title: Pharmacogenetics of glatiramer acetate therapy for multiple sclerosis reveals drug-response markers.
abstract: Genetic-based optimization of treatment prescription is becoming a central research focus in the management of chronic diseases, such as multiple sclerosis, which incur a prolonged drug-regimen adjustment. This study was aimed to identify genetic markers that can predict response to glatiramer acetate (Copaxone) immunotherapy for relapsing multiple sclerosis. For this purpose, we genotyped fractional cohorts of two glatiramer acetate clinical trials for HLA-DRB1*1501 and 61 single nucleotide polymorphisms within a total of 27 candidate genes. Statistical analyses included single nucleotide polymorphism-by-single nucleotide polymorphism and haplotype tests of drug-by-genotype effects in drug-treated versus placebo-treated groups. We report the detection of a statistically significant association between glatiramer acetate response and a single nucleotide polymorphism in a T-cell receptor beta (TRB@) variant replicated in the two independent cohorts (odds ratio=6.85). Findings in the Cathepsin S (CTSS) gene (P=0.049 corrected for all single nucleotide polymorphisms and definitions tested, odds ratio=11.59) in one of the cohorts indicate a possible association that needs to be further investigated. Additionally, we recorded nominally significant associations of response with five other genes, MBP, CD86, FAS, IL1R1 and IL12RB2, which are likely to be involved in glatiramer acetate's mode-of-action, both directly and indirectly. Each of these association signals in and of itself is consistent with the no-association null-hypothesis, but the number of detected associations is surprising vis-à-vis chance expectation. Moreover, the restriction of these associations to the glatiramer acetate-treated group, rather than the placebo group, clearly demonstrates drug-specific genetic effects. These findings provide additional progress toward development of pharmacogenetics-based personalized treatment for multiple sclerosis.
authors.affiliation: Division of Neuroimmunology and Multiple Sclerosis Center, Rappaport Faculty of Medicine and Research Institute, Technion and Carmel Medical Center, Haifa, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Grossman
authors.forename: Nili
authors.initials: N
authors.lastname: Avidan
authors.forename: Clara
authors.initials: C
authors.lastname: Singer
authors.forename: Dan
authors.initials: D
authors.lastname: Goldstaub
authors.forename: Liat
authors.initials: L
authors.lastname: Hayardeny
authors.forename: Eli
authors.initials: E
authors.lastname: Eyal
authors.forename: Edna
authors.initials: E
authors.lastname: Ben-Asher
authors.forename: Tamar
authors.initials: T
authors.lastname: Paperna
authors.forename: Itsik
authors.initials: I
authors.lastname: Pe'er
authors.forename: Doron
authors.initials: D
authors.lastname: Lancet
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Ariel
authors.initials: A
authors.lastname: Miller
mesh_terms: D016001:Confidence Intervals; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D000068717:Glatiramer Acetate; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000235:genetics*; D016017:Odds Ratio; D010455:Peptides / Q000627:therapeutic use*; D010597:Pharmacogenetics; D010919:Placebos; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D005819:Genetic Markers; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D010455:Peptides; D010919:Placebos; D000068717:Glatiramer Acetate