Sex as a modifier of genetic risk for type 1 diabetes.

Abstract

Sex differences influence the pathogenesis of type 1 diabetes (T1D), yet most genetic studies have treated sex as a control covariate rather than a dynamic effect modifier. Sex influences immune cell behaviour, including CD4⁺ and CD8⁺ T cell activation, regulatory T cell stability, B cell autoantibody production, dendritic cell priming and monocyte/macrophage inflammation. Underlying mechanisms include hormone-responsive enhancers, X-escape gene dosage and sex-biassed chromatin states, intersecting with T1D-associated variants to produce sex-specific immune phenotypes. These insights help explain regional variation in sex ratios of T1D incidence, such as male predominance in high-risk populations and female excess in low-risk populations. Biological sex shapes T1D risk across multiple layers, including polygenic load; environmental exposures such as vitamin D deficiency and enteroviral infection; and sex-specific hormonal, chromosomal and epigenetic influences. An integrative G × E × S (genetic × environmental × sex-specific) liability-threshold framework is thus supported. Clinical and translational implications include developing sex-specific polygenic risk scores, biomarker panels and interventional strategies targeting pathways such as hormone signalling, vitamin D metabolism and the microbiome. Future multi-omic, longitudinal studies are warranted to test genotype-sex interactions, integrate sex as a core effect modifier and enable precision prevention and treatment of T1D in both males and females.