Genes predisposing to type 2 diabetes and cardiovascular mortality

Abstract: Cardiovascular complications are frequent in type 2 diabetes (T2D) and cardiovascular death is the most common cause of death for these individuals. A region on chromosome 19 (19q13) has been indicated by several genome scans as a susceptibility locus for T2D or components of the metabolic syndrome (MetS). This gene rich region contains the gene encoding muscle glycogen synthase (GYS1), earlier associated with T2D and myocardial infarction in males, as well as the apolipoprotein E gene (APOE) that has been associated with cardiovascular disease. Previous studies have also demonstrated a role for genetic variation in genes encoding adiponectin (APM1), PPARgamma (PPARG), and PGC-1alpha (PPARGC1A) in T2D and components of MetS. Lower adiponectin serum levels are present in T2D, obesity and cardiovascular disease. The aims of this thesis were to obtain more information on regulation of expression of GYS1 and APM1 genes, and to study if variation in five genes earlier indicated as susceptibility genes for T2D or components of MetS (GYS1, APOE, APM1, PPARG and PPARGC1A) predict cardiovascular mortality in T2D families. The minimal promoter of GYS1 was identified and the transcriptional activity of the promoter was negatively regulated by forskolin whereas no effect of short time treatment with insulin was observed. The XbaI polymorphism in GYS1 was associated with an increased risk for cardiovascular mortality in males, an effect modulated by the level of physical activity, whereas variants in APOE increased the risk for cardiovascular mortality in females. In morbidly obese subjects, adiponectin serum levels correlated with visceral APM1 expression and carriers of the APM1 G276T G-allele had lower expression of adiponectin mRNA in visceral adipose tissue as well as a higher fat percent than non-carriers. Survival analyses revealed that variations in APM1 (G276T) and PPARG (Pro12Ala), and in particular a combination of risk genotypes of these two polymorphisms were associated with an increased risk for cardiovascular mortality in T2D patients. Increasing the knowledge of gene regulation and expression as well as of how an individual's genetic background determines disease susceptibility and how the individual will respond to environmental factors might in the future lead to more specific and individually accustomed treatments of T2D and CVD.