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.

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

Ferlini, Alessandra;
2016

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.
Bello, Luca; Punetha, Jaya; Gordish-Dressman, Heather; Giri, Mamta; Hoffman, Eric P.; Bello, Luca; Barp, Andrea; Vianello, Sara; Pegoraro, Elena; Flanigan, Kevin M.; Flanigan, Kevin M.; Flanigan, Kevin M.; Weiss, Robert B.; Spitali, Pietro; Aartsma-Rus, Annemieke; Aartsma-Rus, Annemieke; Straub, Volker; Lochmüller, Hanns; Muntoni, Francesco; Zaharieva, Irina; Ferlini, Alessandra; Mercuri, Eugenio; Tuffery-Giraud, Sylvie; Claustres, Mireille; Mcdonald, Craig M.; Dunn, Diane M.; Swoboda, Kathryn J.; Gappmaier, Eduard; Howard, Michael T.; Sampson, Jacinda B.; Bromberg, Mark B.; Butterfield, Russell; Kerr, Lynne; Pestronk, Alan; Florence, Julaine M.; Connolly, Anne; Lopate, Glenn; Golumbek, Paul; Schierbecker, Jeanine; Malkus, Betsy; Renna, Renee; Siener, Catherine; Finkel, Richard S.; Bonnemann, Carsten G.; Medne, Livija; Glanzman, Allan M.; Flickinger, Jean; Mendell, Jerry R.; King, Wendy M.; Lowes, Linda; Alfano, Lindsay; Mathews, Katherine D.; Stephan, Carrie; Laubenthal, Karla; Baldwin, Kris; Wong, Brenda; Morehart, Paula; Meyer, Amy; Day, John W.; Naughton, Cameron E.; Margolis, Marcia; Cnaan, Avital; Abresch, Richard T.; Henricson, Erik K.; Morgenroth, Lauren P.; Duong, Tina; Chidambaranathan, V. Viswanathan; Biggar, W. Douglas; Mcadam, Laura C.; Mah, Jean; Tulinius, Mar; Leshner, Robert; Rocha, Carolina Tesi; Thangarajh, Mathula; Kornberg, Andrew; Ryan, Monique; Nevo, Yoram; Dubrovsky, Alberto; Clemens, Paula R.; Abdel-Hamid, Hoda; Connolly, Anne M.; Pestronk, Alan; Teasley, Jean; Bertorini, Tulio E.; North, Kathryn; Webster, Richard; Kolski, Hanna; Kuntz, Nancy; Driscoll, Sherilyn; Carlo, Jose; Gorni, Ksenija; Lotze, Timothy; Day, John W.; Karachunski, Peter; Bodensteiner, John B.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2384512
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