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Identification of rare variants in cardiac sodium channel β4-subunit gene SCN4B associated with ventricular tachycardia

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Abstract

Ventricular tachycardia (VT) causes sudden cardiac death, however, the majority of risk genes for VT remain unknown. SCN4B encodes a β-subunit, Navβ4, for the voltage-gated cardiac sodium channel complex involved in generation and conduction of the cardiac action potential. We hypothesized that genomic variants in SCN4B increase the risk of VT. We used high-resolution melt analysis followed by Sanger sequencing to screen 199 VT patients to identify nonsynonymous variants in SCN4B. Two nonsynonymous heterozygous variants in SCN4B were identified in VT patients, including p.Gly8Ser in four VT patients and p.Ala145Ser in one VT patient. Case–control association studies were used to assess the association between variant p.Gly8Ser and VT in two independent populations for VT (299 VT cases vs. 981 controls in population 1 and 270 VT patients vs. 639 controls in population 2). Significant association was identified between p.Gly8Ser and VT in population 1 (P = 1.21 × 10−4, odds ratio or OR = 11.04), and the finding was confirmed in population 2 (P = 0.03, OR = 3.62). The association remained highly significant in the combined population (P = 3.09 × 10−5, OR = 6.17). Significant association was also identified between p.Gly8Ser and idiopathic VT (P = 1.89 × 10−5, OR = 7.27). Functional analysis with Western blotting showed that both p.Gly8Ser and p.Ala145Ser variants significantly reduced the expression level of Navβ4. Based on 2015 ACMG Standards and Guidelines, p.Gly8Ser and p.Ala145Ser can be classified as the pathogenic and likely pathogenic variant, respectively. Our data suggest that SCN4B is a susceptibility gene for common VT and idiopathic VT and link rare SCN4B variants with large effects (OR = 6.17–7.27) to common VT.

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Abbreviations

VT:

Ventricular tachycardia

SNP:

Single nucleotide polymorphism

LQTS:

Long QT syndrome

BrS:

Brugada syndrome

GWAS:

Genome-wide association studies

MI:

Myocardial infarction

VF:

Ventricular fibrillation

ECG:

Electrocardiogram

AF:

Atrial fibrillation

CT:

Computed tomography

PCR:

Polymerase chain reaction

HRM:

High resolution melt analysis

OR:

Odds ratio

References

  • Ashar FN, Mitchell RN, Albert CM, Newton-Cheh C, Brody JA, Muller-Nurasyid M, Moes A, Meitinger T, Mak A, Huikuri H, Junttila MJ et al (2018) A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. Eur Heart J 3944:3961–3969

    Article  CAS  Google Scholar 

  • Bai Y, Nie S, Jiang G, Zhou Y, Zhou M, Zhao Y, Li S, Wang F, Lv Q, Huang Y, Yang Q et al (2014) Regulation of CARD8 expression by ANRIL and association of CARD8 single nucleotide polymorphism rs2043211 (p. C10X) with ischemic stroke. Stroke 452:383–388

    Article  CAS  Google Scholar 

  • Bauer PO, Wong HK, Oyama F, Goswami A, Okuno M, Kino Y, Miyazaki H, Nukina N (2009) Inhibition of Rho kinases enhances the degradation of mutant huntingtin. J Biol Chem 28419:13153–13164

    Article  Google Scholar 

  • Bezzina CR, Pazoki R, Bardai A, Marsman RF, de Jong J, Blom MT, Scicluna BP, Jukema JW, Bindraban NR, Lichtner P, Pfeufer A et al (2010) Genome-wide association study identifies a susceptibility locus at 21q21 for ventricular fibrillation in acute myocardial infarction. Nat Genet 428:688–691

    Article  CAS  Google Scholar 

  • Bodmer W, Bonilla C (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 406:695–701

    Article  Google Scholar 

  • Capriotti E, Fariselli P, Casadio R (2005) I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res 33:W306–W310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Catterall WA (2000) From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 261:13–25

    Article  Google Scholar 

  • Chakrabarti S, Wu X, Yang Z, Wu L, Yong SL, Zhang C, Hu K, Wang QK, Chen Q (2013) MOG1 rescues defective trafficking of Na(v)1.5 mutations in Brugada syndrome and sick sinus syndrome. Circ Arrhythm Electrophysiol 62:392–401

