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Träfflista för sökning "WFRF:(Nilsson Peter) ;pers:(Lyssenko Valeriya);pers:(Sjögren Marketa);pers:(Nilsson Peter)"

Sökning: WFRF:(Nilsson Peter) > Lyssenko Valeriya > Sjögren Marketa > Nilsson Peter

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1.
  • Zeggini, Eleftheria, et al. (författare)
  • Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes
  • 2008
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1061-4036. ; 40:5, s. 638-645
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)(1-11). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and similar to 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P=5.0 x 10(-14)), CDC123-CAMK1D (P=1.2 x 10(-10)), TSPAN8-LGR5 (P=1.1 x 10(-9)), THADA (P=1.1 x 10(-9)), ADAMTS9 (P=1.2 x 10(-8)) and NOTCH2 (P=4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
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2.
  • Lyssenko, Valeriya, et al. (författare)
  • Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes.
  • 2007
  • Ingår i: Journal of Clinical Investigation. - American Society for Clinical Investigation. - 0021-9738. ; 117:8, s. 2155-2163
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired beta cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish). The risk T allele was associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in carriers of the TT genotype. Overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. In conclusion, the increased risk of T2D conferred by variants in TCF7L2 involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion.
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3.
  • Saxena, Richa, et al. (författare)
  • Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
  • 2007
  • Ingår i: Science. - American Association for the Advancement of Science. - 0036-8075. ; 316:5829, s. 1331-1336
  • Tidskriftsartikel (refereegranskat)abstract
    • New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D - in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 - and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
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5.
  • Sjögren, Marketa, et al. (författare)
  • The search for putative unifying genetic factors for components of the metabolic syndrome.
  • 2008
  • Ingår i: Diabetologia. - 0012-186X. ; 51, s. 2242-2251
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS/HYPOTHESIS: The metabolic syndrome is a cluster of factors contributing to increased risk of cardiovascular disease and type 2 diabetes but unifying mechanisms have not been identified. Our aim was to study whether common variations in 17 genes previously associated with type 2 diabetes or components of the metabolic syndrome and variants in nine genes with inconsistent association with at least two components of the metabolic syndrome would also predict future development of components of the metabolic syndrome, individually or in combination. METHODS: Genetic variants were studied in a large prospective study of 16,143 non-diabetic individuals (mean follow-up time 23 years) from the Malmö Preventive Project. In this study, development of at least three of obesity (BMI >/= 30 kg/m(2)), dyslipidaemia (triacylglycerol >/= 1.7 mmol/l and/or lipid-lowering treatment), hypertension (blood pressure >/= 140/90 mmHg and/or antihypertensive medication) and hyperglycaemia (fasting plasma glucose >/= 5.6 mmol/l and/or known diabetes) was defined as development of the metabolic syndrome. The risk of developing at least three components of the metabolic syndrome or the individual components was calculated by logistic regression adjusted for age at baseline, follow-up time and sex. RESULTS: Polymorphisms in TCF7L2 (rs7903146, OR 1.10, 95% CI 1.04-1.17, p = 0.00097), FTO (rs9939609, OR 1.08, 95% CI 1.02-1.14, p = 0.0065), WFS1 (rs10010131, OR 1.07, 95% CI 1.02-1.13, p = 0.0078) and IGF2BP2 (rs4402960, OR 1.07, 95% CI 1.01-1.13, p = 0.021) predicted the development of at least three components of the metabolic syndrome in both univariate and multivariate analysis; in the case of TCF7L2, WFS1 and IGF2BP this was due to their association with hyperglycaemia (p < 0.00001, p = 0.0033 and p = 0.027, respectively) and for FTO it was due to its association with obesity (p = 0.004). A polymorphism in the GCKR gene predicted dyslipidaemia (rs1260326, OR 1.15, 95% CI 1.09-1.22, p < 0.00001) but not the metabolic syndrome. None of the studied polymorphisms was associated with more than two components of the metabolic syndrome. A composite genotype score of the 17 polymorphisms associated with type 2 diabetes predicted the development of at least three components of the metabolic syndrome (OR 1.04, p < 0.00001) and the development of hyperglycaemia (OR 1.06, p < 0.00001). Carriers of >/=19 risk alleles had 51 and 72% increased risk of developing at least three components of the metabolic syndrome and hyperglycaemia, respectively, compared with carriers of </=12 risk alleles (p < 0.00001 for both). CONCLUSIONS/INTERPRETATION: Polymorphisms in susceptibility genes for type 2 diabetes (TCF7L2, WFS1, IGF2BP2) and obesity (FTO) predispose to the metabolic syndrome by increasing the risk of one specific component of the metabolic syndrome. The findings argue against a unifying genetic component for the metabolic syndrome.
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