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

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). 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) according to clinical criteria. In a second or validation phase, the most significant polymorphisms associated with IFN-β response were genotyped in an independent validation cohort of 555 patients with MS (281 IFN-β responders and 274 nonresponders). 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-β 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-β response: rs2277302 (PELI3; p = 0.008) and rs832032 (GABRR3; p = 0.006). 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-β. Nevertheless, additional genetic and functional studies of PELI3 and GABRR3 are warranted.

Citation

Marta F Bustamante, Carlos Morcillo-Suárez, Sunny Malhotra, Jordi Rio, Laura Leyva, Oscar Fernández, Uwe K Zettl, Joep Killestein, David Brassat, Juan Antonio García-Merino, Antonio J Sánchez, Elena Urcelay, Roberto Alvarez-Lafuente, Lusia M Villar, Jose Carlos Alvarez-Cermeño, Xavier Farré, Jeannette Lechner-Scott, Koen Vandenbroeck, Alfredo Rodríguez-Antigüedad, Jelena S Drulovic, Filippo Martinelli Boneschi, Andrew Chan, Jorge Oksenberg, Arcadi Navarro, Xavier Montalban, Manuel Comabella. Pharmacogenomic study in patients with multiple sclerosis: Responders and nonresponders to IFN-β. Neurology® neuroimmunology & neuroinflammation. 2015 Oct;2(5):e154

PMID: 26445728

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