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

GM Peloso, PL Auer, JC Bis, A Voorman, AC Morrison, NO Stitziel, JA Brody, SA Khetarpal, JR Crosby, M Fomage, Aaron Isaacs, J Jakobsdottir, MF Feitosa, G Davies, JE Huffman, A Manichaikul, B Davis, K Lohman, AY (Aaron) Joon, AV SmithML Grove, P Zanoni, V Redon, S Demissie, K Lawson, U Peters, C Carlson, RD Jackson, KK Ryckman, RH Mackey, JG Robinson, DS Siscovick, PJ Schreiner, JC Mychaleckyj, JS Pankow, A Holman, André Uitterlinden, TB Harris, KD Taylor, JM Stafford, LM Reynolds, RE Marioni, Abbas Dehghan, OH Franco Duran, AP Patele, YC Lu, G Hindy, O Gottesman, EP Bottinger, O Melander, M Orho-Melander, RJF Loos, S Duga, PA Merlini, M Farrall, A Goel, R Asselta, D Girelli, N Martinelli, SH Shah, WE Kraus, MY Li, DJ Rader, MP Reilly, R McPherson, H Watkins, D Ardissino, QY Zhang, JD Wang, MY Tsai, HA Taylor, A Correa, ME Griswold, LA Lange, JM Starr, I Rudan, G Eiriksdottir, LJ (Lenore) Launer, JM Ordovas, D Levy, YDI Chen, AP Reiner, C Hayward, O Polasek, IJ Deary, IB Borecki, YM Liu, V Gudnason, JG Wilson, Cornelia Duijn, C Kooperberg, SS Rich, BM Psaty, JI Rotter, CJ O'Donnell, K Rice, E Boerwinkle, S Kathiresan, LA Cupples

Research output: Contribution to journalArticleAcademicpeer-review

254 Citations (Scopus)

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 languageUndefined/Unknown
Pages (from-to)223-232
Number of pages10
JournalAmerican Journal of Human Genetics
Volume94
Issue number2
DOIs
Publication statusPublished - 2014

Research programs

  • EMC MM-01-39-09-A
  • EMC NIHES-01-64-01

Cite this