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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.
Wednesday,2015-03-04 13:59 America/Los_Angeles — zdrager
| Title | Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. |
| Publication Type | Journal Article |
| Year of Publication | 2014 |
| Authors | Peloso, 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, Cupples, AL |
| Corporate/Institutional Authors | NHLBI GO Exome Sequencing Project |
| Journal | Am J Hum Genet |
| Volume | 94 |
| Issue | 2 |
| Pagination | 223-32 |
| Date Published | 2014 Feb 06 |
| ISSN | 1537-6605 |
| Keywords | 1-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 | <p>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.</p> |
| DOI | 10.1016/j.ajhg.2014.01.009 |
| Alternate Journal | Am. J. Hum. Genet. |
| PubMed ID | 24507774 |
| PubMed Central ID | PMC3928662 |
| Grant List | ETM/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 |