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Published on: December 9, 2015
Pharmacogenomic study in patients with multiple sclerosis: Responders and nonresponders to IFN-β
Marta F Bustamante1, Carlos Morcillo-Suárez1, Sunny Malhotra1
1Servei de Neurologia-Neuroimmunologia (M.F.B., S.M., J.R., X.M., M.C.), Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Institute of Evolutionary Biology (UPF-CSIC) (C.M.-S., X.F., A.N.), PRBB, Barcelona, Spain; National Institute for Bioinformatics (C.M.-S., X.F., A.N.), Universitat Pompeu Fabra, Barcelona, Spain; Servicio de Neurología (L.L., O.F.), Instituto de Neurociencias Clínicas, Hospital Regional Universitario de Málaga, IBIMA, Málaga, Spain; Department of Neurology (U.K.Z.), University of Rostock, Rostock, Germany; Department of Neurology (J.K.), Multiple Sclerosis Centre Amsterdam, Vrije University Medical Centre, Amsterdam, the Netherlands; Pole des neurosciences et INSERM U1043 (D.B.), Université de Toulouse III, Hopital Purpan, Toulouse, France; Neuroinmunología (J.A.G.-M., A.J.S.), Hospital Universitario Puerta de Hierro, Madrid, Spain; Servicio de Neurología (E.U., R.A.-L.), Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain; Department of Neurology and Immunology (L.M.V., J.C.A.-C.), Hospital Ramón y Cajal, IRYCIS, Madrid, Spain; Department of Neurology (J.L.-S.), John Hunter Hospital, Newcastle, Australia; Hunter Medical Research Institute (J.L.-S.), University Newcastle, Australia; University Newcastle (J.L.-S.), Callaghan Campus, Australia; Neurogenomiks Group (K.V.), Universidad del País Vasco (UPV/EHU), Leioa, Spain; IKERBASQUE (K.V.), Basque Foundation for Science, Bilbao, Spain; Achucarro Basque Center for Neuroscience (K.V.), Zamudio, Spain; Servicio de Neurología (A.R.-A.), Hospital de Basurto, Bilbao, Spain; Clinic of Neurology (J.S.D.), Clinical Centre of Serbia (CCS), Faculty of Medicine, University of Belgrade, Serbia; Laboratory of Genetics of Neurological Complex Disorders and Department of Neuro-rehabilitation (F.M.B
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; 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).
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.
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