[Genetic Association of ADRA2A and ADRB3 Genes with Metabolic Syndrome among the Tatars].

An association study was performed for genetic polymorphisms in ADRB3 (rs4994) and ADRA2A (rs1800544, rs553668) genes to estimate their effect on quantitative parameters, including glucose, insulin, and HOMA-IR index in women from the Tatar population of Russia. It has been shown that CT and CC are associated with metabolic syndrome and increased insulin. It was shown that ADRA2A (rs1800544) gene polymorphism was associated with high levels of insulin and an increased HOMA-IR index in GG- and GC-genotype carriers.

[Association of polymorphic variants of FTO and MC4R genes with obesity in a Tatar population].

Obesity is a chronic relapsing disease that leads to numerous ailments and requires lifelong treatment. Genetic predisposition is one of the mostly discussed aspects of obesity development, and genome-wide association studies have provided evidence that several variants of the FTO and MC4R genes are significantly associated with obesity. In this study the association of FTO (rs9939609, rs7202116, and rs9930506) and MC4R (rs12970134 and rs17782313) genes' SNPs with obesity in Tatar women has been analyzed. In the investigation 340 women with obesity (Body Mass Index (BMI) ≥ 30 kg/m2) and 330 women from a control group (BMI up to 24.9 kg/m2) took part. The FTO rs9939609 (p = 0.0002) and rs9930506 (p = 0.0005) SNPs were shown to be associated with obesity risk following an additive model, while the MC4R rs12970134 (p = 0.0076) and rs1778231 (p = 0.021) SNPs were associated by a recessive model. We also showed an association of quantitative parameters (age, weight, and BMI) with two the FTO rs9939609 and rs9930506 SNPs and the association of age and the MC4R rs12970134 SNP. Our study demonstrates the role of genetic variability in FTO and MC4R genes in obesity development in Tatar women from Russia.

[DIO2, TPO, CYP1A1 AND CYP1A2 gene polymorphism in women with thyroid disease].

The analysis of polymorphisms of genes CYP1A1 (2454A > G,-3798T> C); CYP1A2 (-163C > A,-2467delT); TPO (2173A > C, 769G > T); DIO2 (274A > G) in women from the oil organic synthesis plant and the control group with thyroid disease (autoimmune thyroiditis and nodular goiter) has been performed. Molecular genetic markers of predisposition to the development of thyroid disease are: GG genotype and allele G gene DIO2 (274A > G), CT and CC genotypes of the gene CYP1A1 (-3798T > C), associated with the development of nodular goiter, and DD genotypes TD CYP1A2 gene (-2467delT), associated with the development of autoimmune thyroiditis. There was shown an association of polymorphic variants of the gene DIO2 (274A > G) with elevated levels of antibodies to TPO and TPO gene (2173A > C) with elevated levels of free T4.

[DNA repair XRCC1, XPD genes polymorphism as associated with the development of bladder cancer and renal cell carcinoma].

We examined the correlations between the polymorphic alleles of the DNA repair genes XRCC1 (c.839G> A, rs25489; and c.1196A> G, rs25487), XPA (c.-4A> G, rs1800975), and XPD (c.2251A> C, rs13181) and the progression and severity of neoplasias in the bladder and kidney in patients of three distinct ethnic groups, Bashkir, Russians, and Tatar, residing in the Republic of Bashkorostan. The study enrolled 468 cancer patients and 351 healthy individuals. Genotyping for polymorphic alleles was carried out using the PCR-RFLP method. We identified a correlation between allele A of the c.839 G>A locus of the XRCC1 gene and the incidence of the bladder cancer (BC) and kidney cancer (KC) in the Tatar study group, using the additive genetic effects model (Odds Ratio (OR) = 5.23 and OR = 3.90). In turn, the heterozygous G/A genotype was present at a significantly higher frequency in the KC patients of Bashkir ethnic origin, compared with the control group (p = 0.0061, OR= 4.72). Additional analysis with consideration of participants' smoking status showed that the G/A genotype is significantly more frequent in smokers with BC (OR = 1.96, p = 0.05) then in healthy smokers. We also determined, using the recessive genetic model, that the genotype A/A of the c. 1196A>G locus of the XRCC1 gene was correlated with a higher risk of BC in the Russian cohort (OR = 2.29, p = 0.0082) and an increased incidence of KC in the Bashkir group (OR = 4.06, p = 0.05). A similar correlation was obtained for smokers. In contrast, the allele c.2251 A>C in the XPD gene correlated with a lower risk for BC and KC in the Tatars (p = 0.0003, OR = 0.48 and p < 0.0001, OR = 0.37) in the additive model and in the Bashkirs (p = 0.0083, OR = 0.12) and Russians (p = 0.0001, OR = 0.14) in the recessive model. Further, we uncovered that polymorphism c.839 G>A in the XRCC1 gene contributes to the progression of noninvasive and invasive BC and promotes KC at early and advanced stages of the disease. Thus, we identified similar correlations between DNA repair gene polymorphism and the incidence and progression of BC and KC. We propose that this result points to the involvement of common pathogenetic mechanisms in the initiation and progression of the urinary neoplasias.

