Study implicates new gene in multiple sclerosis disease activity.
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.
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.
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 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.
Source: Haley Bridger – Brigham and Women’s Hospital
Image Source: Image is in the public domain
Original Research: Abstract for “A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity” by Federica Esposito, Melissa Sorosina, Linda Ottoboni, Elaine T. Lim, Joseph M. Replogle, Towfique Raj, Paola Brambilla, Giuseppe Liberatore, Clara Guaschino, Marzia Romeo, Thomas Pertel, James M. Stankiewicz, Vittorio Martinelli, Mariaemma Rodegher, Howard L. Weiner, David Brassat, Christophe Benoist, Nikolaos A. Patsopoulos, Giancarlo Comi, Wassim Elyaman, Filippo Martinelli Boneschi and Philip L. De Jager in Annals of Neurology. Published online May 14 2015 doi:10.1002/ana.24429
Abstract
A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity
Objective
A proportion of multiple sclerosis (MS) patients experience disease activity despite treatment. The early identification of the most effective drug is critical to impact long-term outcome and to move toward a personalized approach. The aim of the present study is to identify biomarkers for further clinical development and to yield insights into the pathophysiology of disease activity.
Methods
We performed a genome-wide association study in interferon-β (IFNβ)-treated MS patients followed by validation in 3 independent cohorts. The role of the validated variant was examined in several RNA data sets, and the function of the presumed target gene was explored using an RNA interference approach in primary T cells in vitro.
Results
We found an association between rs9828519G and nonresponse to IFNβ (pdiscovery = 4.43 × 10−8) and confirmed it in a meta-analysis across 3 replication data sets (preplication = 7.78 × 10−4). Only 1 gene is found in the linkage disequilibrium block containing rs9828519: SLC9A9. Exploring the function of this gene, we see that SLC9A9 mRNA expression is diminished in MS subjects who are more likely to have relapses. Moreover, SLC9A9 knockdown in T cells in vitro leads an increase in expression of IFNγ, which is a proinflammatory molecule.
Interpretation
This study identifies and validates the role of rs9828519, an intronic variant in SLC9A9, in IFNβ-treated subjects, demonstrating a successful pharmacogenetic screen in MS. Functional characterization suggests that SLC9A9, an Na+-H+ exchanger found in endosomes, appears to influence the differentiation of T cells to a proinflammatory fate and may have a broader role in MS disease activity, outside of IFNβ treatment.
“A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity” by Federica Esposito, Melissa Sorosina, Linda Ottoboni, Elaine T. Lim, Joseph M. Replogle, Towfique Raj, Paola Brambilla, Giuseppe Liberatore, Clara Guaschino, Marzia Romeo, Thomas Pertel, James M. Stankiewicz, Vittorio Martinelli, Mariaemma Rodegher, Howard L. Weiner, David Brassat, Christophe Benoist, Nikolaos A. Patsopoulos, Giancarlo Comi, Wassim Elyaman, Filippo Martinelli Boneschi and Philip L. De Jager in Annals of Neurology. Published online May 14 2015 doi:10.1002/ana.24429
