Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution.

The elucidation of the molecular basis of familial hypercholesterolemia (FH) by Brown and Goldstein about three decades ago provided the most convincing evidence for a causative relationship between a high plasma level of low-density lipoprotein (LDL) cholesterol and the conditions of atherosclerosis and premature atherosclerotic cardiovascular disease. Today, with a prevalence of about one in 500 individuals, FH remains the most common monogenic disorder of lipoprotein metabolism, and is mainly due to mutations in the LDL receptor (LDLR) gene that lead to the plasma accumulation of cholesterol ester-laden LDL particles. Another form of autosomal dominant hypercholesterolemia, familial defective apolipoprotein B-100, a genocopy of FH caused by defects in the APOB gene that lead to decreased clearance of LDL, is now established as a significant cause of coronary heart disease. Yet another form, due to mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, has been recently identified that similarly causes decreased clearance of LDL by novel mechanisms also involving the hepatic LDLR endocytotic pathway. Recent advances in molecular genotyping technology have yielded a staggering amount of detail about human genetic diversity at the single nucleotide level in both private and public databases including the International HapMap Consortium. This, as well as the availability of ancient human DNA from burial sites and the development of new statistical methods, now provide an unprecedented capacity to study human demography and the ability to examine the genealogical ties between ancient and modern people. The aim of this article is to review the epidemiology of FH, and to attempt to draw inferences from our knowledge at a DNA level of inherited hypercholesterolemia of contemporary people that may contribute to the understanding of human population history and adaptation that resulted in the massive demographic expansion following the adoption of agriculture in the Neolithic period.