[Analysis of polymorphisms of genes associated with immune response and tissue remodeling in occupational chronic bronchitis].

The involvement of polymorphisms of genes encoding immune response-associated molecules (LTA, TNFA, ILB, ILRN, IL8, IL10, VDBP), matrix metalloproteinases (MMP1, MMP2, MMP3, MMP9, MMP12, ADAM33), and tissue and serum inhibitors of proteases (TIMP2, TIMP3, SERPINA1, SERPINA3) in the predisposition to occupational chronic bronchitis was assessed by PCR-RFLP analysis in groups of patients (n = 122) and healthy employees (n = 166). It was found that occupational chronic bronchitis was associated with polymorphisms of VDBP (P(adj) = 0.00005, OR(adj) = 2.06), MMP1 (P(adj) = 0.00002, OR(adj) = 2.57), ADAM33 (P(adj) = 0.0004, OR(adj) = 2.52), and IL8 (P(adj) = 0.0058, OR(adj) = 2.87). The most significant association was observed for the VDBP polymorphism 1296T>G. The VDBP haplotype GC*1S by the loci 1296T>G and 1307C>A was an informative susceptibility marker (P(adj) = 0.0001, OR(adj) = 2.60, 95% CI (1.62-4.19)). There was also a significant interaction between the VDBP polymorphism 1307C>A and the duration of occupational exposure to hazardous factors (P(interaction) = 0.02). Apparently, the investigated polymorphisms of VDBP, MMP1, ADAM33, and IL8 contribute to the genetic susceptibility to chronic bronchitis induced by dust and toxic agents.

[Polymorphism of DNA repair genes (XRCC1, XRCC3, XPC, XPD, XPA) in ethnic groups from Republic of Bashkortostan].

Genotype and allele-frequency distributions of the excision and homologous recombination of DNA repair genes XRCC1 (rs25487 and rs25489), XRCC3 (rs861539), XPC (rs2228001), XPD (rs13181), XPA (rs1800975) were examined in three ethnic groups from the Republic of Bashkortostan (Russia), Russians, Tatars, and Bashkirs. The data obtained were compared to those for other ethnic groups from Russia and worldwide. Statistically significant differences in the allele-frequency distribution of the XPA gene polymorphic locus rs1800975 (p = 0.03) between the samples of Russians and Tatars were demonstrated. Russians and Bashkirs differed in the allele-frequency distribution of the rs861539 polymorphic locus of the XRCC3 gene (p < < 0.0001), and Tatars and Bashkirs, at the rs861539 locus of the XRCC3 gene (p < 0.0001). In Russians and Tatars from the Republic of Bashkortostan, allele frequencies at the DNA repair gene polymorphic loci examined were consistent with those in the population of Northern and Western Europe, while polymorphic allele-frequency distributions in Bashkirs was similar to that observed in the ethnic group of Gujarati Indians.

[Association of polymorph variants of CYP1A2 and CYP1A1 genes with reproductive and thyroid diseases in female workers of petrochemical industry].

The article presents results obtained in study of relationship between polymorph variants of CYP1A1 and CYP1A2 genes with reproductive and thyroid diseases risk in female workers of petrochemical industry, when compared with reference group females. Variants TD and DD of CYP1A2 gene appeared to be associated with nodes formation in uterus and breast in female workers and reference group females. Following liability markers are obtained: homozygous in rare allele genotype CC of CYP1A1 gene for reproductive and thyroid diseaes (fibrous cystic mastopathy and nodular goitre), heterozygous genotype AG of CYP1A1 gene in uterine myoma and fibrous cystic mastopathy, homozygous in deleted T genotype of CYP1A2 gene in autoimmune thyroiditis. Occupational hazards and long length of service at hazardous industries increase effects of rare alleles of the genes studied.

[Comparative analysis of cytogenetic instability in buccal epithelial cells in the urban and rural dwellers of the Republic of Bashkortostan].

