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American journal of human genetics 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, RJ, Duga, S, Merlini, PA, 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, NHLBI GO Exome Sequencing, P, 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, YD, 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, LA
JournalAmerican journal of human genetics
Date Published2014/02/06

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.