中国汉族特发性扩张型心肌病患者LDB3基因多态性与临床表现及植入型心律转复除颤器(ICD)植入的相关性研究（英文）
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摘要
目的:探讨LDB3(LIM domain binding 3)基因多态性与中国汉族特发性扩张型心肌病发病的相关性,并分析LDB3基因多态性对患者临床表现和植入型心律转复除颤器(ICD)植入的影响。创新点:首次明确LDB3基因多态性与中国汉族特发性扩张型心肌病发病密切相关,发现了三个与脑钠肽、舒张压、左室射血分数相关的多态性位点和一个与植入心律转复除颤器相关的多态性位点。方法:本研究纳入我院159例中国汉族特发性扩张型心肌病患者和247例无亲缘关系健康对照并收集基线临床资料。提取外周血DNA后,聚合酶链式反应扩增LDB3基因的14个外显子,经Sanger一代测序,获得基因突变位点。通过关联分析,研究基因多态性与特发性扩张型心肌病发病之间的相关性。根据连锁不平衡系数和基因分布频率进行单倍体分析,研究不同单倍体分型对特发性扩张型心肌病发病的影响。结论:在LDB3基因多态性分析中,发现9个多态性位点符合哈代-温伯格平衡。其中rs4468255位点多态性与中国汉族特发性扩张型心肌病发病密切相关。rs11812601、rs56165849和rs3740346位点多态性与患者舒张压、左室射血分数存在显著关联(P<0.05)。且携带rs4468255多态性的患者更倾向于安装植入型心律转复除颤器。
Objective: Mutations in LIM domain binding 3(LDB3) gene cause idiopathic dilated cardiomyopathy(IDCM), a structural heart disease with a complicated genetic background. However, the association of polymorphisms in the LDB3 gene with susceptibility to IDCM in Chinese populations remains unexplored as dose the impact on clinical presentation. Methods: We sequenced all exons and the adjacent part of introns of the LDB3 gene in 159 Chinese Han IDCM patients and 247 healthy controls. Then we detected the distribution of polymorphisms in the LDB3 gene in all participants and assessed their associations with risk of IDCM. Additionally, we conducted a stratified genotype– phenotype correlation analysis. Results: The A allele of rs4468255 was significantly associated with IDCM(P<0.01). The rs4468255, rs11812601, rs56165849, and rs3740346 were also associated with diastolic blood pressure(DBP) and left ventricular ejection fraction(LVEF)(P<0.05). Notably, a higher frequency of rs4468255 polymorphism was observed in implantable cardioverter defibrillator(ICD) recipients under a recessive model(P<0.01), whereas the significant association disappeared after adjusting for potential confounders. However, in the dominant model, notable correlations could only be observed after adjusting for multi parameters. Conclusions: The rs4468255 was significantly correlated with IDCM of Chinese Han population. A allele of rs4468255 is higher in IDCM patients with ICD implantation, suggesting the influence of genetic background in the generation of this response. In addition, rs11812601, rs56165849, and rs3740346 in LDB3 show association with brain natriuretic peptide, DBP, and LVEF levels in patients with IDCM but did not show any association with IDCM susceptibility.
Objective: Mutations in LIM domain binding 3(LDB3) gene cause idiopathic dilated cardiomyopathy(IDCM), a structural heart disease with a complicated genetic background. However, the association of polymorphisms in the LDB3 gene with susceptibility to IDCM in Chinese populations remains unexplored as dose the impact on clinical presentation. Methods: We sequenced all exons and the adjacent part of introns of the LDB3 gene in 159 Chinese Han IDCM patients and 247 healthy controls. Then we detected the distribution of polymorphisms in the LDB3 gene in all participants and assessed their associations with risk of IDCM. Additionally, we conducted a stratified genotype– phenotype correlation analysis. Results: The A allele of rs4468255 was significantly associated with IDCM(P<0.01). The rs4468255, rs11812601, rs56165849, and rs3740346 were also associated with diastolic blood pressure(DBP) and left ventricular ejection fraction(LVEF)(P<0.05). Notably, a higher frequency of rs4468255 polymorphism was observed in implantable cardioverter defibrillator(ICD) recipients under a recessive model(P<0.01), whereas the significant association disappeared after adjusting for potential confounders. However, in the dominant model, notable correlations could only be observed after adjusting for multi parameters. Conclusions: The rs4468255 was significantly correlated with IDCM of Chinese Han population. A allele of rs4468255 is higher in IDCM patients with ICD implantation, suggesting the influence of genetic background in the generation of this response. In addition, rs11812601, rs56165849, and rs3740346 in LDB3 show association with brain natriuretic peptide, DBP, and LVEF levels in patients with IDCM but did not show any association with IDCM susceptibility.
