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  • Although no GWAS results have been reported so

    2019-04-15

    Although no GWAS results have been reported so far from Asian populations, the candidate gene approach identified SNPs in 4q25 and 1q21 as being associated with AF in Asian populations [19,20]. Conflicting data are reported in terms of 16q22; it is associated with AF in Chinese Han [37], but not in Hong Kong [33]. A summary of GWAS results thus far is presented in Table 3. A GWAS is currently underway in the Japanese population, and the results will be reported in the near future.
    Biological significance of GWAS results The most significant SNP identified in almost all GWASs is present in the gene-desert region, with a transcription factor, Pitx2, as the closest gene. There are 3 isoforms of the Pitx2 product, Pitx2a, b, and c. Among them, Pitx2c is most abundantly expressed in the heart. Pitx2c is expressed only in the left side of the nfps and determines the left-to-right difference in the heart [38]. During the course of heart development, the sinus node-like region that generates spontaneous electrical excitation is present both in the primitive right atrium and the left atrium. When Pitx2c is expressed only in the left atrium at 11.5 day after fertilization, the sinus node-like region in the primitive left atrium disappears and the sinus node becomes localized in the right atrium (Fig. 2) [39]. Currently, the triggering event for AF is believed to be abnormal electrical activity in the myocardial sleeve in the pulmonary vein in the majority of AF cases [40]. Pitx2c plays an important role in the development of the myocardial sleeve (Fig. 3) [41]. The myocardial sleeve develops from the mesenchymal tissue present around the precursors of the pulmonary veins. Until 10.5 day after fertilization, the precursors of pulmonary veins are surrounded by mesenchymal tissue. When Pitx2c is expressed at 11.5 day, Pitx2c induces the differentiation of the mesenchymal tissue into the myocardium. When Nkx2.5 is expressed at 12.5 day, Pitx2c and Nkx2.5 co-operate to stimulate the proliferation of the myocardium along the pulmonary vein towards the lung, thereby generating the myocardial sleeve around the pulmonary veins (Fig. 3). It is not clear whether SNPs in 4q25 near the Pitx2 gene act on AF pathogenesis via the abnormal suppression of sinus node-like automaticity in the left atrium, or abnormal development of the pulmonary vein myocardial sleeve, or both. The other 2 SNPs associated with AF are located in 1q21 (in KCNN3) and in 16q22 (in ZFHX3). The functional association of ZFHX3 with AF is totally unknown. KCNN3 encodes the Ca2+ activated K+ channel that has a small single-channel conductance (SK channel). Within the heart, the SK channel is mainly localized in the atrium, and activation of SK channels contributes to the shortening of the potential duration of atrial action [42], and thereby to the induction of AF. Discovery and development of SK channel inhibitors are currently underway as a new class of anti-AF agent.
    Clinical significance of GWAS results The catheter technique for pulmonary vein isolation (PVI) is routinely used for the treatment and management of AF. The recurrence rate of AF after PVI varies from hospital to a hospital, mainly depending on whether PVI is applied to chronic AF or not, the maximum duration of AF for which PVI is applied, and whether the complex atrial fractionated electrogram-based approach is employed or not. Nevertheless, the recurrence rate appears to be roughly 40–50% after single procedure, and 10–20% after multiple procedures. Husser et al. examined if SNPs in 4q25 correlate with post-PVI recurrence of AF [43]. They analyzed 195 consecutive patients with drug-refractory paroxysmal or persistent AF who underwent PVI. The recurrence at 6 months was 21%; that in patients with any 4q25 SNP was 38%, whereas that in patients without 4q25 SNPs was 8% (p=0.007) (Fig. 4). Although the data is limited and has not been replicated, the data suggest that 4q25 SNPs can be used to stratify the risk of AF recurrence after PVI.