| IRS1 gene variants, dysglycaemic metabolic changes and type-2 diabetes risk. | |
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MedLine Citation:
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PMID: 21917432 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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BACKGROUND AND AIMS: A recent genome-wide association study identified rs2943641C > T, 500 kb from the insulin receptor substrate-1 gene (IRS1), as a type-2 diabetes (T2D) susceptibility locus. We aimed to replicate this association by meta-analysis and examine whether common variants within IRS1, present on the HumanCVD BeadChip, were associated with T2D risk. METHODS AND RESULTS: We genotyped rs2943641 in 2389 prevalent or incident T2D patients and 6494 controls from two prospective and three case studies based in UK and in the European Atherosclerosis Research Study-II (EARSII; n = 714). Thirty-three IRS1 variants had been genotyped in the prospective Whitehall-II study (n = 4752) using the HumanCVD BeadChip. In a fixed-effects meta-analysis of the UK study cohorts rs2943641T allele was associated with 6% lower risk of T2D (p = 0.18), with T-allele carriers having an odds ratio (OR) of 0.89 (95% confidence interval [CI]: 0.80-1.00, p = 0.056) compared to CC subjects. The T-allele was also associated with lower fasting insulin and homeostasis model assessment index of insulin resistance in Whitehall-II and with lower post-load insulin after an oral glucose tolerance test in EARSII (all p < 0.05). None of the IRS1 variants on the chip showed linkage disequilibrium with rs2943641. In silico analysis with follow-up genotyping (total n = 9313) identified that the rare allele of the IRS1 promoter variant rs6725556A > G showed association with reduced T2D risk (OR per G-allele: 0.82, 95%CI: 0.69-0.96, p = 0.015). CONCLUSIONS: We confirm the association of rs2943641T with T2D protection. There is a possible independent effect on risk of a putative IRS1 promoter variant. |
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Authors:
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N Yiannakouris; J A Cooper; S Shah; F Drenos; H A Ireland; J W Stephens; K-W Li; R Elkeles; I F Godsland; M Kivimaki; A D Hingorani; M Kumari; P J Talmud; S E Humphries |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-12 |
Journal Detail:
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Title: Nutrition, metabolism, and cardiovascular diseases : NMCD Volume: - ISSN: 1590-3729 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-15 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9111474 Medline TA: Nutr Metab Cardiovasc Dis Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 Elsevier B.V. All rights reserved. |
Affiliation:
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Harokopio University of Athens, 17671 Athens, Greece. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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