title: 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<5x10(-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.
authors: Donald W. Reynolds Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, Massachusetts, United States of America. dchasman@rics.bwh.harvard.edu
authors: Daniel I
authors: DI
authors: Chasman
authors: Guillaume
authors: G
authors: Paré
authors: Samia
authors: S
authors: Mora
authors: Jemma C
authors: JC
authors: Hopewell
authors: Gina
authors: G
authors: Peloso
authors: Robert
authors: R
authors: Clarke
authors: L Adrienne
authors: LA
authors: Cupples
authors: Anders
authors: A
authors: Hamsten
authors: Sekar
authors: S
authors: Kathiresan
authors: Anders
authors: A
authors: Mälarstig
authors: José M
authors: JM
authors: Ordovas
authors: Samuli
authors: S
authors: Ripatti
authors: Alex N
authors: AN
authors: Parker
authors: Joseph P
authors: JP
authors: Miletich
authors: Paul M
authors: PM
authors: Ridker
mesh_terms: D002784:Cholesterol / Q000097:blood*; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008074:Lipoproteins / Q000097:blood* / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008875:Middle Aged; D008957:Models, Genetic; D010316:Particle Size; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D014280:Triglycerides / Q000097:blood
chemical_list: D008074:Lipoproteins; D014280:Triglycerides; D002784:Cholesterol