Sex-specific genetic loci linked to early and late onset type 2 diabetes

Purpose To investigate the effect of sex and age on the timing of a type 2 diabetes (T2D) diagnosis and the influence T2D-related genes, parental history of T2D, and obesity on T2D development. Methods In this case-control study, 1012 T2D cases and 1008 healthy subjects were selected from the Diabetes in Mexico Study database. Participants were stratified by sex and age at T2D diagnosis (early, ≤45 years; late, ≥46 years). Seventy T2D-associated SNPs were explored and the percentage contribution (R2) of T2D-related genes, parental history of T2D, and obesity (body mass index [BMI] and waist-hip ratio [WHR]) on T2D development was calculated using univariate and multivariate logistic regression models. Results T2D-related genes influenced T2D development most in males who were diagnosed early (R2 = 23.5%; females diagnosed early, R2 = 13.5%; males and females diagnosed late, R2 = 11.9% and R2 = 7.3%, respectively). With an early diagnosis, insulin production genes were more influential in males (76.0% of R2) whilst peripheral insulin resistance genes were more influential in females (52.3% of R2). With a late diagnosis, insulin production genes from chromosome region 11p15.5 notably influenced males while peripheral insulin resistance and inflammation genes notably influenced females. Influence of parental history was higher among those diagnosed early (males, 19.9%; females, 17.5%) versus late (males, 6.4%; females, 5,3%). Unilateral maternal T2D history was more influential than paternal T2D history. BMI influenced T2D development for all, while WHR exclusively influenced males. Conclusions The influence of T2D-related genes, maternal T2D history, and fat distribution on T2D development was greater in males than females. ### Competing Interest Statement H.G.R., L.A.M.J., J.L.G., A.M., J.O.M., and D.A.A.H. are employed by the Fundacion Carlos Slim. All other authors have nothing to disclose. ### Funding Statement This work was funded by the Fundacion Carlos Slim, the Laboratory Huella Genica, and the Faculty of Medicine of the Universidad Nacional Autonoma de Mexico (UNAM). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics and Research Committees of the National Institute of Genomic Medicine and the Federal Commission for the Protection against Health Risks (COFEPRIS) gave ethical approval for this work (CAS/OR/CMN/113300410D0027-0577/2012). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data generated or analyzed during this study are included in this published article and its supplementary information files.