Chromosome 4q25 Variant rs6817105 Bring Sinus Node Dysfunction and Left Atrial Enlargement

Abstract

Genome-wide association studies have reported a strong association of the single nucleotide polymorphism (SNP) rs6817105 (T > C) on chromosome 4q25 with atrial fibrillation (AF), but phenotype alterations conferred by this SNP have not been described. We genotyped SNP rs6817105 and examined the relationships among rs6817105 genotype, clinical characteristics, echocardiographic parameters, and electrophysiological parameters in 574 AF patients and 1,554 non-AF controls. Further, multiple microRNAs (miRNAs) are reported to be involved in atrial remodeling and AF pathogenesis, so we investigated relationships between rs6817105 genotype and serum concentrations of 2555 miRNAs. The rs6817105 minor allele frequency was significantly higher in AF patients than non-AF controls (66% vs. 47%, odds ratio 2.12, p = 4.9 × 10−26). Corrected sinus node recovery time (CSRT) was longer and left atrial volume index (LAVI) was larger in AF patients with the rs6817105 minor allele than patient non-carriers (CSRT: CC 557 ± 315 ms, CT 486 ± 273 ms, TT 447 ± 234 ms, p = 0.001; LAVI: CC 43.6 ± 12.1, CT 42.4 ± 13.6, TT 39.8 ± 11.6, p = 0.030). There were no significant differences between rs6817105 genotype and the serum concentrations of miRNAs. These findings strongly implicate rs6817105 minor allele in sinus node dysfunction and left atrial enlargement.

Genome and atrial fibrillation

“…These cellular and molecular changes induced atrial electrical and structural remodeling and ultimately arrhythmogenesis 16 . Our group also reported that the minor allele frequency of PITX2 single‐nucleotide variant (SNV) rs6817105 (T > C) in chromosome 4q25 was significantly higher in the 574 patients with AF than in the 1554 non‐AF controls and that rs6817105 minor allele variants caused sinus node dysfunction and left atrial enlargement 17 . Although numerous studies have investigated the involvement of PITX2 in AF, the involved mechanisms have yet to be fully elucidated.…”

“… 16 Our group also reported that the minor allele frequency of PITX2 single‐nucleotide variant (SNV) rs6817105 (T > C) in chromosome 4q25 was significantly higher in the 574 patients with AF than in the 1554 non‐AF controls and that rs6817105 minor allele variants caused sinus node dysfunction and left atrial enlargement. 17 Although numerous studies have investigated the involvement of PITX2 in AF, the involved mechanisms have yet to be fully elucidated. Nonetheless, Mun et al generated a PITX2 knockout human induced pluripotent stem cell (iPSC) line using the CRISPR/Cas9 gene, which may be useful for elucidating the aforementioned mechanism in vitro.…”

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

“…A total of 2555 miRNA sequences were detected using the 3D-Gene miRNA Labeling kit and 3D-Gene Human miRNA Oligo Chip (Toray Industries, Inc). We analyzed the relationships between the GJA1 SNP rs1015451 genotype and serum concentrations of the miRNAs in the AF patients 24 .…”