引文
B?nsch D,Antz M,Boczor S,et al.,2002.Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy:the cardiomyopathy trial(CAT).Circulation,105(12):1453-1458.https://doi.org/10.1161/01.CIR.0000012350.99718.AD
Bondue A,Arbustini E,Bianco A,et al.,2018.Complex roads from genotype to phenotype in dilated cardiomyopathy:scientific update from the Working Group of Myocardial function of the European Society of Cardiology.Cardiovasc Res,114(10):1287-1303.https://doi.org/10.1093/cvr/cvy122
Faulkner G,Pallavicini A,Formentin E,et al.,1999.ZASP:a new Z-band alternatively spliced PDZ-motif protein.JCell Biol,146(2):465-475.https://doi.org/10.1083/jcb.146.2.465
Garfinkel AC,Seidman JG,Seidman CE,2018.Genetic pathogenesis of hypertrophic and dilated cardiomyopathy.Heart Fail Clin,14(2):139-146.https://doi.org/10.1016/j.hfc.2017.12.004
Gl?cklhofer CR,Steinfurt J,Franke G,et al.,2018.A novel LMNA nonsense mutation causes two distinct phenotypes of cardiomyopathy with high risk of sudden cardiac death in a large five-generation family.EP Europace,20(12):2003-2013.https://doi.org/10.1093/europace/euy127
Halliday BP,Cleland JGF,Goldberger JJ,et al.,2017.Personalizing risk stratification for sudden death in dilated cardiomyopathy:the past,present,and future.Circulation,136(2):215-231.https://doi.org/10.1161/CIRCULATIONAHA.116.027134
Hershberger RE,Hedges DJ,Morales A,2013.Dilated cardiomyopathy:the complexity of a diverse genetic architecture.Nat Rev Cardiol,10(9):531-547.https://doi.org/10.1038/nrcardio.2013.105
Japp AG,Gulati A,Cook SA,et al.,2016.The diagnosis and evaluation of dilated cardiomyopathy.J Am Coll Cardiol,67(25):2996-3010.https://doi.org/10.1016/j.jacc.2016.03.590
Jiang ZH,Wang HY,Michal JJ,et al.,2016.Genome wide sampling sequencing for SNP genotyping:methods,challenges and future development.Int J Biol Sci,12(1):100-108.https://doi.org/10.7150/ijbs.13498
Kadish A,Dyer A,Daubert JP,et al.,2004.Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.N Engl J Med,350(21):2151-2158.https://doi.org/10.1056/NEJMoa033088
K?ber L,Thune JJ,Nielsen JC,et al.,2016.Defibrillator implantation in patients with nonischemic systolic heart failure.N Engl J Med,375(13):1221-1230.https://doi.org/10.1056/NEJMoa1608029
Lang RM,Badano LP,Mor-Avi V,et al.,2015.Recommendations for cardiac chamber quantification by echocardiography in adults:an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.Eur Heart J Cardiovasc Imaging,16(3):233-270.https://doi.org/10.1093/ehjci/jev014
Levitas A,Konstantino Y,Muhammad E,et al.,2016.D117Nin Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias.Eur JHum Genet,24(5):666-671.https://doi.org/10.1038/ejhg.2015.195
Li ZH,Ai T,Samani K,et al.,2010.A ZASP missense mutation,S196L,leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy.Circ Arrhythm Electrophysiol,3(6):646-656.https://doi.org/10.1161/CIRCEP.109.929240
Lin CS,Guo XG,Lange S,et al.,2013.Cypher/ZASP is a novel A-kinase anchoring protein.J Biol Chem,288(41):29403-29413.https://doi.org/10.1074/jbc.M113.470708
Losurdo P,Stolfo D,Merlo M,et al.,2016.Early arrhythmic events in idiopathic dilated cardiomyopathy.JACC Clin Electrophysiol,2(5):535-543.https://doi.org/10.1016/j.jacep.2016.05.002
Priori SG,Blomstr?m-Lundqvist C,Mazzanti A,et al.,2015.2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death:the task force for the management of patients with ventricular arrhythmias and the prevention of Sudden cardiac death of the European Society of Cardiology(ESC).Endorsed by:Association for European Paediatric and Congenital Cardiology(AEPC).Eur Heart J,36(41):2793-2867.https://doi.org/10.1093/eurheartj/ehv316
Reibis R,Salzwedel A,Bonaventura K,et al.,2017.Improvement of left ventricular ejection fraction in revascularized postmyocardial patients:indication for statistical fallacy.BMC Res Notes,10:244.https://doi.org/10.1186/s13104-017-2562-4
