Integrating Genetic Modifier Genotype With Serum Proteomics in Duchenne Muscular Dystrophy Clinical Trials Links...

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.