Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy.
Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy.
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DOI：
10.1371/journal.pone.0141240
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Pegoraro E
中科院分区：
文献类型：
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作者：
Barp A;Bello L;Politano L;Melacini P;Calore C;Polo A;Vianello S;Sorarù G;Semplicini C;Pantic B;Taglia A;Picillo E;Magri F;Gorni K;Messina S;Vita GL;Vita G;Comi GP;Ermani M;Calvo V;Angelini C;Hoffman EP;Pegoraro E
扩张型心肌病（DCM）是Duchenne型肌营养不良症（DMD）的主要并发症和主要死亡原因。扩张型心肌病的发病是可变的，表明遗传或环境因素的修饰效应。我们的目的是确定以前与DMD中独立性心律失常（LoA）丧失年龄相关的多态性（SPP 1启动子中的rs 28357094，LTBP 4中的rs 10880和VTTT/IAAM单倍型）是否也会改变DCM的发病。通过TaqMan分析对178例DMD患者的多中心队列进行基因分型。我们对DCM发作进行了时间-事件分析，以年龄为时间变量，并将左心室射血分数< 50%和/或舒张末期容积> 70 mL/m2作为事件（由之前正常检查证实< 12个月）;无DCM患者在末次超声心动图随访时删失。患者随访至平均年龄15.9 ± 6.7岁。71/178例患者发生DCM，发病时的中位年龄为20.0岁。糖皮质激素治疗（n = 88未治疗; n = 75治疗; n = 15未知）对DCM发作没有显著的独立影响。在这一人群中，DCM发作前未给予心脏病药物。我们观察到SPP 1 rs 28357094处的显性G等位基因和LTBP 4 rs 10880处的隐性T等位基因的保护作用趋势，这在类固醇治疗的LTBP 4 rs 10880患者中具有统计学显著性（< 50%的T/T患者在随访期间发展为DCM [n = 13]; C/C-C/T的中位DCM发作时间为17.6年，对数秩p = 0.027）。我们报告了DMD遗传修饰剂对心脏并发症的保护作用，如果在独立队列中得到证实，可能有助于危险分层。
Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset. A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up. Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027). We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.