The frequency of cytogenetic instability in buccal epithelial cells was studied in the urban and rural dwellers of the Republic of Bashkortostan. A total of 26256 cells from 24 students who had been born in Ufa and 26951 cells from 25 students who had lived in a rural area before entering the Institute were analyzed. The students' age was 17 to 19 years. The study has indicated that cytogenetic instability and other types of karyological anomalies in the buccal epithelial cells of rural and urban dwellers depend on gender and environmental factors.

[Clinical and genetic criteria of reproductive health disorders in female workers engaged into organic synthesis production].

Chemicals in the air of workplace within organic synthesis enterprises could induce reproductive disorders in the female workers. Analysis of polymorphous variants of P450 cytochrome gens and antioxidant defence system helped to reveal genetic markers for risk of reproductive disorders in the female examinees.

[Contribution of polymorphic variants of the genes of xenobiotic transformation enzymes, antioxidative defense, and DNA repair to the development of individual predisposition to hepatobiliary and reproductive system diseases in petrochemical workers].

The paper gives the basic results of studying the polymorphic loci of the genes of xenobiotic transformation enzymes, antioxidative defense, and DNA repair in petrochemical workers. Polymerase chain reaction-restriction fragment length polymorphism assay was used to identify markers of the predisposition to the development of toxic hepatitis in men and impaired reproduction in women.

[Role of polymorphic markers of antioxidants (NQO1, GSTP1, GPX1) genes in adaptive response to hazardous work conditions in workers].

The authors presented a comparative study of polymorphous loci Ile105Val and Ala114Val in GSTP1 gene, C609T and C464T in NQO1 gene, Pro197Leu in GPX1 gene of workers engaged into ethylbenzene-styrene (JSC "Salavatnefteorgsintez") and of apparently healthy individuals without occupational exposure to toxic chemicals. The same polymorphous markers were studied in workers differentiated according to health state. Occurrence of genotypes Ile/ Val of GSTP1 gene, Pro/Leu in GPX1 gene in the main group were lower vs. that in the reference one. Occurrence of CC genotype of polymorphous locus of C609T in NQO1 gene in the examinees exceeded that in the reference group. Distribution analysis of haplotypes of NQO1 and GSTP1 revealed high occurrence of *A haplotype of GSTP1 gene and low occurrence of *B haplotype in the main group vs. the reference one. The authors proved that molecular genetic marker of toxic liver affection is a heterozygous genotype of Pro/Leu in GPX1 gene and a combination of II/PL/CC genotypes of polymorphous markers Ile105Val in GSTP1 gene, C609T in NQO1 gene, Pro197Leu in GPX1 gene.

[The CYP1B1 and CYP2F1 genes polymorphisms frequency in three ethnic groups of Bashkortostan and chronic obstructive pulmonary disease patients].

Chronic obstructive pulmonary disease is a multifactorial respiratory disorder. Members of the cytochrome P450 family catalyze the oxidative metabolism of exogenous chemicals and activate their substrates into reactive intermediates that may initiate lung injury. The aim of this study was to learn interethnic variation in frequency distribution patterns of CYP1B1 and CYP2F1 genes polymorphic markers and to analyse its association withchronic obstructive pulmonary disease. The polymorphic markers Leu432Val(CYP1B1) and c.14_15insC(CYP2F1) were studied at chronic obstructive pulmonary disease patients (Russian (N=169), Tatar (N=137)) and cases of healthy individuals (Russian (N=191), Tatar (N=198) and Bashkir (N=78)), residents of Bashkortostan by PCR-RFLP method. It was shown that the CYP2F1 gene genotype frequency distribution patterns differed between three ethnic groups (chi2 = 21.29, df=4, P = 0.0001), because of high frequency of c.14_15insC/c.14_15insC genotype in Tatars (6.38%). On the other hand, high frequency (39.74%) of normal/ c.14_15insC genotype was appeared in Bashkirs. Association analysis of CYP2F1 geneinsertion variant with chronic obstructive pulmonary disease have shown high frequency (87.5%) of normal allele in Tatars patients with very severe stage and manifestation of chronic obstructive pulmonary disease after 55 years (chi2 = 3.964, df=1, P = 0.046; OR = = 2.268). It was shown that allele and genotype frequency distribution of Leu432ValCYP1B1 gene not differed between Russian, Tatar and Bashkir ethnic groups. We did not find any association of Leu432Val CYP1B1 gene with chronic obstructive pulmonary disease.

[Polymorphism of the genes for antioxidant defense enzymes and their association with the development of chronic obstructive pulmonary disease in the population of Bashkortostan].

