Polymorphism of genes for xenobiotic metabolism 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 1462V mutation in exon 17 of the CYP1A gene demonstrated close similarity between the genotype and allele frequency distribution patterns in the industrial and control groups. No association between the CYP1A polymorphic 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 STM1 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.     

Tetranucleotide tandem repeat polymorphism of the CFTR gene intron 6B in populations of the Volga-Ural region

The allele and genotype frequencies of the tetranucleotide tandem repeat (TTR) of CFTR intron 6B were analyzed in eight ethnic populations of the Volga-Ural region, including Bashkir, Tatar, Chuvash, Mari, Mordvinian, Udmurt, Komi-Permyak, and Russian. The most common TTR allele 7 varied in frequency from 0.636 in Chuvash to 0.805 in Mordvinians. The frequency of the second common allele 7 ranged from 0.188 in Mordvinians to 0.333 in Chuvash. Allele 8 was found in about 8% of Udmurts and Mari; occurred in a few Bashkirs, Tatars, Mordvinians, and Komi-Permyaks; and was not observed in Russians. The genetic diversity coefficient was minimal in Mordvinians (0.496) and in Tatars (0.505), indicating their low heterogeneity in TTR. The observed heterozygosity was maximal in Udmurts (0.532) and Komi-Permyaks (0.560) and minimal in Mordvinians (0.297). In total, the populations proved to be heterogeneous in TTR allele frequency distribution, the interpopulation difference being significant in most cases.     

Analysis of the spectra of mutations and polymorphic loci of cystic fibrosis transmembrane conductance regulator in the population of Bashkortostan

The spectra of mutations and polymorphic loci of the gene of cystic fibrosis transmembrane conductance regulator (CFTR) was studied in 60 cystic fibrosis (CF) families from Bashkortostan. Mutations delF508, 394delTT, CFTRdele2,3(21 kb), R334W, and S1196X (33.3, 3.3, 1.7, 0.8, and 0.8%, respectively) were identified. The frequencies of tandem tetranucleotide repeat (TTR) alleles were determined for locus IVS6a-GATT of intron 6 of the CFTR gene and two extragenic loci flanking the CFTR gene, D7S23 and MET (probes CS.7 and MetH) in mutant and normal chromosomes. Allelic and haplotypic associations of these loci with the mutations found were estimated. An absolute linkage between the 6TTR allele of locus IVS6a-GATT and the delF508 mutation was ascertained. A considerable linkage disequilibrium between the delF508 mutation and the C2 allele of locus D7S23 and between this mutation and the A1 allele of locus MET was found. Most of the other mutant chromosomes carried marker alleles 7TTR, C1, and A2. It was demonstrated that 67% of CF chromosomes carrying delF508 had haplotype 6-2-1 for loci IVS6a-GATT/D7S23/MET, respectively. The frequency distribution of haplotypes in CF chromosomes without delF508 had a high variance and did not differ significantly from the distribution in normal chromosomes (chi 2 = 9.415; p > 0.05).     

Survival Rate and Enzyme Activities ofLactobacillus acidophilusFollowing Frozen Storage

The ability of two strains of Lactobacillus acidophilus, CRL 640 and CRL 800, to survive and retain their biological activities under frozen storage was determined. Freezing and thawing, as well as frozen storage, damaged the cell membrane, rendering the microorganisms sensitive to sodium chloride and bile salts. Both lactic acid production and proteolytic activity were depressed after 21 days at -20 degreesC, whereas beta-galactosidase activity per cell unit was increased. Cell injury was partially overcome after repair in a salt-rich medium. Copyright 1998 Academic Press.     

Association of <Emphasis Type="Italic">MMP3, MMP9, ADAM33</Emphasis>, and <Emphasis Type="Italic">TIMP3</Emphasis> 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, P _adj = 0.003979, P _cor = 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, P _adj = 0.0012, P _cor = 0.006). Significant interactions were detected between the smoking status and ADAM33 12418 A >G (P _interact = 0.026) and TIMP3 −1296 T>C (P _interact = 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, P _adj = 0.013, P _cor = 0.117). The severity of chronic obstructive pulmonary disease was modified by MMP9 −1562 C>T in the additive model (OR = 1.883, P _adj = 0.028, P _cor = 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.     

