Association of exome sequences with plasma C-reactive protein levels in >9000 participants.

Hum Mol Genet
Authors
Ursula Schick
Paul Auer
Joshua Bis
Honghuang Lin
Peng Wei
Nathan Pankratz
Leslie Lange
Jennifer Brody
Nathan Stitziel
Daniel Kim
Christopher Carlson
Myriam Fornage
Jeffery Haessler
Li Hsu
Rebecca Jackson
Charles Kooperberg
Suzanne Leal
Bruce Psaty
Eric Boerwinkle
Russell Tracy
Diego Ardissino
Svati Shah
Cristen Willer
Ruth Loos
Olle Melander
Ruth McPherson
Kees Hovingh
Muredach Reilly
Hugh Watkins
Domenico Girelli
Pierre Fontanillas
Daniel Chasman
Stacey Gabriel
Richard Gibbs
Deborah Nickerson
Sekar Kathiresan
Ulrike Peters
Josée Dupuis
James Wilson
Stephen Rich
Alanna Morrison
Emelia Benjamin
Myron Gross
Alex Reiner
Cohorts for Heart and Aging Research in Genomic Epidemiology
National Heart, Lung, and Blood Institute GO Exome Sequencing Project
Keywords
Female
Humans
Male
Adult
Genetic Predisposition to Disease
Cohort Studies
Risk Factors
Gene Frequency
Genome-Wide Association Study
Polymorphism, Single Nucleotide
European Continental Ancestry Group
Exome
African Americans
Hepatocyte Nuclear Factor 1-alpha
Cardiovascular Diseases
C-Reactive Protein
Plasma
Receptors, Interleukin-6
Abstract

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P

Year of Publication
2015
Journal
Hum Mol Genet
Volume
24
Issue
2
Pages
559-71
Date Published
2015 Jan 15
ISSN
1460-2083
URL
http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=25187575
DOI
10.1093/hmg/ddu450
PubMed ID
25187575
PubMed Central ID
PMC4334838
Links
Grant list
HHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201000010C / HL / NHLBI NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
5RC2HL102419 / HL / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
N01HC85080 / HC / NHLBI NIH HHS / United States
HHSN2682011000010C / PHS HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100005C / PHS HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
R01HL071862 / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
U01DK085526 / DK / NIDDK NIH HHS / United States
HHSN268201100009C / PHS HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
R25 CA094880 / CA / NCI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
N01HC85081 / HC / NHLBI NIH HHS / United States
F31 MH101905 / MH / NIMH NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
N01HC85079 / HC / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / PHS HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
R25CA094880 / CA / NCI NIH HHS / United States
N01HC85086 / HC / NHLBI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
U01 DK085526 / DK / NIDDK NIH HHS / United States
HHSN2682011000012C / PHS HHS / United States
R01 HL071862 / HL / NHLBI NIH HHS / United States
UM1 CA182913 / CA / NCI NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
N01HC85082 / HC / NHLBI NIH HHS / United States
HHSN268201100007C / PHS HHS / United States
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
HHSN268200800007C / PHS HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
HHSN268201200036C / PHS HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
N01HC85083 / HC / NHLBI NIH HHS / United States
HHSN268201000012C / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / PHS HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
AG023629 / AG / NIA NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
N01 HC55222 / HC / NHLBI NIH HHS / United States
HHSN2682011000011C / PHS HHS / United States

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