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<5×10−8) 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.
Highlights
Standard measures of plasma lipoprotein concentration do not reveal heterogeneity in the size of lipoprotein particles or their content of cholesterol and triglycerides
Genome-wide associations identified novel loci involved with lipoprotein metabolism—including loci that affect the NMR-based measures of concentration or size of low density lipoprotein (LDL), high density lipoprotein (HDL), and very low density lipoprotein (VLDL) particles—all characteristics of lipoprotein profiles that may impact disease risk but are not available by conventional assay
A more precise target for Genome-wide association studies (GWAS) of lipoprotein metabolism would be the concentration of the individual lipoprotein particles according to class (LDL, HDL, VLDL) and size, all of which can be measured by NMR-based methods
Summary
Standard measures of plasma lipoprotein concentration do not reveal heterogeneity in the size of lipoprotein particles or their content of cholesterol and triglycerides. Recognizing this heterogeneity may be essential for understanding qualitative differences in lipid metabolism among individuals. Related findings identify a link between lipoprotein profile and metabolic syndrome, and by inference to diabetes [3]. While these observations remain controversial for prognostic use [4], they point to alterations in lipoprotein metabolism in disease.
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