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

概要

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Minor allele of GJA1 gene
polymorphism is associated
with higher heart rate during atrial
fibrillation
Sho Okamura1, Yuko Onohara1, Hidenori Ochi2,3, Takehito Tokuyama1, Naoya Hironobe1,
Yosaku Okubo1, Yoshihiro Ikeuchi1, Shunsuke Miyauchi1, Kazuaki Chayama3, Yasuki Kihara1 &
Yukiko Nakano1*
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.
Atrial fibrillation (AF) is the most common cardiac arrhythmia that causes ­tachycardia1. There are several treatment strategies for AF. Rate control is one of the most important baseline AF therapies regardless of the stage of
AF, and it is used to either prevent the development of heart failure or reduce the s­ ymptoms2,3. The Swedish Heart
Failure Registry reported that in AF heart failure patients with a reduced ejection fraction, a heart rate (HR) > 100
beats/min was associated with a higher mortality, and β-blocker use was associated with a reduced ­mortality4.
AF is also the most common cause of tachycardia-induced cardiomyopathy in patients without a history of
structural heart d
­ isease5. Adequate rate control can reduce the risk of tachycardia-induced cardiomyopathy
and worsening heart ­failure6. However, the HR varies during AF and varies from one individual to another,
and the sensitivity to medications used for rate control therapy differs from patient to patient. Some patients
are drug-resistant despite using multiple medications. The determinant of the HR during AF has not yet been
clarified. It has been reported that the main determinant of the HR during AF is the conduction characteristics
of the atrioventricular (AV) node and autonomic t­ one7,8, but the individual variability of the HR during AF is
still not completely elucidated. Genetic differences might explain some of the individual variability in the HR
during AF, but there have been a few negative reports about the association of the genetic differences with the
HR during ­AF9,10. However, these studies were investigated under a drug administration with a small sample size.
Previous Genome-Wide Association Studies (GWAS) identified 21 single nucleotide polymorphisms (SNPs)
associated with the HR during ­SR11, and some of those HR-associated SNPs have been reported to be associated

1

Division of Frontier Medical Science, Department of Cardiovascular Medicine, Programs for Biomedical Research,
Graduate School of Biomedical Science, Hiroshima University, 1‑2‑3 Kasumi, Minami‑ku, Hiroshima  734‑8551,
Japan. 2Department of Health Management, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital,
Hiroshima, Japan. 3Department of Gastroenterology and Metabolism, Biomedical Sciences, Graduate School
of Biomedical and Health Sciences, Hiroshima University, Higashihiroshima, Japan. *email: nakanoy@
hiroshima‑u.ac.jp
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Chr

Nearest gene

HR SNP

Alleles

r2

P*

Adjusted# P*

14

MYH6

rs365990

A>G

5.1 × 10–6

0.969

0.767

6

GJA1

rs1015451

T>C

0.037

8.5 × 10–4

1.3 × 10–3

7

ACHE

rs13245899

A>G

4.8 × 10

0.706

0.743

1

CD46

rs11118555

T>A

0.002

0.477

0.494

–4

11

FADS1

rs174549

G>A

0.003

0.375

0.235

6

SLC35F1

rs11153730

T>C

5.3 × 10–5

0.900

0.983

12

LINC00477

rs17287293

A>G

2.3 × 10–4

0.792

0.968

20

KIAA1755

rs6127471

C>T

0.002

0.444

0.589

2

CCDC141

rs17362588

G>A

12

SYT10

rs7980799

C>A

5.3 × 10–4

0.689

0.668

15

HCN4

rs4489968

T>G

0.003

0.379

0.328

3

GNB4

rs7612445

G>T

1.6 × 10–4

0.828

0.805

14

FLRT2

rs17796783

T>C

9.4 × 10–6

0.958

0.916

7

CHRM2

rs2350782

T>C

0.006

0.171

0.098

5

NKX2-5

rs6882776

G>A

0.011

0.074

0.029

7

GNG11

rs180242

A>T

0.001

0.633

0.547

2

B3GNT7

rs13030174

A>C

0.001

0.609

0.948

3

FNDC3B

rs9647379

G>C

0.007

0.161

0.213

12

RFX4

rs2067615

T>A

0.006

0.166

0.121

12

CPNE8

rs826838

T>C

3.8 × 10–4

0.738

0.820

2

TFPI

rs4140885

G>A

3.3 × 10–5

0.922

0.883

Table 1.  Relationship between the HR associated SNPs and total HR in the screening set. AF atrial fibrillation,
HR heart rate, PAF paroxysmal atrial fibrillation. *Uncorrected P value in additive model. # Adjusted by age,
gender, and BMI. R2 coefficient of determination.

with cardiac conduction. We hypothesized that the HR-associated SNPs reported in the GWAS were also associated with the HR during AF.