    Article  CAS  Google Scholar 

  • Chambers JC, Zhao J, Terracciano CM, Bezzina CR, Zhang W, Kaba R, Navaratnarajah M, Lotlikar A, Sehmi JS, Kooner MK, Deng G et al (2010) Genetic variation in SCN10A influences cardiac conduction. Nat Genet 422:149–152

    Article  CAS  Google Scholar 

  • Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R et al (1998) Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 3926673:293–296

    Article  CAS  Google Scholar 

  • Chen S, Wang C, Wang X, Xu C, Wu M, Wang P, Tu X, Wang QK (2015) Significant association between CAV1 variant rs3807989 on 7p31 and atrial fibrillation in a Chinese Han population. J Am Heart Assoc 45(5):pii: e001980. https://doi.org/10.1161/JAHA.115.001980

    Article  CAS  Google Scholar 

  • Deschenes I, Tomaselli GF (2002) Modulation of Kv4.3 current by accessory subunits. FEBS Lett 5281–3:183–188

    Article  Google Scholar 

  • Dormuth CR, Filion KB, Platt RW (2016) Likelihood ratio meta-analysis: new motivation and approach for an old method. Contemp Clin Trials 47:259–265

    Article  PubMed  PubMed Central  Google Scholar 

  • Dumaine R, Wang Q, Keating MT, Hartmann HA, Schwartz PJ, Brown AM, Kirsch GE (1996) Multiple mechanisms of Na + channel—linked long-QT syndrome. Circ Res 785:916–924

    Article  Google Scholar 

  • Grant AO (2009) Cardiac ion channels. Circ Arrhythm Electrophysiol 22:185–194

    Article  Google Scholar 

  • Huang Y, Wang C, Yao Y, Zuo X, Chen S, Xu C, Zhang H, Lu Q, Chang L, Wang F, Wang P et al (2015) Molecular basis of gene-gene interaction: cyclic cross-regulation of gene expression and Post-GWAS gene–gene interaction involved in atrial fibrillation. PLoS Genet 118:e1005393

    Article  CAS  Google Scholar 

  • Huang Y, Wang Z, Liu Y, Xiong H, Zhao Y, Wu L, Yuan C, Wang L, Hou Y, Yu G, Huang Z et al (2016) alphaB-Crystallin interacts with Nav1.5 and regulates ubiquitination and internalization of cell surface Nav1.5. J Biol Chem 29121:11030–11041

    Article  CAS  Google Scholar 

  • Israel CW (2014) Mechanisms of sudden cardiac death. Indian Heart J 66(Suppl 1):S10–S17

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim S, Jhong J-H, Lee J, Koo J-Y (2017) Meta-analytic support vector machine for integrating multiple omics data. BioData Min 101:2

    Article  CAS  Google Scholar 

  • Kostetskii I, Li J, Xiong Y, Zhou R, Ferrari VA, Patel VV, Molkentin JD, Radice GL (2005) Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure. Circ Res 963:346–354

    Article  CAS  Google Scholar 

  • Li J, Patel VV, Kostetskii I, Xiong Y, Chu AF, Jacobson JT, Yu C, Morley GE, Molkentin JD, Radice GL (2005) Cardiac-specific loss of N-cadherin leads to alteration in connexins with conduction slowing and arrhythmogenesis. Circ Res 975:474–481

    Article  CAS  Google Scholar 

  • Li C, Wang F, Yang Y, Fu F, Xu C, Shi L, Li S, Xia Y, Wu G, Cheng X, Liu H et al (2011) Significant association of SNP rs2106261 in the ZFHX3 gene with atrial fibrillation in a Chinese Han GeneID population. Hum Genet 1293:239–246

    Article  Google Scholar 

  • Li RG, Wang Q, Xu YJ, Zhang M, Qu XK, Liu X, Fang WY, Yang YQ (2013) Mutations of the SCN4B-encoded sodium channel β4 subunit in familial atrial fibrillation. Int J Mol Med 321:144–150

    Article  CAS  Google Scholar 

  • Li Q, Zhao Y, Wu G, Chen S, Zhou Y, Li S, Zhou M, Fan Q, Pu J, Hong K, Cheng X et al (2017) De novo FGF12 (fibroblast growth factor 12) functional variation is potentially associated with idiopathic ventricular tachycardia. J Am Heart Assoc 6(8):pii: e006130. https://doi.org/10.1161/JAHA.117.006130

