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This pilot study of 1288 individuals (600 cases and 688 controls) investigated GGT1, GGT5, GGT6, and GGT7 polymorphisms using the MassARRAY-4 system. Conventional single-variant, haplotype, and diplotype analyses were complemented by Model-Based Multifactor Dimensionality Reduction (MB-MDR) with stability assessment and model prioritization. Conventional analysis identified female-specific associations for three GGT5 variants (rs8140505, rs2275984, and rs2267073; Pperm &lt; 0.05). A common GGT5 haplotype was protective in females (Pperm = 0.02). Diplotype analysis revealed joint effects of GGT genotypes on IS risk in females (FDR &lt; 0.05). MB-MDR uncovered complex higher-order interactions (Pperm &lt; 0.0001): in women, 12 models represented second-order interactions between smoking and individual GGT variants. In men, 8 models centered on GGT1 rs5751909 spanning second- to fourth-order interactions with alcohol, smoking, and other GGT family members. All prioritized models passed FDR correction (q &lt; 0.05) and achieved higher weighted composite scores. eQTL data linked these variants to regulatory networks controlling glutathione metabolism, oxidative stress, and inflammation. This study supports a novel hypothesis on the combined involvement of GGT gene family polymorphisms and pro-oxidant environmental factors in ischemic stroke predisposition, demonstrating that disease risk is shaped by sex-specific gene\u2013environment interactions. The pronounced sexual dimorphism highlights the need for sex-specific personalized approaches: smoking cessation may be particularly impactful in women carrying GGT5 risk variants, while alcohol moderation could be prioritized in men with GGT1 risk variants.<\/jats:p>","DOI":"10.3390\/life16050721","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T17:26:18Z","timestamp":1777051578000},"page":"721","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Serum to Genome: \u03b3-Glutamyltransferase Gene Family Variants Shape Ischemic Stroke Risk via Sex-Specific Gene\u2013Environment Interactions"],"prefix":"10.3390","volume":"16","author":[{"given":"Maria","family":"Solodilova","sequence":"first","affiliation":[{"name":"Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Drozdova","sequence":"additional","affiliation":[{"name":"Department of General Hygiene, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8098-8052","authenticated-orcid":false,"given":"Iuliia","family":"Azarova","sequence":"additional","affiliation":[{"name":"Department of Biological and Chemical Technology, Kursk State Medical University, 18 Yamskaya St., Kursk 305041, Russia"},{"name":"Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk 305041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Bykanova","sequence":"additional","affiliation":[{"name":"Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk 305041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3333-0623","authenticated-orcid":false,"given":"Olga","family":"Bushueva","sequence":"additional","affiliation":[{"name":"Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russia"},{"name":"Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk 305041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Puchkova","sequence":"additional","affiliation":[{"name":"Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vyacheslav","family":"Puchkov","sequence":"additional","affiliation":[{"name":"Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxim","family":"Freidin","sequence":"additional","affiliation":[{"name":"Department of Twin Research and Genetic Epidemiology, King\u2019s College London, Westminster Bridge Rd, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1254-6134","authenticated-orcid":false,"given":"Mikhail","family":"Churnosov","sequence":"additional","affiliation":[{"name":"Department of Medical Biological Disciplines, Belgorod State University, 85 Pobedy Street, Belgorod 308015, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6280-247X","authenticated-orcid":false,"given":"Alexey","family":"Polonikov","sequence":"additional","affiliation":[{"name":"Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk 305041, Russia"},{"name":"Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk 305041, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e254","DOI":"10.1161\/CIR.0000000000000950","article-title":"Heart Disease and Stroke Statistics-2021 Update: A Report from the American Heart Association","volume":"143","author":"Virani","year":"2021","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1177\/17474930211065917","article-title":"World Stroke Organization (WSO): Global Stroke Fact Sheet 2022","volume":"17","author":"Feigin","year":"2022","journal-title":"Int. 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