NEWS & VIEWS MULTIPLE SCLEROSIS
A clinically useful genetic variant in multiple sclerosis? Finn Sellebjerg and Annette Bang Oturai Refers to Esposito, F. et al. A pharmacogenetic study implicates SLC9A9 in multiple sclerosis disease activity. Ann. Neurol. http://dx.doi.org/10.1002/ana.24429
A recent study has identified a variant of the SLC9A9 gene that is associated with the clinical response to IFN‑β treatment. IFN‑β induces SLC9A9 expression, resulting in inhibition of proinflammatory T lymphocytes. The findings suggest a key role for this gene in determining the response to IFN‑β in patients with multiple sclerosis. Multiple sclerosis (MS) is an immunemediated disease of the CNS, and initially follows a relapsing–remitting course in most patients. During the past two decades, increasing numbers of drugs were licensed for the treatment of relapsing–remitting MS.1 IFN‑β is widely used for this purpose, and typically reduces the number of relapses by approximately one-third. However, although some patients show an excellent response to IFN‑β treatment, others show an insufficient response, with breakthrough relapses.2 The reason for this dichotomy has been uncertain: some patients might be biologically nonresponsive to IFN‑β, or they might simply have a more aggressive disease that cannot controlled by IFN‑β treatment. Now, a new study by Federica Esposito and colleagues presents evidence that patient responses to IFN‑β can be genetically determined.3
‘‘
…a SNP in the SLC9A9 gene … was associated with the response to treatment with IFN‑β
’’
Several previous studies have investigated whether single nucleotide polymorphisms (SNPs)—common genetic variants scattered throughout the genome—are associated with the response to IFN‑β treatment in patients with MS.4 Although many studies have reported associations between SNPs and treatment response, none of these associations have been confirmed in independent studies. Indeed, in two previous genome-wide association studies (GWAS)
of the response to IFN‑β treatment, there was essentially no overlap in the identified SNPs.5,6 Another recent study failed to confirm an association between the response to IFN‑β treatment and SNPs in several genes that had previously been suggested to predict the response to IFN‑β.7 Instead, the relapse rate before treatment initiation predicted the relapse rate and risk of sustained disability accumulation after treatment with IFN‑β. In the new study, Esposito and co-workers identified a SNP in the SLC9A9 gene (solute carrier family 9, subfamily A [NHE9, cation proton antiporter 9], member 9; also known as sodium/hydrogen exchanger 9) that was associated with the response to treatment with IFN‑β.3 The authors first conducted a GWAS in 146 Italian patients with MS. During 2 years of treatment with IFN‑β, patients were classified as responders, partial responders or nonresponders according to clinical and MRI data. The analysis showed that the SNP rs9828519 was associated with an increased risk of nonresponsiveness to IFN‑β treatment, with the number of nonresponders directly corresponding to the number of G alleles. This association was statistically significant at the genome-wide level (P
A clinically useful genetic variant in multiple sclerosis? Finn Sellebjerg and Annette Bang Oturai Refers to Esposito, F. et al. A pharmacogenetic study implicates SLC9A9 in multiple sclerosis disease activity. Ann. Neurol. http://dx.doi.org/10.1002/ana.24429
A recent study has identified a variant of the SLC9A9 gene that is associated with the clinical response to IFN‑β treatment. IFN‑β induces SLC9A9 expression, resulting in inhibition of proinflammatory T lymphocytes. The findings suggest a key role for this gene in determining the response to IFN‑β in patients with multiple sclerosis. Multiple sclerosis (MS) is an immunemediated disease of the CNS, and initially follows a relapsing–remitting course in most patients. During the past two decades, increasing numbers of drugs were licensed for the treatment of relapsing–remitting MS.1 IFN‑β is widely used for this purpose, and typically reduces the number of relapses by approximately one-third. However, although some patients show an excellent response to IFN‑β treatment, others show an insufficient response, with breakthrough relapses.2 The reason for this dichotomy has been uncertain: some patients might be biologically nonresponsive to IFN‑β, or they might simply have a more aggressive disease that cannot controlled by IFN‑β treatment. Now, a new study by Federica Esposito and colleagues presents evidence that patient responses to IFN‑β can be genetically determined.3
‘‘
…a SNP in the SLC9A9 gene … was associated with the response to treatment with IFN‑β
’’
Several previous studies have investigated whether single nucleotide polymorphisms (SNPs)—common genetic variants scattered throughout the genome—are associated with the response to IFN‑β treatment in patients with MS.4 Although many studies have reported associations between SNPs and treatment response, none of these associations have been confirmed in independent studies. Indeed, in two previous genome-wide association studies (GWAS)
of the response to IFN‑β treatment, there was essentially no overlap in the identified SNPs.5,6 Another recent study failed to confirm an association between the response to IFN‑β treatment and SNPs in several genes that had previously been suggested to predict the response to IFN‑β.7 Instead, the relapse rate before treatment initiation predicted the relapse rate and risk of sustained disability accumulation after treatment with IFN‑β. In the new study, Esposito and co-workers identified a SNP in the SLC9A9 gene (solute carrier family 9, subfamily A [NHE9, cation proton antiporter 9], member 9; also known as sodium/hydrogen exchanger 9) that was associated with the response to treatment with IFN‑β.3 The authors first conducted a GWAS in 146 Italian patients with MS. During 2 years of treatment with IFN‑β, patients were classified as responders, partial responders or nonresponders according to clinical and MRI data. The analysis showed that the SNP rs9828519 was associated with an increased risk of nonresponsiveness to IFN‑β treatment, with the number of nonresponders directly corresponding to the number of G alleles. This association was statistically significant at the genome-wide level (P
