Vitalina Bashinskaya

Variants of MicroRNA Genes: Gender-Specific Associations with Multiple Sclerosis Risk and Severity

Multiple sclerosis (MS) is an autoimmune neuro-inflammatory disease arising from complex interactions of genetic, epigenetic, and environmental factors. Variations in genes of some microRNAs—key post-transcriptional regulators of many genes—can influence microRNAs expression/function and contribute to MS via expression changes of protein-coding target mRNA genes. We performed an association study of polymorphous variants of MIR146A rs2910164, MIR196A2 rs11614913, MIR499A rs3746444 MIR223 rs1044165 and their combinations with MS risk and severity. 561 unrelated patients with bout-onset MS and 441 healthy volunteers were enrolled in the study. We observed associations of MS risk with allele MIR223*T and combination (MIR223*T + MIR146A*G/G) carriage in the entire groups and in women at Bonferroni-corrected significance level (pcorr < 0.05). Besides, MIR146A*G/G association with MS was observed in women with nominal significance (pf = 0.025). No MS associations were found in men. A more severe MS course (MSSS value > 3.5) was associated with the carriage of MIR499A*C/T and, less reliably, of MIR499A*C (pcorr = 0.006 and pcorr = 0.024, respectively) and with the carriage of combinations (MIR499A*C/T + MIR196A2*C) and (MIR499A*C + MIR196A2*C) (pcorr = 0.00078 and pcorr = 0.0059, respectively). These associations also showed gender specificity, as they were not significant in men and substantially reinforced in women. The strongest association with MS severity was observed in women for combination (MIR499A*C/T + MIR196A2*C): pcorr = 4.43 × 10−6 and OR = 3.23 (CI: 1.99–5.26).

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.

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.

Genome-wide association study as a method to analyze the genome architecture in polygenic diseases, with the example of multiple sclerosis

Genome-wide association study (GWAS) provides a powerful tool for investigating the genetic architecture of human polygenic diseases and is generally used to identify the genetic factors of disease susceptibility, clinical phenotypes, and treatment response. The differences in allele frequencies of single nucleotide polymorphisms (SNPs) distributed throughout the genome are analyzed with a microarray technique or other technologies that allow simultaneous genotyping at several tens of thousands to several millions of SNPs per sample. Owing to its power to find out highly reliable differences between patients and controls, GWAS became a common approach to identification of the genetic susceptibility factors in complex diseases of a polygenic nature. Using multiple sclerosis (MS) as a prototype complex disease, the review considers the main achievements and challenges of using GWAS to identify the genes involved in the disease and, therefore, to better understand the pathogenetic molecular mechanisms and genetic risk factors.

Анализ ассоциации полиморфизма генов, кодирующих рецепторы цитокинов, с клиническими характеристиками рассеянного склероза

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.

Analysis of Associations of Polymorphisms of Genes Encoding Cytokine Receptors with the Clinical Features of Multiple Sclerosis

Objectives. To analyze the associations of gene polymorphisms in the IL7RA (rs689932), IL2RA (rs2104286), and TNFRSF1A (rs1800693) genes with the severity and early clinical characteristics of remitting multiple sclerosis (MS). Materials and methods. Genotyping studies were performed on the polymorphic loci of the IL7RA (rs689932), IL2RA (rs2104286), and TNFRSF1A (rs1800693) genes from 508 ethnically Russian patients with debut of remitting MS followed by analysis of associations of variants of these genes with the severity and variants of MS and the duration of the first remission. Results and conclusions. Assessments on the MSSS identified significant increases in the frequency of the TNFRSF1A*T/T genotype in the group of patients with mild MS (MSSS ≤ 3) and of the TNFRSF1A*C allele in the group of patients with moderate and severe MS (MSSS > 3). Depending on the variant of the manifestations of MS, there was a significant increase in the frequency of the TNFRSF1A*T allele in patients with favorable variants of the manifestations of MS (optical neuritis or sensory impairments), while there was a significant increase in the frequency of the TNFRSF1A*C/C allele in patients with unfavorable variants of manifestations. No associations were found between polymorphisms of the genes of interest with the duration of first remission. Associations between variants of the study genes and the clinical characteristics of MS being compared were also sought in relation to the polymorphic locus of the CTLA4 gene (rs231775), for which an association has previously been established between carriership of the CTLA4*G allele and short-duration first remissions (up to one year). Carriership of the (CTLA4*G + TNFRSF1A*C) combination was more significant than carriership of CTLA4*G alone and was associated with this same characteristic. An additional combination was found, the (CTLA4*G/G + IL7RA*T) combination, which was associated with short first remission. No other differences in carriership frequencies of allele combinations were seen in relation to the clinical characteristics of MS.

Impact of 9p21.3 region and atherosclerosis-related genes' variants on long-term recurrent hard cardiac events after a myocardial infarction

Atherosclerotic coronary artery disease (CAD) and myocardial infarction (MI) as its most severe clinical complication remain the leading causes of mortality in the majority of countries. Despite the progress in the treatment of MI, quite often the patients, after the first-time MI, develop subsequently a variety of adverse cardiovascular events. In this retrospective study we evaluated the contribution of allelic variations in 9p21.3 locus and in 21 atherogenesis-related genes to the development of hard cardiac events in a cohort of patients of Russian ethnicity after the first acute MI during long-term follow-up (7-10 years). Death from cardiac causes and recurrent nonfatal MI were considered as key clinical outcomes. We have shown the association of rs1333049 and rs10757278 in 9p21.3 and MTHFR rs1801133 with recurrent unfavorable events, the latter was observed in time-dependent manner. Multilocus analysis additionally suggested the influence of carriage of the CRP and ENOS genes variants at the development of subsequent adverse events after MI. The composite model built for prediction of the individual genetic risk of postinfarction hard cardiac events included 9p21.3 rs1333049*GG and MTHFR*TT and was characterized by area under the curve (AUC) = 0.65. Our data show that 9p21.3 locus and MTHFR gene polymorphisms could influence long-term prognosis of recurrent hard cardiac events in patients who underwent the first MI. It is possible that addition of genotyping at such loci to existing clinical scores could improve their predictability.