Genetic aspects of lone atrial fibrillation in patients without structural heart disease

Cover Page
Open Access Open Access
Restricted Access Subscription or Fee Access

Abstract


Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Among patients with AF the subgroup posessing AF without traditional risk factors is differentiated. Such patients are commonly referred as having “lone AF” and comprise 10–20% of all cases. A number of studies have demonstrated that the background of AF, and in particular lone AF, have a substantial genetic component.

Aims: To evaluate the influence of gene polymorphism to the development of atrial fibrillation in patients without concomitant valvular pathology and coronary artery disease.

Materials and methods: The study included 174 patients with atrial fibrillation and 124 controls without any cardiovascular pathology. All patients were divided into two subgroups: with “lone AF” (n=94) and with concomitant arterial hypertension (n=80). All patients underwent a complex of clinical, instrumental (ECG, echocardiography, computed tomography of the pulmonary veins) and laboratory tests (thyroid hormones, inflammatory markers, fibrosis), as well as genetic analysis (determination of single nucleotide polymorphisms described as AF risk factors in genes AGXT2, PDE4D, SLN, SCN5A, PITX2, PRRX1, ZFHX3, TBX5, CAV1 и HCN4).

Results: For the rare polymorphisms rs12291814 (SLN) and rs137854601 (SCN5A) wasn’t found anyone carrier of the minor allele (C and A, respectively). In the both patient subgroups the minor allele T of rs2200733 in PITX2 (OR=3.18, p<0.0001), minor allele G of rs3903239 in PRRX1, and minor alleles A of 2 polymorphisms rs2106261 and rs7193343 in ZFHX3 gene were revealed as risk factor of AF (OR=2.96, p<0.0001, OR=2.02, p=0.0045, OR=1.64, p=0.04, respectively). We also revealed significant difference between AF and control groups for rs3807989 in CAV1: homozygotic state of minor allele A has a protective effect on the development of arrhythmias (OR=0.39).

Conclusions: We revealed the association between the polymorphisms in genes regulating transcription and the development of atrial fibrillation. These polymorphisms have already described but their frequencies have never investigated in Russian population. But the polymorphisms influence to gene functions stays unclear, although attempts to investigate relationship between genotype and gene expression have been made. When the relationship will be discovered it can help us to modify our approach in treatment to patients with atrial fibrillation.


Elena Z. Golukhova

Bakoulev Center for Cardiovascular Surgery RAMS

Email: egolukhova@yahoo.com
ORCID iD: 0000-0002-6252-0322
SPIN-code: 9334-5672

Russian Federation, 135, Roublevskoye shosse, 121552 Moscow

MD, PhD, Professor

Aygerim Z. Zholbaeva

Bakoulev Center for Cardiovascular Surgery RAMS

Author for correspondence.
Email: zamirbekkyzy@list.ru
ORCID iD: 0000-0002-6918-7016
SPIN-code: 3348-5569

Russian Federation, 135, Roublevskoye shosse, 121552 Moscow

Mari G. Arakelyan

Bakoulev Center for Cardiovascular Surgery RAMS

Email: mariarakelyan@gmail.com
ORCID iD: 0000-0001-5089-0169
SPIN-code: 9161-9888

Russian Federation, 135, Roublevskoye shosse, 121552 Moscow

Naida I. Bulaeva

Bakoulev Center for Cardiovascular Surgery RAMS

Email: naida_bulaeva@yahoo.com
ORCID iD: 0000-0002-5091-0518
SPIN-code: 8979-7098

