New Study Identifies Potential Genetic Markers for Severe MS Symptoms


Three complement genes identified in a new study may serve as markers for monitoring and predicting the progression and severity of multiple sclerosis.

New research has identified changes in early complement genes that may be associated with multiple sclerosis (MS)-caused vision loss. These findings could potentially serve as markers for monitoring and predicting disease progression and severity, according to the study authors.

The study, published in Brain, singled out 3 of these “complement genes,” which are known to play a role in the development of the brain and immune system.

Despite available treatments for relapsing-remitting MS, there is currently no way to stop progressive MS, according to Peter Calabresi, MD, professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and co-director of the Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis.

“We believe that our study opens up a new line of investigation targeting complement genes as a potential way to treat disease progression and nerve cell death,” Calabresi said in a press release.

The researchers conducted a set of genome-wide association studies by using DNA from 374 patients with MS along with high-tech retinal scanning. Using an imaging technique called optimal coherence tomography, the researchers were able to examine the back of each patient’s eyes and assess the damage to the nerve cells in the retinas.

From 2010 to 2017, the researchers performed the imaging on the patients, yielding an average of 4.6 scans per participant over the course of the study. Then, using blood samples, the study authors searched for genetic mutations in patients with the fastest deterioration rates, identifying 23 such DNA variations that mapped to the complement gene C3.

A further analysis examined an existing clinical trial group of another 835 patients with MS who underwent periodic vision testing every year to distinguish their ability to detect contrast. For the test, the participants were required to read 5 letters in a row as with a typical vision chart test, as well as separate vision chart tests with low contrast letters that simulate vision in low light.

With the blood samples from this group, the researchers also identified specific genetic changes in 2 other complement genes: C1QA and CR1. Patients with genetic changes in the C1QA gene were 71% more likely to develop difficulty detecting visual contrast and those with genetic changes in the CR1 gene were at 40% increased risk for developing a reduced ability to detect contract, according to the study.

“Complement proteins have traditionally been thought of as part of the immune system, binding to antibodies and helping them kill infected cells in the body,” Calabresi explained. “A decade ago, however, other researchers discovered that complement proteins bind to the connections between neurons and helps them grow in specific directions. But, too much complement was found to cause damage to the nerve cells, eventually killing them. Our findings fit well into this system.”

First study author Kathyrn Fitzgerald, ScD, assistant professor of neurology at the Johns Hopkins University School of Medicine, indicated that the next step would be conduct further studies in larger populations, including animal studies that examine the function of complement proteins and their mechanism behind killing nerve cells in MS.


Fitzgerald KC, Kim K, Smith MD, et al. Early complement genes are associated with visual system degeneration in multiple sclerosis. Brain. 2019. Doi:

Potential Genetic Markers of Multiple Sclerosis [news release]. Johns Hopkins Medicine’s website. Accessed October 30, 2019.

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