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Rs4968309 in Myosin Light Chain 4 (MYL4)

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Rs4968309 in Myosin Light Chain 4 (MYL4) Advance Publication Circulation Journal ORIGINAL ARTICLE doi: 10.1253/circj.CJ-19-0415 Arrhythmia/Electrophysiology Rs4968309 in Myosin Light Chain 4 (MYL4) Associated With Atrial Fibrillation Onset and Predicts Clinical Outcomes After Catheter Ablation in Atrial Fibrillation Patients Without Structural Heart Disease Yuan Zhong, MD; Kai Tang, MD, PhD; Hailing Li, MD, PhD; Dongdong Zhao, MD, PhD; Wenxin Kou, MD; Shaojie Xu, MD; Jun Zhang, MD; Haotian Yang, MD; Shuang Li, MD, PhD; Rong Guo, MD, PhD; Wenhui Peng, MD, PhD; Yawei Xu, MD, PhD Background: Atrial fibrillation (AF) is the most common arrhythmia with serious complications and a high rate of recurrence after catheter ablation. Recently, mutation of MYL4 was reported as responsible for familial atrial cardiomyopathy and AF. This study aimed to determine the association between polymorphism in MYL4 with the onset and recurrence of AF. Methods and Results: A total of 7 single-nucleotide polymorphisms were selected by linkage disequilibrium and genotyped in 510 consecutive AF patients and 192 controls without structural heart disease. A total of 246 AF patients who underwent cryoballoon ablation had a 1-year scheduled follow-up study for AF recurrence. C allele and CC genotype of rs4968309 and A allele of rs1515751were associated with AF onset both before and after adjustment of covariation (age, sex, hypertension, and diabetes). AF type and left atrial size were different among the genotypes of rs4968309. Moreover, CC genotype of rs4968309 increased susceptibly of AF recurrence after cryoballoon ablation. The prevalence of hypertension was associated with rs1515752, and left atrial size was associated with the genotype of rs2071438. Conclusions: C allele and CC genotype of rs4968309 in MYL4 were associated with AF onset and recurrence. Moreover, the A allele of rs1515751 had a significant association with AF onset. The polymorphisms of MYL4 can predict AF onset and prognosis after ablation in AF patients without structural heart disease. Key Words: Atrial fibrillation; Catheter ablation; MYL4; Single-nucleotide polymorphisms trial fibrillation (AF) is the most common arrhythmia the gap junction protein a 1 (GJA1) gene,13 a homozygous affecting an estimated 1–2% of the population and mutation in the nucleoporin 155 (NUP155) gene,13 and the is associated with serious outcomes such as stroke natriuretic peptide A (NPPA) gene.14 A 1,2 and heart failure. Although catheter ablation is an Recently, using exome sequencing and systematic bioin- effective method of improving life span and quality of life formatics analyses, we identified a rare missense variant for many AF patients, there are still 20–40% of patients of the gene encoding essential myosin light chain type-4 who require further management.3 AF is associated with (MYL4 c.31G>A.p.E11K), causing missense-induced several clinical risk factors, such as diabetes mellitus, loss-of-function in a large multiplex atrial cardiomyopathy obesity, and hypertension, and its development is affected family pedigree.15 Two recent studies have also discussed by genetic background. To date, rare variants of more than the significance of variants in MYL4 in familial atrial 30 genes have been identified as correlating with AF.4–6 cardiomyopathy and AF.16,17 The MYL4 protein forms a Most of these studies have focused on ion channels, including collar around the lever of the myosin heavy chain, close to cardiac sodium, calcium, and potassium.6–12 Linkage and the site forming actin-myosin cross-bridges, and regulates candidate gene studies have also identified rare genetic the interaction.18 This 21.6-kDa protein consisting of 197 variants of non-ion channel-related genes in individuals amino acids virtually disappears from the human ventricle with familial or lone AF, such as a frameshift mutation in after birth, becomes essentially atrial-specific, and reappears Received May 13, 2019; revised manuscript received June 19, 2019; accepted July 2, 2019; J-STAGE Advance Publication released online August 10, 2019 Time for primary review: 15 days Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China ORCID of Hailing LI: 0000-0002-9903-3683 The first two authors contributed equally to this work (Y.Z., K.T.). Mailing address: Yawei Xu, MD, PhD and Hailing Li, MD, PhD, Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai 200072, China. E-mail: [email protected]; [email protected] ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Advance Publication 2 ZHONG Y et al. at the ventricular level in response to ventricular pathology.18 cardioversion, either with