Allelic combinations of immune-response genes associated with glatiramer acetate treatment response in Russian multiple sclerosis patients

Background: Glatiramer acetate (GA) is widely used as a first-line disease-modifying treatment for multiple sclerosis (MS). However, a significant proportion of MS patient appears to experience modest benefit from GA-treatment. Genetic variants affecting the clinical response to GA are believed to be relevant as biomarkers of GA-treatment efficiency. Patients & methods: Nine polymorphisms in candidate genes were analyzed as possible determinants of GA response in 285 Russian MS patients. Special attention was given to identification of response-associated allelic combinations by means of the APSampler algorithm. Results: No significant associations were found for individual polymorphisms. Alleles DRB1*15, TGFB1*T, CCR5*d and IFNAR1*G were the components of the combinations, of which carriage was significantly higher in nonresponders than in responders. Carriers of the most significant combinations: DRB1*15 + TGFB1*T + CCR5*d + IFNARl*G and DRB1*15 + TGFB1*T + CCR5*d (permutation p-values: 0.0056 and 0.013, respectively) had a 14 to 15-times increased risk of ineffective response to GA therapy. Discussion: The results suggest that the influence of immune-response genes on GA-induced response has a polygenic nature. The data are interpreted as evidence of additive and epistatic influences of the genes on GA efficiency for MS treatment. Original submitted 21 June 2011; Revision submitted 31 August 2011