In this study, frequencies of the polymorphic variants of the genes encoding antioxidant enzymes, GSTM1, GSTT1, GSTP1, CAT, GPX1, NQO1, SOD1, and SOD3 were examined in three ethnic groups of healthy subjects from the Republic of Bashkortostan (Russians, Tatars, and Bashkirs). An association of these markers with the development of chronic obstructive pulmonary disease (COPD) was tested. Interethnic differences relative to the distribution of the polymorphic variants of the GSTP1 locus Ile105Val and the NQO1 locus 609C/T were revealed. Relative to the genotype distribution at the Ile 105Val locus of the GSTP1 gene, ethnic group of Bashkirs was found to be statistically significantly different from Tatars (chi2 = 8.819; d.f. = 2; P = 0.012). Relative to the genotype frequency distribution pattern at the NQO1 locus 609C/T, the group of Bashkirs differed from Russians (chi2 = 8.913; df. = 2; P = 0.012). An association of genotype Val/Val of the GSTP1 Ile105Val locus with the risk of COPD in Russians (chi2 = 5.25; P = 0.022; Pcor = 0.044; OR = 4.09), and of the GSTP1 haplotype *D in Tatars, was demonstrated (chi2 = 11.575; P = 0.0014; Pcor = 0.0042; OR = 3.178). Genotype TT of the CAT -262C/T locus marked resistance to the COPD development in Russians (chi2 = 6.82; P = 0.0098; Pcor = = 0.0196; OR = 0.31; 95% CI, 0.119 to 0.77). The risk for COPD in the ethnic group of Tatars was associated with the CAT haplotype (-262)C(1167)T (chi2 = 6.038; P = 0.0147; Pcor = 0.044; OR = 1.71). Analysis of the NQO1 haplotypes at the 465C/T and6009C/T loci showed that haplotype 465C/609T was associated with COPD in Russians (chi2 = 4.571; P = 0.0328; Pcor = 0.01; OR = 1.799). It was demonstrated that Gly allele of the Arg213Gly polymorphic locus of the SOD3 gene marked the risk for COPD in the ethnic group of Tatars (OR = 2.23; 95% CI, 1.22 to 4.1). Thus, GSTP1, CAT, NQO1, and SOD3 polymorphisms play an important role in the development of COPD among the population of Bashkortostan.

[Genetic markers of predisposition to infectious complications in neonatal infants with respiratory distress syndrome].

Neonatal respiratory distress syndrome (NRDS) is the commonest cause of death and morbidity of the newborn. A genetic risk for NRDS is currently recognized. The aim of this study was to determine whether there was an association of the polymorphisms of the SP-B, SP-D genes and the interleukins (IL)-1alpha, IL-10 genes with the development of infectious complications in neonatal infants with the respiratory distress syndrome. It was found that the certain genotypes by the polymorphic loci of surfactant proteins and interleukins might be associated with infectious diseases in the newborn with respiratory distress syndrome.

[Role of xenobiotic biotransformation enzymes in respiratory diseases caused by dust].

Genetic peculiarities particularly xenobiotic detoxification enzymes play important role in pulmonary diseases development. The study was aimed to analyze gene polymorphisms for first (CYP1A1, CYP2E1, EPHX1) and second (GSTM1, GSTT1) phases of xenobiotics biotransformation in relation to occupational respiratory diseases risk.

[Use of new DNA diagnostic technologies in occupational medicine].

With the reduced number of workers and the rise of morbidity, including occupational one, the urgent of occupational medicine is to keep the health of able-bodied citizens. Abnormal human gene variants leading to the emergence of functionally reduced gene products (enzymes) underlie susceptibility to this or that illness. The genes of the xenobiotic metabolism system are most studied in this regard. The knowledge of a role of genetic types in the formation of individual susceptibility to environmental hazards has opened up new avenues for studies of predisposition to occupational diseases.

[Associations of the genotypes of the CYP1A1 gene with predisposition to hydatid disease caused by Echinococcus granulosus strain G1].

DNA samples isolated from peripheral venous blood lymphocytes in 73 children with hydatid disease were studied. The polymorphism of exon 7 (A4889G) of the CYP1A1 gene was analyzed by polymerase chain reaction, followed by hydrolysis with restriction endonuclease HincII. The material for E. granulosus genotypes to be studied was obtained from the germinal layer of larvocysts. The fragment of the mitochondrial gene encoding for the first subunit of cytochome-C-oxidase was as a DNA marker. The amplified E. granulosus DNA fragments underwent direct sequencing and a genotype was identified. The findings have led to the conclusion that carriage of polymorphic allele Val of exon 7 (A4889G) of the CYP1A1 gene in those infested with E. granulosus genotype G1 (common, sheep strain) is a risk factor of the development of the clinical form of echinococcosis granulosus.

