Journal article
Association Study of Exon Variants in the NF-κB and TGFβ Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy
American journal of human genetics, Vol.99(5), pp.1163-1171
11/2016
DOI: 10.1016/j.ajhg.2016.08.023
PMCID: PMC5097949
PMID: 27745838
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.
Details
- Title: Subtitle
- Association Study of Exon Variants in the NF-κB and TGFβ Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy
- Creators
- Luca Bello - Universita degli Studi di PadovaKevin FlaniganRobert B Weiss - University of Utah HospitalKatherine MathewsPietro SpitaliAnnemieke Aartsma-Rus - Human GeneticsFrancesco Muntoni - Great Ormond Street Hospital for Children [London]Irina ZaharievaAlessandra Ferlini - Department of Experimental and Diagnostic Medicine, Section of Medical GeneticsEugenio Mercuri - Università Cattolica del Sacro CuoreSylvie Tuffery-Giraud - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiquesMireille Claustres - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiquesVolker Straub - Department of NeurologyHanns Lochmuller - Newcastle University [Newcastle]Andrea BarpSara Vianello - Department of Neurosciences [Padova, Italy]Elena Pegoraro - Universita degli Studi di PadovaJaya PunethaHeather Gordish-DressmanCraig McDonaldEric HoffmanMamta GiriDiane DunnKathryn Swoboda - Massachusetts General Hospital [Boston]Eduard GappmaierMichael Howard - King‘s College LondonJacinda SampsonMark BrombergRussell ButterfieldLynne KerrJulaine FlorenceGlenn LopatePaul GolumbekJeanine SchierbeckerBetsy MalkusRenee RennaCatherine SienerRichard FinkelCarsten BonnemannLivija MedneAllan GlanzmanJean FlickingerJerry MendellWendy KingLinda LowesLindsay AlfanoCarrie StephanKarla LaubenthalKris BaldwinBrenda Wong - Division of Pediatric NeurologyPaula MorehartAmy MeyerCameron NaughtonMarcia MargolisAvital CnaanRichard AbreschErik HenricsonLauren MorgenrothTina DuongV. Viswanathan ChidambaranathanW. Douglas Biggar - Child Development & Exercise CenterLaura McAdamJean MahMar TuliniusRobert LeshnerCarolina Tesi RochaMathula ThangarajhAndrew Kornberg - Department of NeurologyMonique RyanYoram NevoAlberto DubrovskyPaula ClemensHoda Abdel-HamidAnne ConnollyAlan Pestronk - Washington University in St LouisJean TeasleyTulio BertoriniKathryn North - Institute for Neuromuscular ResearchRichard WEBSTER - Rothamsted ResearchHanna Kolski - Division of Pediatric NeurologyNancy Kuntz - Department of PediatricsSherilyn DriscollJose CarloKsenija GorniTimothy LotzeJohn Day - Stanford School of Medicine [Stanford]Peter KarachunskiJohn Bodensteiner
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.99(5), pp.1163-1171
- Publisher
- Elsevier (Cell Press)
- DOI
- 10.1016/j.ajhg.2016.08.023
- PMID
- 27745838
- PMCID
- PMC5097949
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Grant note
- DOI: 10.13039/501100000272, name: National Institute of Health Research Biomedical Research Centre; DOI: 10.13039/501100003407, name: Italian Ministry of Education; DOI: 10.13039/100007393, name: Association Française contre les Myopathies, award: 15092, 17724; name: Dutch Duchenne Parent Project; DOI: 10.13039/501100000780, name: European Union, award: 241665; name: Neuromics grant, award: 305121; name: RD-Connect grant, award: 305444; name: Italian Duchenne Parent Project; DOI: 10.13039/501100000265, name: Medical Research council Centre for Neuromuscular Diseases Biobanks; name: Eurobiobank; DOI: 10.13039/501100000272, name: National Institute for Health Research Biomedical Research Centre; DOI: 10.13039/501100002426, name: Telethon Italy Foundation, award: GTB12001D; DOI: 10.13039/100000005, name: U.S. Department of Defense, award: W81XWH-12-1-0417; DOI: 10.13039/100000015, name: U.S. Department of Education; DOI: 10.13039/100006663, name: NIDRR, award: H133B031118, H133B090001; DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/100000065, name: NINDS, award: R01 NS085238; DOI: 10.13039/100000002, name: U.S. National Institutes of Health; DOI: 10.13039/100000069, name: NIAMS, award: R01AR061875
- Language
- English
- Date published
- 11/2016
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984070860502771
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