunit rRNA Gene of Plasmodium malariae and Prevalence of Isolates with the Variant Sequence in Sichuan, China

    PubMed Central

    Liu, Qing; Zhu, Shenghua; Mizuno, Sahoko; Kimura, Masatsugu; Liu, Peina; Isomura, Shin; Wang, Xingzhen; Kawamoto, Fumihiko

    1998-01-01

    By two PCR-based diagnostic methods, Plasmodium malariae infections have been rediscovered at two foci in the Sichuan province of China, a region where no cases of P. malariae have been officially reported for the last 2 decades. In addition, a variant form of P. malariae which has a deletion of 19 bp and seven substitutions of base pairs in the target sequence of the small-subunit (SSU) rRNA gene was detected with high frequency. Alignment analysis of Plasmodium sp. SSU rRNA gene sequences revealed that the 5′ region of the variant sequence is identical to that of P. vivax or P. knowlesi and its 3′ region is identical to that of P. malariae. The same sequence variations were also found in P. malariae isolates collected along the Thai-Myanmar border, suggesting a wide distribution of this variant form from southern China to Southeast Asia. PMID:9774600

  6. Generation and Characterization of Environmentally Sensitive Variants of the β-Galactosidase from Lactobacillus delbrueckii subsp. bulgaricus

    PubMed Central

    Yoast, Sienna; Adams, Robin M.; Mainzer, Stanley E.; Moon, Keith; Palombella, Anthony L.; Schmidt, Brian F.

    1994-01-01

    A method is described for generating and screening variants of the β-galactosidase from Lactobacillus delbrueckii subsp. bulgaricus sensitive to several environmental stresses, with potential application in the food industry. Chemical mutagenesis with hydroxylamine or methoxylamine was performed on the β-galactosidase gene carried on an Escherichia coli expression vector. Mutants sensitive to cold, heat, low pH, low magnesium concentration, and the presence of urea were isolated by screening for reduced color development on β-galactosidase indicator plates. The mutations responsible for three variant β-galactosidases were localized, and the base substitutions were determined by DNA sequencing. The amino acid alterations associated with one low-pH-sensitive (pHs) and two urea-sensitive (Us) variants correspond to P584L (pHs1), G400S/R479Q (Us26), and G167E/E168K/E363K/V492M (Us17), respectively. Mutant pHs1 is also heat, cold, low magnesium, and urea sensitive; Us26 is also cold sensitive; and Us17 is also low-pH sensitive. PMID:16349230

  7. 34 CFR 462.1 - What is the scope of this part?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... ADULT EDUCATION, DEPARTMENT OF EDUCATION MEASURING EDUCATIONAL GAIN IN THE NATIONAL REPORTING SYSTEM FOR ADULT EDUCATION General § 462.1 What is the scope of this part? The regulations in this part establish... the National Reporting System for Adult Education (NRS) to measure educational gain of participants in...

  8. 34 CFR 462.14 - How often and under what circumstances must a test be reviewed by the Secretary?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... EDUCATIONAL GAIN IN THE NATIONAL REPORTING SYSTEM FOR ADULT EDUCATION What Process Does the Secretary Use To... 34 Education 3 2010-07-01 2010-07-01 false How often and under what circumstances must a test be reviewed by the Secretary? 462.14 Section 462.14 Education Regulations of the Offices of the Department of...

  9. Tensor products of U{sub q}{sup Prime }sl-caret(2)-modules and the big q{sup 2}-Jacobi function transform

    SciTech Connect

    Gade, R. M.

    2013-01-15

    Four tensor products of evaluation modules of the quantum affine algebra U{sub q}{sup Prime }sl-caret(2) obtained from the negative and positive series, the complementary and the strange series representations are investigated. Linear operators R(z) satisfying the intertwining property on finite linear combinations of the canonical basis elements of the tensor products are described in terms of two sets of infinite sums {l_brace}{tau}{sup (r,t)}{r_brace}{sub r,t Element-Of Z{sub {>=}{sub 0}}} and {l_brace}{tau}{sup (r,t)}{r_brace}{sub r,t Element-Of Z{sub {>=}{sub 0}}} involving big q{sup 2}-Jacobi functions or related nonterminating basic hypergeometric series. Inhomogeneous recurrence relations can be derived for both sets. Evaluations of the simplestmore » sums provide the corresponding initial conditions. For the first set of sums the relations entail a big q{sup 2}-Jacobi function transform pair. An integral decomposition is obtained for the sum {tau}{sup (r,t)}. A partial description of the relation between the decompositions of the tensor products with respect to U{sub q}sl(2) or with respect to its complement in U{sub q}{sup Prime }sl-caret(2) can be formulated in terms of Askey-Wilson function transforms. For a particular combination of two tensor products, the occurrence of proper U{sub q}{sup Prime }sl-caret(2)-submodules is discussed.« less

  10. The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease

    PubMed Central

    Fu, Yi-Ping; Kohaar, Indu; Moore, Lee E.; Lenz, Petra; Figueroa, Jonine D.; Tang, Wei; Porter-Gill, Patricia; Chatterjee, Nilanjan; Scott-Johnson, Alexandra; Garcia-Closas, Montserrat; Muchmore, Brian; Baris, Dalsu; Paquin, Ashley; Ylaya, Kris; Schwenn, Molly; Apolo, Andrea B.; Karagas, Margaret R.; Tarway, McAnthony; Johnson, Alison; Mumy, Adam; Schned, Alan; Guedez, Liliana; Jones, Michael A.; Kida, Masatoshi; Monawar Hosain, GM; Malats, Nuria; Kogevinas, Manolis; Tardon, Adonina; Serra, Consol; Carrato, Alfredo; Garcia-Closas, Reina; Lloreta, Josep; Wu, Xifeng; Purdue, Mark; Andriole, Gerald L.; Grubb, Robert L.; Black, Amanda; Landi, Maria T.; Caporaso, Neil E.; Vineis, Paolo; Siddiq, Afshan; Bueno-de-Mesquita, H. Bas; Trichopoulos, Dimitrios; Ljungberg, Börje; Severi, Gianluca; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth C.; Tjønneland, Anne; Brennan, Paul; Chang-Claude, Jenny; Riboli, Elio; Prescott, Jennifer; Chen, Constance; De Vivo, Immaculata; Govannucci, Edward; Hunter, David; Kraft, Peter; Lindstrom, Sara; Gapstur, Susan M.; Jacobs, Eric J.; Diver, W. Ryan; Albanes, Demetrius; Weinstein, Stephanie J.; Virtamo, Jarmo; Kooperberg, Charles; Hohensee, Chancellor; Rodabough, Rebecca J.; Cortessis, Victoria K.; Conti, David V.; Gago-Dominguez, Manuela; Stern, Mariana C.; Pike, Malcolm C.; Van Den Berg, David; Yuan, Jian-Min; Haiman, Christopher A.; Cussenot, Olivier; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Porru, Stefano; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Grossman, H. Barton; Wang, Zhaoming; Deng, Xiang; Chung, Charles C.; Hutchinson, Amy; Burdette, Laurie; Wheeler, William; Fraumeni, Joseph; Chanock, Stephen J.; Hewitt, Stephen M.; Silverman, Debra T.; Rothman, Nathaniel; Prokunina-Olsson, Ludmila

