title: Polyunsaturated Fatty Acids Modulate the Association between PIK3CA-KCNMB3 Genetic Variants and Insulin Resistance.
abstract: Neighboring genes PIK3CA and KCNMB3 are both important for insulin signaling and β-cell function, but their associations with glucose-related traits are unclear.
  
  
  
  The objective was to examine associations of PIK3CA-KCNMB3 variants with glucose-related traits and potential interaction with dietary fat.
  
  
  
  We first investigated genetic associations and their modulation by dietary fat in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 820). Nine single-nucleotide polymorphisms (SNPs) were selected for analysis, covering more than 80% of the SNPs in the region. We then sought to replicate the findings in the Boston Puerto Rican Health Study (BPRHS) (n = 844).
  
  
  
  For KCNMB3 missense mutation rs7645550, meta-analysis indicated that homeostasis model assessment of insulin resistance (HOMA-IR) was significantly lower in minor allele T homozygotes compared with major allele C carriers (pooled P-value = 0.004); for another SNP rs1183319, which is in moderate LD with rs7645550, minor allele G carriers had higher HOMA-IR compared with non-carriers in both populations (pooled P-value = 0.028). In GOLDN, rs7645550 T allele homozygotes had lower HOMA-IR only when dietary n-3: n-6 PUFA ratio was low (≤0.11, P = 0.001), but not when it was high (>0.11, P-interaction = 0.033). Similar interaction was observed between rs1183319 and n-3: n-6 PUFA ratio on HOMA-IR (P-interaction = 0.001) in GOLDN. Variance contribution analyses in GOLDN confirmed the genetic association and gene-diet interaction. In BPRHS, dietary n-3: n-6 PUFA ratio significantly modulated the association between rs1183319 and HbA1c (P-interaction = 0.034).
  
  
  
  PIK3CA-KCNMB3 variants are associated with insulin resistance in populations of different ancestries, and are modified by dietary PUFA.
authors.affiliation: Department of Food Science and Nutrition, Zhejiang University, Hangzhou, China ; Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America.
authors.forename: Ju-Sheng
authors.initials: JS
authors.lastname: Zheng
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Parnell
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Lee
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Ma
authors.forename: Caren E
authors.initials: CE
authors.lastname: Smith
authors.forename: Kris
authors.initials: K
authors.lastname: Richardson
authors.forename: Duo
authors.initials: D
authors.lastname: Li
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
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: D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D004041:Dietary Fats; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005260:Female; D006239:Haplotypes; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D004041:Dietary Fats; D005231:Fatty Acids, Unsaturated; C403242:KCNMB3 protein, human; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D009419:Nerve Tissue Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human