Independent susceptibility markers for atrial fibrillation on chromosome 4q25.
BACKGROUND
Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus.


RESULTS
Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals.


CONCLUSIONS
We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.
Lubitz
Steven A
SA
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02114, USA.
Sinner
Moritz F
MF
Lunetta
Kathryn L
KL
Makino
Seiko
S
Pfeufer
Arne
A
Rahman
Rosanna
R
Veltman
Caroline E
CE
Barnard
John
J
Bis
Joshua C
JC
Danik
Stephan P
SP
Sonni
Akshata
A
Shea
Marisa A
MA
Del Monte
Federica
F
Perz
Siegfried
S
Müller
Martina
M
Peters
Annette
A
Greenberg
Steven M
SM
Furie
Karen L
KL
van Noord
Charlotte
C
Boerwinkle
Eric
E
Stricker
Bruno H C
BH
Witteman
Jacqueline
J
Smith
Jonathan D
JD
Chung
Mina K
MK
Heckbert
Susan R
SR
Benjamin
Emelia J
EJ
Rosand
Jonathan
J
Arking
Dan E
DE
Alonso
Alvaro
A
Kääb
Stefan
S
Ellinor
Patrick T
PT
D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000453:epidemiology* / Q000235:genetics*; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data
D005819:Genetic Markers