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

Abstract

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 of T2D and IR in BPRHS women homozygous 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 β = −0.008, 95% CI: −0.016 to −0.001, P interaction = 0.004] and insulin (log transformed) (pooled β = −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.

Role of genetic mutations in folate-related enzyme genes on Male Infertility

“…Comparatively speaking, Western European people have a better nutritional status, which may account for a higher frequency of the TT genotype. Thus, the phenomenon of gene-nutrient interaction can partly explain the discrepant allele distribution among different ethnicities 73 . On the other hand, we noted that the sample size and numbers of studies in American and African groups were not ample, which might result in mistaken conclusions 74 .…”

Effects of Combined Calcium and Vitamin D Supplementation on Insulin Secretion, Insulin Sensitivity and β-Cell Function in Multi-Ethnic Vitamin D-Deficient Adults at Risk for Type 2 Diabetes: A Pilot Randomized, Placebo-Controlled Trial

“…IRS-1) and vitamin D status (e.g. those involved in skin production of vitamin D, in vitamin D-binding protein concentrations and vitamin D catabolism) may also alter treatment response [38] . Finally, baseline calcium intake may also affect response to treatment.…”

Nutrigenetics and Nutrigenomics Insights into Diabetes Etiopathogenesis

“…Another study also explored the relationship between the insulin receptor substrate 1 (IRS1) variant rs2943641 and circulating levels of 25-hydroxyvitamin D (25(OH)D). Women homozygous for the minor allele rs2943641T with higher circulating 25(OH)D showed a lower risk of insulin resistance and T2DM compared to carriers of the major allele (rs2943641C) [ 61 ] ( Table 2 ). Gene-whole grain intake interactions have also been established for the glucokinase regulatory protein (GCKR) variant rs780094 in a meta-analysis of 14 cohort studies; this study demonstrated that dietary whole grain intake potentially interacts with the cited variant.…”