<p>Table S3. Glatiramer acetate pharmacogenetic studies in multiple sclerosis: design, results (candidate gene studies).</p><p>Study group Clinical end points Results, associations Study Follow-up Polymorphous (n), Candidate genes with response (+) or [ref.] period loci ethnicity non-responsiveness (–) For non- For responders responders Presence of Relapse-free or one Fusco relapses mild relapse HLA DRB1 HLA DRB1*1501 (+), et al. n=44, Italians 2 years and/or and HLA DQB1 p=0.008 [1] Increase in EDSS No EDSS progression of at least 1 point. Alifirov a et al. n=62, Russians 1 year Time to first relapse IL12В rs3212227 NS [2] Grossm Original study HLA DRB1 and 61 SNPs TCRB rs71878*С (+), n=73, USA an et al. 27 candidate genes, p=0.006; Caucasians [3]* 2 years Relapse-free including: IL12RB2 (discovery and - TCRB rs946685*G(+), cohort) No EDSS progression CTSS p=0.045 n=101, 9 months Replication study MBP TCRB rs71878*C (+), Europeans/ Combined response: - IL1R1 p=0.039; Canadians No clinical relapse CD86 CTSS rs2275235*G (+), c (replication and FAS p=0.049 ; cohort) No more than one T1- IL12RB2 CTSS rs1415148*A (+), enhancing lesion in p=0.0018; the third trimester MBP rs470929*T(+), p=0.0038; ‘T1 lesion-free’ IL1R1 rs956730*A(+), response: p=0.049; No T1-enhancing CD86 rs2001791*T(+), lesions in the third trimester p=0.04; CD86 rs1129055 C (–), p=0.04; Time to first clinical event (clinical relapse, Gross Approximat n=332, changes in MRI lesion burden, increase of rs3135388*A/Aa (+), et al. ely 600 DRB1 rs3135388 Americans EDSS by 1 point, sustained over a 6-month p=0.015/0.048b [4] weeks period) DRB1 HLA class II CTLA4 rs231775 CCR5 rs333 HLA-DRB1*04 (+), Tsareva Relapse free status IL7RA rs6897932 p=0.027; et al. n=285, Russians 2 years and - TNF rs1800629 CCR5 rs333*w/w (+), [5] No EDSS progression IFNB1 rs1051922 p=0.046 IFNG rs2430561 TGFB1 rs1800469 IFNAR1 rs1012335 DRB1 HLA class II CTLA4 rs231775 One or more CCR5 rs333 relapses Tsareva Relapse free status IL7RA rs6897932 and/or et al. n=214, Russians 2 years and TNF rs1800629 NS Increase of at least [6] No EDSS progression IFNB1 rs1051922 1 point in EDSS IFNG rs2430561 over 1 year period TGFB1 rs1800469 IFNAR1 rs1012335 Dhib- n=64, 2 years Relapse-free status One or more HLA-DRB1 DR15 (+), p=0.02; Jalbut Americans and relapses HLA-DQB1 DQ6 (+), p=0.014; et al., No EDSS progression or DR17 (–), p=0.012; [7] Increase of at least DQ2 (–), p=0.002; 1 point in EDSS Haplotypes: DR15-DQ6 (+), p=0.044c DR17-DQ2 (–), p=0.046c 1) One or more Lopez- relapses Relapse-free status Gomez or n=64, Spanish 2 years and TRAILR1 rs20576 NS et al., 2) Increase of at No EDSS progression [8] least 1 point in EDSS NS - not significant; OR – odds ratio; HR – hazard ratio; CI – confidence interval; a reflecting HLA-DRB1*1501/1501 genotype; b p- and HR[95%CI] values (adjusted for baseline confounders) are separated by slash for comparisons of A/G vs A/A and G/G vs A/A; c p-value after multiple comparisons correction. Referemces:</p><p>[1] Fusco C, Andreone V, Coppola G, Luongo V, Guerini F, Pace E et al. HLA-DRB1*1501 and </p><p> response to copolymer-1 therapy in relapsing-remitting multiple sclerosis. Neurology, </p><p>2001;57:1976-9.</p><p>[2] Alifirova VM, Orlova I, Babenko SA, Rudko AA, Puzyrev VP. [The 1188 A/C ILI2B gene </p><p> polymorphism in patients with multiple sclerosis and in healthy subjects of Tomsk region]. </p><p>Zh Nevrol Psikhiatr Im S S Korsakova, 2006;Spec No 3:130-5.</p><p>[3] Grossman I, Avidan N, Singer C, Goldstaub D, Hayardeny L, Eyal E et al. Pharmacogenetics </p><p> of glatiramer acetate therapy for multiple sclerosis reveals drug-response markers. </p><p>Pharmacogenet Genomics, 2007;17:657-66.</p><p>[4] Gross R, Healy BC, Cepok S, Chitnis T, Khoury SJ, Hemmer B et al. Population structure </p><p> and HLA DRB1 1501 in the response of subjects with multiple sclerosis to first-line </p><p> treatments. Journal of neuroimmunology, 2011;233:168-74.</p><p>[5] Tsareva E, Kulakova OG, Makarycheva O, Boiko AN, Shchur SG, Lashch N et al. </p><p>[Pharmacogenomics of multiple sclerosis: association of immune response genes </p><p> polymorphism with copaxone treatment efficacy]. Molekuliarnaia biologiia, 2011;45:963-72.</p><p>[6] Tsareva EY, Kulakova OG, Boyko AN, Shchur SG, Lvovs D, Favorov AV et al. Allelic </p><p> combinations of immune-response genes associated with glatiramer acetate treatment </p><p> response in Russian multiple sclerosis patients. Pharmacogenomics, 2012;13:43-53.</p><p>[7] Dhib-Jalbut S, Valenzuela R, Ito K, Kaufman M, Picone M, Buyske S. HLA DR and DQ </p><p> alleles and haplotypes associated with clinical response to glatiramer acetate in multiple </p><p> sclerosis. Multiple Sclerosis and Related Disorders, 2013;2:340-8.</p><p>[8] Lopez-Gomez C, Pino-Angeles A, Orpez-Zafra T, Pinto-Medel MJ, Oliver-Martos B, Ortega-</p><p>Pinazo J et al. Candidate Gene Study of TRAIL and TRAIL Receptors: Association with </p><p>Response to Interferon Beta Therapy in Multiple Sclerosis Patients. PloS one, 2013;8:e62540.</p>