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Am J Hum Genet DOI:10.1016/j.ajhg.2014.01.009

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

Publication TypeJournal Article
Year of Publication2014
AuthorsPeloso, GM, Auer, PL, Bis, JC, Voorman, A, Morrison, AC, Stitziel, NO, Brody, JA, Khetarpal, SA, Crosby, JR, Fornage, M, Isaacs, A, Jakobsdottir, J, Feitosa, MF, Davies, G, Huffman, JE, Manichaikul, A, Davis, B, Lohman, K, Joon, AY, Smith, AV, Grove, ML, Zanoni, P, Redon, V, Demissie, S, Lawson, K, Peters, U, Carlson, C, Jackson, RD, Ryckman, KK, Mackey, RH, Robinson, JG, Siscovick, DS, Schreiner, PJ, Mychaleckyj, JC, Pankow, JS, Hofman, A, Uitterlinden, AG, Harris, TB, Taylor, KD, Stafford, JM, Reynolds, LM, Marioni, RE, Dehghan, A, Franco, OH, Patel, AP, Lu, Y, Hindy, G, Gottesman, O, Bottinger, EP, Melander, O, Orho-Melander, M, Loos, RJF, Duga, S, Merlini, PAngelica, Farrall, M, Goel, A, Asselta, R, Girelli, D, Martinelli, N, Shah, SH, Kraus, WE, Li, M, Rader, DJ, Reilly, MP, McPherson, R, Watkins, H, Ardissino, D, Zhang, Q, Wang, J, Tsai, MY, Taylor, HA, Correa, A, Griswold, ME, Lange, LA, Starr, JM, Rudan, I, Eiriksdottir, G, Launer, LJ, Ordovas, JM, Levy, D, Chen, Y-DIda, Reiner, AP, Hayward, C, Polasek, O, Deary, IJ, Borecki, IB, Liu, Y, Gudnason, V, Wilson, JG, van Duijn, CM, Kooperberg, C, Rich, SS, Psaty, BM, Rotter, JI, O'Donnell, CJ, Rice, K, Boerwinkle, E, Kathiresan, S, L Cupples, A
Corporate AuthorsNHLBI GO Exome Sequencing Project
JournalAm J Hum Genet
Volume94
Issue2
Pages223-32
Date Published2014 Feb 06
ISSN1537-6605
Keywords1-Alkyl-2-acetylglycerophosphocholine Esterase, Adult, African Continental Ancestry Group, Aged, Alleles, Animals, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Coronary Disease, European Continental Ancestry Group, Female, Gene Frequency, Genetic Association Studies, Genetic Code, Genetic Variation, Humans, Linear Models, Male, Mice, Mice, Inbred C57BL, Microtubule-Associated Proteins, Middle Aged, Phenotype, Sequence Analysis, DNA, Subtilisins, Triglycerides
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0002-9297(14)00010-X
DOI10.1016/j.ajhg.2014.01.009
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract

Alternate JournalAm. J. Hum. Genet.
PubMed ID24507774
PubMed Central IDPMC3928662
Grant ListETM/55 / / Chief Scientist Office / United Kingdom
CZB/4/505 / / Chief Scientist Office / United Kingdom
RC2 HL102923 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 HL107816 / HL / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
R01HL107816 / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
MR/K026992/1 / / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
T32 HL007208 / HL / NHLBI NIH HHS / United States
K08 HL114642 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
U01 HG006380 / HG / NHGRI NIH HHS / United States
090532 / / Wellcome Trust / United Kingdom
MC_PC_U127561128 / / Medical Research Council / United Kingdom
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
T32HL007208 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
G0700704 / / Medical Research Council / United Kingdom
BB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
K08-HL114642 / HL / NHLBI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
R21 HL121422 / HL / NHLBI NIH HHS / United States