Integrating Genetic Modifier Genotype With Serum Proteomics in Duchenne Muscular Dystrophy Clinical Trials Links LTBP4 Genetic Modifier to IL-23/CD93 Pathways in Muscle

Authors

• Utkarsh J. Dang, Carleton University
• Yuan Fang, Old Dominion UniversityFollow
• Daniele Sabbatini, University of Padova
• Elena Pegoraro, University of Padova
• Luca Bello, University of Padova
• Paula R. Clemens, University of Pittsburgh
• Michela Guglieri, Newcastle Upon Tyne
• John van den Anker, Children's National Hospital
• Jesse Damsker, ReveraGen BioPharma
• Laura Hagerty, ReveraGen BioPharma
• Yetrib Hathout, State University of New York at Binghamton
• Michael Ziemba, State University of New York at Binghamton
• Lauren Morgenroth, TRiNDS LLC
• Surajit Bhattacharya, Children's National Hospital, Washington, District of Columbia
• Kanneboyina Nagaraju, State University of New York at Binghamton
• Jyoti K. Jaiswal, Children's National Hospital, Washington, District of Columbia
• Eric P. Hoffman, State University of New York at Binghamton, New York

Document Type

Article

Publication Date

2026

DOI

10.1002/ajmg.a.70277

Publication Title

American Journal of Medical Genetics

Volume

Advance online publication

Pages

1-15

Abstract

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.

Rights

© 2026 The Authors

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License, which permits use and distribution in anymedium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Data Availability

Article states: "Clinical trial data is available via clinicaltrials.gov and at request via https://cinrgresearch.org/publications/data-summary-requests/."

Original Publication Citation

Dang, U. J., Fang, Y., Sabbatini, D., Pegoraro, E., Bello, L., Clemens, P. R., Guglieri, M., van den Anker, J., Damsker, J., Hagerty, L., Hathout, Y., Ziemba, M., Morgenroth, L., Bhattacharya, S., Nagaraju, K., Jaiswal, J. K., & Hoffman, E. P. (2026). Integrating genetic modifier genotype with serum proteomics in duchenne muscular dystrophy clinical trials links LTBP4 genetic modifier to IL-23/CD93 pathways in muscle. American Journal of Medical Genetics Part A. Advance online publication. https://doi.org/10.1002/ajmg.a.70277

Repository Citation

Dang, Utkarsh J.; Fang, Yuan; Sabbatini, Daniele; Pegoraro, Elena; Bello, Luca; Clemens, Paula R.; Guglieri, Michela; Anker, John van den; Damsker, Jesse; Hagerty, Laura; Hathout, Yetrib; Ziemba, Michael; Morgenroth, Lauren; Bhattacharya, Surajit; Nagaraju, Kanneboyina; Jaiswal, Jyoti K.; and Hoffman, Eric P., "Integrating Genetic Modifier Genotype With Serum Proteomics in Duchenne Muscular Dystrophy Clinical Trials Links LTBP4 Genetic Modifier to IL-23/CD93 Pathways in Muscle" (2026). Mathematics & Statistics Faculty Publications. 344.
https://digitalcommons.odu.edu/mathstat_fac_pubs/344