Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese
Open accessAbstract
Objectives This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.Background AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.Methods We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).Results We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.Conclusions The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
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The most important AF risk variants are located close to the paired-like homeodomain transcription factor 2 gene on chromosome 4q25.
“The most important variants are located close to the paired-like homeodomain transcription factor 2 gene on chromosome 4q25.63,64”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [64]
These variants modify the risk of AF up to sevenfold.
“These variants modify the risk of AF up to sevenfold.64”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [64]
Genetic predisposition is independently associated with AF, with HR range 0.4-3.2.
“Genetic predisposition (based on multiple common gene variants associated with AF) 64 HR range 0.4-3.2”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [64]
The association of an AF-GRS in a Japanese population could indicate that an AF-GRS would be useful in other populations.
“However, the association of an AF-GRS in a Japanese population could indicate that an AF-GRS would be useful in other populations.37”
From Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke (2014) · cites this paper as [37]
Lubitz et al. found that an AF-GRS comprising 12 SNPs was associated with AF in populations of European descent and in a case-control study of a Japanese population.
“They found that this AF-GRS was associated with AF in populations of European descent as well as in a case-control study of a Japanese population, thus providing support for the notion that an AF-GRS could be used in diverse ethnic settings.”
From Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke (2014) · cites this paper as [37]
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References 39 · Cited by 148
- Authors
- Lubitz, S. A., Lunetta, K. L., Lin, H., Arking, D. E., Trompet, S., Li, G., Krijthe, B. P., Chasman, D. I., Barnard, J., Kleber, M. E., Dörr, M., Ozaki, K., Smith, A. V., Müller-Nurasyid, M., Walter, S., Agarwal, S. K., Bis, J. C., Brody, J. A., Chen, L. Y., Everett, B. M., Ford, I., Franco, O. H., Harris, T. B., Hofman, A., Kääb, S., Mahida, S., Kathiresan, S., Kubo, M., Launer, L. J., Macfarlane, P. W., Magnani, J. W., McKnight, B., McManus, D. D., Peters, A., Psaty, B. M., Rose, L. M., Rotter, J. I., Silbernagel, G., Smith, J. D., Sotoodehnia, N., Stott, D. J., Taylor, K. D., Tomaschitz, A., Tsunoda, T., Uitterlinden, A. G., Van Wagoner, D. R., Völker, U., Völzke, H., Murabito, J. M., Sinner, M. F., Gudnason, V., Felix, S. B., März, W., Chung, M., Albert, C. M., Stricker, B. H., Tanaka, T., Heckbert, S. R., Jukema, J. W., Alonso, A., Benjamin, E. J., & Ellinor, P. T.
- Affiliations
- Harvard University (US)
- Boston University (US)
- Johns Hopkins University (US)
- Leiden University (NL)
- University of Washington (US)
- Erasmus MC (NL)
- Brigham and Women's Hospital (US)
- Cleveland Clinic (US)
- Heidelberg University (DE)
- Universitätsmedizin Greifswald (DE)
- RIKEN Center for Integrative Medical Sciences (JP)
- University of Iceland (IS)
- University of Minnesota (US)
- University of Glasgow (GB)
- National Institutes of Health (US)
- German Centre for Cardiovascular Research (DE)
- Leeds General Infirmary (GB)
- University of Massachusetts Chan Medical School (US)
- Helmholtz Munich (DE)
- Group Health Cooperative (US)
- University of California, Los Angeles (US)
- Cedars-Sinai Medical Center (US)
- Medical University of Graz (AT)
- Universität Greifswald (DE)
- Ludwig-Maximilians-Universität München (DE)
- Synlab Czech (Czechia) (CZ)
- Tokyo Medical and Dental University (JP)
- Leiden University Medical Center (NL)
- Corresponding author
- Lubitz, Steven A.
- ORCID
- Lubitz, Steven A.
- Lunetta, Kathryn L.
- Lin, Honghuang
- Arking, Dan E.
- Trompet, Stella
- Li, Guo
- Chasman, Daniel I.
- Barnard, John
- Kleber, Marcus E.
- Dörr, Marcus
- Ozaki, Kouichi
- Smith, Albert V.
- Walter, Stefan
- Agarwal, Sunil K.
- Bis, Joshua C.
- Brody, Jennifer A.
- Chen, Lin Y.
- Everett, Brendan M.
- Ford, Ian
- Franco, Oscar H.
- Harris, Tamara B.
- Kääb, Stefan
- Mahida, Saagar
- Kathiresan, Sekar
- Kubo, Michiaki
- Launer, Lenore J.
- Macfarlane, Peter W.
- Magnani, Jared W.
- McManus, David D.
- Peters, Annette
- Psaty, Bruce M.
- Rose, Lynda M.
- Rotter, Jerome I.
- Smith, Jonathan D.
- Stott, David J.
- Taylor, Kent D.
- Tomaschitz, Andreas
- Tsunoda, Tatsuhiko
- Völker, Uwe
- Völzke, Henry
- Murabito, Joanne M.
- Sinner, Moritz F.
- Gudnason, Vilmundur
- Felix, Stephan B.
- März, Winfried
- Chung, Mina
- Albert, Christine M.
- Stricker, Bruno H.
- Tanaka, Toshihiro
- Heckbert, Susan R.
- Jukema, J. Wouter
- Benjamin, Emelia J.
- Ellinor, Patrick T.
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 63
- Issue
- 12
- Pages
- 1200-1210
- ISSN
- 0735-1097 (ISSN-L)
- PMC
- PMC4009240
- OpenAlex
- W2067359381
- Cited by
- 148
- References
- 39
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 10 · 2023: 3 · 2022: 6 · 2021: 12 · 2020: 5 · 2019: 11 · 2018: 20 · 2017: 20 · 2016: 24 · 2015: 14 · 2014: 12
- FWCI
- 15.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Site cant be reached (submittedVersion)
- Open Access CRIS of the University of Bern
- Funders
- AstraZeneca
- Amgen
- Biotronic
- Philips Healthcare
- Otsuka Pharmaceuticals
- 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, genetic susceptibility, polygenic risk score, chromosome 4q25, PITX2, genetic risk markers, European ancestry, Japanese ancestry, evolutionary conservation, regulatory elements, cumulative risk
- MeSH terms
- Homeobox Protein PITX2, Adult, Aged, Aged, 80 and over, Atrial Fibrillation, Chromosome Mapping, Chromosomes, Human, Pair 4, Europe, Female, Genetic Markers, Humans, Japan, Male, Middle Aged, Transcription Factors, Homeodomain Proteins, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, Asian People
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