    2014-01-01

    A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell cycle protein. We performed genetic fine mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2≥0.7) associated with increased bladder cancer risk. From this group we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWAS, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele odds ratio (OR) =1.18 (95%CI=1.09-1.27, p=4.67×10−5 vs. OR =1.01 (95%CI=0.93-1.10, p=0.79) for non-aggressive disease, with p=0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (p=0.013) and, independently, with each rs7257330-A risk allele (ptrend=0.024). Over-expression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E over-expression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. PMID:25320178

  11. Validation of copy number variants associated with prostate cancer risk and prognosis.

    PubMed

    Blackburn, August; Wilson, Desiree; Gelfond, Jonathan; Yao, Li; Hernandez, Javier; Thompson, Ian M; Leach, Robin J; Lehman, Donna M

    2014-01-01

    Two recent studies have reported novel heritable copy number variants on chromosomes 2p, 15q, and 12q to be associated with prostate cancer (PCa) risk in non-Hispanic Caucasians. The goal of this study was to determine whether these findings could be independently confirmed in the Caucasian population from the South Texas area. The study subjects consisted of participants of the San Antonio Biomarkers of Risk for PCa cohort and additional cases ascertained in the same metropolitan area. We genotyped all 7 of the reported copy number variants using real-time quantitative polymerase chain reaction in 1,536 (317 cases and 1,219 controls) non-Hispanic Caucasian men, and additionally, we genotyped 632 (191 cases and 441 controls) Hispanic Caucasian men for one of these variants, a deletion on 2p24.3. Association of the deletion on 2p24.3 with overall PCa risk did not meet our significance criteria but was consistent with previous reports (odds ratio, 1.40; 95% confidence interval 0.99-2.00; P = 0.06). Among Hispanic Caucasians, this deletion is much less prevalent (minor allele frequencies of 0.059 and 0.024 in non-Hispanic and Hispanic Caucasians, respectively) and did not show evidence of association with risk for PCa. Interestingly, among non-Hispanic Caucasians, carrying a homozygous deletion of 2p24.3 was significantly associated with high-grade PCa as defined by Gleason score sum ≥8 (odds ratio, 27.99; 95% confidence interval 1.99-392.6; P = 0.007 [the Fisher exact test]). The remaining 6 copy number variable regions either were not polymorphic in our cohort of non-Hispanic Caucasians or showed no evidence of association. Our findings are consistent with the reported observation that a heritable deletion on 2p24.3 is associated with PCa risk in non-Hispanic Caucasians. Additionally, our observations indicate that the 2p24.3 variant is associated with risk for high-grade PCa in a recessive manner. We were unable to replicate any association with PCa for the

  12. 34 CFR 462.4 - What are the transition rules for using tests to measure educational gain for the National...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... measure educational gain for the National Reporting System for Adult Education (NRS)? 462.4 Section 462.4... ADULT EDUCATION, DEPARTMENT OF EDUCATION MEASURING EDUCATIONAL GAIN IN THE NATIONAL REPORTING SYSTEM FOR... gain for the National Reporting System for Adult Education (NRS)? A State or a local eligible provider...

  13. Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk.

    PubMed

    Guo, Xingyi; Long, Jirong; Zeng, Chenjie; Michailidou, Kyriaki; Ghoussaini, Maya; Bolla, Manjeet K; Wang, Qin; Milne, Roger L; Shu, Xiao-Ou; Cai, Qiuyin; Beesley, Jonathan; Kar, Siddhartha P; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Blot, William; Bogdanova, Natalia; Bojesen, Stig E; Brauch, Hiltrud; Brenner, Hermann; Brinton, Louise; Broeks, Annegien; Brüning, Thomas; Burwinkel, Barbara; Cai, Hui; Canisius, Sander; Chang-Claude, Jenny; Choi, Ji-Yeob; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Darabi, Hatef; Devilee, Peter; Droit, Arnaud; Dörk, Thilo; Fasching, Peter A; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gaborieau, Valerie; García-Closas, Montserrat; Giles, Graham G; Grip, Mervi; Guénel, Pascal; Haiman, Christopher A; Hamann, Ute; Hartman, Mikael; Hollestelle, Antoinette; Hopper, John L; Hsiung, Chia-Ni; Ito, Hidemi; Jakubowska, Anna; Johnson, Nichola; Kabisch, Maria; Kang, Daehee; Khan, Sofia; Knight, Julia A; Kosma, Veli-Matti; Lambrechts, Diether; Le Marchand, Loic; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; McLean, Catriona A; Meindl, Alfons; Muir, Kenneth; Neuhausen, Susan L; Nevanlinna, Heli; Nord, Silje; Olson, Janet E; Orr, Nick; Peterlongo, Paolo; Putti, Thomas Choudary; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Marjanka K; Schmutzler, Rita K; Shen, Chen-Yang; Shi, Jiajun; Shrubsole, Martha J; Southey, Melissa C; Swerdlow, Anthony; Teo, Soo Hwang; Thienpont, Bernard; Toland, Amanda Ewart; Tollenaar, Robert A E M; Tomlinson, Ian P M; Truong, Thérèse; Tseng, Chiu-Chen; van den Ouweland, Ans; Wen, Wanqing; Winqvist, Robert; Wu, Anna; Yip, Cheng Har; Zamora, M Pilar; Zheng, Ying; Hall, Per; Pharoah, Paul D P; Simard, Jacques; Chenevix-Trench, Georgia; Dunning, Alison M; Easton, Douglas F; Zheng, Wei

    2015-11-01

    A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 × 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. ©2015 American Association for Cancer Research.

  14. Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk

    PubMed Central

    Guo, Xingyi; Long, Jirong; Zeng, Chenjie; Michailidou, Kyriaki; Ghoussaini, Maya; Bolla, Manjeet K.; Wang, Qin; Milne, Roger L.; Shu, Xiao-Ou; Cai, Qiuyin; Beesley, Jonathan; Kar, Siddhartha P.; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Blot, William; Bogdanova, Natalia; Bojesen, Stig E.; Brauch, Hiltrud; Brenner, Hermann; Brinton, Louise; Broeks, Annegien; Brüning, Thomas; Burwinkel, Barbara; Cai, Hui; Canisius, Sander; Chang-Claude, Jenny; Choi, Ji-Yeob; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Devilee, Peter; Droit, Arnaud; Dörk, Thilo; Fasching, Peter A.; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gaborieau, Valerie; García-Closas, Montserrat; Giles, Graham G.; Grip, Mervi; Guénel, Pascal; Haiman, Christopher A.; Hamann, Ute; Hartman, Mikael; Hollestelle, Antoinette; Hopper, John L.; Hsiung, Chia-Ni; Ito, Hidemi; Jakubowska, Anna; Johnson, Nichola; Kabisch, Maria; Kang, Daehee; Khan, Sofia; Knight, Julia A.; Kosma, Veli-Matti; Lambrechts, Diether; Marchand, Loic Le; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; McLean, Catriona A.; Meindl, Alfons; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Nord, Silje; Olson, Janet E.; Orr, Nick; Peterlongo, Paolo; Putti, Thomas Choudary; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Shen, Chen-Yang; Shi, Jiajun; Shrubsole, Martha J; Southey, Melissa C.; Swerdlow, Anthony; Teo, Soo Hwang; Thienpont, Bernard; Toland, Amanda Ewart; Tollenaar, Robert A.E.M.; Tomlinson, Ian P.M.; Truong, Thérèse; Tseng, Chiu-chen; van den Ouweland, Ans; Wen, Wanqing; Winqvist, Robert; Wu, Anna; Yip, Cheng Har; Zamora, M. Pilar; Zheng, Ying; Hall, Per; Pharoah, Paul D.P.; Simard, Jacques; Chenevix-Trench, Georgia; Dunning, Alison M.; Easton, Douglas F.; Zheng, Wei

