Genetic modifiers of respiratory function in Duchenne muscular dystrophy
Genetic modifiers of respiratory function in Duchenne muscular dystrophy
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DOI：
10.1002/acn3.51046
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发表时间：
2020-04-28
影响因子：
5.3
通讯作者：
Pegoraro, Elena
中科院分区：
文献类型：
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作者：
Bello, Luca;D'Angelo, Grazia;Pegoraro, Elena
目的呼吸功能不全是Duchenne型肌营养不良症（DMD）的主要并发症。其进展表现出相当大的个体间变异性，这已经不太彻底的特点和理解比骨骼肌。我们收集了来自意大利DMD网络合作中心的大型回顾性队列的肺功能测试（PFT）数据。此外，我们分析了PFT与不同DMD突变类型的相关性，以及与SPP 1，LTBP 4，CD 40和ACTN 3的遗传变异的相关性，这些变异已知可以改变DMD中的骨骼肌无力。遗传关联的研究结果在国际神经肌肉研究合作组杜兴自然史研究中得到独立验证方法和结果对来自327名意大利DMD患者的1852例PFT进行广义估计方程分析，平均随访时间为4.5年，估计用力肺活量（FVC）每年下降-4.2%，1秒用力呼气量减少-5.0%，呼气峰流速（PEF）减少-2.9%。糖皮质激素（GC）治疗与所有PFT指标的较高值相关（在疾病分期中约为+ 15%）。位于DMD内含子44的3'的突变，因此预测改变短肌养蛋白亚型的表达，与较低（约-6%）的PFT值相关，这是在CINRG-DNHS中独立验证的发现。易于跳跃的外显子51和53的缺失与更差的PFT结果独立相关。两个队列的荟萃分析确定了不利的影响SPP 1 rs 28357094和CD 40 rs 1883832次要等位基因FVC和PEF.Interpretation这些研究结果支持GC疗效在延迟呼吸功能不全，并将是有用的设计和解释的临床试验集中在呼吸终点DMD。
Objective Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS).Methods and Results Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, estimated that forced vital capacity (FVC) declined yearly by -4.2%, forced expiratory volume in 1 sec by -5.0%, and peak expiratory flow (PEF) by -2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3' of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately -6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF.Interpretation These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.