This editorial refers to ‘Korean atrial fibrillation network genome-wide association study for early-onset atrial fibrillation identifies novel susceptibility loci’†, by J.-Y. Lee et al., on page 2586.
Atrial fibrillation (AF) is a major global health problem due to its serious associated complications and financial burden on patients, healthcare systems, and society. Approximately 33 million people worldwide today carry the diagnosis of AF.1 Ageing of the population especially in Western countries may in part be responsible for the increasing incidence and prevalence of AF, but the identification of newer risk factors such as race, obstructive sleep apnoea, obesity, and metabolic syndrome may also contribute to this global epidemic. However, some patients develop AF in the absence of established or novel risk factors, suggesting a genetic susceptibility to the condition in the general population. Data from the Framingham study showed that a family history of AF may increase the risk of developing AF in an individual of European descent by up to three-fold.2
The pathophysiology of AF is complex, and much of our current understanding of the genetic basis of AF is derived from studies examining mostly white patients of European descent. However, marked discrepancies in the prevalence of AF and influence of known risk factors between white and non-white populations have become increasingly recognized. It is now established that African Americans are less susceptible to AF than whites of European descent despite a greater burden of traditional risk factors. In a large Japanese community cohort, the prevalence of AF was shown to be only two-thirds that of similarly aged patients in the USA.3 While similar findings have also been confirmed in Chinese cohorts, it remains unknown whether the AF paradox also applies to patients of Hispanic/Latino descent. However, ongoing studies at our centre and others will determine if Hispanic/Latino subjects are also less prone to develop AF as compared with their white counterparts.
Few studies have examined the role of common genetic variants in mediating the AF paradox in non-white populations. Marcus et al.4 were the first to show that the proportion of European ancestry in African Americans was associated with increased susceptibility to AF. The same group also went on to conduct admixture mapping, a technique particularly suited for populations with mixed ancestry such as African Americans, with the goal of identifying novel genetic loci. Roberts et al.5 identified a previously known AF risk allele on chromosome 10q22 that partially mediated a higher risk for AF in European Americans as compared with African Americans. Furthermore, they also showed that this single nucleotide polymorphism (SNP) was not only AF protective and occurred more commonly in blacks but that it also accounted for 11–32% of the reduced risk for AF in this ethnic group. Failure to identify any AF-associated SNPs with admixture mapping at the pre-specified genome-wide significance level may relate to inadequate power. However, it should be appreciated that the meta-analysis involved >5000 African Americans and constituted the largest black cohort that has undergone genome-wide association analysis. Nonetheless, this finding highlights a major challenge when performing genome-wide association studies (GWASs) across racial/ethnic groups, i.e. the need to recruit tens of thousands of individuals with and without AF in order to meet pre-specified statistical significance.
Prior GWASs conducted in mostly white patients of European ancestry have identified 14 AF susceptibility loci (Table 1).6,7 However similar results have not been as well replicated in subsequent GWAS and case–control association studies conducted in Asian populations.8 In this issue of the journal, Lee et al.9 report the results of the latest GWAS from the Korean AF Network. The discovery cohort consisted of 672 Korean patients with early-onset AF (age <60 years6) who had undergone radiofrequency catheter ablation for AF and a control group of 3700 patients without AF from a large community cohort. The replication cohort included 200 patients with AF and 1812 controls. Patients with early-onset AF in the discovery cohort were predominantly male (80%) and most were categorized as having paroxysmal AF (72%). Risk factors were less favourable for both case groups, with the exception of lower prevalence of diabetes in the control group of the replication cohort. Because of differences in baseline characteristics between the groups, analysis was performed using a propensity score matching model.
Table 1.
