期刊
DIABETES
卷 58, 期 2, 页码 505-510出版社
AMER DIABETES ASSOC
DOI: 10.2337/db08-0906
关键词
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资金
- Diabetes UK, British Diabetic Association Research
- U.K. Medical Research Council [G0000649]
- Wellcome Trust [GR072960, 076113]
- European Commission [EURODIA. LSHG-CT-2004-518153]
- MRC [G016121]
- Peninsula Medical School
- Diabetes UK
- Oxford National Institute for Health Research Biomedical Research Centre
- MRC CAiTE [90600705]
- Medical Research Council [G0600705, G0000934] Funding Source: researchfish
- MRC [G0000934, G0600705] Funding Source: UKRI
OBJECTIVE-This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genome-wide patterns of type 2 diabetes, association mid considered the implications for the etiological heterogeneity of type 2 diabetes. RESEARCH DESIGN AND METHODS-We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938 control Subjects: 393,453 single-nucleotide polymorphisms [SNPs]) after stratifying case subjects (into obese and nonobese) according to median BMI (30.2 kg/m(2)). Replication. of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in type 2 diabetes association signal was sought in additional samples. RESULTS-In the obese-type 2 diabetes scan, FTO variants had the strongest type 2 diabetes effect, (rs8050136: relative risk [RR] 1.49 [95% CI 1.34-1.66], P = 1.3 X 10(-13)), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 [1.09-1.35], P = 0.001). reversed in the nonobese scan, with FTO This situation was association undetectable (RR 1.07 [0.97-1.19], P = 0.19) and TCF7L2 predominant (RR 1.53 [1.37-1.71], P = 1.3 X 10(-14)). These patterns, confirmed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: P-DIFF = 1.4 X 10(-7); TCF7L2: P-DIFF = 4.0 X 10(-6)). Other signals displaying evidence of effect size heterogeneity in the gencome-wide analyses (on chromosomes 3, 12, 15, and 18) did not, replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for effect size heterogeneity for the SLC30A8 locus alone (RRobese 1.08 [1.01-1.15]; RRnonobese 1.18 [1.10-1.27]: P-DIFF = 0.04). CONCLUSIONs-This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within type 2 diabetes. Diabetes 58:505-510, 2009
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