Polyunsaturated Fatty Acids Modulate the Association between <i>PIK3CA-KCNMB3</i> Genetic Variants and Insulin Resistance

<div><p>Background</p><p>Neighboring genes <i>PIK3CA</i> and <i>KCNMB3</i> are both important for insulin signaling and β-cell function, but their associations with glucose-related traits are unclear.</p><p>Objective</p><p>The objective was to examine associations of <i>PIK3CA-KCNMB3</i> variants with glucose-related traits and potential interaction with dietary fat.</p><p>Design</p><p>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).</p><p>Results</p><p>For <i>KCNMB3</i> 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 <i>P</i>-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 <i>P</i>-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, <i>P</i> = 0.001), but not when it was high (>0.11, <i>P</i>-interaction = 0.033). Similar interaction was observed between rs1183319 and n-3: n-6 PUFA ratio on HOMA-IR (<i>P</i>-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 (<i>P</i>-interaction = 0.034).</p><p>Conclusion</p><p><i>PIK3CA-KCNMB3</i> variants are associated with insulin resistance in populations of different ancestries, and are modified by dietary PUFA.</p>