Public Release: 

Study implicates new gene in multiple sclerosis disease activity

Genetic variant predicts likelihood of patient's response to treatment

Brigham and Women's Hospital

A new study led by investigators at Brigham and Women's Hospital (BWH) reports the discovery of a genetic variant that is associated with a patient's likelihood of responding to interferon-beta, one of the medications used in treating multiple sclerosis (MS). Published in the Annals of Neurology on May 14, the study also presents evidence that the affected gene, SLC9A9, may have a broader role in regulating the development and activity of certain immune cells that play important roles in inflammatory diseases like MS.

A proportion of MS patients experience disease activity despite treatment. The early identification of the most effective drug for a given individual is critical to impact long-term outcome and to move toward a personalized treatment approach.

To find predictive indicators of a patient's response to treatment, the team, which included researchers from the Ospedale San Raffaele in Milan, Italy, performed a genome-wide association study (GWAS) in MS patients from Brigham and Women's Hospital, San Raffaele Hospital and seven academic MS centers in France, all of whom were being treated with the drug interferon-beta. The variant most predictive of whether or not a patient would respond to the drug was found in the gene SLC9A9.

"This study highlights the fact that genetic variation has a role in the course of a patient's disease in MS, but that this role is modest and will require much larger studies to be understood in detail," said Philip De Jager, MD, PhD, who directs the Program in Translational NeuroPsychiatric Genomics at the Ann Romney Center for Neurologic Diseases at BWH. "We need to expand this type of international, collaborative science."

Discovered in Italian patients, the observation was replicated in other Italian patients as well as patients in Boston and patients in France. "Further work is now needed to validate our results in other collections of patients, particularly patients treated with other MS medications, to evaluate whether the effect of the genetic variant is limited to interferon beta treatment or is relevant to other clinical MS treatments," said Filippo Martinelli-Boneschi, MD, PhD, of San Raffaele Scientific Institute.

The variant detected has a confirmed but weak role in MS. However, laboratory work in this report shows that the loss of the SLC9A9 gene leads immune cells to become much more likely to provoke damaging immune reactions.

"Manipulations of this gene in mice and in human cells will lead us to better understand mechanisms that are involved in the autoimmune response that causes MS," said Wassim Elyaman, PhD, an investigator in the Program in Translational NeuroPsychiatric Genomics at the Ann Romney Center for Neurologic Diseases at BWH.

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A large, ongoing study of MS patients called CLIMB, based out of the Partners Multiple Sclerosis Center, was integral to the current work and will continue to follow patients over the course of treatment to identify predictors of future disease course and the effectiveness of treatments. This work was supported by Giovani Ricercatori 2007 of the Italian Ministry of Health, and by grants R01 NS067305, JF2138A1, and RC2GM093080. Additional support was provided by the National MS Society, Fondazione Italiana Sclerosi, the French MS society Association pour la recherche sur la sclerose en plaques, the Club francophone de la SEP, and the Reseau francais pour la genetique de la SEP. De Jager is a recipient of the prestigious Harry Weaver Neuroscience Scholar of the National MS Society.

Full citation: Federica Esposito et al.: A Pharmacogenetic Study Implicates SLC9A9 in Multiple Sclerosis Disease Activity. Ann Neurol 2015; DOI: 10.1002/ana.24429.

Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 3.5 million annual patient visits, is the largest birthing center in Massachusetts and employs nearly 15,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $650 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH continually pushes the boundaries of medicine, including building on its legacy in transplantation by performing a partial face transplant in 2009 and the nation's first full face transplant in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials group. For more information, resources and to follow us on social media, please visit BWH's online newsroom.

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