    2015-01-01

    Background A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 (conditional p = 2.51 × 10−4; OR = 1.04; 95% CI 1.02–1.07) and rs77928427 (p = 1.86 × 10−4; OR = 1.04; 95% CI 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. PMID:26354892

  15. Characterization of genome-wide association-identified variants for atrial fibrillation in African Americans.

    PubMed

    Delaney, Jessica T; Jeff, Janina M; Brown, Nancy J; Pretorius, Mias; Okafor, Henry E; Darbar, Dawood; Roden, Dan M; Crawford, Dana C

    2012-01-01

    Despite a greater burden of risk factors, atrial fibrillation (AF) is less common among African Americans than European-descent populations. Genome-wide association studies (GWAS) for AF in European-descent populations have identified three predominant genomic regions associated with increased risk (1q21, 4q25, and 16q22). The contribution of these loci to AF risk in African American is unknown. We studied 73 African Americans with AF from the Vanderbilt-Meharry AF registry and 71 African American controls, with no history of AF including after cardiac surgery. Tests of association were performed for 148 SNPs across the three regions associated with AF, and 22 SNPs were significantly associated with AF (P<0.05). The SNPs with the strongest associations in African Americans were both different from the index SNPs identified in European-descent populations and independent from the index European-descent population SNPs (r(2)<0.40 in HapMap CEU): 1q21 rs4845396 (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.13-0.67, P = 0.003), 4q25 rs4631108 (OR 3.43, 95% CI 1.59-7.42, P = 0.002), and 16q22 rs16971547 (OR 8.1, 95% CI 1.46-45.4, P = 0.016). Estimates of European ancestry were similar among cases (23.6%) and controls (23.8%). Accordingly, the probability of having two copies of the European derived chromosomes at each region did not differ between cases and controls. Variable European admixture at known AF loci does not explain decreased AF susceptibility in African Americans. These data support the role of 1q21, 4q25, and 16q22 variants in AF risk for African Americans, although the index SNPs differ from those identified in European-descent populations.

  16. TREM2 Variants in Alzheimer's Disease

    PubMed Central

    Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S.K.; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; Pocock, Jennifer; Lashley, Tammaryn; Williams, Julie; Lambert, Jean-Charles; Amouyel, Philippe; Goate, Alison; Rademakers, Rosa; Morgan, Kevin; Powell, John; St. George-Hyslop, Peter; Singleton, Andrew; Hardy, John

    2013-01-01

    BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.) PMID:23150934

  17. Colitis-associated variant of TLR2 causes impaired mucosal repair due to TFF3 deficiency

    PubMed Central

    Podolsky, Daniel K.; Gerken, Guido; Eyking, Annette; Cario, Elke

    2009-01-01

    Background & aims Goblet cells (GC) facilitate mucosal protection and epithelial barrier repair, yet the innate immune mechanisms that selectively drive GC functions have not been defined. The aim of this study was to determine whether TLR2 and modulation of GC-derived TFF3 are functionally linked in the intestine. Methods GC modulation was assessed using qRT-PCR, western blotting and confocal microscopy. DSS colitis was induced in wild-type, TFF3−/− and TLR2−/− mice. Recombinant TLR2 ligand or TFF3 peptide were orally administered after DSS termination. Caco-2 overexpressing full-length TLR2 or mutant TLR2-R753Q were tested for TFF3 synthesis and functional-related effects in a wounding-assay. Results Data from in-vitro (Ls174T) and ex-vivo models of murine and human GC reveal that TLR2 activation selectively induces synthesis of TFF3. In-vivo studies using TFF3−/− or TLR2−/− mice demonstrate the ability for oral treatment with a TLR2 agonist to confer anti-apoptotic protection of the intestinal mucosa against inflammatory stress-induced damage through TFF3. Recombinant TFF3 rescues TLR2-deficient mice from increased morbidity and mortality during acute colonic injury. Severe ulcerative colitis has recently been found to be associated with the R753Q polymorphism of the TLR2 gene. The relevance of the observed functional effect of TLR2 in regulating GC is confirmed by the finding that the UC-associated TLR2-R753Q variant is functionally deficient in the ability to induce TFF3 synthesis, thus leading to impaired wound healing. Conclusions These data demonstrate a novel function of TLR2 in intestinal GC that links products of commensal bacteria to innate immune protection of the host via TFF3. PMID:19303021

  18. Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency.

    PubMed

    Podolsky, Daniel K; Gerken, Guido; Eyking, Annette; Cario, Elke

    2009-07-01

    Goblet cells (GC) facilitate mucosal protection and epithelial barrier repair, yet the innate immune mechanisms that selectively drive GC functions have not been defined. The aim of this study was to determine whether Toll-like receptor (TLR) 2 and modulation of GC-derived trefoil factor (TFF) 3 are functionally linked in the intestine. GC modulation was assessed using quantitative real-time polymerase chain reaction analysis (qRT-PCR), Western blotting, and confocal microscopy. Dextran sulfate sodium (DSS) colitis was induced in wild-type, TFF3(-/-), and TLR2(-/-) mice. Recombinant TLR2 ligand or TFF3 peptide were orally administered after DSS termination. Caco-2 cells overexpressing full-length TLR2 or mutant TLR2-R753Q were tested for TFF3 synthesis and functional-related effects in a wounding assay. Data from in vitro (Ls174T) and ex vivo models of murine and human GC reveal that TLR2 activation selectively induces synthesis of TFF3. In vivo studies using TFF3(-/-) or TLR2(-/-) mice demonstrate the ability for oral treatment with a TLR2 agonist to confer antiapoptotic protection of the intestinal mucosa against inflammatory stress-induced damage through TFF3. Recombinant TFF3 rescues TLR2-deficient mice from increased morbidity and mortality during acute colonic injury. Severe ulcerative colitis (UC) has recently been found to be associated with the R753Q polymorphism of the TLR2 gene. The relevance of the observed functional effect of TLR2 in regulating GC is confirmed by the finding that the UC-associated TLR2-R753Q variant is functionally deficient in the ability to induce TFF3 synthesis, thus leading to impaired wound healing. These data demonstrate a novel function of TLR2 in intestinal GC that links products of commensal bacteria to innate immune protection of the host via TFF3.

  19. Biological Effects of COMT Haplotypes and Psychosis Risk in 22q11.2 Deletion Syndrome

    PubMed Central

    Gothelf, Doron; Law, Amanda J.; Frisch, Amos; Chen, Jingshan; Zarchi, Omer; Michaelovsky, Elena; Ren-Patterson, Renee; Lipska, Barbara K.; Carmel, Miri; Kolachana, Bhaskar; Weizman, Abraham; Weinberger, Daniel R.

