Pharmacogenomics of multiple sclerosis: Association of immune response gene polymorphisms with copaxone treatment efficacy

A complex association analysis of copaxone (glatiramer acetate) immunotherapy efficacy with allelic polymorphism of the number of immune response genes, including the genes for interferon β (IFNB1), transforming growth factor β1 (TGFB1), interferon γ (IFNG), tumor necrosis factor (TNF), interferon α/β receptor 1 (IFNAR1), CC chemokine receptor 5 (CCR5), interleukin 7 receptor subunit α (IL7RA), cytotoxic T-lymphocyte antigen 4 (CTLA4), and HLA class II histocompatibility antigen β chain (DRB1), was performed using the APSampler algorithm for 285 multiple sclerosis patients of Russian ethnicity. The results demonstrate that the polymorphic variants of CCR5, DRB1, IFNG, TGFB1, IFNAR1, IL7RA, and, possibly, TNF and CTLA4 contribute to the copaxone treatment response. Single alleles of CCR5 and DRB1 genes were reliably associated with treatment efficacy. Allelic variants of the other genes exerted a weaker, though still reliable, effect on the copaxone treatment response, but as part of bi- and triallelic combinations only. The study may provide a basis for a prognostic test allowing an individual choice of immune-modulating treatment for a patient with multiple sclerosis.     

Analysis of linkage and association of alleles of proinflammatory cytokines genes IL-6, IFNg and TNF with multiple sclerosis using transmission disequilibrium test (TDT)

Proinflammatory cytokines Interleukin-6 (IL-6), Interferon-gamma (IFNg) and Tumor necrosis factor (TNF) are known as participants of inflammation and play an important role in pathogenesis of multiple sclerosis (MS). Based on literature data about influence of SNPs G(-308)A of TNF gene, A(+874)T of IFNG gene and G(-174)C of IL-6 gene on production of these cytokines, we investigated association of these polymorphic sites with MS. Linkage and association of alleles of these genes with MS was analyzed by transmission disequilibrium test (TDT). In investigated group of 104 nuclear families of Russian ethnicity it was found that TNF* (-308)A allele transmitted from healthy heterozygous parents to affected children more frequently (p = 0.01). Linkage/association of IFNG and IL-6 alleles with MS was not revealed. Thus, data obtained indicate the participation of TNF gene in MS susceptibility in Russians.     

Polymorphism of the apolipoprotein E gene and risk of multiple sclerosis in ethnic Russians

Multiple sclerosis (MS) is a multifactorial disease of the central nervous system with pronounced hereditary predisposition. The purpose of the study was to test the assumption on the involvement of the apolipoprotein E gene (APOE) polymorphism in exon 4 in the development of MS in ethnic Russians. Samples independently collected in Moscow (106 MS cases and 189 control healthy volunteers), Sverdlovsk oblast (54 and 109, respectively), and the Republic of Bashkortostan (119 and 285, respectively) were examined. Genotypes for 2059C/T and 2197C/T polymorphisms of the APOE gene, which determine the amino acid substitutions C112R and R158C in apolipoprotein E, were analyzed by polymerase chain reaction followed by restriction analysis of amplificates. No statistically significant differences in genotype or allele frequencies were found between the control group and the group of MS cases. The APOE*4 allele is not associated with the risk of MS in ethnic Russians.     

Pharmacogenomics of multiple sclerosis: association of immune response genes polymorphism with copaxone treatment efficacy

Complex association analysis of copaxone (glatiramer acetate) immunotherapy efficacy with allelic polymorphism in the number of immune response genes, which encode interferone beta (IFNB1), transforming growth factor beta1 (TGFB1), interferone gamma (IFNG), tumor necrosis factor (TNF), interferon alpha/beta receptor 1 (IFNAR1), CC chemokine receptor 5 (CCR5), interleukin 7 receptor alpha subunit (IL7RA), cytotoxic T-lymphocyte antigen 4 (CTLA4) and HLA class II histocompatibility antigen beta chain (DRB1) was performed with APSampler algorithm for 285 multiple sclerosis patients of Russian ethnicity. The results show evidence for the contribution of polymorphic variants in CCRS, DRB1, IFNG, TGFB1, IFNAR1, IL7RA and, probably, TNF and CTLA4 genes to copaxone treatment response. Single alleles of CCR5 and DRB1 genes are reliably associated with treatment efficacy. Carriage of allelic variants of other above mentioned genes contribute with reliable effect to copaxone treatment response as part of bi- and three-allelic combinations only. Present investigation may support basis toward the future possibility of prognostic test realization, which can provide a personal choice of immunomodulatory treatment for a patient with multiple sclerosis.     

Linkage and association of proinflammatory cytokines genes <Emphasis Type="Italic">IL-6, IFNG</Emphasis> and <Emphasis Type="Italic">TNF</Emphasis> with multiple sclerosis

Proinflammatory cytokines interleukin-6 (IL-6), interferon-γ (IFNg) and tumor necrosis factor (TNF) play an important role in the pathogenesis of multiple sclerosis. Based on the published data concerning the effects of the SNPs G(−308)A of TNF, A(+874)T of IFNG, and G(−174)C of IL-6 on the production of these cytokines, we investigated the relation of these polymorphisms with multiple sclerosis. Linkage and association of alleles of these genes with multiple sclerosis were analyzed by transmission disequilibrium test. In a group of 104 nuclear families of Russian ethnicity, the TNF*(−308)A allele was more frequently transmitted from healthy heterozygous parents to affected children (p = 0.01). Linkage/association of IFNG and IL-6 alleles with multiple sclerosis was not detected. Thus, the data obtained indicate that TNF is involved in susceptibility to multiple sclerosis in Russians.