{"doi":"10.1111/dom.70124","title":"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<sup>+</sup> and CD8<sup>+</sup> 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.","journal":"Diabetes, Obesity and Metabolism","year":2025,"id":5045,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0474,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-09-18","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":29525,"name":"Hakon Hakonarson","orcid":"0000-0003-2171-3627","position":1,"is_corresponding":false},{"id":51488,"name":"Hui‐Qi Qu","orcid":"0000-0001-9317-4488","position":0,"is_corresponding":true}],"reference_count":100,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}