O. E. Mustafina

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

We have analyzed the genotype frequency dynamics of CASP8, BCL2 and BAX gene polymorphic markers in a group of ethnic Tatars from Bashkortostan aged 21–109 years. Genotyping was carried out using PCR and PCR-RFLP. We have revealed the associations between age and −652(6N)I/D polymorphism of the CASP8 gene (rs3834129), 140016C>T polymorphism of the BCL2 gene (rs12454712), and 919A>G polymorphism of the BAX gene (rs1805419). An increase in the frequency of *C/*C-genotype in BCL2 gene, and a decrease in the frequency of the *I/*D-genotype of CASP8 gene was observed in males of advanced old age. As well as a decreased frequency of *G/*G-genotype of BAX gene among long livers was detected. Females long livers were characterized by an increased number of *I/*D-genotypes of CASP8 gene, *T/*T-genotype of BCL2 gene, and *A/*A-genotype of BAX gene, while the frequency of *D/*D-genotype carriers of CASP8 gene, *C/*C-genotype carriers of BCL2 gene, *A/*G and *G/*G-genotype carriers of BAX gene was reduced.

Allele variants of HLA II genes DRB1 and DQB1 regarding risk for type 1 diabetes mellitus in population of Bashkortostan

Aims. To estimate significance of HLA II DRB1 and DRB2 allele variants for development of type 1 diabetes mellitus (T1DM) in Bashkortostanpopulation (ethnical Russians, Tatar, Bashkir). Materials and methods. We analyzed DNA of 323 patients with T1DM and 683 healthy controls. DNA was derived from venous bloodsamples by phenol-chloroform extraction. DRB1 and DQB1 gene typing was performed by PCR method. Amplification products wereidentified with electrophoresis on a 1% agarose gel. Statistica for Windows v6.0 and MS Excel 98 software were applied for statisticalprocessing of acquired data. Results. Common markers of high risk for T1DM were found to be DRB1*04, DRB1*17, genotype DRB1*04/*17. On the contrary,lower risk was associated with DRB1*15 allele. In ethnical Russians lower risk of T1DM is also determined by DRB1*11 allele andDRB1*01 in Tatars. Predisposition by DQB1-alleles in Russians and Bashkir realizes only within DRB1*04/*17 genotype. However,in Tatar subpopulation DQB1*0302 is an independent risk marker of T1DM development. Conclusion. Common low risk markers for all three ethnic groups are DQB1*0301, DQB1*0602-08 alleles. Their presence negates riskof disease in all studied subpopulations even within DRB1*04/*17-genotype.

Analysis of the associations of polymorphic loci in TP53 and NFKB1 genes with human age and longevity

The TP53 and NFKB1 genes are of considerable interest as human aging and longevity candidate genes. A TP53 gene R72P (rs1042522) polymorphism and NFKB1 gene 2592 + 58T > A (rs4648110) polymorphism allele and genotype frequencies have been estimated in the groups of men and women aged between 21–109 years. No statistically significant differences in genotype and allele frequencies have been detected between the long livers, elderly, and other age groups. The results of logistic regression analysis suggest that TP53 gene R72P polymorphism and NFKB1 gene 2592 + 58T > A polymorphism are associated with age mainly during the elderly and senile age periods and that TP53*R/*R and NFKB1*A/*A genotypes carriers have relatively higher chances to reach age of 80–90 TP53 and NFKB1 genes are also likely to be considered genes are frailty genes rather than longevity genes.

Association of the CCL2C polymorphic markers with essential hypertension

Chemokine CCL2, or monocytic chemoatractant protein 1 (CCL2/MCP-1) plays an important role in the development of cardiovascular diseases. In the present study, genotypes of four polymorphic markers (rs1860190, rs1024611, rs3917887, and rs991804) of the CCL2 gene were identified in the population of Tatars (residents of the Republic of Bashkortostan). Analysis of associations of these markers with essential hypertension (EH) was carried out. It was demonstrated that haplotype CCL2*A*G*D*T was associated with the increased risk of EH (P = 0.01; OR = 1.53).

Allelic Combinations of Immune Response Genes and Risk of Development of Myocardial Infarction

Myocardial infarction (MI) is a multifactorial polygenic disease. It develops because of the complex interaction between many environmental and genetic factors. In this paper, we have studied associations of MI and allele combinations of 17 polymorphic markers of immune response genes in an ethnically homogeneous group of Tatars. The material for analysis was DNA samples of patients (286 men) with onset of MI at the age of 30 to 60 years and 301 essentially healthy men of the control group. Using the APSampler algorithm, we obtained allele combinations with the increased risk of MI in which allele variants CX3CR1*M (rs3732378), VCAM1*C (rs3917010), ICAM1*E (rs5498), LTA*A (rs909253), and TNFRSF1B*M (rs1061622) occurred the most often.

Clinical and molecular genetic analysis of a case of familial multiple sclerosis in the Republic of Bashkortostan

AIMnTo investigate clinical manifestations of multiple sclerosis (MS) and the genetic makeup of six affected members of one family.nnnMATERIAL AND METHODSnSix members of the family of Russian ethnic origin were examined. Pedigree analysis and genotyping of polymorphic markers of candidate genes for multiple sclerosis were performed.nnnRESULTS AND CONCLUSIONnThe accumulation of alleles that were associated with autoimmune diseases according to the results of genome-wide association studies (rs1109670*C, rs3129934*T, rs9523762*G, rs1570538*T) was found in the family. The results confirm the contribution of several genetic variants to familial forms of MS.

The role of Alu polymorphism of PLAT, PKHD1L1, STK38L, and TEAD1 genes in development of a longevity trait

The Alu(I/D) polymorphism of the PLAT (TPA25), PKHD1L1 (Yb8AC702), STK38L (Ya5ac2145), and TEAD1 (Ya5ac2013) genes was for the first time characterized in an ethnically homogeneous group of Tatars living in the Republic of Bashkortostan, and the association of Alu(I/D) polymorphism in each of the genes with age was established. The study group included 1580 individuals unrelated to each other (21–109 years), including 204 with long lives. The STK38L*I/D genotype is positively associated with longevity in a total group of men and women (OR = 1.016, p = 0.034). The probability of detection of the 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 is increased in women who reached the age of longevity. The PKHD1L1*I/D genotype was significant for reaching the age of longevity in men (OR = 1.713, p = 0.03). Thus, a character of change in the genotype frequency according to Alu(I/D) polymorphic sites depending on age is specific for each individual gene.

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.

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 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.

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 (Pperm = 1 × 10–6, OR = 0.44, 95% CI 0.3–0.63), CXCR2*C + CD14*C + CXCL12*G + CCL2*C + CCR5*D (Pperm = 4 × 10–6, OR = 5.78, 95% CI 2.34–14.28), CD14*C + CCL2*C/C + CCR5*D (Pperm = 6.3 × 10–6, OR = 5.81, 95% CI 2.17–15.56), CXCL8*A + CXCR2*C + CD14*T + CXCR4*C (Pperm = 0.01, OR = 3.21, 95% CI 1.63–6.31).