[Multiple sclerosis in the Republic of Bashkortostan: population-specific genetic predictors and the results of a 20-year clinical follow-up study]. / Rasseyannyi skleroz v Respublike Bashkortostan: populyatsionno-spetsificheskie geneticheskie prediktory i rezul'taty 20-letnego klinicheskogo nablyudeniya.

OBJECTIVE: Identification of a complex of genetic predictors of multiple sclerosis (MS) based on previously obtained results in genome-wide association studies of disease markers (GWAS markers) in a population of MS patients and healthy individuals of the Republic of Bashkortostan (Russian Federation) using polygenic detection. MATERIAL AND METHODS: The total study group consisted of 2048 people (641 patients with MS and 1407 healthy individuals) who permanently resided in the Republic of Bashkortostan and belonged to the Bashkir (n=325), Russian (n=772) or Tatar (n=951) nationalities. The analysis of association between MS and polymorphisms previously associated with the disease according to GWAS data was performed. Of the 641 MS patients, 247 were the subject of a 20-year prospective clinical follow-up. RESULTS: The C6orf10 rs3129934*T allele was most significantly associated with MS in Russians (OR=2.00, P=5.85·10-5) and Tatars (OR=2.38, P=8.61·10-7). An increased MS risk in Russians was also associated with the EOMES rs11129295*T (OR=1.56, P=0.007) and IL7R rs1494558*I (OR=1.61, P=0.003) alleles. Meta-analysis confirmed the association of the C6orf10 rs3129934*T, EOMES rs11129295*T and IL7R rs1494558*I alleles with MS in the total group, as well as revealed associations of the INAVA rs7522462*G, IL7R rs10624573*I, CD6 rs17824933*G, GPC5 rs9523762*A and GPR65 rs2119704*C alleles with the disease. Using polygenic analysis, we identified a complex predictor C6orf10 rs3129934*C + INAVA rs7522462*G + CD6 rs17824933*C with a pronounced protective effect against MS in the total group (OR=0.34, PFDR=2.65·10-7). CONCLUSION: We reproduced the association of eight polymorphisms (C6orf10 rs3129934, INAVA rs7522462, IL7R rs10624573, EOMES rs11129295, GPR65 rs2119704, GPC5 rs9523762, CD6 rs17824933 and CD58 rs2300747) with MS, previously identified in GWAS in European populations. Whole exome or genome sequencing may help to reveal the mechanisms underlying the pathogenesis of MS in populations of the Russian Federation.

[Complex association analysis of antioxidant genes polymorphic DNA-markers with age in the ethnic group of Abkhazians.]

For the first time in the ethnic group of Abkhazians, the association analysis of polymorphic DNA-markers of the antioxidant genes CAT (rs1001179), MSRA (rs10098474), GPX1 (rs1050450), GSR (rs1002149), GSTP1 (rs1695), SOD1 (rs2070424), SOD2 (rs4880), PON1 (rs662), PON2 (rs7493) with age was performed. Using ROC-analysis and logistic regression, it was found that the spectrum of alleles and genotypes frequencies of PON1 and GSTP1 genes polymorphic markers change throughout the studied age period (21-107 years old); the distribution of allele and genotype frequencies of CAT and SOD2 genes polymorphic markers changes within the age of 60 years. Multilocus genetic markers of longevity were determined by the Monte Carlo Markov chain method. Among persons in the age range 60-107 years, the frequency of observation of the patterns GSTP1*G/G+PON1*G (OR=6,59, PFDR=0,018) and GSTP1*G/G+SOD1*A (OR=3,4, PFDR=0,041) is statistically significantly increased; the GSTP1*A allele in various combinations with the PON1*A, PON2*C and CAT*C alleles are less common (OR=0,3, PFDR<0,05).

[The analysis of association between multiple sclerosis and genetic markers identified in genome-wide association studies]. / Analiz assotsiatsii s rasseyannym sklerozom geneticheskikh markerov predraspolozhennosti, vyyavlennykh v rezul'tate polnogenomnykh issledovanii.

