Large-Scale Candidate Gene Analysis of HDL Particle Features

• Published in: PloS one Vol. 6; no. 1; p. e14529
• Main Authors: Kaess, Bernhard M., Tomaszewski, Maciej, Braund, Peter S., Stark, Klaus, Rafelt, Suzanne, Fischer, Marcus, Hardwick, Robert, Nelson, Christopher P., Debiec, Radoslaw, Huber, Fritz, Kremer, Werner, Kalbitzer, Hans Robert, Rose, Lynda M., Chasman, Daniel I., Hopewell, Jemma, Clarke, Robert, Burton, Paul R., Tobin, Martin D., Hengstenberg, Christian, Samani, Nilesh J.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.01.2011; Public Library of Science (PLoS)
• Subjects: Antilipemic agents; Association analysis; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL - genetics; Cholesteryl ester transfer protein; Family; Female; Genes; Genetic aspects; Genetics and Genomics/Complex Traits; Genetics and Genomics/Genetics of Disease; Genetics and Genomics/Medical Genetics; Genetics and Genomics/Population Genetics; Genome-Wide Association Study - methods; Genomes; Genomics; Genotype; Genotypes; Health risks; High density lipoprotein; Humans; Lead; Lipase; Lipoproteins (high density); Lipoproteins, HDL - genetics; Low density lipoprotein; Macular degeneration; Magnetic Resonance Spectroscopy; Male; Metabolism; NMR; NMR spectroscopy; Nuclear magnetic resonance; Nuclear magnetic resonance spectroscopy; Particle size; Particulates; Phenotype; Phenotyping; Phospholipid transfer protein; Physiological aspects; Single-nucleotide polymorphism; Spectroscopy; Spectrum analysis; United Kingdom; Womens health; United Kingdom > UK; United States > US; Massachusetts; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0014529

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. 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). We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C.