Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.
BACKGROUND
Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.


RESULTS
Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3.


CONCLUSIONS
We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.
Smith
Nicholas L
NL
Cardiovascular Health Study: Department of Epidemiology, University of Washington, Seattle, WA 98105, USA. nlsmith@u.washington.edu
Felix
Janine F
JF
Morrison
Alanna C
AC
Demissie
Serkalem
S
Glazer
Nicole L
NL
Loehr
Laura R
LR
Cupples
L Adrienne
LA
Dehghan
Abbas
A
Lumley
Thomas
T
Rosamond
Wayne D
WD
Lieb
Wolfgang
W
Rivadeneira
Fernando
F
Bis
Joshua C
JC
Folsom
Aaron R
AR
Benjamin
Emelia
E
Aulchenko
Yurii S
YS
Haritunians
Talin
T
Couper
David
D
Murabito
Joanne
J
Wang
Ying A
YA
Stricker
Bruno H
BH
Gottdiener
John S
JS
Chang
Patricia P
PP
Wang
Thomas J
TJ
Rice
Kenneth M
KM
Hofman
Albert
A
Heckbert
Susan R
SR
Fox
Ervin R
ER
O'Donnell
Christopher J
CJ
Uitterlinden
Andre G
AG
Rotter
Jerome I
JI
Willerson
James T
JT
Levy
Daniel
D
van Duijn
Cornelia M
CM
Psaty
Bruce M
BM
Witteman
Jacqueline C M
JC
Boerwinkle
Eric
E
Vasan
Ramachandran S
RS
D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D010450:Endopeptidases / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006333:Heart Failure / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D064570:Ubiquitin-Specific Proteases; D044465:White People / Q000235:genetics*
D010450:Endopeptidases; C579221:USP3 protein, human; D064570:Ubiquitin-Specific Proteases
Genomics. 2004 Jul;84(1):157-65
15203213
Am J Epidemiol. 1989 Apr;129(4):687-702
2646917
Ann Epidemiol. 1995 Jul;5(4):278-85
8520709
J Mol Cell Cardiol. 2005 Feb;38(2):267-76
15698833
J Am Coll Cardiol. 2000 May;35(6):1628-37
10807470
Eur Heart J. 1999 Mar;20(6):447-55
10213348
Biochem J. 2005 Oct 1;391(Pt 1):87-93
15971998
J Biol Chem. 1999 Sep 17;274(38):26878-84
10480896
Am J Public Health Nations Health. 1951 Mar;41(3):279-81
14819398
J Am Coll Cardiol. 1993 Oct;22(4 Suppl A):6A-13A
8376698
Circ Cardiovasc Genet. 2009 Feb;2(1):73-80
20031568
PLoS Genet. 2007 Jul;3(7):e114
17676998
BMC Med Genet. 2007 Sep 19;8 Suppl 1:S5
17903304
Ann Epidemiol. 1991 Feb;1(3):263-76
1669507
N Engl J Med. 2006 Jul 13;355(2):138-47
16837677
Nature. 2007 Jun 14;447(7146):799-816
17571346
Am J Epidemiol. 2007 Sep 15;166(6):619-33
17644825
Prev Med. 1975 Dec;4(4):518-25
1208363
Am Heart J. 2004 Oct;148(4):710-7
15459605
Eur Heart J. 2004 Sep;25(18):1614-9
15351160
Eur Heart J. 2001 Sep;22(17):1527-60
11492984
Nat Genet. 2009 Jun;41(6):677-87
19430479
Nature. 2002 Jan 10;415(6868):206-12
11805844
Ann Epidemiol. 1995 Jul;5(4):270-7
8520708
Curr Biol. 2007 Nov 20;17(22):1972-7
17980597
Eur J Epidemiol. 2009;24(9):553-72
19728115
Clin Neuropathol. 2009 Jan-Feb;28(1):21-7
19216216
Circulation. 2002 Dec 10;106(24):3068-72
12473553
Eur J Epidemiol. 1991 Jul;7(4):403-22
1833235
Nat Genet. 2009 Nov;41(11):1191-8
19862010
Am J Cardiol. 2008 Apr 1;101(7):1016-22
18359324
Diabetes. 2007 Dec;56(12):2854-62
17717281
Nature. 2007 Jun 7;447(7145):661-78
17554300
Nature. 2008 Feb 21;451(7181):919-28
18288181
Ann Med. 2007;39(2):91-107
17453673
Bioinformatics. 2007 May 15;23(10):1294-6
17384015
Nat Genet. 2006 Aug;38(8):904-9
16862161
J Clin Epidemiol. 1996 Feb;49(2):223-33
8606324
Circulation. 2005 May 31;111(21):2837-49
15927992
J Am Coll Cardiol. 1999 Jun;33(7):1948-55
10362198
Development. 2008 Dec;135(24):4091-9
19004851
J Am Coll Cardiol. 2008 Jan 15;51(2):93-102
18191731
Curr Pharm Des. 2008;14(7):685-98
18336315
N Engl J Med. 1971 Dec 23;285(26):1441-6
5122894
J Immunol. 2002 Nov 1;169(9):4822-30
12391192
Blood. 2009 Mar 26;113(13):3059-69
18984860