Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation.
OBJECTIVE
A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts.


RESULTS
The Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case-control studies. Participants with AF (n = 3508) were more likely to be male and were older than referent participants (n = 12 173; Framingham 82 +/- 10 vs. 71 +/- 13 years; Rotterdam 73 +/- 8 vs. 69 +/- 9 years; Vanderbilt 54 +/- 14 vs. 57 +/- 14 years; AFNet 62 +/- 12 vs. 49 +/- 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95% confidence interval (CI) 1.18-1.59; P = 3.1 x 10(-5)] to 2.52 in AFNet (95% CI 2.22-2.8; P = 1.8 x 10(-49)). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95% CI 1.03-1.75; P = 0.031) and AFNet (OR 1.30; 95% CI 1.13-1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95% CI 0.86-1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95% CI 1.60-2.26; P = 3.3 x 10(-13)) for rs2200733 and of 1.36 (95% CI 1.26-1.47; P = 6.7 x 10(-15)) for rs10033464.


CONCLUSIONS
The non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4.
Kääb
Stefan
S
Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Darbar
Dawood
D
van Noord
Charlotte
C
Dupuis
Josée
J
Pfeufer
Arne
A
Newton-Cheh
Christopher
C
Schnabel
Renate
R
Makino
Seiko
S
Sinner
Moritz F
MF
Kannankeril
Prince J
PJ
Beckmann
Britt M
BM
Choudry
Subbarao
S
Donahue
Brian S
BS
Heeringa
Jan
J
Perz
Siegfried
S
Lunetta
Kathryn L
KL
Larson
Martin G
MG
Levy
Daniel
D
MacRae
Calum A
CA
Ruskin
Jeremy N
JN
Wacker
Annette
A
Schömig
Albert
A
Wichmann
H-Erich
HE
Steinbeck
Gerhard
G
Meitinger
Thomas
T
Uitterlinden
André G
AG
Witteman
Jacqueline C M
JC
Roden
Dan M
DM
Benjamin
Emelia J
EJ
Ellinor
Patrick T
PT
D000368:Aged; D001281:Atrial Fibrillation / Q000150:complications / Q000235:genetics*; D016022:Case-Control Studies; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors