T. V. Viktorova

Polymorphism of Human Mitochondrial DNA

To date, a large data set on the mitochondrial DNA (mtDNA) sequence variation in human populations has been accumulated. The use of direct sequencing of the main noncoding region of mtDNA along with the RFLP analysis provide performance of complex analysis of mtDNA polymorphism in human populations. This approach proved to be effective for obtaining molecular genetic portraits of the world populations, as well as for the elucidation of the human evolutionary history and past migrations.

Association of MMP3, MMP9, ADAM33, and TIMP3 polymorphisms with chronic obstructive pulmonary disease and its progression

PCR-RFLP analysis was performed for 391 cases and 514 control individuals to analyze the contribution of polymorphisms of the matrix metalloproteinase genes MMP1 (−1607 G>GG, rs1799750; −519 A>G, rs494379), MMP2 (−735 C>T, rs2285053), MMP3 (−1171 5A>6A, rs35068180), MMP9 (−1562 C>T, rs3918242; 2660A>G, rs17576), MMP12 (−82 A>G, rs2276109), the disintegrin and metalloproteinase 33 gene ADAM33 (12418 A>G, rs2280091; 13491 C>G, rs2787094), and tissue inhibitors of metalloproteinase genes TIMP2 (−418 G>C, rs8179090) and TIMP3 (−1296 T>C, rs9619311) to chronic obstructive pulmonary disease. Significant association with increased rick of chronic obstructive pulmonary disease was observed for the 6A6A genotype of the MMP3 −1171 5A>6A polymorphism (OR = 2.49, Padj = 0.003979, Pcor = 0.0358 adjusted for age, sex, smoke pack-years, ethnicity) and for the G-G haplotype of ADAM33 polymorphisms 13491 C>G and 12418 A>G (OR = 0.39, Padj = 0.0012, Pcor = 0.006). Significant interactions were detected between the smoking status and ADAM33 12418 A >G (Pinteract = 0.026) and TIMP3 −1296 T>C (Pinteract = 0.044). The risk of emphysema was increased in GG homozygotes by ADAM33 13491 C>G and a risk of emphysema was found (OR = 1.74, Padj = 0.013, Pcor = 0.117). The severity of chronic obstructive pulmonary disease was modified by MMP9 −1562 C>T in the additive model (OR = 1.883, Padj = 0.028, Pcor = 0.252). Thus, polymorphisms of MMP3, MMP9, ADAM33, and TIMP3 can be considered important risk factors for the development and progression of chronic obstructive pulmonary disease; in addition, pathogenetically significant gene-environment interactions were identified. These data contribute to the understanding of hereditary predisposition to chronic obstructive pulmonary disease.

Polymorphisms of the Cytochrome P450 (CYP1A1, CYP2E1) and Microsomal Epoxide Hydrolase (mEPHX) Genes in Cystic Fibrosis and Chronic Respiratory Disease

Frequencies of CYP1A1, CYP2E1, and mEPHX polymorphic variants were analyzed in cystic fibrosis, chronic obstructive lung disease, bronchiectatic disease, chronic nonobstructive bronchitis, and recurring bronchitis. Mutations in CYP1A1 and mEPHX were shown to modify the severity of respiratory disorders in cystic fibrosis, the combination of CYP1A1 genotype Val/Val with the “very slow” mEPHX phenotype being most unfavorable (odds ratio OR = 12.30). Heterozygosity at both CYP1A1 and CYP2E1 was associated with chronic obstructive lung disease and recurring bronchitis (OR = 4.08 and 11.72, respectively). The “very slow” phenotype of mEPHX was predisposing to chronic respiratory disorders regardless of the CYP1A1 or CYP2E1 alleles (OR = 4.06). Basing on the above correlations, a combination of the “very slow” mEPHX phenotype with elevated cytochrome P450 (CYP1A1 and CYP2E1) activities was assumed to expedite severe respiratory disorders.

Polymorphism of Y-Chromosomal Diallelic Loci in Populations of the Volga–Ural Region

Three diallelic polymorphisms of human Y chromosome (DYS287(Y Alupolymorphism, YAP), T/C transition at the RBF5locus (Tat), and G/A transition at the LLY22locus) were studied in eight ethnic populations of the Volga–Ural region, representing Turkic branch of the Altai (Bashkirs, Tatars, and Chuvashes) and Finno-Ugric branch of the Uralic linguistic family (Maris, Mordovians, Udmurts, Komi-Zyryans, and Komi-Permyaks), and in the group of Slavic migrants, belonging to the Indo-European linguistic family (Russians). The Volga–Ural populations were characterized by a low frequency of the Y chromosome Aluinsertion. Examination of an association between the Alupolymorphism and Tatmutation revealed absolute YAP–/C linkage. Analysis of the haplotype frequency distribution patterns constructed from the data on the DYS287and RBF5polymorphisms revealed substantial differences between Udmurts and other populations. The differences were also observed between Komi-Zyryans and the populations of Bashkirs, Mordovians, Komi-Permyaks, and Russians. Analysis of the degree of genetic differentiation pointed to high level of genetic differentiation of the male lineages of the Finno–Ugric ethnic groups. The data on the linkage between the RBF5locus and the LLY22locus mutations indicated the common origin of the Tatmutationin Bashkirs, Mordovians, Udmurts, and Komi-Zyryans, and of a number of ancestralCallele-bearing Y chromosomes in Tatars, Maris, and Chuvashes.

