Study implicates new gene in multiple sclerosis disease activity
A study led by researchers at Brigham and Women’s Hospital (BWH) identifies a genetic variant linked to altered response to interferon‑beta, a commonly used treatment for multiple sclerosis (MS). Published in Annals of Neurology on May 14, the report highlights SLC9A9 as a candidate gene that may influence immune cell behavior and MS disease activity.
Many people with MS continue to experience relapses or disease progression despite therapy. Finding reliable predictors of treatment response is essential for choosing the most effective medication early, reducing long‑term disability, and advancing personalized treatment strategies for MS.
The international team, which included investigators from Ospedale San Raffaele in Milan and seven academic MS centers in France, performed a genome‑wide association study (GWAS) on patients treated with interferon‑beta. The variant most strongly associated with nonresponse to interferon‑beta was located in the SLC9A9 gene.
Although the genetic effect size is modest, the association was discovered in an Italian cohort and replicated across independent collections from Italy, Boston, and France. The multi‑center replication supports the robustness of the finding, but larger studies are needed to fully understand the genetic contribution to treatment response and MS course.
Functional laboratory studies in this report provide biological context for the genetic association. SLC9A9 encodes an endosomal Na+-H+ exchanger and is the only gene in the linkage disequilibrium block containing the associated variant rs9828519. Analysis of RNA datasets showed reduced SLC9A9 mRNA expression in MS subjects who were more likely to experience relapses. In vitro experiments using RNA interference to reduce SLC9A9 expression in primary T cells led to increased production of interferon‑gamma (IFNγ), a proinflammatory cytokine that can exacerbate autoimmune responses.
These functional data suggest that SLC9A9 contributes to T cell differentiation and the balance between proinflammatory and regulatory immune states. Loss of SLC9A9 function appears to skew T cells toward a proinflammatory phenotype, supporting a mechanistic link between this gene and MS disease activity independent of treatment.
“This study demonstrates that genetic variation can influence disease course and pharmacologic response in MS,” said Philip De Jager, MD, PhD, director of the Program in Translational NeuroPsychiatric Genomics at the Ann Romney Center for Neurologic Diseases at BWH. “The effect is modest, so larger international efforts will be needed to map genetic contributors to treatment response and to enable clinical translation.”
Wassim Elyaman, PhD, an investigator in the same program, added that manipulations of SLC9A9 in animal models and human cells will clarify mechanisms driving the autoimmune response in MS and may point to new therapeutic strategies.
The CLIMB study, a large, ongoing MS cohort based at the Partners Multiple Sclerosis Center, provided essential clinical data and will continue to follow patients over time to identify predictors of disease course and treatment effectiveness. Continued longitudinal cohorts and international collaboration are critical to validate pharmacogenetic markers and to test whether identified variants influence response across different MS therapies beyond interferon‑beta.
Funding: This work was supported by Giovani Ricercatori 2007 of the Italian Ministry of Health and by grants R01 NS067305, JF2138A1, and RC2GM093080. Additional support came from 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. Philip De Jager is a recipient of the Harry Weaver Neuroscience Scholar award from the National MS Society.
Source: Haley Bridger, Brigham and Women’s Hospital
Original research: “A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity” by Federica Esposito et al., Annals of Neurology. Published online May 14, 2015. The study reports a genome‑wide association between rs9828519G and nonresponse to interferon‑beta and provides functional evidence linking SLC9A9 to T cell proinflammatory differentiation.
Abstract (concise summary)
Objective: A subset of MS patients experiences disease activity despite treatment. Early identification of the most effective medication is key to improving long‑term outcomes and enabling personalized therapy. This study aimed to identify biomarkers that predict treatment response and to shed light on mechanisms underlying disease activity.
Methods: A genome‑wide association study was performed in interferon‑beta‑treated MS patients, followed by validation in three independent cohorts. The role of the validated variant was examined in RNA datasets, and the function of the candidate gene SLC9A9 was probed using RNA interference in primary human T cells in vitro.
Results: The intronic variant rs9828519G was associated with nonresponse to interferon‑beta in the discovery cohort (p = 4.43 × 10−8) and confirmed in replication meta‑analysis (p = 7.78 × 10−4). SLC9A9 expression was lower in MS subjects prone to relapses. Knockdown of SLC9A9 in T cells increased IFNγ expression, supporting a role in promoting a proinflammatory T cell fate.
Interpretation: This pharmacogenetic investigation implicates SLC9A9 in interferon‑beta treatment response and suggests a broader role for SLC9A9 in MS disease activity by influencing T cell differentiation toward proinflammatory phenotypes. Further validation in larger cohorts and across different MS therapies is warranted.