Russian Federation, 135, Roublevskoye shosse, 121552 Moscow

MD, PhD

Michail M. Minashkin

Diaem Ltd

Email: mminashkin@gmail.com
ORCID iD: 0000-0002-0726-7563
SPIN-code: 5693-0057

Russian Federation, Moscow

  1. Weijs B, Pisters R, Nieuwlaat R, et al. Idiopathic atrial fibrillation revisited in a large longitudinal clinical cohort. Europace. 2012;14(2):184–190. doi: 10.1093/europace/eur379.
  2. Lubitz SA, Yin X, Fontes JD, et al. Association between familial atrial fibrillation and risk of new-onset atrial fibrillation. JAMA. 2010;304(20):2263–2269. doi: 10.1001/jama.2010.1690.
  3. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448(7151):353–357. doi: 10.1038/nature06007.
  4. Martin RI, Babaei MS, Choy MK, et al. Genetic variants associated with risk of atrial fibrillation regulate expression of PITX2, CAV1, MYOZ1, C9orf3 and FANCC. J Mol Cell Cardiol. 2015;85:207–214. doi: 10.1016/j.yjmcc.2015.06.005.
  5. Benjamin EJ, Rice KM, Arking DE, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet. 2009;41(8):879–881. doi: 10.1038/ng.416.
  6. Schreieck J, Dostal S, von Beckerath N, C825T polymorphism of the G-protein beta3 subunit gene and atrial fibrillation: association of the TT genotype with a reduced risk for atrial fibrillation. Am Heart J. 2004;148(3):545–550. doi: 10.1016/j.ahj.2004.03.024.
  7. Zhao LQ, Wen ZJ, Wei Y, et al. Polymorphisms of renin-angiotensin-aldosterone system gene in chinese han patients with nonfamilial atrial fibrillation. PLoS One. 2015;10(2):e0117489. doi: 10.1371/journal.pone.0117489.
  8. Mommersteeg MT, Brown NA, Prall OW, et al. Pitx2c and Nkx2-5 are required for the formation and identity of the pulmonary myocardium. Circ Res. 2007;101(9):902–909. doi: 10.1161/CIRCRESAHA.107.161182.
  9. Lehnart SE, Wehrens XH, Reiken S, et al. Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Cell. 2005;123(1):25–35. doi: 10.1016/j.cell.2005.07.030.
  10. Galli D, Domínguez JN, Zaffran S, et al. Atrial myocardium derives from the posterior region of the second heart field, which acquires left-right identity as Pitx2c is expressed. Development. 2008;135(6):1157–1167. doi: 10.1242/dev.014563.
  11. Hsu J, Hanna P, van Wagoner DR, et al. Whole genome expression differences in human left and right atria ascertained by RNA sequencing. Circ Cardiovasc Genet. 2012;5(3):327–335. doi: 10.1161/CIRCGENETICS.111.961631.
  12. Pérez-Hernández M, Matamoros M, Barana A, et al. Pitx2c increases in atrial myocytes from chronic atrial fibrillation patients enhancing IKs and decreasing ICa,L. Cardiovasc Res. 2016;109(3):431–441. doi: 10.1093/cvr/cvv280.
  13. Van Weerd JH, Christoffels VM. The formation and function of the cardiac conduction system. Development. 2016;143(2):197–210. doi: 10.1242/dev.124883.
  14. Franco D, Christoffels VM, Campione M. Homeobox transcription factor Pitx2: The rise of an asymmetry gene in cardiogenesis and arrhythmogenesis. Trends Cardiovasc Med. 2014;24(1):23–31. doi: 10.1016/j.tcm.2013.06.001.
  15. Yang HJ, Lee YK, Joo CK, et al. A Family with axenfeld-rieger syndrome: report of the clinical and genetic findings. Korean J Ophthalmol. 2015;29(4):249–255. doi: 10.3341/kjo.2015.29.4.249.
  16. Lubitz SA, Lunetta KL, Lin H, et al. Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. J Am Coll Cardiol. 2014;63(12):1200–1210. doi: 10.1016/j.jacc.2013.12.015.
  17. Viviani Anselmi C, Novelli V, Roncarati R, et al. Association of rs2200733 at 4q25 with atrial flutter/fibrillation diseases in an Italian population. Heart. 2008;94(11):1394–1396. doi: 10.1136/hrt.2008.148544.
  18. Henningsen KM, Olesen MS, Haunsoe S, Svendsen JH. Association of rs2200733 at 4q25 with early onset of lone atrial fibrillation in young patients. Scand Cardiovasc J. 2011;45(6):324–326. doi: 10.3109/14017431.2011.594081.
  19. Shi L, Li C, Wang C, et al. Assessment of association of rs2200733 on chromosome 4q25 with atrial fibrillation and ischemic stroke in a Chinese Han population. Hum Genet. 2009;126(6):843–849. doi: 10.1007/s00439-009-0737-3.
  20. Lee KT, Yeh HY, Tung CP, et al. Association of RS2200733 but not RS10033464 on 4q25 with atrial fibrillation based on the recessive model in a Taiwanese population. Cardiology. 2010;116(3):151–156. doi: 10.1159/000318172.