SNP | Locus | Closest gene | MAF (%) | RR (95% CI) | P-value |
---|---|---|---|---|---|
African American13 | |||||
rs998259 | 14q22 | GCH1 | 96.0 | NA | 3.59 × 10–6 |
rs4758417 | 11p15 | HPX | 98.0 | NA | 1.44 × 10–5 |
rs5436 | 17p13 | SLC2A4 | 91.0 | NA | 3.16 × 10–5 |
rs93267 | 8p12 | NRG1 | 92.0 | NA | 1.98 × 10–5 |
rs4246336 | 15p26 | PCSK6 | 43.0 | NA | 3.8 × 10–4 |
rs4611994 | 4q25 | PITX2 | 21.0 | 1.40 (1.16–1.69) | 5.4 × 10–4 |
Chinese14,15 | |||||
rs2200733 | 4q25 | PITX2 | 64.6 | 1.81 (1.21–3.20) | 1.3 × 10–10 |
rs3807989 | 7q31 | CAV1 | 24.5 | 1.42 (1.20–1.68) | 4.77 × 10–5 |
rs2106262 | 16q22 | ZFHX3 | 39.0 | 1.32 (1.15–1.51) | 1.97 × 10–4 |
European6,7 | |||||
rs2200733 | 4q25 | PITX2 | 25.8 | 1.71 (1.54–2.21) | 6.1 × 10–41 |
rs12415501 | 10q24 | NEURL | 16.0 | 1.18 (1.13–1.23) | 6.5 × 10–16 |
rs7193343 | 16q22 | ZFHX3 | 17.6 | 1.25 (1.17–1.3) | 1.8 × 10–15 |
rs13376333 | 1q21 | KCNN3 | 29.5 | 1.56 (1.38–1.77) | 6.3 × 10–12 |
rs3903239 | 1q24 | PRRX1 | 44.7 | 1.14 (1.10–1.18) | 9.1 × 10–11 |
rs10507248 | 12q24 | TBX5 | 73.0 | 1.12 (1.08–1.16) | 5.7 × 10–11 |
s3807989 | 7q31 | CAV1 | 40.4 | 0.88 (0.84–0.91) | 9.6 × 10–11 |
rs1152591 | 14q23 | SYNE2 | 47.6 | 1.13 (1.09–1.18) | 6.2 × 10–10 |
rs13216675 | 6q22 | GJA1 | 68.0 | 1.10 (1.06–1.14) | 2.2 ×10–9 |
rs6490029 | 12q24 | CUX2 | 64.0 | 1.12 (1.08–1.16) | 3.9 × 10–9 |
rs10821415 | 9q22 | C9orf3 | 42.4 | 1.13 (1.08–1.18) | 7.9 × 10–9 |
rs4642101 | 3p25 | CAND2 | 65.0 | 1.10 (1.06–1.14) | 9.8 × 10–9 |
rs7164883 | 15q24 | HCN4 | 16.0 | 1.16 (1.10–1.22) | 1.3 × 10–8 |
rs10824026 | 10q22 | SYNPO2L | 15.8 | 0.85 (0.81–0.9) | 1.7 × 10–8 |
Japanese10 | |||||
rs2220427 | 4q25 | PITX2 | 45.0 | 1.71 (1.63–1.78) | 1.65 × 10–134 |
rs21061 | 16q22 | ZFHX3 | 31.0 | 1.33 (1.27–1.39) | 9.63 × 10–36 |
rs6584555 | 10q24 | NEURL | 12.0 | 1.32 (1.26–1.39) | 2.0 × 10–25 |
rs7698692 | 4q34 | HAND2 | 54.2 | 1.17 (1.13–1.21) | 1.21 × 10–21 |
rs17461925 | 1q32 | PPFIA4 | 82.0 | 1.20 (1.15–1.25) | 8.69 × 10–18 |
rs2047036 | 10q24 | SH3PXD2A | 28.4 | 1.16 (1.12–1.20) | 4.04 × 10–16 |
rs2540953 | 2p14 | SLC1A4-CEP68 | 67.4 | 1.15 (1.11–1.20) | 2.06 × 10–15 |
rs12044963 | 1p13 | KCND3 | 52.0 | 1.14 (1.10–1.17) | 2.52 × 10–15 |
rs2296610 | 10p12 | NEBL | 14.5 | 1.20 (1.15–1.26) | 1.51 × 10–14 |
rs1049334 | 7q31 | CAV1 | 71.0 | 1.20 (1.15–1.26) | 1.83 × 10–14 |
rs6490029 | 12q24 | TBX5/CUX2 | 65.0 | 1.12 (1.08–1.16) | 3.9 × 10–9 |
rs639652 | 1q24 | PRRX1 | 54.0 | 1.13 (1.08–1.18) | 4.43 × 10–9 |
rs13219206 | 6q22 | GJA1-HSF2 | 72.0 | 1.14 (1.09–1.20) | 3.52 × 10–8 |
Korean9 | |||||
rs6817105 | 4q25 | PITX2 | 52.5 | 2.43 (2.12–2.78) | 6.01 × 10–38 |
rs2106261 | 16q22 | ZFHX3 | 34.8 | 2.08 (1.83–2.36) | 3.32 × 10–30 |
rs4615152 | 4q34 | HAND2 | 42.0 | 1.51 (1.35–1.68) | 1.43 × 10–12 |
rs11579055 | 1q32 | PPFIA4 | 69.0 | 1.48 91.30–1.68) | 2.29 × 10–9 |
rs3903239 | 1q24 | PRRX1 | 54.3 | 1.14 (1.24–1.60) | 1.25 × 10–7 |
rs6584555 | 10q24 | NEURL | 12.6 | 1.58 (1.33–1.88) | 2.77 × 10–7 |
rs883079 | 12q24 | TBX5 | 43.2 | 1.19 (1.05–1.35) | 0.006 |
CI, confidence interval; MAF, minor allele frequency; NA, not available; RR, relative risk; SNP, single nucleotide polymorphism.
