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