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Despite well\u2010documented sex\u2010based differences, pharmacogenomic and genome\u2010wide association studies (GWAS) have largely overlooked sex as a biological variable. We conducted the first sex\u2010stratified GWAS of hemoglobin A1c (HbA1c)\u00a0response to sulfonylureas in Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial participants (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u2009871). Variants meeting genome\u2010wide (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20095.0\u2009\u00d7\u200910\n                    <jats:sup>\u20138<\/jats:sup>\n                    ) and suggestive (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20095.0\u2009\u00d7\u200910\n                    <jats:sup>\u20136<\/jats:sup>\n                    ) significance were assessed for replication in the Pharmacogenomics of Metformin (PMET1) cohort. Replicated variants were further analyzed in the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR\u2010MGH) cohort to assess acute insulin and glucose responses to a single glipizide dose. Genome\u2010wide significant loci with sex\u2010specific effects were identified:\n                    <jats:italic>KAZN<\/jats:italic>\n                    ,\n                    <jats:italic>KIF2B<\/jats:italic>\n                    ,\n                    <jats:italic>SLC39A10<\/jats:italic>\n                    , and\n                    <jats:italic>SPINK5<\/jats:italic>\n                    (combined\u2010sex);\n                    <jats:italic>CRACR2A<\/jats:italic>\n                    ,\n                    <jats:italic>KCNK2<\/jats:italic>\n                    , and\n                    <jats:italic>TENM2<\/jats:italic>\n                    (male\u2010only); and\n                    <jats:italic>NACPH2<\/jats:italic>\n                    (female\u2010only). Two suggestive variants in the\n                    <jats:italic>TMEM64<\/jats:italic>\n                    \/\n                    <jats:italic>NECAB1<\/jats:italic>\n                    locus, associated with reduced HbA1c response to sulfonylureas in the male\u2010only ACCORD analysis, were directly replicated in the PMET1 male\u2010only cohort. In SUGAR\u2010MGH, one replicated variant (rs6471250\u2010C) was significantly associated with reduced peak insulin in males (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.035) but not females (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.40), demonstrating sex\u2010specific functional effects. This study identified statistically supported and biologically plausible loci with prior evidence linking nearby genes to pathways relevant to sulfonylurea action, including insulin secretion, insulin regulation\/sensitivity, calcium signaling, potassium\u2010channel biology, and glucose transport. The findings highlight sex\u2010specific differences in sulfonylurea response, providing mechanistic insights and underscoring the importance of sex\u2010specific precision medicine. Identification of genetic variants influencing sex\u2010specific response could inform dosing to optimize sulfonylureas.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70381","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:42:32Z","timestamp":1785152552000},"page":"1004-1015","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Disentangling Sex Differences in Sulfonylurea Drug Response With Genome\u2010Wide Association Studies in Individuals With Type 2 Diabetes"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6179-0515","authenticated-orcid":false,"given":"Joseph H.","family":"Breeyear","sequence":"first","affiliation":[{"name":"Biostatistics and Computational Biology Branch National Institute for Environmental Health Sciences, National Institutes of Health  Durham North Carolina 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Harvard and MIT  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farida S.","family":"Akhtari","sequence":"additional","affiliation":[{"name":"Biostatistics and Computational Biology Branch National Institute for Environmental Health Sciences, National Institutes of Health  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hetal S.","family":"Shah","sequence":"additional","affiliation":[{"name":"Joslin Diabetes Center and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique M.","family":"Hedderson","sequence":"additional","affiliation":[{"name":"Division of Research Kaiser Permanente Northern California  Oakland California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8041-5430","authenticated-orcid":false,"given":"Kathleen M.","family":"Giacomini","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences University of California  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2595-0005","authenticated-orcid":false,"given":"Josyf C.","family":"Mychaleckyj","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Doria","sequence":"additional","affiliation":[{"name":"Joslin Diabetes Center and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Center for Pharmacogenomics and Individualized Therapy UNC  Chapel Hill North Carolina 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