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

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

Author information

1
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA; Department of Neuroscience, University of Padova, 35128 Padova, Italy.
2
The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA; Department of Neurology, The Ohio State University, Columbus, OH 43205, USA.
3
Department of Human Genetics, The University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
4
Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
5
Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK.
6
Dubowitz Neuromuscular Centre, University College London Institute of Child Health, London WC1N 1EH, UK.
7
Department of Medical Sciences, UOL of Medical Genetics, University of Ferrara, 44121 Ferrara, Italy.
8
Paediatric Neuropsychiatry Unit, Policlinico Gemelli, Catholic University, 00168 Rome, Italy.
9
Laboratory of Genetics of Rare Diseases, EA 7402, University of Montpellier, 34093 Montpellier, France.
10
John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK.
11
Department of Neuroscience, University of Padova, 35128 Padova, Italy.
12
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
13
University of California Davis Medical Center, Sacramento, CA 95817, USA.
14
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA. Electronic address: ehoffman@binghamton.edu.

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.

PMID:
27745838
PMCID:
PMC5097949
DOI:
10.1016/j.ajhg.2016.08.023
[Indexed for MEDLINE]
Free PMC Article

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