Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program

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Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program

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Title: Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program
Author: Moore, Allan F.; Jablonski, Kathleen A.; McAteer, Jarred B.; Saxena, Richa; Pollin, Toni I.; Franks, Paul W.; Shuldiner, Alan R.; Knowler, William C.; Altshuler, David Matthew; Florez, Jose Carlos; Hanson, Robert L.

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Citation: Moore, Allan F., Kathleen A. Jablonski, Jarred B. McAteer, Richa Saxena, Toni I. Pollin, Paul W. Franks, Robert L. Hanson, et al. 2008. Extension of type 2 diabetes genome-wide association scan Results in the Diabetes Prevention Program. Diabetes 57(9): 2503-2510.
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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.
Published Version: doi://10.2337/db08-0284
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518503/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10021560
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