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Lookup NU author(s): Professor Michela GuglieriORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2026 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.Genetic modifiers of Duchenne muscular dystrophy (DMD) that alter disease severity or response to therapy have been reported using natural history or registry data sets of older corticosteroid-treated patients. We tested associations of genetic modifiers on motor function outcomes in young (4 to < 7 years) steroid naïve clinical trial participants. Participants in clinical trials (VBP15-002/003 [n = 48]; VBP15-004 [n = 121]; DNA available for n = 110) were genotyped for eight published genetic modifier loci, and associations of genotypes with baseline motor function defined via an age-adjusted linear model. Corticosteroid drug response was modeled by genotype-stratified placebo vs. steroid treatment at 12- and 24-weeks posttreatment (mixed model for repeated measures). Serum proteome profiles (SomaScan) were stratified by modifier genotype, and modifier-associated biomarkers mapped to muscle cell types using snSeq datasets. Two loci showed association with baseline motor outcomes (LTBP4, DYNLT5). LTBP4 genotype (rs1131620) was associated with baseline (pretreatment) motor function for all five motor tests studied (time to stand from supine velocity, time to run/walk 10 m velocity, time to climb 4 stairs velocity, 6-min walk distance, and NorthStar Ambulatory Assessment). DYNLT5 genotype (rs1060575) was associated with time to stand from supine velocity, time to climb 4 stairs velocity, and time to run/walk 10 m velocity. Stratification of baseline proteome profiles by LTBP4 genotype and mapping of genotype-associated serum proteins to specific cell types in muscle (snRNAseq) suggested that IL-23, IL-6, and IL-17D interacting pathways in muscle capillaries are contributors to disease progression. In contrast, the DYNLT5 genotype was associated with proteosome and chaperonin pathways. Trial Registration: clinicaltrials.gov identifier: NCT02760264, NCT02760277, NCT03439670.
Author(s): Dang UJ, Fang Y, Sabbatini D, Pegoraro E, Bello L, Clemens PR, Guglieri M, van den Anker J, Damsker J, Hagerty L, Hathout Y, Ziemba M, Morgenroth L, Bhattacharya S, Nagaraju K, Jaiswal JK, Hoffman EP
Publication type: Article
Publication status: Published
Journal: American Journal of Medical Genetics, Part A
Year: 2026
Pages: epub ahead of print
Online publication date: 18/08/2026
Acceptance date: 05/08/2026
Date deposited: 01/09/2026
ISSN (print): 1552-4825
ISSN (electronic): 1552-4833
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/ajmg.a.70277
DOI: 10.1002/ajmg.a.70277
Data Access Statement: Clinical trial data is available via clinicaltrials.gov and at request via https://cinrgresearch.org/publications/data-summary-requests/.
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