Sex as a modifier of genetic risk for type 1 diabetes

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.