Sheikh F,Bang ML,Lange S,et al.,2007.“Z”eroing in on the role of Cypher in striated muscle function,signaling,and human disease.Trends Cardiovasc Med,17(8):258-262.https://doi.org/10.1016/j.tcm.2007.09.002
Strickberger SA,Hummel JD,Bartlett TG,et al.,2003.Amiodarone versus implantable cardioverter-defibrillator:randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia-AMIOVIRT.J Am Coll Cardiol,41(10):1707-1712.https://doi.org/10.1016/S0735-1097(03)00297-3
Tamburro P,Wilber D,1992.Sudden death in idiopathic dilated cardiomyopathy.Am Heart J,124(4):1035-1045.https://doi.org/10.1016/0002-8703(92)90989-9
Towbin JA,Bowles NE,2002.The failing heart.Nature,415(6868):227-233.https://doi.org/10.1038/415227a
van der Zwaag PA,van Rijsingen IAW,de Ruiter R,et al.,2013.Recurrent and founder mutations in the Netherlandsphospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy.Neth Heart J,21(6):286-293.https://doi.org/10.1007/s12471-013-0401-3
Vatta M,Mohapatra B,Jimenez S,et al.,2003.Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.J Am Coll Cardiol,42(11):2014-2027.https://doi.org/10.1016/j.jacc.2003.10.021
Weintraub RG,Semsarian C,Macdonald P,2017.Dilated cardiomyopathy.Lancet,390(10092):400-414.https://doi.org/10.1016/S0140-6736(16)31713-5
Wolff G,Lin YF,Karathanos A,et al.,2017.Implantable cardioverter/defibrillators for primary prevention in dilated cardiomyopathy post-DANISH:an updated metaanalysis and systematic review of randomized controlled trials.Clin Res Cardiol,106(7):501-513.https://doi.org/10.1007/s00392-017-1079-0
Yu HJ,Yuan C,Westenbroek RE,et al.,2018.The AKAPCypher/Zasp contributes toβ-adrenergic/PKA stimulation of cardiac CaV1.2 calcium channels.J Gen Physiol,150(6):883-889.https://doi.org/10.1085/jgp.201711818
Zheng M,Cheng HQ,Li XD,et al.,2009.Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death.Hum Mol Genet,18(4):701-713.https://doi.org/10.1093/hmg/ddn400
Zheng M,Cheng HQ,Banerjee I,et al.,2010.ALP/Enigma PDZ-LIM domain proteins in the heart.J Mol Cell Biol,2(2):96-102.https://doi.org/10.1093/jmcb/mjp038
Bondue A,Arbustini E,Bianco A,et al.,2018.Complex roads from genotype to phenotype in dilated cardiomyopathy:scientific update from the Working Group of Myocardial function of the European Society of Cardiology.Cardiovasc Res,114(10):1287-1303.https://doi.org/10.1093/cvr/cvy122
Faulkner G,Pallavicini A,Formentin E,et al.,1999.ZASP:a new Z-band alternatively spliced PDZ-motif protein.JCell Biol,146(2):465-475.https://doi.org/10.1083/jcb.146.2.465
Garfinkel AC,Seidman JG,Seidman CE,2018.Genetic pathogenesis of hypertrophic and dilated cardiomyopathy.Heart Fail Clin,14(2):139-146.https://doi.org/10.1016/j.hfc.2017.12.004
Gl?cklhofer CR,Steinfurt J,Franke G,et al.,2018.A novel LMNA nonsense mutation causes two distinct phenotypes of cardiomyopathy with high risk of sudden cardiac death in a large five-generation family.EP Europace,20(12):2003-2013.https://doi.org/10.1093/europace/euy127
Halliday BP,Cleland JGF,Goldberger JJ,et al.,2017.Personalizing risk stratification for sudden death in dilated cardiomyopathy:the past,present,and future.Circulation,136(2):215-231.https://doi.org/10.1161/CIRCULATIONAHA.116.027134
Hershberger RE,Hedges DJ,Morales A,2013.Dilated cardiomyopathy:the complexity of a diverse genetic architecture.Nat Rev Cardiol,10(9):531-547.https://doi.org/10.1038/nrcardio.2013.105
Japp AG,Gulati A,Cook SA,et al.,2016.The diagnosis and evaluation of dilated cardiomyopathy.J Am Coll Cardiol,67(25):2996-3010.https://doi.org/10.1016/j.jacc.2016.03.590
Jiang ZH,Wang HY,Michal JJ,et al.,2016.Genome wide sampling sequencing for SNP genotyping:methods,challenges and future development.Int J Biol Sci,12(1):100-108.https://doi.org/10.7150/ijbs.13498
Kadish A,Dyer A,Daubert JP,et al.,2004.Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.N Engl J Med,350(21):2151-2158.https://doi.org/10.1056/NEJMoa033088