drugs or by direct current The corresponding ventricular protein, MYL3, is essential cardioversion. Coronary artery disease was defined as the for normal ventricular function. MYL3 mutations cause occurrence of exercise- and stress-related chest symptoms hypertrophic cardiomyopathy.19 Our further study indi- caused by ≥70% narrowing of 1 or more of the major cated that loss-of-function MYL4 variants cause progressive coronary arteries and ≥50% in the left main coronary atrial cardiomyopathy in humans and rats, and MYL4 is a artery.24 The LAd and left ventricular ejection fraction key gene required for atrial contractile, electrical, and (LVEF) were measured by transthoracic ultrasonic testing. structural integrity.15 Heart failure patients were New York Heart Association Monogenic mutations in lone and familial AF, although class IV25 or LVEF <40%.26 Body mass index (BMI) was rare, have been recognized as both gain- and loss-of- calculated as weight divided by height squared. Hyperten- function mutations in the same gene and can cause AF.20 sion was defined as blood pressure >140/90 mmHg or the Genome-wide association studies have indicated that use of antihypertensive medication. Diabetes was diagnosed common single-nucleotide polymorphisms (SNPs) have a according to the WHO criteria. Cryoballoon ablation for role in the development of AF. Common genetic variants 246 AF patients was performed by qualified physicians using associated with AF may be adopted in the clinical setting, a standard ablation procedure that has been previously such as risk stratification of the development of AF, esti- reported in detail.27 mation of the efficacy of pulmonary vein isolation, and indication of anticoagulant therapy. Excepting the rare gene SNPs Selection and DNA Genotyping variants, SNPs associated with AF may identify individuals DNA was extracted from peripheral blood using standard at an increased risk and enable stratification of ablation phenol chloroform extraction techniques. The 192 control therapy or peri-interventional management. There has been cohort and 288 AF patients were randomly selected for a study based on large-scale gene sequencing of Icelanders direct sequencing of MYL4. Genotyping was performed in that identified SNPs (rs185183057, rs28588212, rs117626672, the remaining the samples with TaqMan allelic discrimi- rs117626672) in MYL4 that predisposed to AF.21,22 In this nation by means of an ABI 7900HT (Applied Biosystems, study, we scanned all sites of MYL4 by gene sequencing in Foster City, CA, USA). The TaqMan assay kits and small Chinese cohorts with and without AF and found a probes were obtained from Applied Biosystems. All PCR new SNP rs4968309 differing significantly in the AF and data were analyzed using ABI Prism SDS software version non-AF cohorts. Next, we selected 6 SNPs in MYL4 2.3. The samples that PCR failed to detect or distinguish according to linkage disequilibrium via Haploview and production were excluded. Based on the results of sequencing, genotyping for all 7 SNPs to expand the participation. we found that rs4968309 differed significantly in the AF Through baseline data analysis and follow-up of patients and non-AF cohorts. Next, we selected 6 SNPs in MYL4 after catheter ablation, we investigated whether those SNPs according to linkage disequilibrium via Haploview. were associated with AF onset or recurrence after ablation in AF patients without structural heart disease. Follow-up Study All participants were monitored by qualified physicians Methods during their hospital stay and the procedure (i.e., the first 24–48 h) with ECGs and Holter studies. For patients who Study Design and Subjects’ Characteristics underwent cryoballoon ablation there were scheduled Our study complied with the Declaration of Helsinki and visits at 1, 3, 6, and 12 months after discharge, or earlier was approved by the hospital’s ethical review board if symptoms were consistent. 24-h Holter and 12-lead (Shanghai Tenth People’s Hospital, Tongji University ECG were necessary to determine the rapid recurrence of School of Medicine, Shanghai, China). Written informed atrial arrhythmias. Recurrence of AF was defined as any consent was given by all subjects before their participation recording of AF on ECG or an episode >30 s on 24-h in the study. This was an observational study of 510 Holter after a blanking period of 3 months or a repeat consecutive AF patients from the Department of Cardiology, ablation at any time. Atrial tachycardia was defined as a Shanghai Tenth People’s Hospital who were diagnosed regular, organized supraventricular rhythm at a constant with non-valvular AF according to the diagnostic criteria atrial rate >100 beats/min. Based on the morphology and
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