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A pharmacogenetic study implicates SLC9A9 in multiple sclerosis disease activity.

PubMed: Related Articles

A pharmacogenetic study implicates SLC9A9 in multiple sclerosis disease activity.

Ann Neurol. 2015 Apr 25;

Authors: Esposito F, Sorosina M, Ottoboni L, Lim ET, Replogle JM, Raj T, Brambilla P, Liberatore G, Guaschino C, Romeo M, Pertel T, Stankiewicz JM, Martinelli V, Rodegher M, Weiner HL, Brassat D, Benoist C, Patsopoulos NA, Comi G, Elyaman W, Martinelli Boneschi F, De Jager PL

Abstract
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 IFNβ-treated MS patients followed by validation in three independent cohorts. The role of the validated variant was examined in several RNA datasets, 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 non-response to IFNβ (Pdiscovery =4.43x10(-8) ) and confirmed it in a meta-analysis across three replication datasets (Preplication =7.78x10(-4) ). Only one 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 knock-down in T cells in vitro leads an increase of IFNγ expression, which is a pro-inflammatory 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 pro-inflammatory fate and may have a broader role in MS disease activity, outside of IFNβ-treatment. This article is protected by copyright. All rights reserved.

PMID: 25914168 [PubMed - as supplied by publisher] http://dlvr.it/9bzDQP