Association Analysis of Variation in/near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761 and CDKN2B with Type 2 Diabetes and Related Quantitative Traits in Pima Indians

Abstract

Objective: In recent genome-wide association studies, variants in CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, CDKN2B, LOC387761 and FTO were associated with risk for type 2 diabetes (T2D) in Caucasians. We investigated the asssociation of these SNPs, as well as some additional tag SNPs, with T2D and related quantitative traits in Pima Indians.

Research Design and Methods: Forty-seven SNPs were genotyped in 3501 Pima Indians informative for T2D and BMI, among whom 370 had measures of quantitative traits.

Results: FTO provided the strongest evidence for replication, where SNPs were associated with T2D (OR=1.20 per copy of the risk allele, p=0.03) and BMI (p=0.002). None of the other previously reported SNPs was associated with T2D; however, associations were found between CDKAL1 and HHEX variants and acute insulin response (AIR), where the Caucasian risk alleles for T2D were associated with reduced insulin secretion in normoglycemic Pimas. Multiallelic analyses of carrying risk alleles for multiple genes showed correlations between number of risk alleles and T2D, and impaired insulin secretion in normoglycemic subjects (p=0.006 and 0.0001 for T2D and AIR, respectively), supporting the hypothesis that many of these genes influence diabetes risk by affecting insulin secretion.

Conclusion: Variation in FTO impacts BMI, but the implicated common variants in the other genes did not confer a significant risk for T2D in Pimas. 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.