Results

Relationship between the 21 h‑associated SNPs reported in the GWAS and total HR during AF
in screening set.  Table 1 shows the relationship between the 21 h-related SNPs reported by the GWAS and

the total HR during the 24-h Holter monitoring. The GJA1 SNP rs1015451 (T>C) genotypes were significantly
associated with the total HR after a Bonferroni correction. The total HR during AF was higher in the persistent AF patients with the GJA1 SNP rs1015451 minor allele than in those without it in the screening set (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; TT vs
CC: P = 2.5 × 10−3, TT vs TC: P = 1.5 × 10−2, TC vs CC: P = 0.12, Fig. 1). The other SNPs were not significantly
associated with the total HR. When the relationship between the HR and SNP was examined using the age,
gender, and BMI as covariates, no significant SNP other than GJA1 was observed.

Relationship between the clinical characteristics, echocardiographic parameters, and GJA1
SNP rs1015451 genotypes.  The age, gender, body mass index, and duration of AF were similar among

the 3 GJA1 SNP rs1015451 genotypes. The rates of diabetes, hypertension, strokes, structural heart disease, and
heart failure were also similar among the 3 GJA1 SNP genotypes. There were no differences in the left atrial (LA)
diameter, LA volume, or left ventricular ejection fraction (LVEF) between the 3 GJA1 SNP genotypes (Table 2).

Relationship between the EPS parameters and the GJA1 SNP rs1015451 genotypes.  The rela-

tionship between the electrophysiological study (EPS) parameters and GJA1 SNP rs1015451 genotypes is shown
in Table 3. The GJA1 SNP rs1015451 genotypes were significantly associated with the intra-atrial conduction
time. The intra-atrial conduction times from the high right atrium (HRA) to the His bundle electrogram (HBE)
and from the HRA to the distal coronary sinus (CS) were shorter in the patients with the GJA1 SNP rs1015451
minor allele than in those without it (HRA to HBE: TT 39.7 ± 14.0 ms, TC 36.8 ± 15.1 ms, CC 29.6 ± 11.1 ms,
P = 6.1 × 10−4, HRA to distal CS: TT 111.6 ± 23.1  ms, TC 108.6 ± 22.2  ms, CC 98.8 ± 18.6  ms, P = 6.4 × 10−3).
Furthermore, the AF cycle length was significantly shorter in the persistent AF patients with the GJA1 SNP
rs1015451 minor allele than in those without it (TT 155 ± 21 ms, TC 149 ± 18 ms, CC 133 ± 16 ms, P = 2.2 × 10−4).
However, the maximum sinus node recovery time (SNRT), corrected SNRT (CSRT), atrial to the His bundle
(AH) interval, His bundle to the first ventricular activation (HV) interval, 1:1 AV nodal conduction, and effective refractory period (ERP) of the AV node were similar among the 3 GJA1 SNP rs1015451 genotypes.

Multivariate analysis of the total HR during AF in patients with persistent AF.  In the univari-

ate analysis, the GJA1 SNP rs1015451 genotypes, female gender, lower LVEF, higher 1:1 AV nodal conduction,

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Figure 1.  Relationship between the GJA1 single nucleotide polymorphism (SNP) rs1015451 genotypes and
total heart rate (HR) in the patients with persistent atrial fibrillation (AF) in the screening set. The GJA1
SNP rs1015451 minor allele (C) was associated with a high total HR in the patients with persistent AF in the
screening set (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; TT vs CC: P = 2.5 × 10−3, TT vs TC: P = 1.5 × 10−2, TC vs CC: P = 0.12). ...

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