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OBJECTIVE - In recent genome-wide association studies, variants in CDKALl, SLC30A8, HHEX, EXT2, IGF2BP2, CDKN2B, LOC387761, and FTO were associated with risk for type 2 diabetes in Caucasians. We investigated the association of these single nucleotide polymorphisms (SNPs) and some additional tag SNPs with type 2 diabetes and related quantitative traits in Pima Indians.
RESEARCH DESIGN AND METHODS- Forty-seven SNPs were genotyped in 3,501 Pima Indians informative for type 2 diabetes and BMI, among whom 370 had measures of quantitative traits.
RESULTS - FTO provided the strongest evidence for replication, where SNPs were associated with type 2 diabetes (odds ratio = 1.20 per copy of the risk allele, P = 0.03) and BMI (P = 0.002). None of the other previously reported SNPs were associated with type 2 diabetes; however, associations were found between CDKALl and HHEX variants and acute insulin response (AIR), where the Caucasian risk alleles for type 2 diabetes were associated with reduced insulin secretion in normoglycemic Pima Indians. Multiallelic analyses of carrying risk alleles for multiple genes showed correlations between number of risk alleles and type 2 diabetes and impaired insulin secretion in normoglycemic subjects (P = 0.006 and 0.0001 for type 2 diabetes and AIR, respectively), supporting the hypothesis that many of these genes influence diabetes risk by affecting insulin secretion.
CONCLUSIONS- Variation in FTO impacts BMI, but the implicated common variants in the other genes did not confer a significant risk for type 2 diabetes in Pima Indians. However, confidence intervals for their estimated effects were consistent with the small effects reported in Caucasians, and the multiallelic "genetic risk profile" identified in Caucasians is associated with diminished early insulin secretion in Pima Indians. Diabetes 58: 478-488, 2009
Although it has been known for decades that both type 2 diabetes and obesity have a genetic basis (1), remarkably few susceptibility genes with robust and reproducible effects have been identified for these diseases. The recent introduction of large-scale, high-density genome-wide association (GWA) technology has revolutionized this field. Within the past year, six high-density (>300 K) GWA studies to identify genes affecting risk for type 2 diabetes among Caucasians have been published, and replicated associations were reported with single nucleotide polymorphisms (SNPs) in/near the genes transcription factor 7-like 2 (TCF7L2), CDK5...