Complex Analysis for Antiprotease–Protease Enzyme Gene Polymorphisms in Patients with Chronic Obstructive Pulmonary Diseases

A molecular genetic analysis of genes encoding the protease inhibitors α1-antitrypsin (PI) and α1-antichymotrypsin (AACT) was performed in patients with chronic obstructive pulmonary disease (COPD) (n = 239), cystic fibrosis (n = 57), and bronchiectasis (n = 33). In addition, the sample included children with chronic infant lung disease (n = 151) and nonobstructive chronic bronchitis (n = 34). Mutations Z and S of the α1-antitrypsin gene (Glu342Lys and Glu264Val, respectively) resulting in severe enzyme deficiency and polymorphisms in the 3′-untranslated region of the same gene (G1237A) and in the signal peptide for α1-antichymotrypsin gene (Ala – 15Thr) were studied. No significant differences in the allele and genotype frequencies of these polymorphisms were revealed between the groups of patients and the control group. Promoter polymorphism G–1607GG in the interstitial collagenase gene (MMP1) was studied in patients with COPD, bronchiectasis, and chronic nonobstructive bronchitis. In COPD patients, the frequency of genotype GG/GG proved to be significantly higher than in the control group: 30.6 and 18.0%, respectively; χ2 = 6.58, p < 0.05; OR = 1.99 (95% CI 1.1–3.59). Thus, genetic polymorphism in the promoter of the MMP1 gene may be associated with an individual susceptibility to COPD.

Polymorphism of Xenobiotic Metabolism Genes in Petrochemical Workers

Genetic polymorphism of xenobiotic metabolizing enzymes responsible for individual susceptibility to different environmental factors was examined in a cohort of petrochemical workers occupationally exposed to adverse action of chemical compounds. Molecular genetic analysis of the I462V mutation in exon 7 of the CYP1A1gene demonstrated close similarity between the genotype and allele frequency distribution patterns in the industrial and control groups. No association between the CYP1A1polymorphic alleles and genotypes and the duration of service and concomitant diseases was observed. The odds ratio of the disease development in the workers carrying heterozygous CYP1A1 mutant allele was 2.2. Analysis of the GSTM1 gene polymorphism demonstrated a decrease in the frequency of the homozygous deletion carriers in the workers compared to the control group. There were no substantial differences between the industrial and control groups with respect to the frequencies of rapid and slow acetylator genotypes revealed at the analysis of the NAT2 gene polymorphism. However, considering the concomitant diseases, in the corresponding industrial subgroup a clear trend towards lower frequency of rapid acetylators was demonstrated. In addition, the odds ratio of the disease development for the workers with slow acetylator phenotype was 1.7.

Polymorphism of the Arylamine N-Acetyltransferase 2 Gene in Ethnic Populations of the Volga–Ural Region

The role of genetic factors in human sensitivity to adverse environmental factors is an important problem of molecular epidemiology. Based on studies of the polymorphisms of the xenobiotic metabolism genes, several hypotheses have been advanced to explain the high individual variation in predisposition to various disorders or in drug sensitivity [1–4]. Of special interest are the works that focus on genotype and allele frequency distributions of polymorphisms of the xenobiotic metabolism genes in various ethnic groups, and make it possible to explain higher frequencies of certain disorders in a particular region.

Allelic Variants of TNF Superfamily Genes Serve as Markers of Disease Severity in Patients with Chronic Obstructive Pulmonary Disease and Bronchiectatic Disease

The distribution of allelic variants of genes of theTNFsuperfamily (TNFA andLTA) was studied in 172 patients with chronic obstructive pulmonary disease (COPD), bronchiectatic disease (n = 22), and in healthy individuals (n = 169). Analysis of the TNFA gene locus –308G → A revealed no differences between the examined groups. Analysis of the LTA gene polymorphic locus +252A → G showed that in patients with COPD, the frequency of the Gallele was significantly higher than that in the control group (χ2 = 3.98, P < 0.05). The presence of this allele in the genotype was correlated with the degree of COPD severity. Thus, in patients with stage II COPD, heterozygous AG genotype predominated (51.3%), whereas in patients with stage III COPD, the frequency of AG genotype was reduced to 32.7% at the expense of increased frequency of GG genotype (14.6%) (χ2 = 6.78, P < 0.05; OR = 4.6, CI 1.37–15.96). The distribution of combined TNFA andLTA genotypes was also studied. In the group of COPD patients, the proportion of individuals with a combination of normal GGTNFA genotype and heterozygous AGLTA genotype was significantly higher (28.5 versus 18.4% in control; χ2 = 4.14, P< 0.05; OR = 1.75, CI = 1.01–3.04). Genotype combinations were characterized at various clinical stages of COPD and bronchiectatic disease (BED). Thus, we have shown for the first time ever that LTA gene alleles and their combinations with the polymorphic variants of the TNFA gene are associated with predisposition to COPD and severity of this disease.

Polymorphism of Human Glutatione S-Transferase Gene in the Populations of the Volga-Ural Region

The frequency of the GstM1 gene deletion homozygotes in eight populations of the Volga–Ural region belonging according to linguistic classification to Turkic (Bashkirs, Tatars, and Chuvashs), Finno–Ugric (Maris, Komis, Mordovians, and Udmurts), and Eastern–Slavic (Russians) ethnic groups, was examined by means of PCR technique. The frequency of the deletion homozygotes varied from 41.4% in Bashkirs to 61.3% in Mordovians. The mean deletion frequency comprised 50.1%, which was consistent with the data for European populations (χ2= 0.009).

TNF Family Gene Polymorphisms (TNF –308G/A and LTA +252A/G) and Alcoholic Liver Disease

Hyperfunctioning of the immune system has recently been considered as a possible factor in alcoholic liver damage. There is no doubt that a certain role is played by cytokines, which occupy the central place in cell-to-cell communication and regulation of immune disorders and proliferative responses in alcoholic liver disease (ALD). The contribution of the immune component may be considered in terms of genetic predisposition and the possibility of ALD development after the cessation of ethyl alcohol abuse.