    2013-01-01

    Background 22q11.2 deletion syndrome (22q11.2DS) is the most common genetic syndrome associated with schizophrenia. The catechol-o-methyltransferase (COMT) gene is located in the obligatory deletion region, and possible associations between COMT variants and neuropsychiatric manifestations in 22q11.2DS have been reported. The purpose of the current study was to evaluate the effect of COMT hemizygosity and molecular haplotypes on gene expression and enzyme activity and its association with psychotic symptoms in 22q11.2DS. Methods Lymphoblast samples were drawn from 53 individuals with 22q11.2DS and 16 typically developing controls. We measured COMT mRNA and protein expression and enzyme activity using standard procedures. The presence of a psychotic disorder and cognitive deficits were also evaluated using structured testing. Results There was a ~50% reduction in COMT mRNA, protein and enzyme activity levels in 22q11.2DS samples. Haplotype analysis revealed clear phenotypic differences between various Val-containing haplotypes on COMT-3′UTR extended mRNA, S-COMT and MB proteins and enzyme activity. The G variant of rs165599, a 3′UTR SNP, was associated with low levels of COMT expression and with the presence of psychosis and lower performance IQ scores in our 22q11.2DS sample. Finally, we demonstrate that the COMT rs74745580 ‘T’ mutation is associated with absent S-COMT expression and very low COMT activity in two 22q11.2DS individuals. Conclusions Our findings confirm a robust effect of COMT hemizygosity on COMT activity and show complex interactions of variants within the COMT gene that influence COMT biology and confound conclusions based on associations with the Val158Met genotype alone. PMID:23992923

  20. Identification of the Q969R gain-of-function polymorphism in the gene encoding porcine NLRP3 and its distribution in pigs of Asian and European origin.

    PubMed

    Tohno, Masanori; Shinkai, Hiroki; Toki, Daisuke; Okumura, Naohiko; Tajima, Kiyoshi; Uenishi, Hirohide

    2016-10-01

    The nucleotide-binding domain, leucine-rich-containing family, pyrin-domain containing-3 (NLRP3) inflammasome comprises the major components caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and NLRP3. NLRP3 plays important roles in maintaining immune homeostasis mediated by intestinal microorganisms and in the immunostimulatory properties of vaccine adjuvants used to induce an immune response. In the present study, we first cloned a complementary DNA (cDNA) encoding porcine ASC because its genomic sequence was not completely determined. The availability of the ASC cDNA enabled us to reconstitute porcine NLRP3 inflammasomes using an in vitro system that led to the identification of the immune functions of porcine NLRP3 and ASC based on the production of interleukin-1β (IL-1β). Further, we identified six synonymous and six nonsynonymous single-nucleotide polymorphisms (SNPs) in the coding sequence of NLRP3 of six breeds of pigs, including major commercial breeds. Among the nonsynonymous SNPs, the Q969R polymorphism is associated with an increased release of IL-1β compared with other porcine NLRP3 variants, indicating that this polymorphism represents a gain-of-function mutation. This allele was detected in 100 % of the analyzed Chinese Jinhua and Japanese wild boars, suggesting that the allele is maintained in the major commercial native European breeds Landrace, Large White, and Berkshire. These findings represent an important contribution to our knowledge of the diversity of NLRP3 nucleotide sequences among various pig populations. Moreover, efforts to exploit the gain of function induced by the Q969R polymorphism promise to improve pig breeding and husbandry by conferring enhanced resistance to pathogens as well as contributing to vaccine efficacy.

  1. The Q223R polymorphism in the leptin receptor associates with objectively measured light physical activity in free-living Japanese.

    PubMed

    Murakami, Haruka; Iemitsu, Motoyuki; Fuku, Noriyuki; Sanada, Kiyoshi; Gando, Yuko; Kawakami, Ryoko; Miyachi, Motohiko

    2014-04-22

    Physical activity (PA) is associated with reductions in the risk of all-cause mortality and in the prevalence of cardiovascular disease and stroke. Nevertheless, a large proportion of the general population may not be sufficiently active. PA level has been reported to be influenced by genetic factors, and we investigated whether Q223R polymorphism in the leptin receptor (LEPR) gene was associated with PA level. A total of 556 Japanese adults aged 24-65years old participated in this cross-sectional study. The duration and intensity of PA were objectively evaluated by triaxial accelerometry. Q223R polymorphism was determined by the TaqMan method. The distribution of Q223R polymorphism was: QQ 0.7%, QR 22.6%, and RR 76.6%. The relation between the LEPR genotype and PA level was analyzed by ANCOVA with age and sex as covariates in the Q dominant genetic model. There were significant differences between LEPR genotypes and the time spent in light PA or inactive time. The subjects with RR genotype showed significantly shorter time spent in light PA (RR genotype: 559.4±102.9min/day, QQ/QR genotype: 579.9±103.1min/day) and longer inactive time (RR genotype: 815.5±107.5min/day, QQ/QR genotype: 792.3±107.7min/day) than the subjects with QQ/QR genotype (P<0.05). There were no such differences in the time spent in moderate or vigorous PA. These results suggest that the variety of PA level, especially spontaneous PA in humans, is partly caused by diversity in the LEPR gene. Copyright © 2014. Published by Elsevier Inc.

  2. Genetic variants associated with susceptibility to psychosis in late-onset Alzheimer's disease families.

    PubMed

    Barral, Sandra; Vardarajan, Badri N; Reyes-Dumeyer, Dolly; Faber, Kelley M; Bird, Thomas D; Tsuang, Debby; Bennett, David A; Rosenberg, Roger; Boeve, Bradley F; Graff-Radford, Neill R; Goate, Alison M; Farlow, Martin; Lantigua, Rafael; Medrano, Martin Z; Wang, Xinbing; Kamboh, M Ilyas; Barmada, Mahmud Muhiedine; Schaid, Daniel J; Foroud, Tatiana M; Weamer, Elise A; Ottman, Ruth; Sweet, Robert A; Mayeux, Richard

    2015-11-01

    Psychotic symptoms are frequent in late-onset Alzheimer's disease (LOAD) patients. Although the risk for psychosis in LOAD is genetically mediated, no genes have been identified. To identify loci potentially containing genetic variants associated with risk of psychosis in LOAD, a total of 263 families from the National Institute of Aging-LOAD cohort were classified into psychotic (LOAD+P, n = 215) and nonpsychotic (LOAD-P, n = 48) families based on the presence/absence of psychosis during the course of LOAD. The LOAD+P families yielded strong evidence of linkage on chromosome 19q13 (two-point [2-pt] ​logarithm of odds [LOD] = 3.8, rs2285513 and multipoint LOD = 2.7, rs541169). Joint linkage and association in 19q13 region detected strong association with rs2945988 (p = 8.7 × 10(-7)). Linkage results for the LOAD-P families yielded nonsignificant 19q13 LOD scores. Several 19q13 single-nucleotide polymorphisms generalized the association of LOAD+P in a Caribbean Hispanic (CH) cohort, and the strongest signal was rs10410711 (pmeta = 5.1 × 10(-5)). A variant located 24 kb upstream of rs10410711 and rs10421862 was strongly associated with LOAD+P (pmeta = 1.0 × 10(-5)) in a meta-analysis of the CH cohort and an additional non-Hispanic Caucasian dataset. Identified variants rs2945988 and rs10421862 affect brain gene expression levels. Our results suggest that genetic variants in genes on 19q13, some of which are involved in brain development and neurodegeneration, may influence the susceptibility to psychosis in LOAD patients. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  3. A 725 kb deletion at 22q13.1 chromosomal region including SOX10 gene in a boy with a neurologic variant of Waardenburg syndrome type 2.

    PubMed

    Siomou, Elisavet; Manolakos, Emmanouil; Petersen, Michael; Thomaidis, Loretta; Gyftodimou, Yolanda; Orru, Sandro; Papoulidis, Ioannis

    2012-11-01

    Waardenburg syndrome (WS) is a rare (1/40,000) autosomal dominant disorder resulting from melanocyte defects, with varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four clinical subtypes (WS1-S4). Six genes have been identified to be associated with the different subtypes of WS, among which SOX10, which is localized within the region 22q13.1. Lately it has been suggested that whole SOX10 gene deletions can be encountered when testing for WS. In this study we report a case of a 13-year-old boy with a unique de novo 725 kb deletion within the 22q13.1 chromosomal region, including the SOX10 gene and presenting clinical features of a neurologic variant of WS2. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  4. Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9.

