title: Independent susceptibility markers for atrial fibrillation on chromosome 4q25.
abstract: 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.
authors: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02114, USA.
authors: Steven A
authors: SA
authors: Lubitz
authors: Moritz F
authors: MF
authors: Sinner
authors: Kathryn L
authors: KL
authors: Lunetta
authors: Seiko
authors: S
authors: Makino
authors: Arne
authors: A
authors: Pfeufer
authors: Rosanna
authors: R
authors: Rahman
authors: Caroline E
authors: CE
authors: Veltman
authors: John
authors: J
authors: Barnard
authors: Joshua C
authors: JC
authors: Bis
authors: Stephan P
authors: SP
authors: Danik
authors: Akshata
authors: A
authors: Sonni
authors: Marisa A
authors: MA
authors: Shea
authors: Federica
authors: F
authors: Del Monte
authors: Siegfried
authors: S
authors: Perz
authors: Martina
authors: M
authors: Müller
authors: Annette
authors: A
authors: Peters
authors: Steven M
authors: SM
authors: Greenberg
authors: Karen L
authors: KL
authors: Furie
authors: Charlotte
authors: C
authors: van Noord
authors: Eric
authors: E
authors: Boerwinkle
authors: Bruno H C
authors: BH
authors: Stricker
authors: Jacqueline
authors: J
authors: Witteman
authors: Jonathan D
authors: JD
authors: Smith
authors: Mina K
authors: MK
authors: Chung
authors: Susan R
authors: SR
authors: Heckbert
authors: Emelia J
authors: EJ
authors: Benjamin
authors: Jonathan
authors: J
authors: Rosand
authors: Dan E
authors: DE
authors: Arking
authors: Alvaro
authors: A
authors: Alonso
authors: Stefan
authors: S
authors: Kääb
authors: Patrick T
authors: PT
authors: Ellinor
mesh_terms: 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
chemical_list: D005819:Genetic Markers