Of PCSK9, cholesterol homeostasis and parasitic infections: Possible survival benefits of loss-offunction PCSK9 genetic polymorphisms

Cholesterol is important for cell membrane structure and functions as well as for production of steroid hormones and bile acids. It is transported through the body as lipoprotein particles of varying density and composition. Cholesterol homeostasis is maintained through finely tuned mechanisms regulating dietary uptake, hepatic biosynthesis and secretion as well as plasma clearance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cellular uptake of plasma low-density lipoprotein-cholesterol (LDL-C) by promoting LDL receptor (LDLR) degradation. Two nonsense single-nucleotide polymorphisms (SNPs) at the PCSK9 locus have been associated with life-long hypocholesterolemia and a remarkable reduction of the risk for coronary heart disease (CHD) in African-Americans. These loss-of-function SNPs presumably render PCSK9 less capable of inducing LDLR catabolism, effectively increasing LDLR availability and allowing efficient removal of plasma LDL-C. The combined frequency of heterozygosity for these nonsense SNPs is similar to 3-4% in populations of African descent. Homozygosity for either SNP, which would aggravate hypocholesterolemia, is reportedly rare. Whether such an aggravation would represent a health risk is still a matter of debate. From an evolutionary point of view, the cardioprotective effect of these nonsense SNPs may be a secondary phenotype made evident by the dyslipidemia-inducing lifestyle of today's North America. Their relatively high frequency in African-Americans must be interpreted in the context of the ancestral environment of these subjects in Africa, where diet and lifestyle were presumably less predisposing to atherosclerosis and where parasitic infections were major causes of morbidity and mortality before reproductive age. Parasites feed on host cholesterol for successful infection. The nonsense PCSK9 SNPs may have been positively selected because they reduced susceptibility to severe parasitic infections through cholesterol restriction. If so, these SNPs should be significantly more frequent in Sub-Saharan Africa where parasitic diseases, malaria in particular, have been and still are major selective forces. (c) 2007 Elsevier Ltd. All. rights reserved.