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

and Cholesterol Content in Genome-Wide Analysis. PLoS Genet 5(11): e1000730. doi:10.1371/journal.pgen.1000730 Forty-Three Loci Associated with Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis Daniel I. Chasman 0 Guillaume Pare 0 Samia Mora 0 Jemma C. Hopewell 0 Gina Peloso 0 Robert Clarke 0 L. Adrienne Cupples 0 Anders Hamsten 0 Sekar Kathiresan 0 Anders Ma larstig 0 Jose M. 0 Ordovas 0 Samuli Ripatti 0 Alex N. Parker 0 Joseph P. Miletich 0 Paul M. Ridker 0 Goncalo R. Abecasis, University of Michigan, United States of America 0 1 Donald W. Reynolds Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital , Boston , Massachusetts, United States of America, 2 Division of Preventive Medicine, Brigham and Women's Hospital , Boston , Massachusetts, United States of America, 3 Division of Cardiology, Brigham and Women's Hospital , Boston , Massachusetts, United States of America , 4 PROCARDIS Consortium , 5 Clinical Trial Service Unit, University of Oxford , Oxford , United Kingdom , 6 Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America, 7 Framingham Heart Study, Boston University School of Medicine, Boston, Massachusetts, United States of America, 8 Atherosclerosis Research Unit, Department of Medicine Solna , Karolinska Institutet , Stockholm, Sweden, 9 Broad Institute of Massachusetts Institute of Technology and Harvard University , Cambridge, Massachusetts , United States of America, 10 USDA Human Nutrition Research Center on Aging, Tufts University , Boston , Massachusetts, United States of America, 11 Institute for Molecular Medicine Finland , FIMM, Helsinki, Finland, 12 Amgen , Inc., Cambridge, Massachusetts, United States of America , 13 Amgen , Inc. , Thousand Oaks, California , United States of America 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,561028) 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. - Competing Interests: Alex Parker and Joseph Miletich are employees of Amgen. Standard measures of plasma lipoprotein concentration do not reveal heterogeneity in the size of lipoprotein particles or their content of cholesterol and triglycerides. Yet recognizing this heterogeneity may be essential for understanding qualitative differences in lipid metabolism among individuals. Some reports identify a pattern in the size distribution of lipoprotein subfractions as intimately connected with coronary heart disease [1,2]. 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. The variation in particle size and lipid content can be quantified accurately by NMR-based methods that determine lipoprotein particle concentration according to lipid class and particle size. Thus, NMR methods can measure concentration of large and small low density lipoprotein (LDL) particles as well as concentration of the related intermediate density lipoprotein (IDL) particles, and similarly concentration of small, medium, and large high density lipoprotein (HDL) or very low density lipoprotein (VLDL) particles. HDL and LDL particle concentraGenome-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 Womens Genome Health Study, we have performed a GWAS for 22 lipoprotein measures derived from NMRbased 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. tion can also be estimated by chemical measures of apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) protein concentration, respectively, but neither these assays nor other standard clinical assays provide information about particle size distribution, and consequently the apportionment of cholesterol and triglycerides to different sized particles. The greater precision in characterizing lipoprotein profiles using NMR-based techniques provides an opportunity for correspondingly greater detail in understandi (...truncated)