Genetic Modifiers of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy is the most common form of muscular dystrophy, and considered the most clinically devastating. The primary genetic defect is mutations in the 2.5 million bp dystrophin gene, and consequent loss of the dystrophin protein from the membrane cytoskeleton of muscle fibers. Affected patients show wide variation in natural history (age at presentation, and severity of progression), with all clinical reports showing standard deviations greater than the mean for most measures. Chronic administration of corticosteroids is the only pharmacological approach to slowing disease progression. However, patient response to glucocorticoids also shows standard deviations greater than the mean. These data strongly suggest the existence of genetic modifiers of both natural history, and response to steroids in Duchenne muscular dystrophy. The identification of genetic modifiers would permit better prognostic data, as well as key pharmacogenetic information when prescribing steroids, or designing clinical trials. In an NIH funded study of 1,200 college-age volunteers, we have recently identified a series of muscle quantitative trait loci (QTLs) that explain variation of muscle size, strength, and response to resistance training. One of these QTL loci is a 12kb haplotype upstream of the key signaling protein, AKT1, and this locus alone explains 9% of all variation in muscle strength. As AKT1 is involved in both muscle strength, and signaling responses to glucocorticoids, we hypothesize that our "haplotype 2" of AKT1 will prove a strong genetic modifier of DMD. The proposed DMD patient population and muscle phenotyping will come from three recently funded clinical studies carried out by the CINRG network (Core B), drawing from a CINRG census of 1,760 DMD patients.

Aim 1 will study 200 DMD subjects in two corticosteroid clinical trials, and study genetic modifiers of steroid responsiveness. A pre-existing validation cohort from University of Padova has been recruited. Aim 2 will study 395 DMD patients in a funded natural history study for genetic modifiers of disease onset and progression. Aim 3 will conduct a SNP discovery program focused on glucocorticoid responsive pathways in muscle, with new loci then tested in the populations in Aims 1 and 2. This is a "clinical project" that takes advantage of the previously established infrastructure of the CINRG clinical trial network (18 sites in 10 countries), including novel sensitive and reliable tests for DMD patient strength using a video interface coupled to QMT. This Project makes extensive use of all three Cores (Administrative, Human Clinical Core (CINRG), and Bioinformatics and Computing Core.