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

Lookup NU author(s): Professor Annemieke Aartsma-Rus, Professor Volker StraubORCiD, Professor Hanns Lochmuller


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© 2016 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.

Publication metadata

Author(s): Bello L, Punetha J, Gordish-Dressman H, Giri M, Hoffman EP, Bello L, Barp A, Vianello S, Pegoraro E, Flanigan KM, Weiss RB, Spitali P, Aartsma-Rus A, Straub V, Lochmuller H, Muntoni F, Zaharieva I, Ferlini A, Mercuri E, Tuffery-Giraud S, Claustres M, McDonald CM, Dunn DM, Swoboda KJ, Gappmaier E, Howard MT, Sampson JB, Bromberg MB, Butterfield R, Kerr L, Pestronk A, Florence JM, Connolly A, Lopate G, Golumbek P, Schierbecker J, Malkus B, Renna R, Siener C, Finkel RS, Bonnemann CG, Medne L, Glanzman AM, Flickinger J, Mendell JR, King WM, Lowes L, Alfano L, Mathews KD, Stephan C, Laubenthal K, Baldwin K, Wong B, Morehart P, Meyer A, Day JW, Naughton CE, Margolis M, Cnaan A, Abresch RT, Henricson EK, Morgenroth LP, Duong T, Chidambaranathan VV, Biggar WD, McAdam LC, Mah J, Tulinius M, Leshner R, Rocha CT, Thangarajh M, Kornberg A, Ryan M, Nevo Y, Dubrovsky A, Clemens PR, Abdel-Hamid H, Connolly AM, Pestronk A, Teasley J, Bertorini TE, North K, Webster R, Kolski H, Kuntz N, Driscoll S, Carlo J, Gorni K, Lotze T, Day JW, Karachunski P, Bodensteiner JB

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2016

Volume: 99

Issue: 5

Pages: 1163-1171

Print publication date: 03/11/2016

Online publication date: 13/10/2016

Acceptance date: 29/08/2016

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2016.08.023


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