K?ber L,Thune JJ,Nielsen JC,et al.,2016.Defibrillator implantation in patients with nonischemic systolic heart failure.N Engl J Med,375(13):1221-1230.https://doi.org/10.1056/NEJMoa1608029
Lang RM,Badano LP,Mor-Avi V,et al.,2015.Recommendations for cardiac chamber quantification by echocardiography in adults:an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.Eur Heart J Cardiovasc Imaging,16(3):233-270.https://doi.org/10.1093/ehjci/jev014
Levitas A,Konstantino Y,Muhammad E,et al.,2016.D117Nin Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias.Eur JHum Genet,24(5):666-671.https://doi.org/10.1038/ejhg.2015.195
Li ZH,Ai T,Samani K,et al.,2010.A ZASP missense mutation,S196L,leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy.Circ Arrhythm Electrophysiol,3(6):646-656.https://doi.org/10.1161/CIRCEP.109.929240
Lin CS,Guo XG,Lange S,et al.,2013.Cypher/ZASP is a novel A-kinase anchoring protein.J Biol Chem,288(41):29403-29413.https://doi.org/10.1074/jbc.M113.470708
Losurdo P,Stolfo D,Merlo M,et al.,2016.Early arrhythmic events in idiopathic dilated cardiomyopathy.JACC Clin Electrophysiol,2(5):535-543.https://doi.org/10.1016/j.jacep.2016.05.002
Priori SG,Blomstr?m-Lundqvist C,Mazzanti A,et al.,2015.2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death:the task force for the management of patients with ventricular arrhythmias and the prevention of Sudden cardiac death of the European Society of Cardiology(ESC).Endorsed by:Association for European Paediatric and Congenital Cardiology(AEPC).Eur Heart J,36(41):2793-2867.https://doi.org/10.1093/eurheartj/ehv316
Reibis R,Salzwedel A,Bonaventura K,et al.,2017.Improvement of left ventricular ejection fraction in revascularized postmyocardial patients:indication for statistical fallacy.BMC Res Notes,10:244.https://doi.org/10.1186/s13104-017-2562-4
Sheikh F,Bang ML,Lange S,et al.,2007.“Z”eroing in on the role of Cypher in striated muscle function,signaling,and human disease.Trends Cardiovasc Med,17(8):258-262.https://doi.org/10.1016/j.tcm.2007.09.002
Strickberger SA,Hummel JD,Bartlett TG,et al.,2003.Amiodarone versus implantable cardioverter-defibrillator:randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia-AMIOVIRT.J Am Coll Cardiol,41(10):1707-1712.https://doi.org/10.1016/S0735-1097(03)00297-3
Tamburro P,Wilber D,1992.Sudden death in idiopathic dilated cardiomyopathy.Am Heart J,124(4):1035-1045.https://doi.org/10.1016/0002-8703(92)90989-9
Towbin JA,Bowles NE,2002.The failing heart.Nature,415(6868):227-233.https://doi.org/10.1038/415227a
van der Zwaag PA,van Rijsingen IAW,de Ruiter R,et al.,2013.Recurrent and founder mutations in the Netherlandsphospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy.Neth Heart J,21(6):286-293.https://doi.org/10.1007/s12471-013-0401-3
Vatta M,Mohapatra B,Jimenez S,et al.,2003.Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction.J Am Coll Cardiol,42(11):2014-2027.https://doi.org/10.1016/j.jacc.2003.10.021
Weintraub RG,Semsarian C,Macdonald P,2017.Dilated cardiomyopathy.Lancet,390(10092):400-414.https://doi.org/10.1016/S0140-6736(16)31713-5
Wolff G,Lin YF,Karathanos A,et al.,2017.Implantable cardioverter/defibrillators for primary prevention in dilated cardiomyopathy post-DANISH:an updated metaanalysis and systematic review of randomized controlled trials.Clin Res Cardiol,106(7):501-513.https://doi.org/10.1007/s00392-017-1079-0
Yu HJ,Yuan C,Westenbroek RE,et al.,2018.The AKAPCypher/Zasp contributes toβ-adrenergic/PKA stimulation of cardiac CaV1.2 calcium channels.J Gen Physiol,150(6):883-889.https://doi.org/10.1085/jgp.201711818
Zheng M,Cheng HQ,Li XD,et al.,2009.Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death.Hum Mol Genet,18(4):701-713.https://doi.org/10.1093/hmg/ddn400
Zheng M,Cheng HQ,Banerjee I,et al.,2010.ALP/Enigma PDZ-LIM domain proteins in the heart.J Mol Cell Biol,2(2):96-102.https://doi.org/10.1093/jmcb/mjp038