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

Luca Bello 1 Kevin Flanigan Robert Weiss 2 Pietro Spitali Annemieke Aartsma-Rus 3 Francesco Muntoni 4 Irina Zaharieva Alessandra Ferlini 5 Eugenio Mercuri 6 Sylvie Tuffery-Giraud 7 Mireille Claustres 7, 8 Volker Straub 9 Hanns Lochmuller 10 Andrea Barp Sara Vianello 11 Elena Pegoraro 1 Jaya Punetha Heather Gordish-Dressman Mamta Giri Craig Mcdonald Eric Hoffman Diane Dunn Kathryn Swoboda 12 Eduard Gappmaier Michael Howard 13 Jacinda Sampson Mark Bromberg Russell Butterfield Lynne Kerr Julaine Florence Glenn Lopate Paul Golumbek Jeanine Schierbecker Betsy Malkus Renee Renna Catherine Siener Richard Finkel Carsten Bonnemann Livija Medne Allan Glanzman Jean Flickinger Jerry Mendell Wendy King Linda Lowes Lindsay Alfano Katherine Mathews Carrie Stephan Karla Laubenthal Kris Baldwin Brenda Wong 14 Paula Morehart Amy Meyer Cameron Naughton Marcia Margolis Avital Cnaan Richard Abresch Erik Henricson Lauren Morgenroth Tina Duong V. Viswanathan Chidambaranathan W. Douglas Biggar 15 Laura Mcadam Jean Mah Mar Tulinius Robert Leshner Carolina Tesi Rocha Mathula Thangarajh Andrew Kornberg 16 Monique Ryan Yoram Nevo Alberto Dubrovsky Paula Clemens Hoda Abdel-Hamid Anne Connolly Alan Pestronk 17 Jean Teasley Tulio Bertorini Kathryn North 18 Richard Webster 19 Hanna Kolski 20 Nancy Kuntz 21 Sherilyn Driscoll Jose Carlo Ksenija Gorni Timothy Lotze John Day 22 Peter Karachunski John Bodensteiner
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.
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Luca Bello, Kevin Flanigan, Robert Weiss, Pietro Spitali, Annemieke Aartsma-Rus, et al.. Association Study of Exon Variants in the NF-κB and TGFβ Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy. The American Journal of Human Genetics, 2016, 99 (5), pp.1163-1171. ⟨10.1016/j.ajhg.2016.08.023⟩. ⟨hal-02436506⟩

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