Minor allele of GJA1 gene polymorphism is associated with higher heart rate during atrial fibrillation

Abstract

Atrial fibrillation (AF) tachycardia causes heart failure and requires more attention. The genetic background of individual heart rate (HR) variations during AF are unclear. We hypothesized that HR-associated single nucleotide polymorphisms (SNPs) reported in Genome-Wide Association Studies (GWAS) are also associated with HR during AF. We enrolled patients with persistent AF (311 for screening and 146 for replication) who underwent AF ablation and were genotyped for the 21 h-associated SNPs reported in GWAS. The patients underwent 24-h Holter monitoring before AF ablation and electrophysiological study after AF ablation during sinus rhythm. Only the GJA1 SNP rs1015451 (T>C) was significantly associated with total HR (TT 110,643 ± 17,542 beats/day, TC 116,350 ± 19,060 beats/day, CC 122,163 ± 25,684 beats/day, P = 8.5 × 10−4). We also confirmed this significant association in the replication set. The intra-atrial conduction was faster in AF patients with the GJA1 minor allele than in those without it. Multivariate analysis revealed the presence of a GJA1 SNP rs1015451 additive model, female gender, lower left ventricular ejection fraction, and higher 1:1 atrioventricular nodal conduction were independently associated with higher HR during AF. The GJA1 SNP might be a new genetic marker for AF tachycardia.

Genome and atrial fibrillation

“…Our group showed that the GJA1 SNP rs1015451 (T > C) minor allele, which encodes the connexin-43, was significantly associated with higher AF heart rate. 48 However, this SNV is not consistent with AF-related SNVs and is one of the heart rate-related SNVs during sinus rhythm. 49 Zeemering et al, who performed RNA sequencing in the right and left atrial appendage tissue of AF patients, detected genes associated with persistent but could not find a gene associated with heart failure.…”

“…Our group showed that the GJA1 SNP rs1015451 (T > C) minor allele, which encodes the connexin‐43, was significantly associated with higher AF heart rate. 48 However, this SNV is not consistent with AF‐related SNVs and is one of the heart rate‐related SNVs during sinus rhythm. 49 …”

“…This consequently causes slow conduction and prolongs the effective refractory period of the atrioventricular node, promoting low heart rates during AF. Our group showed that the GJA1 SNP rs1015451 (T > C) minor allele, which encodes the connexin‐43, was significantly associated with higher AF heart rate 48 . However, this SNV is not consistent with AF‐related SNVs and is one of the heart rate‐related SNVs during sinus rhythm 49…”

Association between the APOE gene polymorphism and lipid profile and the risk of atrial fibrillation

“…Hsu et al [ 34 ] reported that subjects with AF carrying the ALDH2*2 polymorphism showed more severe oxidative stress in their atria compared with non-carriers and suggested that ALDH2 may protect from AF-related remodeling. In a single-center retrospective study, Okamura and colleagues [ 36 ] analyzed the SNPs reported in a GWAS analysis of patients with persistent AF and demonstrated that the GJA1 SNP rs1015451 has increased the risk for a higher heart rate during AF. Furthermore, Liu et al [ 37 ] reported that the ACE2 SNP rs4646188 was related to a larger left atrial end-systolic diameter and associated with a higher AF risk among Uygur patients.…”

“…With the progress in genome-wide association (GWAS) analysis in recent years, genomics has made considerable progress in the prediction of complex human diseases, such as CAD and AF [32]. To date, over 50 pathogenic gene mutations have been revealed to cause AF, which mainly involve cellular signal molecules [33], myocardial structural proteins [34], ion [35] and gap junction channels [36]. Hsu et al [34] reported that subjects with AF carrying the ALDH2*2 polymorphism showed more severe oxidative stress in their atria compared with non-carriers and suggested that ALDH2 may protect from AF-related OR in adjusted model was adjusted for LAD, LVDd, LVSd, LVEF, ALT, AST, UN, Scr, UA, CAD, HF, use of ACEIs, BBs, MRAs, digoxin and diuretics OR: odds ratio; CI: confidence interval.…”