OBJECTIVE: Our aim was to analyse the association with multiple sclerosis of the genetic markers of autoimmune disorders identified in genome-wide association studies in ethnically homogenous groups of Russians and Tatars residing in the Republic of Bashkortostan. MATERIAL AND METHODS: We performed genotyping of the genetic variants rs2069762 in IL2 gene, rs759648 in PVT1 gene, rs1800682 in FAS gene and rs12708716 in CLEC16A gene in the study group consisting of 1724 people (547 patients with multiple sclerosis, 1177 representatives of the control group). We analysed the association of the studied genetic markers with multiple sclerosis using logistic regression under additive genetic model implemented in PLINK program with sex a covariate. RESULTS: In the group of Tatars, we detected an association of PVT1 rs759648*Callele with multiple sclerosis (OR=1.42, p=0,023). Meta-analysis of the study results in the two ethnic groups we confirmed the association of the PVT1 rs759648*C allele with the disease (random effects model and fixed effect model: OR=1.29, p=0,018). CONCLUSION: Our results provide an evidence of an association between multiple sclerosis and the PVT1 rs759648 allele in the populations of Russian and Tatars from the Republic of Bashkortostan. No association with any other studied polymorphic variant was found in the two ethnic groups.

[Analysis of FOXO1A and FOXO3A Gene Allele Association with Human Longevity].

Seeking human longevity association with gene polymorphisms in transcription factors in the Tatar ethnic group, we conducted an analysis for age-related genotype, frequencies in polymorphic sites of FOXO1A (rs4943794, 72327C>G) and FOXO3A (rs3800231, 35-2764A>G) genes. Genotyping was conducted by using the PCR-RFLP approach. According to the results of logistic regression analysis, during maturity and old age periods, a decrease in the number of FOXO1A*G/*G (OR = 0.984, P = 0.004) genotype carriers occurs and an increase in the number of FOXO1A*C/*G (OR = 1.035, P = 0.014) and FOXO1A*C/*C (OR = 1.024, P = 0.033) genotype carriers occurs in the sample of subjects before gender adjustments. In the sample of long-livers, the number of FOXO1A*C/*C (OR = 0.772, P = 0.028) genotype carriers decreased among women, while the number of FOXO3A*G/*G (OR = 1.008, P = 0.0001) genotype carriers increased among both men and women. Therefore, the FOXO1A gene polymorphic site rs4943794 is associated with an acquisition of old and senescent age in a sample before gender adjustments and with women's longevity. FOXO3A gene polymorphic site rs3800231 is associated with longevity in both women and men.

Combinations of Polymorphic Markers of Chemokine Genes, Their Receptors and Acute Phase Protein Genes As Potential Predictors of Coronary Heart Diseases.

Atherosclerosis, the main factor in the development of coronary heart diseases (CHD), is an inflammatory response to endothelial layer damage in the arterial bed. We have analyzed the association between CHD and the polymorphic markers of genes that control the synthesis of proteins involved in the processes of adhesion and chemotaxis of immunocompetent cells: rs1024611 (-2518A>G, CCL2 gene), rs1799864 (V64I, CCR2 gene), rs3732378 (T280M, CX3CR1 gene), rs1136743 (A70V, SAA1 gene), and rs1205 (2042C>T, CRP gene) in 217 patients with CHD and 250 controls. Using the Monte Carlo method and Markov chains (APSampler), we revealed a combination of alleles/genotypes associated with both a reduced and increased risk of CHD. The most significant alleles/genotypes areSAA1*T/T+CRP*C+CX3CR1*G/A (P perm = 0.0056, OR = 0.07 95%CI 0.009-0.55), SAA1*T+CRP*T+CCR2*G/A+CX3CR1*G (P perm = 0.0063, OR = 14.58 95%CI 1.88-113.04), SAA1*T+CCR2*A+CCL2* G/G (P perm = 0.0351, OR = 10.77 95%CI 1.35-85.74).

[Association of polymorphic markers of chemokine genes, their receptors, and CD14 gene with coronary atherosclerosis].

Atherosclerosis represents an inflammatory response to the disturbance of the endothelial layer in the arterial bloodstream. In the present study, an analysis of associations of polymorphic markers for the genes controlling synthesis of proteins involved in atherosclerosis pathogenesis in coronary atherosclerosis (CA) patients (217 subjects) and in a control group (250 subjects) was conducted. The following genes were examined: rs991804 (CCL2 gene), rs1126579 (CXCR2 gene), rs4074 (CXCL1 gene), rs4073 (CXCL8 gene), rs333 (CCR5 gene), rs2471859 (CXCR4 gene), rs1801157 (CXCL12 gene), and rs2569190 (CD14 gene). Using the Monte Carlo and Markov chain (APSampler) method, allele/genotype combinations associated with both low and high CA risk were revealed. The most important findings included the following: CXCR4*T/T + CCL2*C + CCR5*I/I (P perm = 1 × 10­6, OR = 0.44, 95% CI 0.3­0.63), CXCR2*C + CD14*C + CXCL12*G + CCL2*C + CCR5*D (P perm = 4 × 10­6, OR = 5.78, 95% CI 2.34­14.28), CD14*C + CCL2*C/C + CCR5*D (P perm = 6.3 × 10­6, OR = 5.81, 95% CI 2.17­15.56), CXCL8*A + CXCR2*C + CD14*T + CXCR4*C (P perm = 0.01, OR = 3.21, 95% CI 1.63­6.31).

