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

Gina M Peloso, Paul L Auer, Joshua C Bis, Arend Voorman, Alanna C Morrison, Nathan O Stitziel, Jennifer A Brody, Sumeet A Khetarpal, Jacy R Crosby, Myriam Fornage, Aaron Isaacs, Johanna Jakobsdottir, Mary F Feitosa, Gail Davies, Jennifer E Huffman, Ani Manichaikul, Brian Davis, Kurt Lohman, Aron Y Joon, Albert V SmithMegan L Grove, Paolo Zanoni, Valeska Redon, Serkalem Demissie, Kim Lawson, Ulrike Peters, Christopher Carlson, Rebecca D Jackson, Kelli K Ryckman, Rachel H Mackey, Jennifer G Robinson, David S Siscovick, Pamela J Schreiner, Josyf C Mychaleckyj, James S Pankow, Albert Hofman, Andre G Uitterlinden, Tamara B Harris, Kent D Taylor, Jeanette M Stafford, Lindsay M Reynolds, Riccardo E Marioni, Abbas Dehghan, Oscar H Franco, Aniruddh P Patel, Yingchang Lu, George Hindy, Omri Gottesman, Erwin P Bottinger, Olle Melander, NHLBI GO Exome Sequencing Project

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)223-32
Number of pages10
JournalAmerican Journal of Human Genetics
Volume94
Issue number2
DOIs
Publication statusPublished - 6 Feb 2014
Externally publishedYes

Keywords

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase/genetics
  • Adult
  • African Continental Ancestry Group/genetics
  • Aged
  • Alleles
  • Animals
  • Cholesterol, HDL/blood
  • Cholesterol, LDL/blood
  • Cohort Studies
  • Coronary Disease/blood
  • 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
  • Middle Aged
  • Phenotype
  • Sequence Analysis, DNA
  • Subtilisins/genetics
  • Triglycerides/blood

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