Korean Circ J.  2019 Apr;49(4):338-349. 10.4070/kcj.2018.0161.

A Genetic Risk Score for Atrial Fibrillation Predicts the Response to Catheter Ablation

• Choe WS
• Kang JH
• Choi EK
• Shin SY
• Lubitz SA
• Ellinor PT
• Oh S
• Lim HE

• KMID: 2441137
• DOI: http://doi.org/10.4070/kcj.2018.0161

Abstract

BACKGROUND AND OBJECTIVES
The association of susceptibility loci for atrial fibrillation (AF) with AF recurrence after ablation has been reported, although with controversial results. In this prospective cohort analysis, we aimed to investigate whether a genetic risk score (GRS) can predict the rhythm outcomes after catheter ablation of AF.
METHODS
We determined the association between 20 AF-susceptible single nucleotide polymorphisms (SNPs) and AF recurrence after catheter ablation in 746 patients (74% males; age, 59±11 years; 56% paroxysmal AF). A GRS was calculated by summing the unweighted numbers of risk alleles of selected SNPs. A Cox proportional hazard model was used to identify the association between the GRS and risk of AF recurrence after catheter ablation.
RESULTS
AF recurrences after catheter ablation occurred in 168 (22.5%) subjects with a median follow-up of 23 months. The GRS was calculated using 5 SNPs (rs1448818, rs2200733, rs6843082, rs6838973 at chromosome 4q25 [PITX2] and rs2106261 at chromosome 16q22 [ZFHX3]), which showed modest associations with AF recurrence. The GRS was significantly associated with AF recurrence (hazard ratio [HR] per each score, 1.13; 95% confidence interval [CI], 1.03-1.24). Patients with intermediate (GRS 4-6) and high risks (GRS 7-10) showed HRs of 2.00 (95% CI, 0.99-4.04) and 2.66 (95% CI, 1.32-5.37), respectively, compared to patients with low risk (GRS 0-3).
CONCLUSIONS
Our novel GRS using 5 AF-susceptible SNPs was strongly associated with AF recurrence after catheter ablation in Korean population, beyond clinical risk factors. Further efforts are warranted to construct a generalizable, robust genetic prediction model which can guide the optimal treatment strategies.

Keyword

Atrial fibrillation; Genetics; Catheter ablation; Recurrence

MeSH Terms

Alleles
Atrial Fibrillation*
Catheter Ablation*
Catheters*
Cohort Studies
Follow-Up Studies
Genetics
Humans
Male
Polymorphism, Single Nucleotide
Proportional Hazards Models
Prospective Studies
Recurrence
Risk Factors

Figure

• 

  Figure 1 Distribution of the GRS among (A) the total cohort population and (B) subjects who experienced recurrence after AF ablation (blue bars) and who remained in sinus rhythm (orange bars). AF = atrial fibrillation; GRS = genetic risk score.

• 

  Figure 2 Kaplan-Meier curves depicting the proportion of subjects without recurrence after AF ablation according to risk groups stratified by the GRS. AF = atrial fibrillation; GRS = genetic risk score.

• 

  Figure 3 Graded HRs of recurrence after catheter ablation according to the risk groups stratified by the GRS. Bar graphs indicate the proportions of subjects in each risk group. CI = confidence interval; GRS = genetic risk score; HR = hazard ratio. *Compared with the low-risk group (GRS 0–3).

Reference

1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA. 2001; 285:2370–2375.

2. Kim MH, Johnston SS, Chu BC, Dalal MR, Schulman KL. Estimation of total incremental health care costs in patients with atrial fibrillation in the United States. Circ Cardiovasc Qual Outcomes. 2011; 4:313–320.

3. Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998; 339:659–666.

4. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the heart rhythm society. J Am Coll Cardiol. 2014; 64:e1–e76.

5. Sawhney N, Anousheh R, Chen WC, Narayan S, Feld GK. Five-year outcomes after segmental pulmonary vein isolation for paroxysmal atrial fibrillation. Am J Cardiol. 2009; 104:366–372.

