{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:03:41Z","timestamp":1755216221292,"version":"3.43.0"},"reference-count":63,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":27,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20220714"],"award-info":[{"award-number":["BK20220714"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82200888","82373685","82070803"],"award-info":[{"award-number":["82200888","82373685","82070803"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Diabetes"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify genetic loci that exhibit potential interactions with smoking status on insulin sensitivity and islet \u03b2\u2010cell function within normal glucose tolerance (NGT) populations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>All participants underwent an OGTT to confirm NGT status, followed by assessments of insulin sensitivity and \u03b2\u2010cell function. Analyses were performed in NGT participants from Nanjing (<jats:italic>N<\/jats:italic>\u2009=\u20094808) and Jurong (<jats:italic>N<\/jats:italic>\u2009=\u2009508) for discovery and validation, respectively. Smoking status was categorized into nonsmokers and smokers. After excluding ineligible individuals, a two\u2010stage genome\u2010wide interaction association analysis (GWIS) was conducted in NGT individuals, with the discovery phase (<jats:italic>N<\/jats:italic>\u2009=\u20091377) identifying gene\u2013environment interactions and the validation phase (<jats:italic>N<\/jats:italic>\u2009=\u2009485) confirming significant loci. Subsequent analyses included stratified analysis and expression quantitative trait locus (eQTL) colocalization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>GWIS identified ten SNPs in three loci, including rs4713207 (<jats:italic>OR14J1<\/jats:italic>, <jats:italic>P<\/jats:italic><jats:sub>meta<\/jats:sub>\u2009=\u20093.95\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>) for insulin resistance, rs17708475 (<jats:italic>NKAIN2, P<\/jats:italic><jats:sub>meta<\/jats:sub>\u2009=\u20094.83\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>) for insulin sensitivity, and rs201613 (<jats:italic>MYH3, P<\/jats:italic><jats:sub>meta<\/jats:sub>\u2009=\u20091.05\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>) 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 (<jats:italic>p<\/jats:italic>\u2009=\u20092.15\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>), while an opposite effect was observed in wild\u2010type individuals (<jats:italic>p<\/jats:italic>\u2009=\u20090.022). Colocalization analysis indicated that the smoking\u2010related interaction near rs4713207 is driven by a shared causal variant influencing <jats:italic>HCG4<\/jats:italic> (PP.H4\u2009=\u20090.70) and <jats:italic>ZNF311<\/jats:italic> (PP.H4\u2009=\u20090.74) expression in the pancreas.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings reveal gene\u2010smoking interactions that affect insulin sensitivity and \u03b2\u2010cell function, providing new insights into the heterogeneity of metabolic phenotypes and advancing personalized risk assessment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1753-0407.70131","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T10:15:34Z","timestamp":1753697734000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gene\u2010Smoking Interaction in Insulin Sensitivity and \u03b2\u2010Cell Function Among Normal Glucose 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