Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks

Am J Hum Genet. 2014 Feb 6;94(2):223-32. doi: 10.1016/j.ajhg.2014.01.009.

Abstract

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism
  • Adult
  • African Continental Ancestry Group / genetics
  • Aged
  • Alleles
  • Animals
  • Cholesterol, HDL / blood
  • Cholesterol, HDL / genetics*
  • Cholesterol, LDL / blood
  • Cholesterol, LDL / genetics*
  • Cohort Studies
  • Coronary Disease / blood
  • Coronary Disease / genetics*
  • European Continental Ancestry Group / genetics
  • Female
  • Gene Frequency*
  • Genetic Association Studies
  • Genetic Code
  • Genetic Variation*
  • Humans
  • Linear Models
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Middle Aged
  • Phenotype
  • Sequence Analysis, DNA
  • Subtilisins / genetics
  • Subtilisins / metabolism
  • Triglycerides / blood*

Substances

  • Cholesterol, HDL
  • Cholesterol, LDL
  • Microtubule-Associated Proteins
  • Triglycerides
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • PAFAH1B2 protein, human
  • PCSK7 protein, human
  • Pcsk7 protein, mouse
  • Subtilisins