    Google Scholar 

  • Medeiros-Domingo A, Kaku T, Tester DJ, Iturralde-Torres P, Itty A, Ye B, Valdivia C, Ueda K, Canizales-Quinteros S, Tusie-Luna MT, Makielski JC et al (2007) SCN4B-encoded sodium channel β4 subunit in congenital long-QT syndrome. Circulation 1162:134–142

    Article  Google Scholar 

  • Nguyen HM, Miyazaki H, Hoshi N, Smith BJ, Nukina N, Goldin AL, Chandy KG (2012) Modulation of voltage-gated K + channels by the sodium channel beta1 subunit. Proc Natl Acad Sci USA 10945:18577–18582

    Article  Google Scholar 

  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 175:405–424

    Article  Google Scholar 

  • Shen GQ, Li L, Seidelmann SB, Rao S, Fan C, Park JE, Xi Q, Li J, Hu Y, Olivieri O et al (2007) An LRP8 variant is associated with familial and premature coronary artery disease and myocardial infarction. Am J Hum Genet 814:780–791

    Article  CAS  Google Scholar 

  • Shen GQ, Li L, Rao S, Abdullah KG, Ban JM, Lee BS, Park JE, Wang QK (2008) Four SNPs on chromosome 9p21 in a South Korean population implicate a genetic locus that confers high cross-race risk for development of coronary artery disease. Arterioscler Thromb Vasc Biol 282:360–365

    Article  CAS  Google Scholar 

  • Shi L, Li C, Wang C, Xia Y, Wu G, Wang F, Xu C, Wang P, Li X, Wang D, Xiong X et al (2009) Assessment of association of rs2200733 on chromosome 4q25 with atrial fibrillation and ischemic stroke in a Chinese Han population. Hum Genet 1266:843–849

    Article  Google Scholar 

  • Shimizu H, Tosaki A, Ohsawa N, Ishizuka-Katsura Y, Shoji S, Miyazaki H, Oyama F, Terada T, Shirouzu M, Sekine SI, Nukina N et al (2017) Parallel homodimer structures of the extracellular domains of the voltage-gated sodium channel β4 subunit explain its role in cell–cell adhesion. J Biol Chem 29232:13428–13440

    Article  Google Scholar 

  • Tan BH, Pundi KN, Van Norstrand DW, Valdivia CR, Tester DJ, Medeiros-Domingo A, Makielski JC, Ackerman MJ (2010) Sudden infant death syndrome-associated mutations in the sodium channel beta subunits. Heart Rhythm 76:771–778

    Article  Google Scholar 

  • Wan X, Wang Q, Kirsch GE (2000) Functional suppression of sodium channels by β(1)-subunits as a molecular mechanism of idiopathic ventricular fibrillation. J Mol Cell Cardiol 3210:1873–1884

    Article  CAS  Google Scholar 

  • Wang Q, Shen J, Li Z, Timothy K, Vincent GM, Priori SG, Schwartz PJ, Keating MT (1995a) Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. Hum Mol Genet 49:1603–1607

    Article  Google Scholar 

  • Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT (1995b) SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 805:805–811

    Article  Google Scholar 

  • Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ et al (1996) Positional cloning of a novel potassium channel gene: kVLQT1 mutations cause cardiac arrhythmias. Nat Genet 121:17–23

    Article  Google Scholar 

  • Wang Q, Chen Q, Li H, Towbin JA (1997) Molecular genetics of long QT syndrome from genes to patients. Curr Opin Cardiol 123:310–320

    Article  Google Scholar 

  • Wang Q, Chen Q, Towbin JA (1998) Genetics, molecular mechanisms and management of long QT syndrome. Ann Med 301:58–65

    Article  Google Scholar 

  • Wang P, Yang Q, Wu X, Yang Y, Shi L, Wang C, Wu G, Xia Y, Yang B, Zhang R, Xu C et al (2010) Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population. Biochem Biophys Res Commun 3981:98–104

    Article  CAS  Google Scholar 

  • Wang F, Xu CQ, He Q, Cai JP, Li XC, Wang D, Xiong X, Liao YH, Zeng QT, Yang YZ, Cheng X et al (2011) Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nat Genet 434:345–349

