Background and Aim: Type 2 diabetes (T2D), is affected by high morbidity and mortality rates, thus imposing a severe burden on health care systems. Although T2D typically affects middle‐aged and older persons, it also presents in young adults whit a more severe metabolic phenotype and increased cardiovascular risk than older patients. Both environmental and genetic factors contribute to the development of T2D. The genetic load is believed to be heavier in early-onset patients but data supporting this hypothesis are sparse and inconsistent. Also unknown is if rare variants contribute, in combination with common polymorphisms, in shaping the age of T2D onset. Thus, we sought to investigate, among T2D patients chosen at the extremes of the distribution of age at diagnosis, whether both rare deleterious variants in monogenic diabetes-genes and common GWAS-derived SNPs play a role in determining the risk of early-onset disease. Methodology: Among 9601 T2D Italian patient, 300 individuals with age at T2D onset <35 years (i.e. cases) and 300 with age at T2D onset >65 years (super controls) were studied by targeted NGS of 27 monogenic diabetes-genes and by genotyping (i.e. Taqman assays) 25 GWAS-SNPs established to associate with T2D. An unweighted genetic risk score (GRS) was computed from the above-mentioned SNPs. Results: Rare deleterious variants in monogenic diabetes-genes were significantly over-represented in cases than in controls (OR 6.5, 95% CI 1.9-22.1, p=0.0027). In detail, 18 case patients carried 19 variants in 13 genes while 3 control patients carried 3 variants in 3 genes. The GWAS-SNPs derived GRS was significantly higher in case vs. control patients (14.6 ± 1.5 vs 14.1 ± 1.5, respectively; p=0.0003). No interaction among rare and common variants has been observed in determining age at diabetes onset (p for interaction=0.36). Conclusions: Our data show for the first time a sizeable influence of both highly penetrant monogenic diabetes variants and common T2D genetic susceptibility in increasing the risk of early disease manifestation. Unraveling the genetic signature of early-onset diabetes may be relevant to precision medicine when among high-risk individuals those to be subjected to an early and more costly prevention strategy need to be identified.
Unraveling the genetic background of early-onset type 2 diabetes: a step forward toward precision medicine / Pezzilli, S; Tohidirad, M; Biagini, T; Mercuri, L; Alberico, F; Scarale, Mg; Garofolo, M; Mannino, G; Lamacchia, O; Filardi, T; Andreozzi, F; Baroni, Mg; Buzzetti, R; Cavallo, Mg; Copetti, M; Cossu, E; D'Angelo, P; De Cosmo, S; Di Mauro, L; Leonetti, F; Morano, S; Morviducci, L; Pozzilli, P; Pugliese, G; SUMMER Study in Diabetes, Group; Sesti, G; Penno, G; Mazza, T; Trischitta, V; Prudente, S.. - (2019). (Intervento presentato al convegno SIGU 2019 tenutosi a Rome; Italy).
Unraveling the genetic background of early-onset type 2 diabetes: a step forward toward precision medicine
Pezzilli S;Tohidirad M;Biagini T;Filardi T;Baroni MG;Buzzetti R;Cavallo MG;Morano S;Morviducci L;Pozzilli P;Sesti G;Mazza T;Trischitta V;Prudente S.
2019
Abstract
Background and Aim: Type 2 diabetes (T2D), is affected by high morbidity and mortality rates, thus imposing a severe burden on health care systems. Although T2D typically affects middle‐aged and older persons, it also presents in young adults whit a more severe metabolic phenotype and increased cardiovascular risk than older patients. Both environmental and genetic factors contribute to the development of T2D. The genetic load is believed to be heavier in early-onset patients but data supporting this hypothesis are sparse and inconsistent. Also unknown is if rare variants contribute, in combination with common polymorphisms, in shaping the age of T2D onset. Thus, we sought to investigate, among T2D patients chosen at the extremes of the distribution of age at diagnosis, whether both rare deleterious variants in monogenic diabetes-genes and common GWAS-derived SNPs play a role in determining the risk of early-onset disease. Methodology: Among 9601 T2D Italian patient, 300 individuals with age at T2D onset <35 years (i.e. cases) and 300 with age at T2D onset >65 years (super controls) were studied by targeted NGS of 27 monogenic diabetes-genes and by genotyping (i.e. Taqman assays) 25 GWAS-SNPs established to associate with T2D. An unweighted genetic risk score (GRS) was computed from the above-mentioned SNPs. Results: Rare deleterious variants in monogenic diabetes-genes were significantly over-represented in cases than in controls (OR 6.5, 95% CI 1.9-22.1, p=0.0027). In detail, 18 case patients carried 19 variants in 13 genes while 3 control patients carried 3 variants in 3 genes. The GWAS-SNPs derived GRS was significantly higher in case vs. control patients (14.6 ± 1.5 vs 14.1 ± 1.5, respectively; p=0.0003). No interaction among rare and common variants has been observed in determining age at diabetes onset (p for interaction=0.36). Conclusions: Our data show for the first time a sizeable influence of both highly penetrant monogenic diabetes variants and common T2D genetic susceptibility in increasing the risk of early disease manifestation. Unraveling the genetic signature of early-onset diabetes may be relevant to precision medicine when among high-risk individuals those to be subjected to an early and more costly prevention strategy need to be identified.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