    PubMed

    Danhauser, Katharina; Herebian, Diran; Haack, Tobias B; Rodenburg, Richard J; Strom, Tim M; Meitinger, Thomas; Klee, Dirk; Mayatepek, Ertan; Prokisch, Holger; Distelmaier, Felix

    2016-03-01

    Coenzyme Q10 (CoQ10) has an important role in mitochondrial energy metabolism by way of its functioning as an electron carrier in the respiratory chain. Genetic defects disrupting the endogenous biosynthesis pathway of CoQ10 may lead to severe metabolic disorders with onset in early childhood. Using exome sequencing in a child with fatal neonatal lactic acidosis and encephalopathy, we identified a homozygous loss-of-function variant in COQ9. Functional studies in patient fibroblasts showed that the absence of the COQ9 protein was concomitant with a strong reduction of COQ7, leading to a significant accumulation of the substrate of COQ7, 6-demethoxy ubiquinone10. At the same time, the total amount of CoQ10 was severely reduced, which was reflected in a significant decrease of mitochondrial respiratory chain succinate-cytochrome c oxidoreductase (complex II/III) activity. Lentiviral expression of COQ9 restored all these parameters, confirming the causal role of the variant. Our report on the second COQ9 patient expands the clinical spectrum associated with COQ9 variants, indicating the importance of COQ9 already during prenatal development. Moreover, the rescue of cellular CoQ10 levels and respiratory chain complex activities by CoQ10 supplementation points to the importance of an early diagnosis and immediate treatment.

  5. Paraoxonase 1 (PON1) gene-108C>T and p.Q192R polymorphisms and arylesterase activity of the enzyme in patients with dementia.

    PubMed

    Bednarska-Makaruk, Małgorzata Ewa; Krzywkowski, Tomasz; Graban, Alla; Lipczyńska-Łojkowska, Wanda; Bochyńska, Anna; Rodo, Maria; Wehr, Hanna; Ryglewicz, Danuta Krystyna

    2013-01-01

    Paraoxonase 1 (PON1) activity was determined using phenylacetate as substrate (arylesterase activity) in 304 individuals with dementia--136 recognised as probable Alzheimer's disease (AD), 64 as dementia of vascular origin (VaD) and 104 as mixed dementia (MD) and in 129 persons without symptoms of dementia and in a good general health. -108C>T polymorphism in the PON1 gene promoter and p.Q192R polymorphism in the coding region were identified. PON1 activity was significantly lower in demented patients as compared with controls particularly in dementia of a neurodegenerative character (AD and MD). The prevalence of PON1-108T allele carriers was significantly higher in the AD group than in controls. The frequencies of the p.Q192R genotypes did not differ significantly between the investigated groups. An association of the rare T-R haplotype with dementia, particularly with dementia of the neurodegenerative type, was found. Multivariate regression analysis showed a significant association of PON1 activity with PON1 -108C>T and p.Q192R polymorphisms. The influence not only of promoter -108C>T, but also of p.Q192R polymorphism on PON1 arylesterase activity was observed. One has to admit that this kind of polymorphism does not preclude interference with the enzyme activity. It could be concluded that the PON1 gene promoter polymorphism plays an additional role in Alzheimer's disease development. It seems however that PON1 activity has a dominating influence on the dementia risk.

  6. Gender-stratified analysis of DLG5 R30Q in 4707 patients with Crohn disease and 4973 controls from 12 Caucasian cohorts.

    PubMed

    Browning, B L; Annese, V; Barclay, M L; Bingham, S A; Brand, S; Büning, C; Castro, M; Cucchiara, S; Dallapiccola, B; Drummond, H; Ferguson, L R; Ferraris, A; Fisher, S A; Gearry, R B; Glas, J; Henckaerts, L; Huebner, C; Knafelz, D; Lakatos, L; Lakatos, P L; Latiano, A; Liu, X; Mathew, C; Müller-Myhsok, B; Newman, W G; Nimmo, E R; Noble, C L; Palmieri, O; Parkes, M; Petermann, I; Rutgeerts, P; Satsangi, J; Shelling, A N; Siminovitch, K A; Török, H-P; Tremelling, M; Vermeire, S; Valvano, M R; Witt, H

    2008-01-01

    DLG5 p.R30Q has been reported to be associated with Crohn disease (CD), but this association has not been replicated in most studies. A recent analysis of gender-stratified data from two case-control studies and two population cohorts found an association of DLG5 30Q with increased risk of CD in men but not in women and found differences between 30Q population frequencies for males and females. Male-female differences in population allele frequencies and male-specific risk could explain the difficulty in replicating the association with CD. DLG5 R30Q genotype data were collected for patients with CD and controls from 11 studies that did not include gender-stratified allele counts in their published reports and tested for male-female frequency differences in controls and for case-control frequency differences in men and in women. The data showed no male-female allele frequency differences in controls. An exact conditional test gave marginal evidence that 30Q is associated with decreased risk of CD in women (p = 0.049, OR = 0.87, 95% CI 0.77 to 1.00). There was also a trend towards reduced 30Q frequencies in male patients with CD compared with male controls, but this was not significant at the 0.05 level (p = 0.058, OR = 0.87, 95% CI 0.74 to 1.01). When data from this study were combined with previously published, gender-stratified data, the 30Q allele was found to be associated with decreased risk of CD in women (p = 0.010, OR = 0.86, 95% CI 0.76 to 0.97), but not in men. DLG5 30Q is associated with a small reduction in risk of CD in women.

  7. Frontotemporal dementia with Pick-type histology associated with Q336R mutation in the tau gene.

    PubMed

    Pickering-Brown, S M; Baker, M; Nonaka, T; Ikeda, K; Sharma, S; Mackenzie, J; Simpson, S A; Moore, J W; Snowden, J S; de Silva, R; Revesz, T; Hasegawa, M; Hutton, M; Mann, D M A

    2004-06-01

    In this report, we describe the clinical and neuropathological features of a case of familial frontotemporal dementia (FTD), with onset at 58 years of age and disease duration of 10 years, associated with a novel mutation, Q336R, in the tau gene (tau). In vitro studies concerning the properties of tau proteins bearing this mutation, with respect to microtubule assembly and tau filament aggregation, are reported. Clinically, the patient showed alterations in memory, language and executive functions and marked behavioural change consistent with FTD, although the extent of memory impairment was more than is characteristic of FTD. At autopsy, there was degeneration of the frontal and temporal lobes associated with the presence of hyperphosphorylated tau proteins in swollen (Pick) cells and intraneuronal inclusions (Pick bodies). By immunohistochemistry, the Pick bodies contained both 3-repeat and 4-repeat tau proteins although, because no fresh tissues were available for analysis, the exact isoform composition of the aggregated tau proteins could not be determined. Neurons within frontal cortex contained neurofibrillary tangle-like structures, comprising both straight and twisted tubules, or Pick bodies in which the filaments were short and randomly orientated. In vitro, and in common with other tau missense mutations, Q336R caused an increase in tau fibrillogenesis. However, in contrast to most other tau missense mutations, Q336R increased, not decreased, the ability of mutant tau to promote microtubule assembly. Nonetheless, this latter functional change may likewise be detrimental to neuronal function by inducing a compensatory phosphorylation that may yield increased intracellular hyperphosphorylated tau species that are also liable to fibrillize. We believe the mutation is indeed pathogenic and disease causing and not simply a coincidental rare and benign polymorphism. Since this mutation is segregating with the FTD clinical and neuropathological phenotype, it has

