Independent Susceptibility Markers for Atrial Fibrillation on Chromosome 4q25
Open accessAbstract
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 =1.2×10 −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.
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The 12 SNPs in the AF-GRS are all the SNPs that have been reported to be associated with AF at a genome-wide significance level (P<5×10−8).
“These are all the SNPs that have been reported to be associated with AF at a genome-wide significance level (P<5×10−8), including 4 SNPs at PITX2 locus.18-23”
From Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke (2014) · cites this paper as [19]
The AF-GRS comprises 12 SNPs that had been previously shown to be associated with AF at genome-wide significance.
“The AF-GRS comprised 12 SNPs that had been previously shown to be associated with AF at genome-wide significance.”
From Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke (2014) · cites this paper as [19]
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- Authors
- Lubitz, S. A., Sinner, M. F., Lunetta, K. L., Makino, S., Pfeufer, A., Rahman, R., Veltman, C. E., Barnard, J., Bis, J. C., Danik, S. P., Sonni, A., Shea, M. A., del Monte, F., Perz, S., Müller, M., Peters, A., Greenberg, S. M., Furie, K. L., van Noord, C., Boerwinkle, E., Stricker, B. H. C., Witteman, J., Smith, J. D., Chung, M. K., Heckbert, S. R., Benjamin, E. J., Rosand, J., Arking, D. E., Alonso, A., Kääb, S., & Ellinor, P. T.
- Affiliations
- Brigham and Women's Hospital (US)
- From the Cardiovascular Research Center (S.A.L., S.M., P.T.E.), Massachusetts General Hospital, Charlestown, Mass; Division of Preventive Medicine (S.A.L.), Brigham and Women’s Hospital, Boston, Mass; Department of Medicine I (M.F.S., M.M., S.K.), University Hospital Grosshadern and Institute of Medical Informatics, Biometry and Epidemiology (M.M.), Ludwig Maximilians University, Munich, Germany; National Heart, Lung, and Blood Institute’s Framingham Heart Study (K.L.L., E.J.B.), Framingham, Mass;...
- ORCID
- Lubitz, Steven A.
- Sinner, Moritz F.
- Lunetta, Kathryn L.
- Makino, Seiko
- Barnard, John
- Bis, Joshua C.
- Sonni, Akshata
- Peters, Annette
- Greenberg, Steven M.
- Furie, Karen L.
- Boerwinkle, Eric
- Stricker, Bruno H.C.
- Smith, Jonathan D.
- Chung, Mina K.
- Heckbert, Susan R.
- Benjamin, Emelia J.
- Rosand, Jonathan
- Arking, Dan E.
- Ellinor, Patrick T.
- Venue
- Circulation
- Published
- 2010-09-07
- Volume
- 122
- Issue
- 10
- Pages
- 976-984
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC2978508
- OpenAlex
- W2157337073
- Cited by
- 156
- References
- 35
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 10 · 2019: 7 · 2018: 9 · 2017: 11 · 2016: 13 · 2015: 12 · 2014: 16 · 2013: 13 · 2012: 26
- FWCI
- 12.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- American Heart Association
- Cleveland Clinic
- Cedars-Sinai Medical Center
- Kompetenznetz Vorhofflimmern
- European Commission
- Cure Cancer Australia Foundation
- Fondation Leducq
- Bundesministerium für Bildung und Forschung
- Erasmus Medisch Centrum
- National Institutes of Health (n01hc045133-001, n01hc085079-024, n01hc015103-009, 5rc1hl099452-02, n01hc55021-47-0-1, n01hc55020-39-0-0, n01hc55016-37-0-0, n01hc055022-024, n01hc085086-022, n01hc55019-35-0-1, n01hc55018-38-0-1, n01hc55222-0-0-0, n01hc075150-004, n01hc035129-010, n01hc55015-48-0-1)
- National Heart, Lung, and Blood Institute (N01 HC085086, N01 HC055016, N01 HC085079, R01HL087652, N01 HC055020, N01 HC035129, R01HL104156, N01 HC055018, N01 HC015103, P50HL077107, R01HL087641, N01 HC055022, R01HL059367, U01HL080295, N01 HC055019, N01 HC055222, R01HL090620, T32HL007575, RC1HL101056, N01 HC075150, N01 HC055021, N01 HC055015, N01 HC045133, R01HL092577, R01HL086694, RC1-HL099452)
- National Institute on Drug Abuse (R21DA027021)
- National Human Genome Research Institute (U01HG004402)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063491)
- National Institute of Neurological Disorders and Stroke (R01NS059727, P50NS051343)
- National Center for Research Resources (UL1RR024989, M01RR000425)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- atrial fibrillation, chromosome 4q25, genetic susceptibility, single nucleotide polymorphisms, haplotype-tagging SNPs, rs2200733, replication, European ancestry
- MeSH terms
- Aged, Aged, 80 and over, Atrial Fibrillation, Chromosome Mapping, Chromosomes, Human, Pair 4, Female, Genetic Markers, Haplotypes, Humans, Male, Middle Aged, Risk Factors, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People
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