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Title: Circulating 25-hydroxyvitamin D, IRS1 variant rs2943641 and insulin resistance: replication of a gene-nutrient interaction in four populations of different ancestries

item ZHENG, JU-SHENG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Parnell, Laurence
item SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LEE, YU-CHI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item JAMAL-ALLIAL, AZIZA - Northeastern University
item MA, YIYI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LI, DUO - Zhejiang University
item TUCKER, KATHERINE - Northeastern University
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Lai, Chao Qiang

Submitted to: Clinical Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/28/2013
Publication Date: N/A
Citation: N/A

Interpretive Summary: Type 2 diabetes is an increasingly common age-related disease. Insulin resistance (IR), the body’s inability to effectively manage blood sugar levels via insulin, results from a combination of genetic and environmental factors and it may be the prelude to type 2 diabetes (T2D). Dietary factors are at the root of both IR and T2D and recent research highlights the role of vitamin D in the development of a number of age-related diseases, including T2D. However, whereas recommended levels of vitamin D intake seem to lower risk of IR and T2D, supplementing people with vitamin D has not been shown to be universally protective. Genetic factors may explain some of the observed variability in results. Along these lines, a common genetic variant (rs2943641) at the insulin receptor substrate 1 (IRS1) gene has shown in some studies to be associated with T2D. Therefore, we tested whether the combination of vitamin D intake status, defined as blood vitamin D levels, and the rs2943641 gene variant, might influence IR and T2D risk. The study was conducted first on a population of Hispanics living in the Boston area and then the results were replicated on three other ethnic groups, including African-American, non-Hispanic white and Hispanic subjects participating in the Multi-Ethnic Study of Atherosclerosis (MESA). Our results support that higher plasma vitamin D levels are associated with lower risk of T2D, and that vitamin D may actually influence individual genetic risk of IR and T2D as well. Specifically, we found that higher vitamin D was associated with lower IR and T2D in women with two copies of the minor form of the rs2943641 variant. Taken together, we provide novel findings demonstrating that high vitamin D status is associated with lower risk of IR and T2D, particularly in women with one particular form of IRS1 gene. These results are important because they suggest that changing the diet by adding vitamin D may help to reduce T2D selectively in women who carry this particular genetic risk factor.

Technical Abstract: Associations of either insulin receptor substrate 1 (IRS1) variants or circulating 25-hydroxyvitamin D (25(OH)D) with type 2 diabetes and insulin resistance 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. Interaction between IRS1 rs2943641 and circulating 25(OH)D on HOMA-insulin resistance (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 populations (n=1241) of the Multi-Ethnic Study of Atherosclerosis (MESA) with genotypes of three IRS1 variants rs2972144, rs1515104 and rs2673142, which are tag SNPs and in strong linkage disequilibria with rs2943641. 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 three MESA populations, HOMA-IR and insulin decreased more evidently with higher circulating 25(OH)D in women of the rs2943641TT genotype than in those carriers of the major allele (rs2943641C). Meta-analysis 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, -0.001; P-interaction=0.004) and insulin (log transformed) (pooled beta=-0.006, 95%CI: -0.011, -0.002; P-interaction=0.023) in 3065 women of the four populations. In summary, participants with different genotypes of IRS1 rs2943641 exhibit differential benefit from high circulating 25(OH)D for the reduction of insulin resistance and type 2 diabetes risk. This gene-nutrient interaction, which appears to be limited to women, warrants further examination in randomized controlled trials of vitamin D supplementation.