Association Study of Exon Variants in the NF-kB and TGFb Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy

Bello L, Flanigan KM, Weiss RB, United Dystrophinopathy Project, Spitali P, Aartsma-Rus A, Muntoni F, Zaharieva I, Ferlini A, Mercuri E, Tuffery-Giraud S, Claustres M, Straub V, Lochmuller H, Barp A, Vianello S, Pegoraro E, Punetha J, Gordish-Dressman H, Giri M, McDonald CM, Hoffman EP, Cooperative International Neuromuscular ResearchGroup

American Journal of Human Genetics 99, 1–9, November 3, 2016, November 2016
DOI: 10.1016/j.ajhg.2016.08.023


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 b [TGFb]-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 ¼ 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 3 106). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-kB and TGFb pathways. The minor allele at rs1883832, in the 50-untranslated region of CD40, was associated with earlier LoA (p ¼ 3.5 3 105). 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 ¼ 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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