Clinical Implications of Lipid Genetics for Cardiovascular Disease.

Cardiovascular disease is the leading cause of morbidity and mortality in the developed world. Epidemiologic data support a strong relationship of atherosclerotic cardiovascular disease (ASCVD) with both elevated low-density lipoprotein cholesterol (LDL-C), and reduced high-density lipoprotein cholesterol (HDL-C). The study of the human genetics of plasma lipid traits, both rare Mendelian disorders as well as common variants, has illuminated multiple genes and pathways involved in the regulation of LDL-C and HDL-C levels. Mendelian disorders of extremes of LDL-C and Mendelian randomization studies of common gene variants associated with LDL-C strongly support a causal relationship between LDL-C and ASCVD, independent of mechanism. In contrast, Mendelian disorders of extremes of HDL-C and Mendelian randomization studies of common genetic variants for HDL-C are inconsistent in their support of a causal relationship between HDL-C and ASCVD. In contrast to LDL-C, a causal relationship between HDL-C and ASCVD may be dependent on the specific mechanism leading to variation in HDL-C levels.