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Genotype-phenotype associations in atrial fibrillation: meta-analysis

  • Zhen Hu
  • Deling ZouEmail author
Article

Abstract

Purpose

Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) associated with atrial fibrillation (AF). The relationship between SNPs and the incidence of stroke, heart failure, and the recurrence rate of AF after cardioversion has been reported. This meta-analysis focuses on the genotype-phenotype associations in AF.

Methods

We searched PubMed/Medline and Embase for literature providing the phenotypic parameters and genotypes of RS10033464, RS13376333, RS2106261, RS2200733, and RS7193343. We selected literature published in English and reviewed the full text of included studies to perform a meta-analysis.

Results

Fifteen papers, and 7034 patients with AF, were included. The mean risk gene frequency of the investigated variants was between 12 and 43%. The mean age of patients was between 50 and 70 and 70–80% of them were male. The stroke and heart failure frequencies in AF patients with RS2200733 were 10 and 7%, respectively. There was no significant difference in left ventricular ejection fraction and left ventricular end-diastolic diameter for all risk genotypes. For the AF recurrence after cardioversion treatment with direct current electric conversion, catheter ablation therapy, and anti-arrhythmic drugs. The early AF recurrence rate was 46% in RS10033464 and RS13376333 patients, and the late AF recurrence rate was 53% in RS2200733 patients.

Conclusions

Pooled analysis showed a significantly high prevalence of stroke (10%) in RS2200733 AF patients. AF patients with the studied SNPs had preserved left ventricular systolic function (i.e., ejection fraction greater than 50%). AF patients with RS10033464 presented larger left atrium diameter (44 mm (95% CI 42.02–45.98)) than those with other SNPs. The late AF recurrence rate was highest in RS2200733 patients (53% (95% CI 0.43–0.64)). This study aids our understanding of the existing genetic findings and the function-altering “strongest” SNPs.

