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

Shunsuke Tomomori,Yuko Onohara,Yasuki Kihara,Shou Okamura,Hidetoshi Tahara,Akinori Sairaku,Yukie Nishiyama,Yukiko Nakano,Kazuaki Chayama,Naoya Hironobe,Hiroshi Kawazoe,Hidenori Ochi,Takehito Tokuyama,Chikaaki Motoda,Michitaka Amioka,Yousaku Okubo,Hiroya Matsumura

doi:10.1038/s41598-018-32453-8

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.

Highlights

In 2012, Ellinor et al identified six AF susceptibility loci (PRRX1, CAV1, C9orf[3], SYNPO2L, SYNE2, and HCN4) in addition to three previously reported loci (PITX2, ZFHX3, and KCNN3) by a genome-wide association study (GWAS) conducted in individuals of European ancestry
Sinus node dysfunction was independently associated with the rs6817105 minor allele in these AF patients
We showed the top 50 miRNAs, whose expression levels were higher in patients with the PITX2 single nucleotide polymorphisms (SNPs) minor C allele than those without (Supplementary Table S2)

Summary

Introduction

In 2012, Ellinor et al identified six AF susceptibility loci (PRRX1, CAV1, C9orf[3], SYNPO2L, SYNE2, and HCN4) in addition to three previously reported loci (PITX2, ZFHX3, and KCNN3) by a genome-wide association study (GWAS) conducted in individuals of European ancestry. It is reported that human PITX2 insufficiency results in cellular and molecular changes leading to atrial electrical and structural remodeling linked to arrhythmogenesis[6]. Many recent reports have implicated various microRNAs (miRNAs) in the electrical and anatomical remodeling associated with AF progression. Lu et al reported that miR-328 contributes to the adverse atrial electrical remodeling in dogs and patients with AF7. Cardin et al reported that miR-21 knockdown significantly suppressed left atrial fibrotic remodeling, tissue fibrosis, and AF persistence in rats with heart failure after experimental myocardial infarction[8]. We investigate the relationships between SNP rs6817105 on chromosome 4q25 identified by previous GWAS3,4 and clinical phenotypes of AF, and serum concentrations of 2555 miRNAs

Methods

Results

Conclusion