Gene-Smoking Interaction in Insulin Sensitivity and β-Cell Function Among Normal Glucose Tolerance Individuals

To identify genetic loci that exhibit potential interactions with smoking status on insulin sensitivity and islet β-cell function within normal glucose tolerance (NGT) populations.

All participants underwent an OGTT to confirm NGT status, followed by assessments of insulin sensitivity and β-cell function. Analyses were performed in NGT participants from Nanjing (N = 4808) and Jurong (N = 508) for discovery and validation, respectively. Smoking status was categorized into nonsmokers and smokers. After excluding ineligible individuals, a two-stage genome-wide interaction association analysis (GWIS) was conducted in NGT individuals, with the discovery phase (N = 1377) identifying gene-environment interactions and the validation phase (N = 485) confirming significant loci. Subsequent analyses included stratified analysis and expression quantitative trait locus (eQTL) colocalization.

GWIS identified ten SNPs in three loci, including rs4713207 (OR14J1, P_meta = 3.95 × 10^-8) for insulin resistance, rs17708475 (NKAIN2, P_meta = 4.83 × 10^-8) for insulin sensitivity, and rs201613 (MYH3, P_meta = 1.05 × 10^-8) for disposition index. Stratified analyses revealed differential effects of smoking across genotypes at these loci. Specifically, smoking was associated with increased insulin resistance in rs4713207 homozygotes (p = 2.15 × 10^-5), while an opposite effect was observed in wild-type individuals (p = 0.022). Colocalization analysis indicated that the smoking-related interaction near rs4713207 is driven by a shared causal variant influencing HCG4 (PP.H4 = 0.70) and ZNF311 (PP.H4 = 0.74) expression in the pancreas.

Our findings reveal gene-smoking interactions that affect insulin sensitivity and β-cell function, providing new insights into the heterogeneity of metabolic phenotypes and advancing personalized risk assessment.