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Sökning: WFRF:(Saxena Richa)

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  • Föregående 12[3]4Nästa
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21.
  • Lyssenko, Valeriya, et al. (författare)
  • Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
  • 2009
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 41:1, s. 82-88
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.
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22.
  • Lyssenko, Valeriya, et al. (författare)
  • Pleiotropic Effects of GIP on Islet Function Involve Osteopontin
  • 2011
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 1939-327X. ; 60:9, s. 2424-2433
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE-The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic beta-cell function by potentiating insulin secretion and beta-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS-Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies.Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of beta-cell viability and proliferation. RESULTS-The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. CONCLUSIONS-These findings support beta-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional beta-cell mass in humans. Diabetes 60:2424-2433, 2011
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23.
  • Moore, Allan F, et al. (författare)
  • Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program
  • 2008
  • Ingår i: Diabetes. - Alexandria : American diabetes association. - 0012-1797 .- 1939-327X. ; 57:9, s. 2503-2510
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo.RESEARCH DESIGN AND METHODS: We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2, CDKAL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.RESULTS: None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 (P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in beta-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment (P = 0.01) and possibly lifestyle modification (P = 0.05).CONCLUSIONS: We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B.
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24.
  • Nikpay, Majid, et al. (författare)
  • A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
  • 2015
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718 .- 1061-4036. ; 47:10, s. 1121-1121
  • Tidskriftsartikel (refereegranskat)abstract
    • Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
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25.
  • Orho-Melander, Marju, et al. (författare)
  • Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations
  • 2008
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 1939-327X. ; 57:11, s. 3112-3121
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE-Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCYR locus in samples of non-European ancestry and to fine-map across the associated genomic interval. RESEARCH DESIGN AND METHODS-We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the similar to 417-kb region of linkage disequilibrium. spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval. RESULTS-We provide comprehensive evidence that GCYR rs780094 is associated with opposite effects on fasting plasma triglyceride (P-meta = 3 x 10(-56)) and glucose (P-meta = 1 x 10(-13)) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 x 10(-5)). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r(2) = 0.93 with rs780094) as the strongest association signal in the region. CONCLUSIONS-These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism. Diabetes 57:3112-3121, 2008
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26.
  • Palmer, Nicholette D, et al. (författare)
  • A genome-wide association search for type 2 diabetes genes in African Americans.
  • 2012
  • Ingår i: PLOS ONE. - San Francisco : Public Library of Science. - 1932-6203. ; 7:1, s. e29202-
  • Tidskriftsartikel (refereegranskat)abstract
    • African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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27.
  • Prokopenko, Inga, et al. (författare)
  • Variants in MTNR1B influence fasting glucose levels
  • 2009
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718 .- 1061-4036. ; 41:1, s. 77-81
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
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28.
  • Prokunina-Olsson, Ludmila, et al. (författare)
  • Tissue-specific alternative splicing of TCF7L2
  • 2009
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906. ; 18:20, s. 3795-3804
  • Tidskriftsartikel (refereegranskat)abstract
    • Common variants in the transcription factor 7-like 2 (TCF7L2) gene have been identified as the strongest genetic risk factors for type 2 diabetes (T2D). However, the mechanisms by which these non-coding variants increase risk for T2D are not well-established. We used 13 expression assays to survey mRNA expression of multiple TCF7L2 splicing forms in up to 380 samples from eight types of human tissue (pancreas, pancreatic islets, colon, liver, monocytes, skeletal muscle, subcutaneous adipose tissue and lymphoblastoid cell lines) and observed a tissue-specific pattern of alternative splicing. We tested whether the expression of TCF7L2 splicing forms was associated with single nucleotide polymorphisms (SNPs), rs7903146 and rs12255372, located within introns 3 and 4 of the gene and most strongly associated with T2D. Expression of two splicing forms was lower in pancreatic islets with increasing counts of T2D-associated alleles of the SNPs: a ubiquitous splicing form (P = 0.018 for rs7903146 and P = 0.020 for rs12255372) and a splicing form found in pancreatic islets, pancreas and colon but not in other tissues tested here (P = 0.009 for rs12255372 and P = 0.053 for rs7903146). Expression of this form in glucose-stimulated pancreatic islets correlated with expression of proinsulin (r(2) = 0.84-0.90, P < 0.00063). In summary, we identified a tissue-specific pattern of alternative splicing of TCF7L2. After adjustment for multiple tests, no association between expression of TCF7L2 in eight types of human tissue samples and T2D-associated genetic variants remained significant. Alternative splicing of TCF7L2 in pancreatic islets warrants future studies. GenBank Accession Numbers: FJ010164-FJ010174.
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29.
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30.
  • Saxena, Richa, et al. (författare)
  • Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals
  • 2006
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 1939-327X. ; 55:10, s. 2890-2895
  • Tidskriftsartikel (refereegranskat)abstract
    • Recently, common noncoding variants in the TCF7L2 gene were strongly associated with increased risk of type 2 diabetes in samples from Iceland, Denmark, and the U.S. We genotyped 13 single nucleotide polymorphisms (SNPs) across TCF7L2 in 8,310 individuals in family-based and case-control designs from Scandinavia, Poland, and the U.S. We convincingly confirmed the previous association of TCF7L2 SNPs with the risk of type 2 diabetes (rs7903146T odds ratio 1.40 [95% CI 1.30-1.50], P = 6.74 x 10(-20)). In nondiabetic individuals, the risk genotypes were associated with a substantial reduction in the insulinogenic index derived from an oral glucose tolerance test (risk allele homozygotes have half the insulin response to glucose of noncarriers, P = 0.003) but not with increased insulin resistance. These results suggest that TCF7L2 variants may act through insulin secretion to increase the risk of type 2 diabetes.
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