Genetic control of the HDL proteome

Nathalie Pamir; Calvin Pan; Deanna L. Plubell; Patrick M. Hutchins; Chongren Tang; Jake Wimberger; Angela Irwin; Thomas Q. de Aguiar Vallim; Jay W. Heinecke; Aldons J. Lusis

as well as larger HDL species that contain a large core of cholesteryl esters (Kontush et al., 2013; Yetukuri et al., 2010) . In humans, discrete classes of HDL based on size can be identified. In mice, HDL sizes are more continuous (LeBoeuf and Lusis, 1983 ) and represent one monodisperse peak. The size and levels of HDL vary in both human and mouse populations (Joshi et al., 2016; Pamir et al., 2016) . There are clear functional differences associated with the various size classes of HDL. In particular, the small lipid-poor particles are the best acceptors of cholesterol from cells and thus should be particularly important in mediating reverse cholesterol transport, whereas larger particles, associated with proteins such as paraoxonase 1 (PON1) and APOE, are likely to be important in protecting against inflammation. HDL particles containing proteins such as serum amyloid A (SAA) species tend to lack anti-inflammatory properties (Vaisar et al., 2015) . HDL-C levels have a skewed normal distribution in the general population, and the median levels vary by sex and ethnicity. Linkage based studies from the early 1980's have tried to identify the genetic factors that influence plasma HDL-C levels, but many findings have not been replicated due to polygenic nature of this trait, with contributions from multiple small-effect gene variants. Meta-analyses and GWAS results do, however, support the association of HDL-C with variation in CETP, LIPC, LPL, ABCA1, endothelial lipase (LIPG) and LCAT (Hegele, 2009; Thompson et al., 2008) . Multiple genetic factors could be present in an individual, creating a polygenic network of HDL-C determinants (Cohen et al., 2004) . These determinants include monogenic effectors, such rare homozygous mutations in ABCA1, LCAT, and APOA1 causing extremely low HDL-C (Brooks-Wilson et al., 1999; Kuivenhoven et al., 1996; Ng et al., 1994) , and rare homozygous mutations in CETP, LIPC, and SCARB1, causing extremely elevated HDL-C . The mouse models of these variants have been supportive of the human findings (Wang and Paigen, 2005) (Wang & Paigen, 2005) . Polygenic determinants have been recently investigated using targeted next-generation sequencing in patients with extremely low and high HDL-C. About 30% of individuals at the extremes of HDL-C had rare large effect and common small effect variants explaining the trait (Dron et al., 2017) . Whereas the genetic determinants of plasma HDL-C levels have been well studied, the genetic determinants of HDL proteome and lipidome have never been previously investigated.