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 rs9828519(G) 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.


CONCLUSIONS
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.
Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.|Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Federica
F
Esposito
Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Melissa
M
Sorosina
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA.
Linda
L
Ottoboni
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
Elaine T
ET
Lim
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA.|Program for Medical and Population Genetics, Broad Institute, Cambridge, MA.|Program in Translational Neuropsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, MA.
Joseph M
JM
Replogle
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA.|Program for Medical and Population Genetics, Broad Institute, Cambridge, MA.|Program in Translational Neuropsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, MA.
Towfique
T
Raj
Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Paola
P
Brambilla
Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.|Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Giuseppe
G
Liberatore
Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.|Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Clara
C
Guaschino
Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.
Marzia
M
Romeo
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
Thomas
T
Pertel
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
James M
JM
Stankiewicz
Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.|Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Vittorio
V
Martinelli
Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.|Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Mariaemma
M
Rodegher
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
Howard L
HL
Weiner
Department of Neurology, Purpan Hospital and Mixed Unit of Research 1043, University of Toulouse, Toulouse, France.
David
D
Brassat
Harvard Medical School, Boston, MA.|Program for Medical and Population Genetics, Broad Institute, Cambridge, MA.
Christophe
C
Benoist
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.|Program for Medical and Population Genetics, Broad Institute, Cambridge, MA.|Program in Translational Neuropsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, MA.
Nikolaos A
NA
Patsopoulos
Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.|Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Giancarlo
G
Comi
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.|Program in Translational Neuropsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, MA.
Wassim
W
Elyaman
Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.|Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Filippo
F
Martinelli Boneschi
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.|Program for Medical and Population Genetics, Broad Institute, Cambridge, MA.|Program in Translational Neuropsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, MA.
Philip L
PL
De Jager
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D015331:Cohort Studies; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D066298:In Vitro Techniques; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D034741:RNA, Small Interfering; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
D000276:Adjuvants, Immunologic; D016207:Cytokines; D034741:RNA, Small Interfering; C478541:SLC9A9 protein, human; D017923:Sodium-Hydrogen Exchangers; D000068576:Interferon beta-1b; D016899:Interferon-beta; D000068556:Interferon beta-1a