GENETIC DETERMINANTS OF TYPE 2 DIABETES AND ASSOCIATED CARDIOMETABOLIC DISORDERS / DETERMINANTI GENETICI DI DIABETE MELLITO DI TIPO 2 E FENOTIPI CARDIOMETABOLICI ASSOCIATI

T2D is a complex disease characterized by a high prevalence and incidence worldwide, and recognizes genetic and non-genetic (environmental) risk factors as underlying determinants. CVD are currently one of the leading causes of death and are also often clinically associated to T2D. Recent large-scale genome-wide association studies (GWAS) have identified common genetic risk variants associated with a higher propensity of developing T2D, CVD and intermediate cardiometabolic phenotypes. The goal of the research project herein presented was three-fold: (1) to critically revise the available literature about the genetic determinants of type 2 diabetes (T2D), coronary heart disease (CHD) and intermediate phenotypes (sub-diabetic hyperglycemia, measures of subclinical atherosclerosis (SCA) and associated risk conditions), aimed at searching for potential overlapping areas of shared genetic background; (2) to verify whether the genetic determinants of T2D, and particularly those associated with insulin resistance, are also associated with measures of SCA; (3) to verify whether a genetic risk score comprised of the genetic determinants of T2D, myocardial infarction, stroke, atrial fibrillation, sudden cardiac death, coronary heart disease, is associated with an excess risk of all-cause mortality and/or CVD death. In detail, the present research exercise aimed at exploring the common genetic background of T2D, CVD and sub-diabetic forms of hyperglycemia by means of three exemplifying studies herein outlined. The first study verified whether the genetic risk for T2D, as represented by the aggregate burden of T2D risk loci (either as a whole or by distinct functional sub-groups, representative of loci with prior evidence of association with defective beta-cell function and/or increased insulin resistance), is associated with SCA traits in multi-ethnic cohorts. The second study verified the hypothesis that the common genetic variability at loci gatekeepers of the insulin signaling transduction pathway are associated with insulin resistance, beta-cell dysfunction, pathologic electrocardiogram, and/or increased SCA in patients affect by newly-diagnosed T2D. The third study verified whether the composite of the genetic determinants of T2D and intermediate CVD risk traits is associated with a higher mortality in the Framingham Offspring Study.