Contribution of rare and common genetic variants to early-onset type 2 diabetes

Background and aims: Early-onset type 2 diabetes (T2D) shows a more aggressive metabolic phenotype as well as an higher risk of chronic diabetes complications and premature mortality as compared to the usual T2D diagnosed in middle-aged patients. Unfortunately, the intrinsic pathogenic signatures of early-onset T2D are not completely understood. While there are several strong evidences on the contribution provided by worse behavioral and environmental risk factors, data on the genetic background are sparse and inconclusive. Both rare and common genetic variants play a role in the risk of T2D, but their contribution in shaping the age of diabetes onset is still unknown. Thus, we sought to investigate whether either both rare deleterious variants in monogenic diabetes-genes and/or common T2D susceptibility SNPs play a role in determining the risk of early-onset T2D. Materials and methods: by using the extreme-phenotype approach, 600 individuals with age at diabetes onset <35 (n=300, cases) or >65 (n=300, controls) years, as selected among 9,700 Italian patients, were investigated. All 600 DNAs were subjected to targeted resequencing of 27 monogenic diabetes-genes and to genotyping of 22 GWAS-derived T2D-SNPs then used to create an un-weighted genetic risk score (GRS). Results: Rare (i.e. minor allele frequency, MAF <1%) and possibly deleterious (i.e. with an estimated impact on protein function) alleles (n=51, carried by 47 individuals) from 27 monogenic diabetes genes significantly increased by 71% the risk of early-onset type 2 diabetes. A progressively stronger association was observed for progressively rarer variants (OR, 95% CI =2.06, 1.16-3.68, p=0.014; 2.46, 1.65-5.19 p=0.018 for MAF <0.1% and <0.01%, respectively) with ultra-rare ones (MAF<0.001%) being associated with a 6.5-fold increased risk (OR, 95% CI =6.51, 1.92-22.1, p=0.003). A similar, though less pronounced, trend was observed when previously reported MODY-causing mutations (n=8) were excluded, with only ultra-rare variants remaining significantly associated with early-onset T2D (OR, 95% CI =4.84, 1.38-16.92 p=0.01). Additionally, each allele of the GRS including 22 susceptibility SNPs for T2D increased the risk of early diabetes by approximately 20%. When the 600 study subjects were stratified according to the two geographical regions of recruitment: 324 subjects (182 cases vs. 142 controls) from Central-Southern Italy and 276 (118 vs. 158) from the Rome urban area, a similar association with early-onset T2D for both rare variants and GRS was observed in the two subgroups, with no evidence of heterogeneity, thus providing an internal validation of our findings. Conclusion: our data show for the first time a sizeable influence of both rare and possibly deleterious variants in monogenic-diabetes genes and of common type 2 diabetes susceptibility variants in increasing the risk of early-onset type 2 diabetes.