Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks

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• 作者：Gina聽M. Peloso ; Paul聽L. Auer ; Joshua聽C. Bis ; Arend Voorman ; Alanna聽C. Morrison ; Nathan聽O. Stitziel ; Jennifer聽A. Brody ; Sumeet聽A. Khetarpal ; Jacy聽R. Crosby ; Myriam Fornage ; Aaron Isaacs ; Johanna Jakobsdottir ; Mary聽F. Feitosa ; Gail Davies ; Jennifer聽E. Huffman ; Ani Manichaikul ; Brian Davis ; Kurt Lohman ; Aron聽Y. Joon ; Albert聽V. Smith ; Megan聽L. Grove ; et al.
• 刊名：The American Journal of Human Genetics
• 出版年：6 February, 2014
• 年：2014
• 卷：94
• 期：2
• 页码：223-232
• 全文大小：382 K

文摘

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 鈥淓xome Array鈥?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^{鈭?/sup>], 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.}