Large-Scale Candidate Gene Analysis of HDL Particle Features

Background HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis. Methodology/Principal Findings We measured plasma HDL-C and determined mean HDL particle size and particle number by NMR spectroscopy in 2024 individuals from 512 British Caucasian families. Genotypes were 49,094 SNPs in >2,100 cardiometabolic candidate genes/loci as represented on the HumanCVD BeadChip version 2. False discovery rates (FDR) were calculated to account for multiple testing. Analyses on classical HDL-C revealed significant associations (FDR<0.05) only for CETP (cholesteryl ester transfer protein; lead SNP rs3764261: p = 5.6*10−15) and SGCD (sarcoglycan delta; rs6877118: p = 8.6*10−6). In contrast, analysis with HDL mean particle size yielded additional associations in LIPC (hepatic lipase; rs261332: p = 6.1*10−9), PLTP (phospholipid transfer protein, rs4810479: p = 1.7*10−8) and FBLN5 (fibulin-5; rs2246416: p = 6.2*10−6). The associations of SGCD and Fibulin-5 with HDL particle size could not be replicated in PROCARDIS (n = 3,078) and/or the Women's Genome Health Study (n = 23,170). Conclusions We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C.

[1]  Tanya M. Teslovich,et al.  Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids , 2010, Nature.

[2]  R. Collins,et al.  Genetic variants associated with Lp(a) lipoprotein level and coronary disease. , 2009, The New England journal of medicine.

[3]  P. Ridker,et al.  Forty-Three Loci Associated with Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis , 2009, PLoS genetics.

[4]  J. Després,et al.  HDL particle size and the risk of coronary heart disease in apparently healthy men and women: the EPIC-Norfolk prospective population study. , 2009, Atherosclerosis.

[5]  Kirsi H. Pietiläinen,et al.  HDL Subspecies in Young Adult Twins: Heritability and Impact of Overweight , 2009, Obesity.

[6]  S. Mora Advanced lipoprotein testing and subfractionation are not (yet) ready for routine clinical use. , 2009, Circulation.

[7]  H. Superko Advanced Lipoprotein Testing and Subfractionation Are Clinically Useful , 2009, Circulation.

[8]  Samia Mora,et al.  Lipoprotein Particle Profiles by Nuclear Magnetic Resonance Compared With Standard Lipids and Apolipoproteins in Predicting Incident Cardiovascular Disease in Women , 2009, Circulation.

[9]  N. Wareham,et al.  High-Density Lipoprotein Particle Size and Concentration and Coronary Risk , 2009, Annals of Internal Medicine.

[10]  R. Collins,et al.  Common variants at 30 loci contribute to polygenic dyslipidemia , 2009, Nature Genetics.

[11]  Christian Gieger,et al.  Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts , 2009, Nature Genetics.

[12]  Mark I. McCarthy,et al.  Concept, Design and Implementation of a Cardiovascular Gene-Centric 50 K SNP Array for Large-Scale Genomic Association Studies , 2008, PloS one.

[13]  Nilesh J Samani,et al.  Common Variants in Genes Underlying Monogenic Hypertension and Hypotension and Blood Pressure in the General Population , 2008, Hypertension.

[14]  Hans Robert Kalbitzer,et al.  The lipoprotein subfraction profile: heritability and identification of quantitative trait loci Published, JLR Papers in Press, December 28, 2007. , 2008, Journal of Lipid Research.

[15]  A. Nègre-Salvayre,et al.  Metabolic syndrome features small, apolipoprotein A-I-poor, triglyceride-rich HDL3 particles with defective anti-apoptotic activity. , 2008, Atherosclerosis.

[16]  Dolores Corella,et al.  Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans , 2008, Nature Genetics.

[17]  A. Stefanović,et al.  Association of oxidative stress and PON1 with LDL and HDL particle size in middle‐aged subjects , 2007, European journal of clinical investigation.

[18]  G. Abecasis,et al.  Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. , 2007, Human molecular genetics.

[19]  R. Mecham,et al.  Fibulin-5 mutations: mechanisms of impaired elastic fiber formation in recessive cutis laxa. , 2006, Human molecular genetics.

[20]  D. Rader Molecular regulation of HDL metabolism and function: implications for novel therapies. , 2006, The Journal of clinical investigation.

[21]  Dean Y. Li,et al.  Altered vascular remodeling in fibulin-5-deficient mice reveals a role of fibulin-5 in smooth muscle cell proliferation and migration. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[23]  M. Ushio-Fukai,et al.  Fibulin-5 Is a Novel Binding Protein for Extracellular Superoxide Dismutase , 2004, Circulation research.

[24]  V. Sheffield,et al.  Missense variations in the fibulin 5 gene and age-related macular degeneration. , 2004, The New England journal of medicine.

[25]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  C. Curcio,et al.  Apolipoprotein B in cholesterol-containing drusen and basal deposits of human eyes with age-related maculopathy. , 2003, The American journal of pathology.

[27]  J. Colin,et al.  Is age-related macular degeneration associated with serum lipoprotein and lipoparticle levels? , 2002, Clinica chimica acta; international journal of clinical chemistry.

[28]  D. Freedman,et al.  Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) trial. , 2002, The American journal of cardiology.

[29]  Masashi Yanagisawa,et al.  Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo , 2002, Nature.

[30]  K. Campbell,et al.  Disruption of the Sarcoglycan–Sarcospan Complex in Vascular Smooth Muscle A Novel Mechanism for Cardiomyopathy and Muscular Dystrophy , 1999, Cell.

[31]  M. Taniwaki,et al.  DANCE, a Novel Secreted RGD Protein Expressed in Developing, Atherosclerotic, and Balloon-injured Arteries* , 1999, The Journal of Biological Chemistry.

[32]  D. Freedman,et al.  Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectroscopy to coronary artery disease. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[33]  L. Almasy,et al.  Multipoint quantitative-trait linkage analysis in general pedigrees. , 1998, American journal of human genetics.

[34]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[35]  D W Bennett,et al.  Quantification of plasma lipoproteins by proton nuclear magnetic resonance spectroscopy. , 1991, Clinical chemistry.

[36]  D. Rao,et al.  Twin study of genetic and environmental effects on lipid levels , 1988, Genetic epidemiology.