Rare Genetic Variants and High-Density Lipoprotein

Although static plasma concentration of high-density lipoprotein cholesterol (HDL-C), usually measured in the fasting state, is an excellent marker of atherosclerosis risk, its direct causal role in atherogenesis has lately been called into question.1 Strong evidence refuting a causal protective role for HDL has come from studies of rare genetic variants that affect plasma HDL-C concentrations. Initially, u003e3 decades ago, deletion of the adjacent APOA1 and APOC3 genes was found to be associated with reduced HDL-C and premature atherosclerosis in 2 sisters, consistent with an atheroprotective role for HDL.2 But since then observations in families with very low HDL-C because of rare loss-of-function variants in either APOA1 , LCAT , or ABCA1 genes have shown variable associations with increased atherosclerosis risk.3–6 Other families with markedly elevated HDL-C because of rare loss-of-function variants in LIPC (hepatic lipase) paradoxically had increased atherosclerosis risk,7 whereas risk was variable in families with rare loss-of-function variants in CETP and elevated HDL-C.8 Heterozygotes for the ultrarare p.P297S variant in SCARB1 (scavenger receptor SR-B1) had increased HDL-C, reduced cholesterol efflux, altered platelet function, decreased adrenal steroidogenesis but no reduction in atherosclerosis risk.9 Large Mendelian randomization studies in unrelated subjects similarly showed no relationship between common variants in several loci that modulated HDL-C levels and atherosclerosis risk.10–12A new chapter of the HDL genetics story was recently written when Zanoni et al13 reported patients with a rare loss-of-function mutation in the SCARB1 gene encoding SR-B1. The multi-institutional effort led by Daniel Rader, Chair of the Department of Genetics at the University of Pennsylvania, set out to discover rare human DNA variants among large numbers of individuals with extreme levels of plasma lipoproteins.13 The team used targeted next generation sequencing of genomic DNA from 328 patients …