Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 99, Issue 5, Pages 1163-1171Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2016.08.023
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Funding
- Italian Ministry of Education PhD grant for the Doctorate School of Medical, Clinical, and Experimental Science at the University of Padova
- Association Francaise contre les Myopathies [15092, 17724]
- Dutch Duchenne Parent Project
- European Union [241665, 305121, 305444]
- Italian Duchenne Parent Project
- Medical Research council Centre for Neuromuscular Diseases Biobanks
- Telethon Italy Foundation [GTB12001D]
- U.S. Department of Defense [W81XWH-12-1-0417]
- U.S. Department of Education/NIDRR [H133B031118, H133B090001]
- U.S. National Institutes of Health/NIAMS [R01AR061875]
- Medical Research Council [MR/N027302/1] Funding Source: researchfish
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The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor beta [TGF beta]-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the Cooperative International Research Group Duchenne Natural History Study (CINRG-DNHS). We focused on protein-altering variants (Exome Chip) and included glucocorticoid treatment as a covariate. As expected, due to the small population size, no SNPs displayed an exome-wide significant p value (< 1.8 x 10(-6)). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-kappa B and TGF beta pathways. The minor allele at rs1883832, in the 5'-untranslated region of CD40, was associated with earlier LoA (p = 3.5 x 10(-5)). This allele diminishes the expression of CD40, a co-stimulatory molecule for T cell polarization. We validated this association in multiple independent DMD cohorts (United Dystrophinopathy Project, Bio-NMD, and Padova, total n = 660), establishing this locus as a DMD modifier. This finding points to cell-mediated immunity as a relevant pathogenetic mechanism and potential therapeutic target in DMD.
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