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

## TL;DR

This study finds that smoking interacts with specific genes to influence insulin sensitivity and pancreatic cell function in people with normal glucose levels.

## Contribution

The study identifies novel gene-smoking interactions affecting insulin sensitivity and β-cell function in normoglycemic individuals.

## Key findings

- GWIS identified three loci with significant gene–smoking interactions affecting insulin resistance, sensitivity, and disposition index.
- Smoking increased insulin resistance in homozygotes of rs4713207 but had the opposite effect in wild-type individuals.
- Colocalization analysis linked rs4713207 interactions to HCG4 and ZNF311 expression in the pancreas.

## Abstract

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.

Gene‐smoking interactions in insulin sensitivity and β‐cell function in normoglycemic individuals.