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

Abstract

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.