Circulating 25-Hydroxyvitamin D, IRS1 Variant rs2943641, and Insulin Resistance: Replication of a Gene- Nutrient Interaction in 4 Populations of Different Ancestries

BACKGROUND: Associations of either insulin receptor substrate 1 (IRS1) variants or circulating 25- hydroxyvitamin D [25(OH) D] with type 2 diabetes (T2D) and insulin resistance (IR) are inconsistent. This study sought to determine whether circulating 25(OH) D modulates the association of a potentially functional variant at IRS1 (rs2943641) with insulin resistance. METHOD: Interaction between IRS1 rs2943641 and circulating 25(OH) D on homeostasis model assessment for IR (HOMA- IR) was examined in the Boston Puerto Rican Health Study (BPRHS) (n = 1144). Replication was performed in the African- American (n = 1126), non- Hispanic white (n = 1967), and Hispanic (n = 1241) populations of the Multi- Ethnic Study of Atherosclerosis (MESA) with genotypes of 3 IRS1 variants, rs2972144, rs1515104, and rs2673142, which are tag single nucleotide polymorphisms (SNPs) and in strong linkage disequilibrium with rs2943641. RESULTS: Higher circulating 25(OH) D was associated with lower risk ofT2DandIR inBPRHSwomenhomozygous for minor allele rs2943641T. Consistently, in each of 3 MESA populations, HOMA- IR and insulin decreased more evidently with higher circulating 25(OH) D in women of the rs2943641TT genotype than in carriers of the major allele (rs2943641C). Metaanalysis indicated significant and consistent interactions between circulating 25(OH) D and IRS1 variants on HOMA- IR (log transformed) [pooled beta = -0.008, 95% CI: - 0.016 to -0.001, P interaction =0.004] and insulin (log transformed) (pooled beta = -0.006, 95% CI: -0.011 to -0.002, P interaction -0.023) in 3065 women of the 4 populations. CONCLUSIONS: Participants with different genotypes of IRS1 rs2943641 exhibit differential benefit from high circulating 25(OH) D for the reduction of insulin resistance and T2D risk. This gene- nutrient interaction, which appears to be limited to women, warrants further examination in randomized controlled trials of vitamin D supplementation. (C) 2013 American Association for Clinical Chemistry