  8. Microgranular variant of acute promyelocytic leukemia with der(17) ins(17;15): A case report and review of the literature

    PubMed Central

    GUAN, HONGZAI; LIU, JING; GUO, XIAOFANG; WU, CHUNMEI; YU, HUAWEI

    2015-01-01

    Acute promyelocytic leukemia (APL) with variant translocations is rare. The patient of the present case report, a 2-year-old male with a microgranular variant of APL carrying der(17) ins(17;15) translocation, exhibited fever and epistaxis. The complete blood count showed marked leukocytosis with 72% atypical promyelocytes, anemia and thrombocytopenia. Conventional cytogenetic analysis of the bone marrow cells revealed a karyotype of 47, XY, add(3)(q29), −7, ins(17;15)(q12;q14q22),+21,+mar. The promyelocytic leukemia/retinoic acid receptor α (PML/RARα) rearrangement and insertion were confirmed by fluorescence in situ hybridization. The PML/RARα transcripts were not detected by the reverse transcription polymerase chain reaction, and the patient was diagnosed with microgranular variant M3 APL. The patient achieved remission after a 30-day treatment and was still in remission during a recent follow-up. The present findings suggest that the ins(17;15) variant in APL may not be associated with an unfavorable prognosis. In summary, we reported an extremely rare case of APL with der(17) ins(17;15) abnormality in a pediatric patient and reviewed the literature. PMID:26622430

  9. P/Q-type calcium channel modulators

    PubMed Central

    Nimmrich, V; Gross, G

    2012-01-01

    P/Q-type calcium channels are high-voltage-gated calcium channels contributing to vesicle release at synaptic terminals. A number of neurological diseases have been attributed to malfunctioning of P/Q channels, including ataxia, migraine and Alzheimer's disease. To date, only two specific P/Q-type blockers are known: both are peptides deriving from the spider venom of Agelenopsis aperta, ω-agatoxins. Other peptidic calcium channel blockers with activity at P/Q channels are available, albeit with less selectivity. A number of low molecular weight compounds modulate P/Q-type currents with different characteristics, and some exhibit a peculiar bidirectional pattern of modulation. Interestingly, there are a number of therapeutics in clinical use, which also show P/Q channel activity. Because selectivity as well as the exact mode of action is different between all P/Q-type channel modulators, the interpretation of clinical and experimental data is complicated and needs a comprehensive understanding of their target profile. The situation is further complicated by the fact that information on potency varies vastly in the literature, which may be the result of different experimental systems, conditions or the splice variants of the P/Q channel. This review attempts to provide a comprehensive overview of the compounds available that affect the P/Q-type channel and should help with the interpretation of results of in vitro experiments and animal models. It also aims to explain some clinical observations by implementing current knowledge about P/Q channel modulation of therapeutically used non-selective drugs. Chances and challenges of the development of P/Q channel-selective molecules are discussed. PMID:22670568

  10. A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis.

    PubMed

    Panganiban, Ronald A; Sun, Maoyun; Dahlin, Amber; Park, Hae-Ryung; Kan, Mengyuan; Himes, Blanca E; Mitchel, Jennifer A; Iribarren, Carlos; Jorgenson, Eric; Randell, Scott H; Israel, Elliot; Tantisira, Kelan; Shore, Stephanie; Park, Jin-Ah; Weiss, Scott T; Wu, Ann Chen; Lu, Quan

    2018-01-09

    Genetic variants in the chromosomal region 17q21 are consistently associated with asthma. However, mechanistic studies have not yet linked any of the associated variants to a function that could influence asthma, and as a result, the identity of the asthma gene(s) remains elusive. We sought to identify and characterize functional variants in the 17q21 locus. We used the Exome Aggregation Consortium browser to identify coding (amino acid-changing) variants in the 17q21 locus. We obtained asthma association measures for these variants in both the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (16,274 cases and 38,269 matched controls) and the EVE Consortium study (5,303 asthma cases and 12,560 individuals). Gene expression and protein localization were determined by quantitative RT-PCR and fluorescence immunostaining, respectively. Molecular and cellular studies were performed to determine the functional effects of coding variants. Two coding variants (rs2305480 and rs11078928) of the gasdermin B (GSDMB) gene in the 17q21 locus were associated with lower asthma risk in both GERA (odds ratio, 0.92; P = 1.01 × 10 -6 ) and EVE (odds ratio, 0.85; joint P EVE  = 1.31 × 10 -13 ). In GERA, rs11078928 had a minor allele frequency (MAF) of 0.45 in unaffected (nonasthmatic) controls and 0.43 in asthma cases. For European Americans in EVE, the MAF of rs2305480 was 0.45 for controls and 0.39 for cases; for all EVE subjects, the MAF was 0.32 for controls and 0.27 for cases. GSDMB is highly expressed in differentiated airway epithelial cells, including the ciliated cells. We found that, when the GSDMB protein is cleaved by inflammatory caspase-1 to release its N-terminal fragment, potent pyroptotic cell death is induced. The splice variant rs11078928 deletes the entire exon 6, which encodes 13 amino acids in the critical N-terminus, and abolishes the pyroptotic activity of the GSDMB protein. Our study identified a functional asthma variant in the

  11. New genetic variants of influenza A(H1N1)pdm09 detected in Cuba during 2011-2013.

    PubMed

    Arencibia, Amely; Acosta, Belsy; Muné, Mayra; Valdés, Odalys; Fernandez, Leandro; Medina, Isel; Savón, Clara; Oropesa, Suset; Gonzalez, Grehete; Roque, Rosmery; Gonzalez, Guelsys; Hernández, Bárbara; Goyenechea, Angel; Piñón, Alexander

    2015-06-01

    Influenza A(H1N1)pdm09 virus has evolved continually since its emergence in 2009. For influenza virus strains, genetic changes occurring in HA1 domain of the hemagglutinin cause the emergence of new variants. The aim of our study is to establish genetic associations between 35 A(H1N1)pdm09 viruses circulating in Cuba in 2011-2012 and 2012-2013 seasons, and A/California/07/2009 strain recommended by WHO as the H1N1 component of the influenza vaccine. The phylogenetic analysis revealed the circulation of clades 3, 6A, 6B, 6C and 7. Mutations were detected in the antigenic site or in the receptor-binding domains of HA1 segment, including S174P, S179N, K180Q, S202T, S220T and R222K. Substitutions S174P, S179N, K180Q and R222K were detected in Cuban strains for the first time. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. High-resolution analysis of copy number variants in adults with simple-to-moderate congenital heart disease.

    PubMed

    Zhao, Wei; Niu, Guannan; Shen, Botao; Zheng, Yang; Gong, Fangchao; Wang, Xianfu; Lee, Jiyun; Mulvihill, John J; Chen, Xiaohui; Li, Shibo

    2013-12-01

    As patients with congenital heart disease (CHD) increasingly survive to childbearing age, it becomes important to understand the genetic origins of CHD. In children, CHD is frequently caused by chromosomal imbalances. We searched for submicroscopic imbalances in adults with CHD focusing on simple-to-moderate phenotypes, without associated dysmorphic features, a group not previously examined. A total of 100 Han Chinese adults with a diverse range of isolated CHD and 65 ethnically matched controls were screened using whole-genome array comparative genomic hybridization. Forty-five large (>100 kb) rare copy number variants (CNVs) were identified in 36/100 patients. These variants were not listed in the Database of Genomic Variants nor found in controls. In three of these genomic imbalances (22q11.2, 18q23, 3q21.3), genes that play an important role in cardiac development were implicated, including CRKL, NFATC1, PLXNA1, the latter has not been associated with human CHD before. This study detected a 0.7 Mb 22q11.2 deletion, which marginally overlapped the common 3 Mb 22q11.2 deletion, in one patient with a perimembranous ventricular septal defect without any extracardiac manifestation. Furthermore, we detected a novel inherited aberration dup (16q23.1). Although a causal relationship with CHD remains to be established, this CNVs profile provides a spectrum of genomic imbalances in this condition, and improves the CNV-phenotype correlations. © 2013 Wiley Periodicals, Inc.

