Neuromuscular Center, Department of Neurosciences, University of Padova, 35128 Padova, Italy
Neurology. 2011 Jan 18;76(3):219-26. doi: 10.1212/WNL.0b013e318207afeb. Epub 2010 Dec 22.
Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, suggesting genetic or environmental modifiers.
Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied.
Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003).
Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.
杜氏肌营养不良症（DMD）是最常见的单基因致死性疾病。患者在发病和进展以及对糖皮质激素的反应方面存在很大的个体差异，这表明存在遗传或环境修饰因子。
我们使用两个 DMD 队列作为测试和验证组来定义遗传修饰因子：一个是帕多瓦纵向队列（n=106），另一个是合作国际神经肌肉研究组（CINRG）的横断面自然史队列（n=156）。从严重型和轻度型 DMD 患者的 mRNA 谱中选择要进行基因分型的单核苷酸多态性，并研究影响代谢和正常志愿者肌肉表型的多态性的全基因组关联研究。
在 SPP1（骨桥蛋白）基因启动子中的多态性 rs28357094 观察到对疾病进展和对糖皮质激素反应的影响。G 等位基因（显性模型；占 35%的受试者）与进展更快相关（帕多瓦队列对数秩检验 p=0.003），握力降低 12%-19%（CINRG 队列 p=0.0003）。
骨桥蛋白基因型是杜氏肌营养不良症疾病严重程度的遗传修饰因子。在 DMD 临床试验中，将基因型数据作为协变量或纳入标准，可以减少个体间的变异性，并提高试验的敏感性，尤其是在年龄较大的患者中。