Keywords

Atrial fibrillation Genotype-phenotype association SNPs Meta-analysis 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Muse ED, Wineinger NE, Spencer EG, Peters M, Henderson R, Zhang Y, et al. Validation of a genetic risk score for atrial fibrillation: a prospective multicenter cohort study [J]. PLoS Med. 2018;15(3):e1002525.CrossRefGoogle Scholar
  2. 2.
    Lubitz SA, Parsons OE, Anderson CD, Benjamin EJ, Malik R, Weng LC, et al. WTCCC2, International Stroke Genetics Consortium, and AFGen Consortia. Atrial fibrillation genetic risk and ischemic stroke mechanisms [J]. Stroke. 2017;48(6):1451–6.CrossRefGoogle Scholar
  3. 3.
    Gudbjartsson DF, Arnar DO, Helgadottir A, Gretarsdottir S, Holm H, Sigurdsson A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25 [J]. Nature. 2007;448(7151):353–7.CrossRefGoogle Scholar
  4. 4.
    Benjamin EJ, Rice KM, Arking DE, Pfeufer A, van Noord C, Smith AV, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry[J]. Nat Genet. 2009;41(8):879–81.CrossRefGoogle Scholar
  5. 5.
    Ellinor PT, Lunetta KL, Glazer NL, Pfeufer A, Alonso A, Chung MK, et al. Common variants in KCNN3 are associated with lone atrial fibrillation [J]. Nat Genet. 2010;42(3):240–4.CrossRefGoogle Scholar
  6. 6.
    Paludan-Muller C, Svendsen JH, Olesen MS. The role of common genetic variants in atrial fibrillation [J]. J Electrocardiol. 2016;49(6):864–70.CrossRefGoogle Scholar
  7. 7.
    Gudbjartsson DF, Holm H, Gretarsdottir S, Thorleifsson G, Walters GB, Thorgeirsson G, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke [J]. Nat Genet. 2009;41(8):876–8.CrossRefGoogle Scholar
  8. 8.
    Kayvanpour E, Sedaghat-Hamedani F, Amr A, Lai A, Haas J, Holzer DB, et al. Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals [J]. Clin Res Cardiol. 2017;106(2):127–39.CrossRefGoogle Scholar
  9. 9.
    Kiliszek M, Kozluk E, Franaszczyk M, Lodzinski P, Piatkowska A, Ploski R, et al. The 4q25, 1q21, and 16q22 polymorphisms and recurrence of atrial fibrillation after pulmonary vein isolation [J]. Arch Med Sci. 2016;12(1):38–44.CrossRefGoogle Scholar
  10. 10.
    Mints Y, Yarmohammadi H, Khurram IM, Hoyt H, Hansford R, Zimmerman SL, et al. Association of common variations on chromosome 4q25 and left atrial volume in patients with atrial fibrillation [J]. Clin Med Insights: Cardiol. 2015;9:39–45.Google Scholar
  11. 11.
    Parvez B, Shoemaker MB, Muhammad R, Richardson R, Jiang L, Blair MA, et al. Common genetic polymorphism at 4q25 locus predicts atrial fibrillation recurrence after successful cardioversion [J]. Heart Rhythm. 2013;10(6):849–55.CrossRefGoogle Scholar
  12. 12.
    Parvez B, Vaglio J, Rowan S, Muhammad R, Kucera G, Stubblefield T, et al. Symptomatic response to antiarrhythmic drug therapy is modulated by a common single nucleotide polymorphism in atrial fibrillation [J]. J Am Coll Cardiol. 2012;60(6):539–45.CrossRefGoogle Scholar
  13. 13.
    Husser D, Adams V, Piorkowski C, Hindricks G, Bollmann A. Chromosome 4q25 variants and atrial fibrillation recurrence after catheter ablation [J]. J Am Coll Cardiol. 2010;55(8):747–53.CrossRefGoogle Scholar
  14. 14.
    Park JK, Lee JY, Yang PS, Kim TH, Shin E, Park J, et al. Good responders to catheter ablation for long-standing persistent atrial fibrillation: clinical and genetic characteristics [J]. J Cardiol. 2017;69(3):584–90.CrossRefGoogle Scholar
  15. 15.
    Choi EK, Park JH, Lee JY, et al. Korean atrial fibrillation (AF) network: genetic variants for AF do not predict ablation success [J]. J Am Heart Assoc. 2015;4(8):e2046.CrossRefGoogle Scholar
  16. 16.
    Luo Z, Yan C, Zhang W, Shen X, Zheng W, Chen F, et al. Association between SNP rs13376333 and rs1131820 in the KCNN3 gene and atrial fibrillation in the Chinese Han population [J]. Clin Chem Lab Med. 2014;52(12):1867–73.CrossRefGoogle Scholar
  17. 17.
    Chen F, Yang Y, Zhang R, Zhang S, Dong Y, Yin X, et al. Polymorphism rs2200733 at chromosome 4q25 is associated with atrial fibrillation recurrence after radiofrequency catheter ablation in the Chinese Han population [J]. Am J Transl Res. 2016;8(2):688–97.Google Scholar
  18. 18.
    Liu Y, Ni B, Lin Y, Chen XG, Fang Z, Zhao L, et al. Genetic polymorphisms in ZFHX3 are associated with atrial fibrillation in a Chinese Han population [J]. PLoS ONE. 2014;9(7).  https://doi.org/10.1371/journal.pone.0101318.
  19. 19.
    Zhao LQ, Zhang GB, Wen ZJ, Huang CK, Wu HQ, Xu J, et al. Common variants predict recurrence after nonfamilial atrial fibrillation ablation in Chinese Han population [J]. Int J Cardiol. 2017;227:360–6.CrossRefGoogle Scholar
  20. 20.
    Ferran A, Alegret JM, Subirana I, Aragones G, Lluis-Ganella C, Romero-Menor C, et al. Association between rs2200733 and rs7193343 genetic variants and atrial fibrillation in a Spanish population, and meta-analysis of previous studies [J]. Rev Esp Cardiol (Engl Ed). 2014;67(10):822–9.Google Scholar
  21. 21.
    Kolek MJ, Parvez B, Muhammad R, Shoemaker MB, Blair MA, Stubblefield T, et al. A common variant on chromosome 4q25 is associated with prolonged PR interval in subjects with and without atrial fibrillation [J]. Am J Cardiol. 2014;113(2):309–13.CrossRefGoogle Scholar
  22. 22.
    Goodloe AH, Herron KJ, Olson TM. Uncovering an intermediate phenotype associated with rs2200733 at 4q25 in lone atrial fibrillation [J]. Am J Cardiol. 2011;107(12):1802–5.CrossRefGoogle Scholar
  23. 23.
    Shi L, Li C, Wang C, Xia Y, Wu G, Wang F, et al. Assessment of association of rs2200733 on chromosome 4q25 with atrial fibrillation and ischemic stroke in a Chinese Han population [J]. Hum Genet. 2009;126(6):843–9.CrossRefGoogle Scholar
  24. 24.
    Weng LC, Choi SH, Klarin D, Smith JG, Loh PR, Chaffin M, et al. Heritability of atrial fibrillation [J]. Circ Cardiovasc Genet. 2017;10(6).  https://doi.org/10.1161/CIRCGENETICS.117.001838.
  25. 25.
    Sun L, Tian L, Xu J, Zhang Z, Liu X. Chromosome 4q25 variants and age at onset of ischemic stroke [J]. Mol Neurobiol. 2017;54(5):3388–94.CrossRefGoogle Scholar
  26. 26.
    Sun L, Zhang Z, Xu J, Xu G, Liu X. Chromosome 4q25 variants rs2200733, rs10033464, and rs1906591 contribute to ischemic stroke risk [J]. Mol Neurobiol. 2016;53(6):3882–90.CrossRefGoogle Scholar
  27. 27.
    Kirchhof P, Breithardt G, Camm AJ, Crijns HJ, Kuck KH, Vardas P, et al. Improving outcomes in patients with atrial fibrillation: rationale and design of the early treatment of atrial fibrillation for stroke prevention trial [J]. Am Heart J. 2013;166(3):442–8.CrossRefGoogle Scholar
  28. 28.
    Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS [J]. Eur Heart J. 2016;37(38):2893–962.CrossRefGoogle Scholar
  29. 29.
    Mommersteeg MT, Brown NA, Prall OW, et al. Pitx2c and Nkx2-5 are required for the formation and identity of the pulmonary myocardium [J]. Circ Res. 2007;101(9):902–9.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of CardiologyShengJing Hospital of China Medical UniversityShenyangChina

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