The authors found that 5 of the 14 susceptibility loci previously identified by GWAS of patients of European ancestry were reproducibly associated with AF in this cohort of Korean patients with early-onset AF who underwent catheter ablation. The five shared genetic loci were (according to decreasing magnitude of AF association): 4q25/PITX2 rs17042171, 16q22/ZFHX3 rs2106261, 10q24/NEURL rs6584554, 1q24/PRRX1 rs3903239, and 12q24/TBX5 rs883079. Another significant finding of the study was the discovery of two novel risk loci at 1q32.1 (PPFIA4) and 4q34 (HAND2) specifically associated with early-onset AF in the Korean cohort.
The findings of the present study raise and highlight some of the challenges when conducting GWASs in diverse racial/ethnic groups. First, one potential explanation for why only 5 of the 14 AF risk loci identified in Europeans were replicated in the Korean cohort may relate to inadequate power. Low et al.10 recently identified common AF risk alleles at chromosome 1q32 and 4q34 loci but also demonstrated additional novel susceptibility loci near the genes for KCND3, SLC1A4-CEP68, NEBL, and SH3PXD2A in a GWAS of a large Japanese cohort. While the GWAS in the Korean cohort was performed in a highly selected group of patients with early-onset AF who underwent ablation for symptom control, Low et al.10 examined a much larger cohort (>8000 AF cases, >28 000 controls) and it can only be postulated whether additional power would have replicated the other four AF risk loci in a similarly sized Korean cohort. Secondly, compared with European cohorts, the minor allele frequency (MAF) was higher for common variants at PITX2, rs6817105 (52.5% vs. 13.1%) and ZFHX3, rs2106261 (34.8% vs. 17.6%), but lower for KCNN3, rs6666258 (1.8% vs. 29.9%) and HCN4, rs7164883 (8.4% vs. 16%) in the Korean cohort. So, differing MAFs across racial/ethnic groups may be another explanation for why only five AF risk loci were replicated in the Korean cohort (Table 1). Thirdly, it is possible that AF susceptibility loci are truly genetically heterogeneous across racial/ethnic groups, and this hypothesis is supported not only by the study of Lee et al.9 but also by the recent AF GWAS report in a Japanese cohort where an additional five novel AF risk loci were identified. Nonetheless, it should be emphasized that common genetic variants at the chromosome 4q25 and 16q22 loci have consistently been associated with AF and replicated across multiple diverse racial and ethnic groups.
The findings of the study of Lee et al.9 are novel in that the identification of two novel AF risk SNPs in a Korean cohort with early-onset AF may help elucidate reasons for ethnic variation in AF patterns between patients of European and Asian descent and affect future treatment approaches. The investigators performed expression quantitative trait locus (eQTL) mapping of the two AF risk loci. The top SNP rs11579055 at chromosome 1q32 was associated with increased expression of PPFIA4 in whole blood. PPFIA4 encodes liprin-α4, which regulates cell–matrix interaction and synapse maturation.11 Along with the discovery of a susceptibility locus at 10q24 (SH3PXD2A),10 the findings seem to suggest that axon guidance and focal cell adhesion may play a unique role in the pathogenesis of AF in patients of Asian descent. The other susceptibility locus on chromosome 4q34 is near the HAND2 gene which expresses a protein believed to be involved in regenerative cardiomyocyte proliferation and is also known to play a role in cardiac morphogenesis.12 However, to confirm causality between a genetic variant and AF nowadays mandates functional characterization in a heterologous expression system and/or expression in a mammalian model. Functional characterization of ion channel genetic variants using heterologous expression may be insufficient as it may miss the impact of key associated proteins. Hence, expression of a mutated ion channel or protein should entail expression in a mammalian model system.
