[Genetic Markers for Personalized Therapy of Polygenic Diseases: Pharmacogenetics of Multiple Sclerosis].

Pharmacogenetics (PG) investigates the inherited variants of the human genome that underlie individual differences in drug metabolic transformation, delivery, and mechanism of action. Not only the contributions of individual genes, but also their cumulative effect should be considered in the case of polygenic diseases, which include the majority of human diseases. Multiple sclerosis (MS) is a severe autoimmune neurodegenerative disorder of the central nervous system (CNS) and is polygenic in nature. Understanding the role that the immune system plays in the pathogenesis of MS helped to design drugs for its pathogenetic therapy. These drugs are known as the disease-modifying treatments (DMTs). Among these are interferon ß (IFN-ß) and glatiramer acetate (GA), whose treatment efficacy and long-term safety have been proven in many clinical trials. However their efficacy on MS course varies from highly effective to lack of response. Prognostic genetic biomarkers of treatment efficacy can help to identify the MS patient groups where a particular drug is preferential or even strictly indicated to use. The review summarizes the findings from pharmacogenetic studies evaluating the efficacy of IFN-ß and GA in MS patients, including the author's original data.

[Association analysis of cytokine receptors' genes polymorphisms with clinical features of multiple sclerosis]. / Analiz assotsiatsii polimorfizma genov, kodiruyushchikh retseptory tsitokinov, s klinicheskimi kharakteristikami rasseyannogo skleroza.

AIM: To study the association of polymorphisms in the IL2RA and TNFRSF1A genes with severity and early clinical manifestations of remitted multiple sclerosis (MS). MATERIAL AND METHODS: Five hundred and eight patients of Russian ethnicity with bout-onset MS were genotyped for IL7RA (rs6897932), IL2RA (rs2104286) and TNFRSF1A (rs1800693) polymorphisms. Association analysis of the gene variants with disease severity, variants of MS manifestation, and first remission duration was performed. RESULTS AND CONCLUSION: Dividing the MS patients by disease severity, estimated with the MSSS, we found a significant increase in the TNFRSF1A*T/T genotype carriage in patients with milder MS course (MSSS≤3), and, respectively, in the TNFRSF1A*C allele carriage in patients with moderate to severe MS (MSSS> 3). Dividing the MS patients into two groups according to their MS manifestation variants, we revealed a significant increase in the TNFRSF1A*T allele carriage in patients with favorable variants of MS manifestation (optic neuritis or sensory disturbances), and of the TNFRSF1A*C/C genotype in patients with unfavorable variants (motor disorders, brain stem disorders, impaired coordination, pelvic disorders, mental disorders or polysymptomatic onset). No associations with first remission duration were observed. Multi-locus analysis to search for allelic combinations associated with the studied clinical features of MS was applied. In this analysis, a polymorphic variant of CTLA4 gene (rs231775), for which we have previously reported the association of the CTLA4*G allele with short first remission (less than 1 year), was also included. The carriage of biallelic combination (CTLA4*G + TNFRSF1A*C) was associated with short first remission more significantly than the carriage of CTLA4*G by itself. One more biallelic combination associated with short first remission (CTLA4*G/G + IL7RA*T), was identified. No other biallelic combinations significantly associated with the clinical features studied were observed.

GWAS-identified multiple sclerosis risk loci involved in immune response: validation in Russians.

Multiple sclerosis (MS) is a chronic neuro-inflammatory disease of complex etiology. The results of GWAS, a high-throughput method to discover genetic architecture of MS, require replication in independent ethnic groups. We performed a replication study of nine GWAS-identified SNPs in immune response in Russians. Associations of CLEC16A and IL2RA with MS were validated. Besides, we observed the associations of CLEC16A and IRF8 in women, and IL7RA and CD58 in men. With multi-locus association analysis two protective biallelic combinations: (TNFRSF1A*T+CLEC16A*A) and (TNFRSF1A*T+IRF8*A) were identified in women. Associations of CLEC16A*G/G and both biallelic combinations in women with MS survived the permutation test.

Family Analysis of Linkage and Association of HLA-DRB1, CTLA4, TGFB1, IL4, CCR5, RANTES, MMP9 and TIMP1 Gene Polymorphisms with Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). Proteins of the immune system, as well as proteins that are involved in the infiltration of activated immune cells in the CNS, play an important role in the pathogenesis of MS. We investigated the association and linkage with MS of the following immune-system genes polymorphisms: HLA-DRB1,CTLA4,TGFB1,IL4,CCR5 andRANTES, as well as of the matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinase  1 (TIMP1) genes polymorphisms. For this purpose we used the transmission disequilibrium test (TDT). The group investigated was comprised of 100 nuclear families of Russian ethnicity, each consisting of an affected offspring and his nonaffected parents. It was found that HLA-DRB1*15alleleandMMP9*-1562C allele were transmitted from healthy heterozygous parents to affected children more frequently than alternative alleles (p  =  0.02 andp  =  0.04, respectively). Another family-based method, AFBAC (affected family-based control), showed MS association with HLA-DRB1*15, but not with theMMP9*-1562C allele.