[Association of variable rs1801282 locus of PPARG2 gene with diabetic nephropathy].

The association of the variable rs1801282 locus of the PPARG2 gene (peroxisome proliferator-activated receptor gamma) with type 2 diabetes mellitus and its complications was analyzed in inhabitants of the Republic of Bashkortostan. The genotype frequencies of the variable rs1801282 locus of the PPARG2 gene did not significantly differ in groups of healthy persons and patients with type 2 diabetes in all three considered inheritance models (codominant, dominant, and recessive). At the same time, it was demonstrated that the risk of one of the diabetic complications, i.e., diabetic nephropathy, was associated with the variable rs1801282 locus of the PPARG2 gene. Diabetic nephropathy was more common in patients with the C/C genotype (62.7%) compared to the C/G and G/G genotypes (37.5%), P = 0.036. The G allele is protective in regard to diabetic nephropathy (OR = 0.36) in patients with type 2 diabetes mellitus.

[Alu insertion-deletion polymorphism of COL13A1 and LAMA2 genes: The analysis of association with longevity].

The distribution of allele and genotype frequencies of Alu(I/D) polymorphic sites in the COL13A1 and LAMA2 genes coding extracellular matrix protein subunits was characterized in an ethnically homogeneous group (Tatars from the Republic of Bashkortostan, Russia). It was established that the frequency of individuals with the COL13A1*D/*D genotype was higher in the senile age period. The LAMA2*I/*D genotype was predisposing to longevity among women. According to the observed results, the frequency of the LAMA2*I/*D genotype was increased in senile individuals older than 90 years. The observed associations can be explained on the basis of the contemporary view by the importance of Alu elements in gene expression regulation at transcriptional and post-transcriptional levels, the involvement of collagen and laminin in maintaining the structure and function of the extracellular matrix, and the relationship between the extracellular matrix state, pathological changes and aging.

[Role of PLAT, PKHD1L1, STK38L and TEAD1 genes Alu-polymorphism for longevity].

The distribution of allele and genotype frequencies of Alu(I/D)-polymorphic sites in PLAT (TPA25), PKHD1L1 (Yb8AC702), STK38L (Ya5ac2145) и TEAD1 (Ya5ac2013) genes was first characterized in the ethnically homogeneous group (Tatars from the Republic of Bashkortostan, Russia), and was established (found) the association of each gene polymorphism with age. The study group consisted of 1580 unrelated individuals aged between 21 and 109 years, including 204 long-livers. It was found that STK38L*I/D genotype had positive association with longevity in the total group (OR=1,016, p=0,034). Long-lived women had a high probability of detection of PKHD1L1*I/I (OR=1,289, p=0,009), PLAT*D/D (OR=1,175, p=0,016) and TEAD1*I/I (OR=1,047, p=0,042) genotypes. PKHD1L1*I/D genotype was a significant factor in providing of male longevity (OR=1,713, p=0,030). Therefore, age-dependent changes in genotype frequencies are specific for each studied gene.

[Association between inflanummatory gene polymorphisms and the risk of myocardial infarction].

Allele and genotype frequency distributions of polymorphism rs2076059 (3832T>C) within the SELE gene rs6131 (S290N), within the SELP gene, rs1131498 (F206L), within the SELL gene, rs5498 (K469E) within the ICAM1 gene, rs35569394 (-2549(18)I/D) within the VEGFA gene, and rs1024611 (-2518A>G) within the CCL2 gene were examined in a group of patients after myocardial infarction (MI)(280 individuals) and in a control group (312 individuals). An implementation of the Markov chain and Monte-Carlo method (AP- Sampler) revealed the allele combinations associated with decreased and increased risk of MI. Among these the most important allele combinations were SELE*C + SELP*S + CCL2*A (FDR = 0.0005; OR = 0.42) SELP*S + CCL2*A (FDR = 0.0009; OR= 0.36}, SELL*F + VEGFA*I+ CCL2*G/G(FDR = 0.0009; OR = 4.17) VEGFA*I+ CCL2*G/G (FDR = 0.0009; OR = 3.76), SELE*C + CCL2*A (FDR = 0.0023; OR = 0.47), and SELL*I+ CCL2*G/G (FDR = 0.003; OR = 3.15).

