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

Luca Bello, Jaya Punetha, Heather Gordish-Dressman, Mamta Giri, Eric P. Hoffman, Andrea Barp, Sara Vianello, Elena Pegoraro, Kevin M. Flanigan, Robert B. Weiss, Pietro Spitali, Annemieke Aartsma-Rus, Volker Straub, Hanns Lochmüller, Francesco Muntoni, Irina Zaharieva, Alessandra Ferlini, Eugenio Mercuri, Sylvie Tuffery-Giraud, Mireille ClaustresCraig M. McDonald, Diane M. Dunn, Kathryn J. Swoboda, Eduard Gappmaier, Michael T. Howard, Jacinda B. Sampson, Mark B. Bromberg, Russell Butterfield, Lynne Kerr, Alan Pestronk, Julaine M. Florence, Anne Connolly, Glenn Lopate, Paul Golumbek, Jeanine Schierbecker, Betsy Malkus, Renee Renna, Catherine Siener, Richard S. Finkel, Carsten G. Bonnemann, Livija Medne, Allan M. Glanzman, Jean Flickinger, Jerry R. Mendell, Wendy M. King, Linda Lowes, Lindsay Alfano, Katherine D. Mathews, Carrie Stephan, Karla Laubenthal, Kris Baldwin, Brenda Wong, Paula Morehart, Amy Meyer, John W. Day, Cameron E. Naughton, Marcia Margolis, Avital Cnaan, Richard T. Abresch, Erik K. Henricson, Lauren P. Morgenroth, Tina Duong, V. Viswanathan Chidambaranathan, W. Douglas Biggar, Laura C. McAdam, Jean Mah, Mar Tulinius, Robert Leshner, Carolina Tesi Rocha, Mathula Thangarajh, Andrew Kornberg, Monique Ryan, Yoram Nevo, Alberto Dubrovsky, Paula R. Clemens, Hoda Abdel-Hamid, Anne M. Connolly, Jean Teasley, Tulio E. Bertorini, Kathryn North, Richard Webster, Hanna Kolski, Nancy Kuntz, Sherilyn Driscoll, Jose Carlo, Ksenija Gorni, Timothy Lotze, Peter Karachunski, John B. Bodensteiner

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60 Scopus citations


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.

Original languageEnglish
Pages (from-to)1163-1171
Number of pages9
JournalAmerican journal of human genetics
Issue number5
StatePublished - Nov 3 2016


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