title: 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.
  
  
  METHODS
  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.
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA;
authors.forename: Ju-Sheng
authors.initials: JS
authors.lastname: Zheng
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Parnell
authors.forename: Caren E
authors.initials: CE
authors.lastname: Smith
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Lee
authors.forename: Aziza
authors.initials: A
authors.lastname: Jamal-Allial
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Ma
authors.forename: Duo
authors.initials: D
authors.lastname: Li
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Tucker
authors.forename: José M
authors.initials: JM
authors.lastname: Ordovás
authors.forename: Chao-Qiang
authors.initials: CQ
authors.lastname: Lai
mesh_terms: D005006:Ethnicity; D005260:Female; D006304:Health Status; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000097:blood* / Q000235:genetics; D007333:Insulin Resistance / Q000208:ethnology* / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011647:Puerto Rico / Q000208:ethnology; D012307:Risk Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D055504:Insulin Receptor Substrate Proteins; D014807:Vitamin D; C104450:25-hydroxyvitamin D