  13. A mouse model for a partially inactive obesity-associated human MC3R variant

    PubMed Central

    Lee, Bonggi; Koo, Jashin; Yun Jun, Joo; Gavrilova, Oksana; Lee, Yongjun; Seo, Arnold Y.; Taylor-Douglas, Dezmond C.; Adler-Wailes, Diane C.; Chen, Faye; Gardner, Ryan; Koutzoumis, Dimitri; Sherafat Kazemzadeh, Roya; Roberson, Robin B.; Yanovski, Jack A.

    2016-01-01

    We previously reported children homozygous for two MC3R sequence variants (C17A+G241A) have greater fat mass than controls. Here we show, using homozygous knock-in mouse models in which we replace murine Mc3r with wild-type human (MC3RhWT/hWT) and double-mutant (C17A+G241A) human (MC3RhDM/hDM) MC3R, that MC3RhDM/hDM have greater weight and fat mass, increased energy intake and feeding efficiency, but reduced length and fat-free mass compared with MC3RhWT/hWT. MC3RhDM/hDM mice do not have increased adipose tissue inflammatory cell infiltration or greater expression of inflammatory markers despite their greater fat mass. Serum adiponectin levels are increased in MC3RhDM/hDM mice and MC3RhDM/hDM human subjects. MC3RhDM/hDM bone- and adipose tissue-derived mesenchymal stem cells (MSCs) differentiate into adipocytes that accumulate more triglyceride than MC3RhWT/hWT MSCs. MC3RhDM/hDM impacts nutrient partitioning to generate increased adipose tissue that appears metabolically healthy. These data confirm the importance of MC3R signalling in human metabolism and suggest a previously-unrecognized role for the MC3R in adipose tissue development. PMID:26818770

  14. Novel association of the R230C variant of the ABCA1 gene with high triglyceride levels and low high-density lipoprotein cholesterol levels in Mexican school-age children with high prevalence of obesity.

    PubMed

    Gamboa-Meléndez, Marco Alberto; Galindo-Gómez, Carlos; Juárez-Martínez, Liliana; Gómez, F Enrique; Diaz-Diaz, Eulises; Ávila-Arcos, Marco Antonio; Ávila-Curiel, Abelardo

    2015-08-01

    Metabolic syndrome (MetS) is a disorder that includes a cluster of several risk factors for the development of type 2 diabetes and cardiovascular disease. The R230C variant of the ABCA1 gene has been associated with low HDL-cholesterol in several studies, but its association with MetS in children remains to be determined. The aim of this study was to analyze the association of the R230C variant with MetS and other metabolic traits in school-aged Mexican children. The study was performed in seven urban primary schools in the State of Mexico. Four hundred thirty-two Mexican school-age children 6-13 years old were recruited. MetS was identified using the International Diabetes Federation definition. The R230C variant of the ABCA1 gene was genotyped to seek associations with MetS and other metabolic traits. The prevalence of MetS was 29% in children aged 10-13 years. The R230C variant was not associated with MetS (OR = 1.65; p = 0.139). Furthermore, in the whole population, the R230C variant was associated with low HDL-cholesterol levels (β coefficient = -3.28, p <0.001). Interestingly, in the total population we found a novel association of this variant with high triglyceride levels (β coefficient = 14.34; p = 0.027). We found a new association of the R230C variant of the ABCA1 gene with high triglyceride levels. Our findings also replicate the association of this variant with low HDL-cholesterol levels in Mexican school-age children. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

  15. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

    PubMed Central

    Adoue, Véronique; Michailidou, Kyriaki; Canisius, Sander; Lemaçon, Audrey; Droit, Arnaud; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Chang-Claude, Jenny; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dos-Santos-Silva, Isabel; Eriksson, Mikael; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Goldberg, Mark S.; González-Neira, Anna; Grenaker-Alnæs, Grethe; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A.; Hamann, Ute; Hallberg, Emily; Hooning, Maartje J.; Hopper, John L.; Jakubowska, Anna; Jones, Michael; Kabisch, Maria; Kataja, Vesa; Lambrechts, Diether; Marchand, Loic Le; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Maranian, Mel; Margolin, Sara; Marme, Frederik; Milne, Roger L.; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Olswold, Curtis; Peto, Julian; Plaseska-Karanfilska, Dijana; Pylkäs, Katri; Radice, Paolo; Rudolph, Anja; Sawyer, Elinor J.; Schmidt, Marjanka K.; Shu, Xiao-Ou; Southey, Melissa C.; Swerdlow, Anthony; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Vachon, Celine; Van Den Ouweland, Ans M. W.; Wang, Qin; Winqvist, Robert; Investigators, kConFab/AOCS; Zheng, Wei; Benitez, Javier; Chenevix-Trench, Georgia; Dunning, Alison M.; Pharoah, Paul D. P.; Kristensen, Vessela; Hall, Per; Easton, Douglas F.; Pastinen, Tomi; Nord, Silje; Simard, Jacques

    2016-01-01

    There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas. PMID:27792995

  16. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

    PubMed

    Hamdi, Yosr; Soucy, Penny; Adoue, Véronique; Michailidou, Kyriaki; Canisius, Sander; Lemaçon, Audrey; Droit, Arnaud; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brand, Judith S; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Chang-Claude, Jenny; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dos-Santos-Silva, Isabel; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G; Goldberg, Mark S; González-Neira, Anna; Grenaker-Alnæs, Grethe; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A; Hamann, Ute; Hallberg, Emily; Hooning, Maartje J; Hopper, John L; Jakubowska, Anna; Jones, Michael; Kabisch, Maria; Kataja, Vesa; Lambrechts, Diether; Le Marchand, Loic; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Maranian, Mel; Margolin, Sara; Marme, Frederik; Milne, Roger L; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Olswold, Curtis; Peto, Julian; Plaseska-Karanfilska, Dijana; Pylkäs, Katri; Radice, Paolo; Rudolph, Anja; Sawyer, Elinor J; Schmidt, Marjanka K; Shu, Xiao-Ou; Southey, Melissa C; Swerdlow, Anthony; Tollenaar, Rob A E M; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Vachon, Celine; Van Den Ouweland, Ans M W; Wang, Qin; Winqvist, Robert; Zheng, Wei; Benitez, Javier; Chenevix-Trench, Georgia; Dunning, Alison M; Pharoah, Paul D P; Kristensen, Vessela; Hall, Per; Easton, Douglas F; Pastinen, Tomi; Nord, Silje; Simard, Jacques

    2016-12-06

    There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.

