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Independent susceptibility markers for atrial fibrillation on chromosome 4q25.

TitleIndependent susceptibility markers for atrial fibrillation on chromosome 4q25.
Publication TypeJournal Article
Year of Publication2010
AuthorsLubitz SA, Sinner MF, Lunetta KL, Makino S, Pfeufer A, Rahman R, Veltman CE, Barnard J, Bis JC, Danik SP, Sonni A, Shea MA, Del Monte F, Perz S, Müller M, Peters A, Greenberg SM, Furie KL, van Noord C, Boerwinkle E, Stricker BHC, Witteman J, Smith JD, Chung MK, Heckbert SR, Benjamin EJ, Rosand J, Arking DE, Alonso A, Kääb S, Ellinor PT
JournalCirculation
Volume122
Issue10
Pagination976-84
Date Published2010 Sep 07
ISSN1524-4539
KeywordsAged, Aged, 80 and over, Atrial Fibrillation, Chromosome Mapping, Chromosomes, Human, Pair 4, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Haplotypes, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors
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.

METHODS AND 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.

DOI10.1161/CIRCULATIONAHA.109.886440
Alternate JournalCirculation
PubMed ID20733104
PubMed Central IDPMC2978508
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
R01 NS059727-04 / NS / NINDS NIH HHS / United States
T32 HL007575-26A1 / HL / NHLBI NIH HHS / United States
UL1 RR024989 / RR / NCRR NIH HHS / United States
R21 DA027021 / DA / NIDA NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
R01 HL104156 / HL / NHLBI NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
T32 HL007575 / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
RC1 HL099452 / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
RC1 HL101056 / HL / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL090620 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
P50 NS051343 / NS / NINDS NIH HHS / United States
R01 NS059727 / NS / NINDS NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
M01 RR000425 / RR / NCRR NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R21 DA027021-02 / DA / NIDA NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
RC1 HL101056-02 / HL / NHLBI NIH HHS / United States
P50 HL077107 / HL / NHLBI NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States