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Pharmacogenomic study in patients with multiple sclerosis: Responders and nonresponders to IFN-?.

ABSTRACT: OBJECTIVES: We aimed to investigate the association between polymorphisms located in type I interferon (IFN)-induced genes, genes belonging to the toll-like receptor (TLR) pathway, and genes encoding neurotransmitter receptors and the response to IFN-? treatment in patients with multiple sclerosis (MS). METHODS: In a first or screening phase of the study, 384 polymorphisms were genotyped in 830 patients with MS classified into IFN-? responders (n = 416) and nonresponders (n = 414) according to clinical criteria. In a second or validation phase, the most significant polymorphisms associated with IFN-? response were genotyped in an independent validation cohort of 555 patients with MS (281 IFN-? responders and 274 nonresponders). RESULTS: Seven single nucleotide polymorphisms (SNPs) were selected from the screening phase for further validation: rs832032 (GABRR3; p = 0.0006), rs6597 (STUB1; p = 0.019), rs3747517 (IFIH1; p = 0.010), rs2277302 (PELI3; p = 0.017), rs10958713 (IKBKB; p = 0.003), rs2834202 (IFNAR1; p = 0.030), and rs4422395 (CXCL1; p = 0.017). None of these SNPs were significantly associated with IFN-? response when genotyped in an independent cohort of patients. Combined analysis of these SNPs in all patients with MS (N = 1,385) revealed 2 polymorphisms associated with IFN-? response: rs2277302 (PELI3; p = 0.008) and rs832032 (GABRR3; p = 0.006). CONCLUSIONS: These findings do not support an association between polymorphisms located in genes related to the type I IFN or TLR pathways or genes encoding neurotransmitter receptors and the clinical response to IFN-?. Nevertheless, additional genetic and functional studies of PELI3 and GABRR3 are warranted.

SUBMITTER: Bustamante MF

PROVIDER: S-EPMC4582905 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Pharmacogenomic study in patients with multiple sclerosis: Responders and nonresponders to IFN-β.

Bustamante Marta F MF Morcillo-Suárez Carlos C Malhotra Sunny S Rio Jordi J Leyva Laura L Fernández Oscar O Zettl Uwe K UK Killestein Joep J Brassat David D García-Merino Juan Antonio JA Sánchez Antonio J AJ Urcelay Elena E Alvarez-Lafuente Roberto R Villar Lusia M LM Alvarez-Cermeño Jose Carlos JC Farré Xavier X Lechner-Scott Jeannette J Vandenbroeck Koen K Rodríguez-Antigüedad Alfredo A Drulovic Jelena S JS Martinelli Boneschi Filippo F Chan Andrew A Oksenberg Jorge J Navarro Arcadi A Montalban Xavier X Comabella Manuel M

Neurology(R) neuroimmunology & neuroinflammation 20150924 5

<h4>Objectives</h4>We aimed to investigate the association between polymorphisms located in type I interferon (IFN)-induced genes, genes belonging to the toll-like receptor (TLR) pathway, and genes encoding neurotransmitter receptors and the response to IFN-β treatment in patients with multiple sclerosis (MS).<h4>Methods</h4>In a first or screening phase of the study, 384 polymorphisms were genotyped in 830 patients with MS classified into IFN-β responders (n = 416) and nonresponders (n = 414) a ...[more]

PMID: 26445728

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Project description:BACKGROUND:Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNbeta in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNbeta therapy. METHODOLOGY:Large scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNbeta therapy. Differential gene expression was analyzed by Significance Analysis of Microarrays. Subsequent expression analyses on specific genes were performed after three and six months of treatment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated in vitro with IFNbeta. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation. PRINCIPAL FINDINGS:Pharmacogenomics revealed a marked variation in the pharmacological response to IFNbeta between patients. A total of 126 genes were upregulated in a subset of patients whereas in other patients these genes were downregulated or unchanged after one month of IFNbeta therapy. Most interestingly, we observed that the extent of the pharmacological response correlates negatively with the baseline expression of a specific set of 15 IFN response genes (R = -0.7208; p = 0.0016). The negative correlation was maintained after three (R = -0.7363; p = 0.0027) and six (R = -0.8154; p = 0.0004) months of treatment, as determined by gene expression levels of the most significant correlating gene. Similar results were obtained in an independent group of patients (n = 30; R = -0.4719; p = 0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNbeta indicating that differential responsiveness to IFNbeta is an intrinsic feature of peripheral blood cells at baseline. CONCLUSION:These data imply that the expression levels of IFN response genes in the peripheral blood of MS patients prior to treatment could serve a role as biomarker for the differential clinical response to IFNbeta.

Dataset Information

Pharmacogenomic study in patients with multiple sclerosis: Responders and nonresponders to IFN-?.

Publications

Pharmacogenomic study in patients with multiple sclerosis: Responders and nonresponders to IFN-β.

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