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

Am J Hum Genet
Authors
Keywords
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 limited.

Year of Publication
2014
Journal
Am J Hum Genet
Volume
94
Issue
2
Pages
223-32
Date Published
2014 Feb 06
ISSN
1537-6605
URL
DOI
10.1016/j.ajhg.2014.01.009
PubMed ID
24507774
PubMed Central ID
PMC3928662
Links
Grant list
ETM/55 / Chief Scientist Office / United Kingdom
CZB/4/505 / Chief Scientist Office / United Kingdom
RC2 HL102923 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 HL107816 / HL / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
R01HL107816 / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
MR/K026992/1 / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
T32 HL007208 / HL / NHLBI NIH HHS / United States
K08 HL114642 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
U01 HG006380 / HG / NHGRI NIH HHS / United States
090532 / Wellcome Trust / United Kingdom
MC_PC_U127561128 / Medical Research Council / United Kingdom
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
T32HL007208 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
G0700704 / Medical Research Council / United Kingdom
BB/F019394/1 / Biotechnology and Biological Sciences Research Council / United Kingdom
K08-HL114642 / HL / NHLBI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
R21 HL121422 / HL / NHLBI NIH HHS / United States