In summary, Lee et al.9 identified and replicated the two most common AF susceptibility loci identified in patients of European descent in a Korean cohort with early-onset AF and uncovered two additional novel AF risk SNPs. The present study’s findings along with a recent GWAS in a Japanese cohort strongly support the concept of genetic heterogeneity in AF susceptibility loci across racial/ethnic groups. Such knowledge may not only elucidate the underlying molecular mechanisms of AF in diverse racial/ethnic groups but also permit a more ‘personalized’ mechanism-based approach to the management of this common and morbid condition.
Funding
This work was in part supported by NIH R01 HL092217 and R01 HL124935.
Conflict of interest: none declared.
References
- 1. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, Gillum RF, Kim YH, McAnulty JH Jr, Zheng ZJ, Forouzanfar MH, Naghavi M, Mensah GA, Ezzati M, Murray CJ.. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837–847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Fox CS, Parise H, D’Agostino RB Sr., Lloyd-Jones DM, Vasan RS, Wang TJ, Levy D, Wolf PA, Benjamin EJ.. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA 2004;291:2851–2855. [DOI] [PubMed] [Google Scholar]
- 3. Inoue H, Fujiki A, Origasa H, Ogawa S, Okumura K, Kubota I, Aizawa Y, Yamashita T, Atarashi H, Horie M, Ohe T, Doi Y, Shimizu A, Chishaki A, Saikawa T, Yano K, Kitabatake A, Mitamura H, Kodama I, Kamakura S.. Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination. Int J Cardiol 2009;137:102–107. [DOI] [PubMed] [Google Scholar]
- 4. Marcus GM, Alonso A, Peralta CA, Lettre G, Vittinghoff E, Lubitz SA, Fox ER, Levitzky YS, Mehra R, Kerr KF, Deo R, Sotoodehnia N, Akylbekova M, Ellinor PT, Paltoo DN, Soliman EZ, Benjamin EJ, Heckbert SR.. European ancestry as a risk factor for atrial fibrillation in African Americans. Circulation 2010;122:2009–2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Roberts JD, Hu D, Heckbert SR, Alonso A, Dewland TA, Vittinghoff E, Liu Y, Psaty BM, Olgin JE, Magnani JW, Huntsman S, Burchard EG, Arking DE, Bibbins-Domingo K, Harris TB, Perez MV, Ziv E, Marcus GM.. Genetic investigation into the differential risk of atrial fibrillation among black and white individuals. JAMA Cardiol 2016;1:442–450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Ellinor PT, Lunetta KL, Albert CM, Glazer NL, Ritchie MD, Smith AV, Arking DE, Muller-Nurasyid M, Krijthe BP, Lubitz SA, Bis JC, Chung MK, Dorr M, Ozaki K, Roberts JD, Smith JG, Pfeufer A, Sinner MF, Lohman K, Ding J, Smith NL, Smith JD, Rienstra M, Rice KM, Van Wagoner DR, Magnani JW, Wakili R, Clauss S, Rotter JI, Steinbeck G, Launer LJ, Davies RW, Borkovich M, Harris TB, Lin H, Volker U, Volzke H, Milan DJ, Hofman A, Boerwinkle E, Chen LY, Soliman EZ, Voight BF, Li G, Chakravarti A, Kubo M, Tedrow UB, Rose LM, Ridker PM, Conen D, Tsunoda T, Furukawa T, Sotoodehnia N, Xu S, Kamatani N, Levy D, Nakamura Y, Parvez B, Mahida S, Furie KL, Rosand J, Muhammad R, Psaty BM, Meitinger T, Perz S, Wichmann HE, Witteman JC, Kao WH, Kathiresan S, Roden DM, Uitterlinden AG, Rivadeneira F, McKnight B, Sjogren M, Newman AB, Liu Y, Gollob MH, Melander O, Tanaka T, Stricker BH, Felix SB, Alonso A, Darbar D, Barnard J, Chasman DI, Heckbert SR, Benjamin EJ, Gudnason V, Kaab S.. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 2012;44:670–675. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Sinner MF, Tucker NR, Lunetta KL, Ozaki K, Smith JG, Trompet S, Bis JC, Lin H, Chung MK, Nielsen JB, Lubitz SA, Krijthe BP, Magnani JW, Ye J, Gollob MH, Tsunoda T, Muller-Nurasyid M, Lichtner P, Peters A, Dolmatova E, Kubo M, Smith JD, Psaty BM, Smith NL, Jukema JW, Chasman DI, Albert CM, Ebana Y, Furukawa T, Macfarlane PW, Harris TB, Darbar D, Dorr M, Holst AG, Svendsen JH, Hofman A, Uitterlinden AG, Gudnason V, Isobe M, Malik R, Dichgans M, Rosand J, Van Wagoner DR, METASTROKE Consortium, AFGen Consortium, Benjamin EJ, Milan DJ, Melander O, Heckbert SR, Ford I, Liu Y, Barnard J, Olesen MS, Stricker BH, Tanaka T, Kääb S, Ellinor PT.. Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. Circulation 2014;130:1225–1235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Lubitz SA, Lunetta KL, Lin H, Arking DE, Trompet S, Li G, Krijthe BP, Chasman DI, Barnard J, Kleber ME, Dorr M, Ozaki K, Smith AV, Muller-Nurasyid M, Walter S, Agarwal SK, Bis JC, Brody JA, Chen LY, Everett BM, Ford I, Franco OH, Harris TB, Hofman A, Kaab S, Mahida S, Kathiresan S, Kubo M, Launer LJ, Macfarlane PW, Magnani JW, McKnight B, McManus DD, Peters A, Psaty BM, Rose LM, Rotter JI, Silbernagel G, Smith JD, Sotoodehnia N, Stott DJ, Taylor KD, Tomaschitz A, Tsunoda T, Uitterlinden AG, Van Wagoner DR, Volker U, Volzke H, Murabito JM, Sinner MF, Gudnason V, Felix SB, Marz W, Chung M, Albert CM, Stricker BH, Tanaka T, Heckbert SR, Jukema JW, Alonso A, Benjamin EJ, Ellinor PT.. Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. J Am Coll Cardiol 2014;63:1200–1210. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Lee JY,, Kim TH,, Yang PS, Lim HE, Choi EK, Shim J, Shin E, Uhm JS, Kim JS, Joung B, Oh S, Lee MH, Kim YH, Pak HN.. Korean atrial fibrillation network genome-wide association study for early-onset atrial fibrillation identifies novel susceptibility loci. Eur Heart J 2017;38:2586–2594. [DOI] [PubMed] [Google Scholar]
- 10. Low SK, Takahashi A, Ebana Y, Ozaki K, Christophersen IE, Ellinor PT, Consortium AF, Ogishima S, Yamamoto M, Satoh M, Sasaki M, Yamaji T, Iwasaki M, Tsugane S, Tanaka K, Naito M, Wakai K, Tanaka H, Furukawa T, Kubo M, Ito K, Kamatani Y, Tanaka T.. Identification of six new genetic loci associated with atrial fibrillation in the Japanese population. Nat Genet 201;in press. [DOI] [PubMed] [Google Scholar]
- 11. Asperti C, Astro V, Totaro A, Paris S, de Curtis I.. Liprin-alpha1 promotes cell spreading on the extracellular matrix by affecting the distribution of activated integrins. J Cell Sci 2009;122:3225–3232. [DOI] [PubMed] [Google Scholar]
- 12. Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN, Acharya A, Smith CL, Tallquist MD, Neilson EG, Hill JA, Bassel-Duby R, Olson EN.. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 2012;485:599–604. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Schnabel RB, Kerr KF, Lubitz SA, Alkylbekova EL, Marcus GM, Sinner MF, Magnani JW, Wolf PA, Deo R, Lloyd-Jones DM, Lunetta KL, Mehra R, Levy D, Fox ER, Arking DE, Mosley TH, Muller-Nurasyid M, Young TR, Wichmann HE, Seshadri S, Farlow DN, Rotter JI, Soliman EZ, Glazer NL, Wilson JG, Breteler MM, Sotoodehnia N, Newton-Cheh C, Kaab S, Ellinor PT, Alonso A, Benjamin EJ, Heckbert SR.. Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute’s Candidate Gene Association Resource (CARe) project. Circ Cardiovasc Genet 2011;4:557–564. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Shi L, Li C, Wang C, Xia Y, Wu G, Wang F, Xu C, Wang P, Li X, Wang D, Xiong X, Bai Y, Liu M, Liu J, Ren X, Gao L, Wang B, Zeng Q, Yang B, Ma X, Yang Y, Tu X, Wang QK.. Assessment of association of rs2200733 on chromosome 4q25 with atrial fibrillation and ischemic stroke in a Chinese Han population. Hum Genet 2009;126:843–849. [DOI] [PubMed] [Google Scholar]
- 15. Chen S, Wang C, Wang X, Xu C, Wu M, Wang P, Tu X, Wang QK.. Significant association between CAV1 variant rs3807989 on 7p31 and atrial fibrillation in a Chinese Han population. J Am Heart Assoc 2015;4:e001980. [DOI] [PMC free article] [PubMed] [Google Scholar]