title: Evidence of a polygenic origin of extreme high-density lipoprotein cholesterol levels.
abstract: OBJECTIVE
  There are several known monogenic causes of high and low high-density lipoprotein cholesterol (HDL-C) levels, but traditional sequencing studies have had limited success in identifying mutations in the majority of individuals with extreme HDL-C levels. The aim of this study was to assess the power of a targeted high-throughput sequencing strategy to elucidate the genetic basis of extreme HDL-C phenotypes.
  
  
  RESULTS
  We sequenced 195 genes with either established or implicated roles in lipid and lipoprotein metabolism plus 78 lipid-unrelated genes in patients with HDL-C <1st (n=40) or >99th (n=40) percentile values, and the results were compared with those of 498 individuals representative of the Dutch general population and 95 subjects with normal HDL-C (between 40th and 60th percentile values). The extreme HDL cohort carried more rare nonsynonymous variants in the lipid geneset than both the general population (odds ratio, 1.39; P=0.019) and normal HDL-C (odds ratio, 1.43; P=0.040) cohorts. The prevalence of such variants in the lipid-related and lipid-unrelated genesets was similar in the control groups, indicative of equal mutation rates. In the extreme HDL cohort, however, there was enrichment of rare nonsynonymous variants in the lipid versus the control geneset (odds ratio, 2.23; P<0.0001), and 70% of the lipid-related variants altered conserved nucleotides. The lipid geneset comprised 4 nonsense, 10 splice-site, and 8 coding indel variants, whereas the control geneset contained only 1 such variant. In the lipid geneset, 87% and 28% of the patients carried ≥ 2 and ≥ 5 rare variants.
  
  
  CONCLUSIONS
  This study suggests that most extreme HDL-C phenotypes have a polygenic origin.
authors.affiliation: Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. m.m.motazacker@amc.uva.nl
authors.forename: Mohammad Mahdi
authors.initials: MM
authors.lastname: Motazacker
authors.forename: Jorge
authors.initials: J
authors.lastname: Peter
authors.forename: Marco
authors.initials: M
authors.lastname: Treskes
authors.forename: Carol C
authors.initials: CC
authors.lastname: Shoulders
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
mesh_terms: D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D008076:Cholesterol, HDL / Q000097:blood*; D019295:Computational Biology; D030541:Databases, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020412:Multifactorial Inheritance; D009426:Netherlands; D016017:Odds Ratio; D010641:Phenotype; D018570:Risk Assessment; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D008076:Cholesterol, HDL
keywords: genetic variation; high-density lipoprotein cholesterol; lipid metabolism; low-density lipoprotein cholesterol; polygenic traits; triglycerides