title: Large-scale candidate gene analysis of HDL particle features.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Cardiovascular Science, University of Leicester, Leicester, United Kingdom.
authors.forename: Bernhard M
authors.initials: BM
authors.lastname: Kaess
authors.forename: Maciej
authors.initials: M
authors.lastname: Tomaszewski
authors.forename: Peter S
authors.initials: PS
authors.lastname: Braund
authors.forename: Klaus
authors.initials: K
authors.lastname: Stark
authors.forename: Suzanne
authors.initials: S
authors.lastname: Rafelt
authors.forename: Marcus
authors.initials: M
authors.lastname: Fischer
authors.forename: Robert
authors.initials: R
authors.lastname: Hardwick
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Debiec
authors.forename: Fritz
authors.initials: F
authors.lastname: Huber
authors.forename: Werner
authors.initials: W
authors.lastname: Kremer
authors.forename: Hans Robert
authors.initials: HR
authors.lastname: Kalbitzer
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Rose
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.forename: Jemma
authors.initials: J
authors.lastname: Hopewell
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: Paul R
authors.initials: PR
authors.lastname: Burton
authors.forename: Martin D
authors.initials: MD
authors.lastname: Tobin
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
mesh_terms: D002318:Cardiovascular Diseases; D008076:Cholesterol, HDL / Q000235:genetics*; D005190:Family; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008075:Lipoproteins, HDL / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010641:Phenotype; D006113:United Kingdom
chemical_list: D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL