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Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks

Research output: Contribution to journalArticle

  • 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 Fomage
  • Aaron Isaacs
  • Johanna Jakobsdottir
  • Mary F. Feitosa
  • Gail Davies
  • Jennifer E. Huffman
  • Ani Manichaikul
  • Brian Davis
  • Kurt Lohman
  • Aron Y. Joon
  • Albert V. Smith
  • Megan 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 Holman
  • 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. Patele
  • John M. Starr
  • Igor Rudan
  • Caroline Hayward
  • Ozren Polasek
  • Ian J. Deary
  • NHLBI GO Exome Sequencing Project

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)223-232
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - 6 Feb 2014


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.

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