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
Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks / 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, 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, 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, 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. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - 94:2(2014), pp. 223-232. [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
Ardissino D;
2014-01-01
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 limitedI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