    Article  CAS  Google Scholar 

  • Wang C, Wu M, Qian J, Li B, Tu X, Xu C, Li S, Chen S, Zhao Y, Huang Y, Shi L et al (2016) Identification of rare variants in TNNI3 with atrial fibrillation in a Chinese GeneID population. Mol Genet Genomics 2911:79–92

    Article  CAS  Google Scholar 

  • Wang P, Qin W, Wang P, Huang Y, Liu Y, Zhang R, Li S, Yang Q, Wang X, Chen F, Liu J et al (2018) Genomic variants in NEURL, GJA1 and CUX2 significantly increase genetic susceptibility to atrial fibrillation. Sci Rep 81:3297

    Article  CAS  Google Scholar 

  • Wu L, Yong SL, Fan C, Ni Y, Yoo S, Zhang T, Zhang X, Obejero-Paz CA, Rho HJ, Ke T, Szafranski P et al (2008) Identification of a new co-factor, MOG1, required for the full function of cardiac sodium channel Nav 1.5. J Biol Chem 28311:6968–6978

    Article  CAS  Google Scholar 

  • Xiong H, Yang Q, Zhang X, Wang P, Chen F, Liu Y, Wang P, Zhao Y, Li S, Huang Y, Chen S et al (2019) Significant association of rare variant p.Gly8Ser in cardiac sodium channel β4-subunit SCN4B with atrial fibrillation. Ann Hum Genet. https://doi.org/10.1111/ahg.12305

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu C, Yang Q, Xiong H, Wang L, Cai J, Wang F, Li S, Chen J, Wang C, Wang D, Xiong X et al (2014) Candidate pathway-based genome-wide association studies identify novel associations of genomic variants in the complement system associated with coronary artery disease. Circ Cardiovasc Genet 76:887–894

    Article  CAS  Google Scholar 

  • Xue Y, Liu Z, Cao J, Ma Q, Gao X, Wang Q, Jin C, Zhou Y, Wen L, Ren J (2011) GPS 2.1: enhanced prediction of kinase-specific phosphorylation sites with an algorithm of motif length selection. Protein Eng Des Sel 243:255–260

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the study participants for their invaluable support of this study, and other members of the GeneID team members for assistance. This work was supported by the National Natural Science Foundation of China Grants (81630002, 31430047 and 81600263) (C.X. and P.W.), Hubei Province’s Innovative Team Grant (2017CFA014) (X.C.), and NIH/NHLBI grant R01 HL126729 (Q.K.W.).

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Author notes

  1. Qin Yang, Hongbo Xiong, Chengqi Xu, Yuan Huang, and Xin Tu contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China

    Qin Yang

  2. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, 430074, People’s Republic of China

    Qin Yang, Hongbo Xiong, Chengqi Xu, Yuan Huang, Xin Tu, Fenfen Fu, Zhijie Wang, Longfei Wang, Yuanyuan Zhao, Sisi Li, Yufeng Huang, Dan Wang, Yufeng Yao, Fan Wang, Yongbo Wang, Yu Xue, Pengyun Wang & Qing K. Wang

  3. Renmin Hospital, Wuhan University, Wuhan, People’s Republic of China

    Gang Wu

  4. School of Life Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, People’s Republic of China

    Chuchu Wang

  5. Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Qiuyun Chen & Qing K. Wang

  6. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA

    Qiuyun Chen & Qing K. Wang

  7. Department of Cardiology, East Hospital, Tongji University, Shanghai, Beijing, 100037, People’s Republic of China

    Jielin Pu

  8. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Qing K. Wang

  9. Tongji University Affiliated East Hospital, Beijing, 100037, People’s Republic of China

    Jielin Pu

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  1. Qin Yang
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  2. Hongbo Xiong
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  6. Gang Wu
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  8. Zhijie Wang
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  20. Qiuyun Chen
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  22. Qing K. Wang
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Correspondence to Qiuyun Chen, Jielin Pu or Qing K. Wang.

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This study was approved by the ethics committee on human subject research at Huazhong University of Science and Technology and local hospitals.

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Yang, Q., Xiong, H., Xu, C. et al. Identification of rare variants in cardiac sodium channel β4-subunit gene SCN4B associated with ventricular tachycardia. Mol Genet Genomics 294, 1059–1071 (2019). https://doi.org/10.1007/s00438-019-01567-7

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