From Serum to Genome: γ-Glutamyltransferase Gene Family Variants Shape Ischemic Stroke Risk via Sex-Specific Gene-Environment Interactions.

Serum gamma-glutamyltransferase (GGT) is a biomarker for cardiovascular disease, but the role of its encoding gene family in ischemic stroke (IS) is unknown. 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 < 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 < 0.05). MB-MDR uncovered complex higher-order interactions (Pperm < 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 < 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-environment 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.