[Age-dependent CYP1A2 gene polymorphism -163C>A in three ethnic groups of Bashkortostan Republic residents].

On a sample of 1240 persons from Bashkortostan, including Russian, Bashkirs and Tatars, the analysis of allele and genotype frequencies distribution of CYP1A2 gene polymorphism -163C>A was performed by PCR-RFLP in view of belonging to a particular age cohort. In Russian and Bashkirs ethnic groups we observed age-dependent decrease of CYP1A2*C allele and CYP1A2*CI*C genotype frequencies (in Russian statistically significant for allele and genotype, the Bashkirs--only for allele) and a statistically significant increase of CYP1A2*A allele and CYP1A2*A/*A genotype frequencies. The set reduction in the frequency of the wild allele CYP1A2*C and increasing the frequency of the mutant allele CYP1A2*A with age may be due to greater survival of persons who are carriers of that allelic variants of CYP1A2 gene, providing a more efficient metabolism of xenobiotics.

[Combinations of cytokine gene network polymorphic markers as potential predictors of myocardial infarction].

With the intent to identify informative predictors of myocardial infarction (MI) development in an ethnically homogenous group of Russian men after MI (255 subjects) and in a corresponding control group (257 subjects), an analysis of genotype frequency distribution for polymorphic DNA markers (SNP) rs16944 (-511C>T, IL1B gene), rs1800796 (-572G>C, IL6 gene), rs1800872 (-592C>A, IL10 gene), rs3212227 (1159AA, TNF), rs909253 (252A>C, LTA), rs767455 (36A>G, TNFRSF1A) was conducted. Using the Monte Carlo method and a Markov chain (APSampler), allele combinations associated both with decreased and increased MI risk were revealed. The most significant results were obtained for IL6*C/C (P = 3 x 10(-4), OR = 6.3 CI 2.37-16.75 10(-4)), LTA*A+IL6*G/G (FDR = 2.3, OR = 0.25 CI 0.14-0.46), LTA*G/G + IL12B*A/A (FDR = 0.0053, OR = 4.92 CI 1.8-13.33), TNF*G + LTA*G/G + TNFRSF1A*A (FDR = 0.013, OR = 4.38, CI 1.6-12.01), TNFRSF1A*G + IL10*A/A + IL12B*C (FDR = 0.016, OR = 8.79, CI 2.17-35.63), TNF*G + LTA*G?G + IL10*C (FDR = 0.0105, OR = 3.54 CI 1.55-8.09).

[Association of polymorphic markers of CASP8, BCL2 and BAX genes with aging and longevity].

We performed the analysis of genotype frequency dynamics of CASP8, BCL2 and BAX genes polymorphic markers between 21 and 109 years in the group of Ethnic Tatars from Bashkortostan. Genotyping was carried out using PCR and PCR-RFLP. We found associations between age and -652(6N)I/D polymorphism of CASP8 gene (rs3834129), 140016C>T polymorphism of BCL2 gene (rs12454712) and 919A>G polymorphism of BAX gene (rs1805419). An increase of genotype frequency of BCL2*C/*C and decrease of genotype frequency of CASP8*I/*D was observed in male of senile age; and also decrease of genotype frequency of BAX*G/*G among long-livers. In female of longevity age, the number of CASP8*I/*D, BCL2*T/*T and BAX*A/*A genotype carriers was higher and number of CASP8*DI/*D, BCL2*C/*C, BAX*A/*G and BAX *G/*G genotype carriers was reduced.

[Association analysis of polymorphic loci of TP53 and NFKB1 genes with human age and longevity].

TP53 and NFKB1 genes represent considerable interest as candidate genes of human aging and longevity. The allele and genotype frequency distributions of TP53 R72P (rs1042522) polymorphism and NFKB1 2592 + 58T > A (rs4648110) polymorphism were characterized in groups of men and women of 21-109 years in the given research. No statistically significant distinctions in allele and genotype frequencies between long-livers, old people and other age groups were revealed. On the basis of logistic regression analysis results it is obviously possible to make the conclusion that polymorphism R72P of TP53 gene and polymorphism 2592 + 58T > A of NFKB1 genes is associated with the age mainly throughout elderly and senile ranges of years. Relative chances to achieve the age of 80-90 years are higher in carriers of TP53*R/*R and NFKB1*A/*A genotypes. It is also possible to believe that TP53 and NFKB1 genes are frailty genes, instead of longevity ones.