Genetic Variant in Duchenne MD Linked to Earlier Loss of Ambulation, Study Finds

Patients with Duchenne muscular dystrophy (DMD) who carry a variant in the CD40 gene, which encodes a protein of the immune system, have loss of ambulation at an earlier age, according to a study published in the American Journal of Human Genetics.

The study, “Association Study Of Exon Variants In The NF-Κb And Tgfβ Pathways Identifies CD40 As A Modifier Of Duchenne Muscular Dystrophy,” was conducted by Luca Belo, MD, and his colleagues from the State University of New York.

DMD is caused by mutations in the gene that encodes dystrophin, a protein that plays an important role in the proper functioning of muscle cells. However, changes in the coding sequence of certain genes – changes which are called polymorphisms – may influence the development of the disease in patients, and are called disease modifiers.

Previous studies have identified polymorphisms in two genes – SPP1, encoding osteopontin, and LTBP4, encoding TGFβ-binding protein 4 – establishing them as Duchenne MD modifiers.

To identify other DMD modifiers that could influence the when ambulation is lost in patients, researchers analyzed the DNA of a group of 109 Duchenne patients with European or European-American ancestry from the Cooperative International Research Group Duchenne Natural History Study. The team focused on 438 polymorphisms in 384 genes previously implicated in DMD.

A minor variant, known as rs1883832, was found on the CD40 gene, which encodes a protein of the immune system. This variant causes a reduction in the expression levels of the protein, altering the function of the immune system. It was associated with an earlier loss of ambulation in patients who carried it.

“If you have [Duchenne muscular dystrophy], and you carry a common genetic variant, [that is] a single nucleotide polymorphism in the CD40 gene, you will have faster progression of muscle weakness, and are at risk of losing ambulation earlier — around one year on average,” Bello said in a news release.

To validate this finding, researchers repeated the study in three additional independent groups: the Padova Duchenne MD group of 95 patients showed a 0.3 year earlier average loss of ambulation; the United Dystrophinopathy Project group (243 patients), that showed a 0.5 year earlier average loss of ambulation; and the BIO-NMD group of 246 patients that showed a 0.6 year earlier average loss of ambulation.

“We think that none of the three [Duchenne MD] genetic modifiers described so far — SPP1, LTBP4, and CD40 — should be used as a prognostic factor by itself, as so many other factors are at play, and the predictive power of genotyping one [polymorphism] in one patient is very small,” Bello said.

“However, we think that we have added one more piece to the puzzle of understanding how the genetic background influences the disease course of [Duchenne MD], and we hope this will eventually lead to an improved ‘precision medicine’ approach to [Duchenne MD] care.”