6. Ouyang F, Tilz R, Chun J, et al. Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Circulation. 2010; 122:2368–2377.

7. Berruezo A, Tamborero D, Mont L, et al. Pre-procedural predictors of atrial fibrillation recurrence after circumferential pulmonary vein ablation. Eur Heart J. 2007; 28:836–841.

8. Park JH, Oh YS, Kim JH, et al. Effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on patients following ablation of atrial fibrillation. Korean Circ J. 2009; 39:185–189.

9. Hussein AA, Saliba WI, Martin DO, et al. Plasma B-type natriuretic peptide levels and recurrent arrhythmia after successful ablation of lone atrial fibrillation. Circulation. 2011; 123:2077–2082.

10. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007; 448:353–357.

11. Benjamin EJ, Rice KM, Arking DE, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet. 2009; 41:879–881.

12. Ellinor PT, Lunetta KL, Glazer NL, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet. 2010; 42:240–244.

13. Ellinor PT, Lunetta KL, Albert CM, et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet. 2012; 44:670–675.

14. 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; 63:1200–1210.

15. Sinner MF, Tucker NR, Lunetta KL, et al. Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. Circulation. 2014; 130:1225–1235.

16. Husser D, Adams V, Piorkowski C, Hindricks G, Bollmann A. Chromosome 4q25 variants and atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol. 2010; 55:747–753.

17. Benjamin Shoemaker M, Muhammad R, Parvez B, et al. Common atrial fibrillation risk alleles at 4q25 predict recurrence after catheter-based atrial fibrillation ablation. Heart Rhythm. 2013; 10:394–400.

18. Choi EK, Park JH, Lee JY, et al. Korean atrial fibrillation (AF) network: genetic variants for AF do not predict ablation success. J Am Heart Assoc. 2015; 4:e002046.

19. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Europace. 2018; 20:e1–e160.

20. Burgess S, Thompson SG. Use of allele scores as instrumental variables for Mendelian randomization. Int J Epidemiol. 2013; 42:1134–1144.

21. Everett BM, Cook NR, Conen D, Chasman DI, Ridker PM, Albert CM. Novel genetic markers improve measures of atrial fibrillation risk prediction. Eur Heart J. 2013; 34:2243–2251.

22. Tada H, Shiffman D, Smith JG, et al. Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke. Stroke. 2014; 45:2856–2862.

23. Muse ED, Wineinger NE, Spencer EG, et al. Validation of a genetic risk score for atrial fibrillation: a prospective multicenter cohort study. PLoS Med. 2018; 15:e1002525.

24. Parvez B, Shoemaker MB, Muhammad R, et al. Common genetic polymorphism at 4q25 locus predicts atrial fibrillation recurrence after successful cardioversion. Heart Rhythm. 2013; 10:849–855.

25. Parvez B, Vaglio J, Rowan S, et al. Symptomatic response to antiarrhythmic drug therapy is modulated by a common single nucleotide polymorphism in atrial fibrillation. J Am Coll Cardiol. 2012; 60:539–545.

26. Shoemaker MB, Bollmann A, Lubitz SA, et al. Common genetic variants and response to atrial fibrillation ablation. Circ Arrhythm Electrophysiol. 2015; 8:296–302.

27. Park JK, Lee JY, Yang PS, et al. Good responders to catheter ablation for long-standing persistent atrial fibrillation: clinical and genetic characteristics. J Cardiol. 2017; 69:584–590.

28. Mohanty S, Hall AW, Mohanty P, et al. Novel association of polymorphic genetic variants with predictors of outcome of catheter ablation in atrial fibrillation: new directions from a prospective study (DECAF). J Interv Card Electrophysiol. 2016; 45:7–17.

29. 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; 101:902–909.

30. Nojiri S, Joh T, Miura Y, et al. ATBF1 enhances the suppression of STAT3 signaling by interaction with PIAS3. Biochem Biophys Res Commun. 2004; 314:97–103.