Association of polymorphisms of the CYP1A1 and CYP1A2 cytochrome P450 genes with chronic obstructive pulmonary disease in Bashkortostan

The frequencies of polymorphisms of CYP1A1 (2455A/G, 3801T/C) and CYP1A2 (?2464T/delT, ?163C/A) were determined in healthy residents of Bashkortostan (Russians, Tatars, and Bashkirs) and tested for association with chronic obstructive pulmonary disease (COPD). Interethnic differences in the frequency distribution of the CYP1A1 and CYP1A2 polymorphisms were significant. In Tatars and Russians, the CYP1A1 and CYP1A2 haplotype frequencies were similar (χ² = 0.973, df = 3, P = 1.00 and χ² = 1.546, df = 3, P = 0.92, respectively). In Bashkirs, the CYP1A1 haplotype frequencies significantly differed from those in Russians and Tatars (χ² = 12.328, df = 3, P = 0.008 and χ² = 9.218, df = 3, P = 0.034, respectively) owing to a high frequency of CYP1A1*2B (10.17%). Similarly, Bashkirs differed from Russians and Tatars in the CYP1A2 haplotype frequencies (χ² = 18.779, df = 3, P = 0.0001 and χ² = 14.326, df = 3, P = 0.003, respectively). The frequency of the CYP1A2*1D haplotype in Bashkirs was 11.02% in contrast to 2.36% in Tatars and 1.61% in Russians. Allele *D of the CYP1A2 ?2467delT polymorphism was associated with COPD in Tatars (OR = 1.83, 95%CI 1.24–2.71, χ² = 9.48, P = 0.003). CYP1A2*1D was associated with an increased risk of COPD (8.65% vs. 2.36% in controls, χ² = 9.733, P = 0.0027, P _cor = 0.008, OR = 3.908, 95%CI 1.56–10.19). Haplotype CYP1A2*1A was significantly less frequent in patients with COPD (21.05% vs. 30.74%, χ² = 6.319, P = 0.0127, P _cor = 0.038, OR = 0.6012, 95%CI 0.402–0.898). The CYP1A1 polymorphisms were not associated with COPD in residents of Bashkortostan.     

Polymorphism in promoter regions of matrix metalloproteinases (<Emphasis Type="Italic">MMP1</Emphasis>, <Emphasis Type="Italic">MMP9</Emphasis>, and <Emphasis Type="Italic">MMP12</Emphasis>) in chronic obstructive pulmonary disease patients

Our studies have shown that the genotype and allele frequencies of polymorphisms G(?1607)GG of MMP1 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%; χ² = 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 (χ² = 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%; χ² = 4.78; P = 0.029; P _cor = 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 T frequency 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 (χ² = 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.     

Analysis of the Polymorphic Markers within the CFTR Gene in Cystic Fibrosis Patients and Healthy Donors from Bashkortostan

The differences in the polymorphic allele frequency distribution patterns of the biallelic (M470V and TUB20) and microsatellite (IVS6aGATT, IVS8CA, and IVS17CA) markers within the CFTR gene between normal and delF508 chromosomes have been established. For most of the marker loci similar distribution of the allele frequencies on normal and mutant chromosomes without delF508 was demonstrated. Certain polymorphic alleles displayed substantial linkage disequilibrium with the delF508 mutation. Analysis of the IVS6aGATT-IVS8CA-M470V-IVS17CA-TUB20 haplotypes association on normal and mutant chromosomes provided identification of the delF508 ancestral haplotype. It was suggested that delF508 mutant chromosomes were introduced into the modern Bashkir gene pool as a result of Slavic migrations from the Eastern Europe. The IVS6aGATT-IVS8CA-M470V-IVS17CA-TUB20major haplotype (77272) revealed was statistically significantly most frequently found on the mutant chromosomes without the delF508 mutation. This finding suggests that the Bashkir cystic fibrosis patients, mostly belonging to the Turkic-speaking families, possessed specific CFTR gene defect associated with the given haplotype.     

The Role of Serum Amyloid A1, Adhesion Molecules,Chemokines, and Chemokine Receptors Genes in Chronic Obstructive Pulmonary Disease

Russian Journal of Genetics - Chronic obstructive pulmonary disease (COPD) is a multifactorial chronic inflammatory disease of the respiratory system. A key phenomenon of COPD pathogenesis is...