TY - JOUR
T1 - Pharmacogenomic study in patients with multiple sclerosis Responders and nonresponders to IFN-β
AU - Bustamante, Marta F.
AU - Morcillo-Suárez, Carlos
AU - Malhotra, Sunny
AU - Rio, Jordi
AU - Leyva, Laura
AU - Fernández, Oscar
AU - Zettl, Uwe K.
AU - Killestein, Joep
AU - Brassat, David
AU - García-Merino, Juan Antonio
AU - Sánchez, Antonio J.
AU - Urcelay, Elena
AU - Alvarez-Lafuente, Roberto
AU - Villar, Lusia M.
AU - Alvarez-Cermeño, Jose Carlos
AU - Farré, Xavier
AU - Lechner-Scott, Jeannette
AU - Vandenbroeck, Koen
AU - Rodríguez-Antigüedad, Alfredo
AU - Drulovic, Jelena S.
AU - Boneschi, Filippo Martinelli
AU - Chan, Andrew
AU - Oksenberg, Jorge
AU - Navarro, Arcadi
AU - Montalban, Xavier
AU - Comabella, Manuel
PY - 2015/10/1
Y1 - 2015/10/1
N2 - © 2015 American Academy of Neurology. 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-β 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-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). 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; p5 0.010), rs2277302 (PELI3; p5 0.017), rs10958713 (IKBKB; p5 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). 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-β. Nevertheless, additional genetic and functional studies of PELI3 and GABRR3 are warranted.
AB - © 2015 American Academy of Neurology. 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-β 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-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). 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; p5 0.010), rs2277302 (PELI3; p5 0.017), rs10958713 (IKBKB; p5 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). 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-β. Nevertheless, additional genetic and functional studies of PELI3 and GABRR3 are warranted.
U2 - 10.1212/NXI.0000000000000154
DO - 10.1212/NXI.0000000000000154
M3 - Article
SN - 2332-7812
VL - 2
SP - e154
JO - Neurology: Neuroimmunology and NeuroInflammation
JF - Neurology: Neuroimmunology and NeuroInflammation
IS - 5
ER -