  21. Bhanushali A, Nair A, Jagdale G, et al. Association of genetic variants at the 4q25 locus with atrial fibrillation in indian population. J Clin Lab Anal. 2017;31(1). doi: 10.1002/jcla.22017.
  22. Chen F, Yang Y, Zhang R, et al. Polymorphism rs2200733 at chromosome 4q25 is associated with atrial fibrillation recurrence after radiofrequency catheter ablation in the Chinese Han population. Am J Transl Res. 2016;8(2):688–697.
  23. Shoemaker MB, Bollmann A, Lubitz SA, et al. Common genetic variants and response to atrial fibrillation ablation. Circ Arrhythm Electrophysiol. 2015;8(2):296–302. doi: 10.1161/CIRCEP.114.001909.
  24. Huang H, Darbar D. Gene-guided therapy for catheter-ablation of atrial fibrillation: are we there yet? J Interv Card Electrophysiol. 2016;45(1):3–5. doi: 10.1007/s10840-015-0086-1.
  25. Lin H, Mueller-Nurasyid M, Smith AV, et al. Gene-gene interaction analyses for atrial fibrillation. Sci Rep. 2016;6:35371. doi: 10.1038/srep35371.
  26. Aguirre LA, Alonso ME, Badía-Careaga C, et al. Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP. BMC Biol. 2015;13:26. doi: 10.1186/s12915-015-0138-0.
  27. Syeda F, Holmes AP, Yu TY, et al. PITX2 modulates atrial membrane potential and the antiarrhythmic effects of sodium-channel blockers. J Am Coll Cardiol. 2016;68(17):1881–1894. doi: 10.1016/j.jacc.2016.07.766.
  28. Gore-Panter SR, Hsu J, Hanna P, et al. Atrial Fibrillation associated chromosome 4q25 variants are not associated with PITX2c expression in human adult left atrial appendages. PLoS One. 2014;9(1):e86245. doi: 10.1371/journal.pone.0086245.
  29. Gore-Panter SR, Hsu J, Barnard J, e al. PANCR, the PITX2 adjacent noncoding RNA, is expressed in human left atria and regulates PITX2c expression. Circ Arrhythm Electrophysiol. 2016;9(1):e003197. doi: 10.1161/CIRCEP.115.003197.
  30. Ye J, Tucker NR, Weng LC, et al. A functional variant associated with atrial fibrillation regulates PITX2c expression through TFAP2a. Am J Hum Genet. 2016;99(6):1281–1291. doi: 10.1016/j.ajhg.2016.10.001.
  31. Lin H, Dolmatova EV, Morley MP, et al. Gene expression and genetic variation in human atria. Heart Rhythm. 2014;11(2):266–271. doi: 10.1016/j.hrthm.2013.10.051.
  32. Huang Y, Wang C, Yao Y, et al. Molecular basis of gene-gene interaction: cyclic cross-regulation of gene expression and post-GWAS gene-gene interaction involved in atrial fibrillation. PLoS Genet. 2015;11(8):e1005393. doi: 10.1371/journal.pgen.1005393.
  33. Ellinor PT, Lunetta KL, Albert CM, e al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet. 2012;44(6):670–675. doi: 10.1038/ng.2261.
  34. Ihida-Stansbury K, McKean DM, Gebb SA, et al. Paired-related homeobox gene Prx1 is required for pulmonary vascular development. Circ Res. 2004;94(11):1507–1514. doi: 10.1161/01.RES.0000130656.72424.20.
  35. Jones FS, Meech R, Edelman DB, et al. Prx1 controls vascular smooth muscle cell proliferation and tenascin-C expression and is upregulated with Prx2 in pulmonary vascular disease. Circ Res. 2001;89(2):131–138. doi: 10.1161/hh1401.093582.
  36. Lin H, Sinner MF, Brody JA, et al. Targeted sequencing in candidate genes for atrial fibrillation: the cohorts for heart and aging research in genomic epidemiology (CHARGE) targeted sequencing study. Heart Rhythm. 2014;11(3):452–457. doi: 10.1016/j.hrthm.2013.11.012.
  37. Tsai CT, Hsieh CS, Chang SN, et al. Next-generation sequencing of nine atrial fibrillation candidate genes identified novel de novo mutations in patients with extreme trait of atrial fibrillation. J Med Genet. 2015;52(1):28–36. doi: 10.1136/jmedgenet-2014-102618.
  38. Liu Y, Ni B, Lin Y, et al. The rs3807989 G/A polymorphism in CAV1 is associated with the risk of atrial fibrillation in Chinese Han populations. Pacing Clin Electrophysiol. 2015;38(2):164–170. doi: 10.1111/pace.12494.
  39. Tucker NR, Dolmatova EV, Lin H, et al. Diminished PRRX1 expression is associated with increased risk of atrial fibrillation and shortening of the cardiac action potential. Circ Cardiovasc Genet. 2017;10(5). pii: e001902. doi: 10.1161/CIRCGENETICS.117.001902.

Supplementary files

There are no supplementary files to display.

Views

Abstract - 192

PDF (Russian) - 1

Cited-By


PlumX

Dimensions



Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies