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

Am J Hum Genet. 2016 Nov 3;99(5):1163-1171. doi: 10.1016/j.ajhg.2016.08.023. Epub 2016 Oct 13.

Abstract

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 β [TGFβ]-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 × 10-6). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-κB and TGFβ pathways. The minor allele at rs1883832, in the 5'-untranslated region of CD40, was associated with earlier LoA (p = 3.5 × 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.

MeSH terms

  • Adolescent
  • Alleles
  • CD40 Antigens / genetics*
  • CD40 Antigens / metabolism
  • Case-Control Studies
  • Child
  • Dystrophin / genetics
  • Dystrophin / metabolism
  • European Continental Ancestry Group / genetics
  • Exons
  • Genes, Modifier
  • Genome-Wide Association Study
  • Glucocorticoids / pharmacology
  • Humans
  • Latent TGF-beta Binding Proteins / genetics
  • Latent TGF-beta Binding Proteins / metabolism
  • Muscular Dystrophy, Duchenne / genetics*
  • Mutation
  • NF-kappa B / genetics*
  • NF-kappa B / metabolism
  • Osteopontin / genetics
  • Osteopontin / metabolism
  • Polymorphism, Single Nucleotide*
  • Transforming Growth Factor beta / genetics*
  • Transforming Growth Factor beta / metabolism

Substances

  • CD40 Antigens
  • Dystrophin
  • Glucocorticoids
  • LTBP4 protein, human
  • Latent TGF-beta Binding Proteins
  • NF-kappa B
  • SPP1 protein, human
  • Transforming Growth Factor beta
  • Osteopontin