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Peloso, Gina M.; Auer, Paul L.; Bis, Joshua C.; Voorman, Arend; Morrison, Alanna C.; Stitziel, Nathan O.; Brody, Jennifer A.; Khetarpal, Sumeet A.; Crosby, Jacy R.; Fornage, Myriam; Isaacs, Aaron; Jakobsdottir, Johanna; Feitosa, Mary F.; Davies, Gail; Huffman, Jennifer E.; Manichaikul, Ani; Davis, Brian; Lohman, Kurt; Joon, Aron Y.; Smith, Albert V.; Grove, Megan L.; Zanoni, Paolo; Redon, Valeska; Demissie, Serkalem; Lawson, Kim; Peters, Ulrike; Carlson, Christopher; Jackson, Rebecca D.; Ryckman, Kelli K.; Mackey, Rachel H.; Robinson, Jennifer G.; Siscovick, David S.; Schreiner, Pamela J.; Mychaleckyj, Josyf C.; Pankow, James S.; Hofman, Albert; Uitterlinden, Andre G.; Harris, Tamara B.; Taylor, Kent D.; Stafford, Jeanette M.; Reynolds, Lindsay M.; Marioni, Riccardo E.; Dehghan, Abbas; Franco, Oscar H.; Patel, Aniruddh P.; Lu, Yingchang; Hindy, George; Gottesman, Omri; Bottinger, Erwin P.; Melander, Olle; Orho-Melander, Marju; Loos, Ruth J.F.; Duga, Stefano; Merlini, Piera Angelica; Farrall, Martin; Goel, Anuj; Asselta, Rosanna; Girelli, Domenico; Martinelli, Nicola; Shah, Svati H.; Kraus, William E.; Li, Mingyao; Rader, Daniel J.; Reilly, Muredach P.; McPherson, Ruth; Watkins, Hugh; Ardissino, Diego; Zhang, Qunyuan; Wang, Judy; Tsai, Michael Y.; Taylor, Herman A.; Correa, Adolfo; Griswold, Michael E.; Lange, Leslie A.; Starr, John M.; Rudan, Igor; Eiriksdottir, Gudny; Launer, Lenore J.; Ordovas, Jose M.; Levy, Daniel; Chen, Y.-D. Ida; Reiner, Alexander P.; Hayward, Caroline; Polasek, Ozren; Deary, Ian J.; Borecki, Ingrid B.; Liu, Yongmei; Gudnason, Vilmundur; Wilson, James G.; van Duijn, Cornelia M.; Kooperberg, Charles; Rich, Stephen S.; Psaty, Bruce M.; Rotter, Jerome I.; O’Donnell, Christopher J.; Rice, Kenneth; Boerwinkle, Eric; Kathiresan, Sekar; Cupples, L. Adrienne
American journal of human genetics, 02/2014, Letnik: 94, Številka: 2Journal Article
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.
