ABSTRACT
Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
Subject(s)
Coronary Artery Disease/genetics , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Adult , Aged , Asian People , Cell Line , Female , Gene Regulatory Networks , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Risk Factors , White People/geneticsABSTRACT
The metabolic syndrome is a multifaceted clinical entity resulting from the interaction of genetic, hormonal, and lifestyle factors. Over the past two decades, the number of people diagnosed with the syndrome has steadily increased and is associated with the global epidemic of obesity and diabetes. The metabolic syndrome is characterized by the clustering of disorders which includes high blood pressure, high (pro)insulin concentrations, excess body weight with central obesity, and an altered lipid profile (dyslipidaemia) that increase the likelihood to develop micro- and macrovascular complications, including coronary heart disease or stroke. Each of these disorders is by itself a risk factor for other diseases including diabetes mellitus. In combination, morbidity and mortality are dramatically increased. Because the defining thresholds for establishing the diagnosis of the metabolic syndrome are controversial, the NCEP: ATP III and the WHO have made specific suggestions. The current definitions of the metabolic syndrome can be used as predictors of vascular complications. Risk assessment and subsequent selection of probands for intervention, such as weight reduction and increased physical activity are recommended for the clinical management of the metabolic syndrome.
Subject(s)
Metabolic Syndrome/diagnosis , Albuminuria/etiology , Animals , Endothelium, Vascular/physiology , Humans , Inflammation/etiology , Metabolic Syndrome/epidemiology , Metabolic Syndrome/therapy , PrevalenceABSTRACT
The metabolic syndrome is a highly prevalent multifaceted clinical entity. Obesity, which is part of the metabolic syndrome, is the fastest growing health-related problem worldwide. Since currently prevalence data of the metabolic syndrome are lacking from Germany, we have applied ATP III-criteria in two urban and rural cohorts. Our population-based studies provide evidence that the prevalence of the metabolic syndrome increases with age. It was found to be more prevalent in a rural population and in this group it clustered in males. As a consequence of our population-based studies evidence that especially the rural population is at high risk for future macrovascular complications is substantiated. The urgent need for preventive measures aimed at reducing the significantly increased health risk is underscored.
