Forty-Three Loci Associated with Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis

Abstract

While conventional LDL-C, HDL-C, and triglyceride measurements reflect aggregate properties of plasma lipoprotein fractions, NMR-based measurements more accurately reflect lipoprotein particle concentrations according to class (LDL, HDL, and VLDL) and particle size (small, medium, and large). The concentrations of these lipoprotein sub-fractions may be related to risk of cardiovascular disease and related metabolic disorders. We performed a genome-wide association study of 17 lipoprotein measures determined by NMR together with LDL-C, HDL-C, triglycerides, ApoA1, and ApoB in 17,296 women from the Women's Genome Health Study (WGHS). Among 36 loci with genome-wide significance (P−8) in primary and secondary analysis, ten (PCCB/STAG1 (3q22.3), GMPR/MYLIP (6p22.3), BTNL2 (6p21.32), KLF14 (7q32.2), 8p23.1, JMJD1C (10q21.3), SBF2 (11p15.4), 12q23.2, CCDC92/DNAH10/ZNF664 (12q24.31.B), and WIPI1 (17q24.2)) have not been reported in prior genome-wide association studies for plasma lipid concentration. Associations with mean lipoprotein particle size but not cholesterol content were found for LDL at four loci (7q11.23, LPL (8p21.3), 12q24.31.B, and LIPG (18q21.1)) and for HDL at one locus (GCKR (2p23.3)). In addition, genetic determinants of total IDL and total VLDL concentration were found at many loci, most strongly at LIPC (15q22.1) and APOC-APOE complex (19q13.32), respectively. Associations at seven more loci previously known for effects on conventional plasma lipid measures reveal additional genetic influences on lipoprotein profiles and bring the total number of loci to 43. Thus, genome-wide associations identified novel loci involved with lipoprotein metabolism—including loci that affect the NMR-based measures of concentration or size of LDL, HDL, and VLDL particles—all characteristics of lipoprotein profiles that may impact disease risk but are not available by conventional assay. Genome-wide association studies (GWAS) of plasma lipoprotein fractions hold great promise for understanding lipid metabolism and its central role in cardiovascular disease and related disorders. Conventional assays for lipoprotein status determine total cholesterol content of low- or high-density lipoprotein particles (LDL-C or HDL-C, respectively) or total plasma triglyceride content (as an estimate of very-low density lipoprotein particle concentration [VLDL]). All three measures have been targets for recent GWAS. However, a more precise target for GWAS of lipoprotein metabolism would be the concentration of the individual lipoprotein particles according to class (LDL, HDL, VLDL) and size (small, medium, and large), all of which can be measured by NMR-based methods. In a population of 17,296 women of European ancestry from the Women's Genome Health Study, we have performed a GWAS for 22 lipoprotein measures derived from NMR-based and conventional assays. We find 43 genetic loci involved in lipoprotein metabolism, including 10 novel loci. The results offer a clearer picture of common genetic influences on lipoprotein metabolism than available previously, including genetic effects on the distribution of LDL, HDL, and VLDL particle size, as well as on IDL and VLDL particle concentration, neither of which can be assessed by conventional measures.