  17. Structure-Function Analysis of Friedreich's Ataxia Mutants Reveals Determinants of Frataxin Binding and Activation of the Fe-S Assembly Complex

    SciTech Connect

    Bridwell-Rabb, Jennifer; Winn, Andrew M; Barondeau, David P

    2012-08-01

    Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease associated with the loss of function of the protein frataxin (FXN) that results from low FXN levels due to a GAA triplet repeat expansion or, occasionally, from missense mutations in the FXN gene. Here biochemical and structural properties of FXN variants, including three FRDA missense mutations (N146K, Q148R, and R165C) and three related mutants (N146A, Q148G, and Q153A), were determined in an effort to understand the structural basis for the loss of function. In vitro assays revealed that although the three FRDA missense mutations exhibited similar losses of cysteine desulfurase and Fe-Smore » cluster assembly activities, the causes for these activation defects were distinct. The R165C variant exhibited a k cat/K M higher than that of native FXN but weak binding to the NFS1, ISD11, and ISCU2 (SDU) complex, whereas the Q148R variant exhibited the lowest k cat/K M of the six tested FXN variants and only a modest binding deficiency. The order of the FXN binding affinities for the SDU Fe-S assembly complex was as follows: FXN > Q148R > N146A > Q148G > N146K > Q153A > R165C. Four different classes of FXN variants were identified on the basis of their biochemical properties. Together, these structure-function studies reveal determinants for the binding and allosteric activation of the Fe-S assembly complex and provide insight into how FRDA missense mutations are functionally compromised.« less

  18. CORRELATIONS IN HORIZONTAL BRANCH OSCILLATIONS AND BREAK COMPONENTS IN XTE J1701-462 AND GX 17+2

    SciTech Connect

    Bu, Qing-cui; Chen, Li; Zhang, Liang

    2015-01-20

    We studied the horizontal branch oscillations (HBO) and the band-limited components observed in the power spectra of the transient neutron star low-mass X-ray binary XTE J1701-462 and the persistent ''Sco-like'' Z source GX 17+2. These two components were studied based on the state-resolved spectra. We found that the frequencies of XTE J1701-462 lie on the known correlations (WK and PBK), showing consistency with other types of X-ray binaries (black holes, atoll sources, and millisecond X-ray pulsars). However, GX 17+2 is shifted from the WK correlation like other typical Z sources. We suggest that the WK/PBK main track forms a boundarymore » that separates persistent sources from transient sources. The characteristic frequencies of break and HBO are independent of accretion rate in both sources, though it depends on spectral models. We also report the energy dependence of the HBO and break frequencies in XTE J1701-462 and how the temporal properties change with spectral state in XTE J1701-462 and GX 17+2. We studied the correlation between rms at the break and the HBO frequency. We suggest that HBO and break components for both sources probably arise from a similar physical mechanism: Comptonization emission from the corona. These two components could be caused by the same kind of oscillation in a corona with uneven density, and they could be generated from different areas of the corona. We further suggest that different proportions of the Comptonization component in the total flux cause the different distribution between GX 17+2 and XTE J1701-462 in the rms{sub break}-rms{sub HBO} diagram.« less

  19. The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions.

    PubMed

    Carrion, Maria Dolores Perez; Marsicano, Silvia; Daniele, Federica; Marte, Antonella; Pischedda, Francesca; Di Cairano, Eliana; Piovesana, Ester; von Zweydorf, Felix; Kremmer, Elisabeth; Gloeckner, Christian Johannes; Onofri, Franco; Perego, Carla; Piccoli, Giovanni

    2017-07-14

    Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson's disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics. Biochemical analysis demonstrated that different proteins are bound at the two extremities, namely β3-Cav2.1 at N-terminus part and β-Actin and Synapsin I at C-terminus domain. A sequence variant (G2385R) harboured within the C-terminal WD40 domain increases the risk for PD. Complementary biochemical and imaging approaches revealed that the G2385R variant alters strength and quality of LRRK2 interactions and increases fusion of synaptic vesicles. Our data suggest that the G2385R variant behaves like a loss-of-function mutation that mimics activity-driven events. Impaired scaffolding capabilities of mutant LRRK2 resulting in perturbed vesicular trafficking may arise as a common pathophysiological denominator through which different LRRK2 pathological mutations cause disease.

  20. R516Q mutation in Melanoma differentiation-associated protein 5 (MDA5) and its pathogenic role towards rare Singleton-Merten syndrome; a signature associated molecular dynamics study.

    PubMed

    Raghuraman, P; Sudandiradoss, C

    2018-02-20

    Singleton-Merten syndrome, a critical and rare multifactorial disorder that is closely linked to R516Q mutation in MDA5 protein associated with an enhanced interferon response in the affected individual. In the present study, we provide conclusive key evidence on R516Q mutation and their connectivity towards sequence-structural basis dysfunction of MDA5 protein. Among the various mutations, we found R516Q is the most pathogenic mutation based on mutational signature Q-A-[RE]-G-R-[GA]-R-A-[ED]-[DE]-S-[ST]-Y-[TSAV]-L-V designed from our work. Further, we derived a distant ortholog for this mutational signature from which we identified 343 intra-residue interactions that fall communally in the position required to maintain the structural and functional integration of protein architecture. This identification served us to understand the critical role of hot spots in residual aggregation that holds a native form of folding conformation in the functional region. In addition, the long-range molecular dynamics simulation demarcated the residual dependencies of conformational transition in distinct regions ( L29 360-370 α18 , α19 380-410 L31 , α21 430-480 L33-α22-L35 and α24 510-520 L38 ) occurring upon R516Q mutation. Together, our results emphasise that the dislocation of functional hot spots Pro229, Arg414, Val498, Met510, Ala513, Gly515 and Arg516 in MDA5 protein which is important for interior structural packing and fold arrangements. In a nutshell, our findings are perfectly conceded with other experimental reports and will have potential implications in immune therapeutical advancement for rare singleton-merten syndrome.

  1. Complementation of UPLC-Q-TOF-MS and CESI-Q-TOF-MS on identification and determination of peptides from bovine lactoferrin.

    PubMed

    Chen, Hui; Shi, Pujie; Fan, Fengjiao; Tu, Maolin; Xu, Zhe; Xu, Xianbing; Du, Ming

    2018-05-01

    Digested peptides of bovine lactoferrin as the functional hydrolysates were identified by the Q-TOF tandem mass spectrometry (Q-TOF-MS) coupled with ultra performance liquid chromatograph (UPLC) and capillary electrophoresis (CE). The former (UPLC-Q-TOF-MS) identified 106 peptides while the latter (CE-Q-TOF-MS) characterized 102 peptides after comparison of peptides in terms of their molecular weight (MW), mass-to-charge ratio (m/z), and isoelectric point (pI). In addition, the hydrophilic value, net charge (q), and molecular radius (r) of the peptides were calculated, and a correlation analysis of the two methods was conducted between the retention time (RT) and r/q ratio of the peptides in order to elucidate the different separation principles of the unique peptides. It was shown that the peptides with larger hydrophilic value were beneficial to be separated by UPLC, while the peptides with larger r/q ratio were beneficial to be separated by CE. Combination of the above mentioned two complementary techniques have confidently improved the sequence coverage of lactoferrin and enhanced the identification of peptides, which makes it up to 65.8% in this study. Copyright © 2018. Published by Elsevier B.V.

  2. Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1

    PubMed Central

    Cai, Qiuyin; Zhang, Ben; Sung, Hyuna; Low, Siew-Kee; Kweon, Sun-Seog; Lu, Wei; Shi, Jiajun; Long, Jirong; Wen, Wanqing; Choi, Ji-Yeob; Noh, Dong-Young; Shen, Chen-Yang; Matsuo, Keitaro; Teo, Soo-Hwang; Kim, Mi