[Polymorphism in promoter regions of matrix metalloproteinases (MMP1, MMP9, and MMP12) in chronic obstructive pulmonary disease patients].

Our studies have shown that the genotype and allele frequencies of polymorphisms G(-1607)GG of MMPI gene, C(-1562)T of MMP9 gene and A(-82)G of MMP12 gene do not significantly differ in the samples of chronic obstructive pulmonary disease (COPD) patients (N = 318) and healthy controls (N = 319) dwelling in Bashkortostan Republic. However, association of (-1562)T allele of the MMP9 gene with the severity of COPD disease progression has been revealed. In COPD patients at stage 4 of the disease, the frequency of allele T was significantly higher that in patients with the stages 2 and 3 (15.89% versus 8.38%; chi2 = 7.804, d.f. = 1, P = = 0.005; OR = 2.06 95% CI 1.22-3.49). The distribution of the genotype frequencies of C(-1562)T polymorphism of MMP9 gene significantly differed between the patients with various COPD severity (chi2 = 9.849, d.f. = 2, P = 0.007). The individuals with rare genotype TT were revealed only among patients with severe COPD form (3.97% versus 0%; chi2 = 4.78, P = 0.029, Pcor = 0.058). Analysis of this polymorphism in patients with early COPD onset (younger than 55 years old) has shown a significant increase in the allele Tfrequency in the group of patients with severe COPD (stage 4 according to GOLD) compared to the patients of the same age but with less severe COPD progression (chi2 = 5.26, d.f. = 1, P = 0.022). As the major clinical characteristics of stage 4 COPD is the development of pulmonary emphysema as well as bronchial walls deformation, we suggest that the increased expression of MMP9 gene caused by genetic polymorphism in the gene promoter is important in the early development of serious complications of the disease.

[Association of cytochrome P450 genes polymorphisms (CYP1A1 and CYP1A2) with the development of chronic obstructive pulmonary disease in Bashkortostan].

To assess the role that polymorphisms of cytochrome P450 genes play in genetic predisposition to chronic obstructive pulmonary disease (COPD), the allele and genotype distributions of CYPIA1 (2455 A/G, 3801T/C) and CYP1A2 (-2464T/delT, -163C/A) genes were studied in Tatar and Russian COPD patients and in cases of healthy individuals (Russian, Tatar and Bashkir), residents of Bashkortostan. It was shown that the CYP1A1 and CYP1A2 genes haplotypes frequency distribution patterns do not differed between Tatars and Russians ethnic groups (chi2 = 0.973, df = 3, p = 1.00 and chi2 = 1.546, df = 3, p = 0.92, respectively). Analysis of the the CYP1A1 and CYP1A2 genes haplotypes revealed statistically significant differences in the haplotypes frequency distributions between Bashkirs versus Russians and Tatars (chi2 = 12.328, df= 3,p = 0.008; chi2 = 9.218, df=3, p = 0.034, respectively for CYP1A1 gene and (chi2 = 18.779, df=3, p = 0.0001, chi = 14.326, df=3, p = 0.003, respectively for CYP1A2 gene). The (-2467)delT allele and CYP1A2*1D haplotype of CYPIA2 gene was associated with higher risk of COPD in Tatar ethnic group (OR = 1.83, 95% CI 1.24-2.71, chi2 = 9.48, p = 0.003 and chi2 = 9.733, p = 0.0027, Pcor = 0.008; OR = 3.908, 95% CI 1.56-10.19, respectively). On the other hand the CYP1A2*1A haplotype had protective effect (chi2 = 6.319, p = 0.0127, Pcor = 0.038; OR = 0.6012, 95% CI 0.402-0.898). But at the same time we did not find any differences in the genotypes and haplotypes frequency distributions of the CYP1A2 gene within the patients and healthy groups in Russian ethnic group. We also did not find any association of CYP1A1 gene with COPD in ethnic groups of Bashkortostan.

[Genomic typing of the Echinococcus granulosus isolates from the areas of Southern Urals].

Nine larvocysts of Echinococcus granulosus isolated from nine patients and one cyst derived from a naturally infested cattle have been examined. Genomic typing was carried out in order to identify strains of E. granulosus. All DNA samples were shown to have the same genotype, E. granulosus G1.