Aleksey V. Larionov

Associations of DNA-repair gene polymorphisms with a genetic susceptibility to ionizing radiation in residents of areas with high radon (222Rn) concentration

Abstract Purpose: To investigate the individual radiosensitivity of the human genome in long-term residents of areas with high radon concentration. Materials and methods: The materials used for this investigation were venous blood samples extracted from children living in the boarding school of Tashtagol (Kemerovo Region, Russia). Cytogenetic damage assessment was performed using the cytokinesis-block micronucleus assay (CBMN) on peripheral blood lymphocytes. PCR, gel electrophoresis and product detection using a transilluminator were used to determine polymorphisms in the genes ADPRT (rs 1136410), hOGG1 (rs 1052133), NBS1 (rs 1805794), XRCC1 (rs 25487), XpC (rs 2228001), XpD (rs 13181), and XpG (rs 17655). Statistical analysis was performed using nonparametric methods. To ensure accurate results, FDR-correction for multiple comparisons was performed. Results: We discovered a significant increase in the frequency of binucleated lymphocytes with micronuclei (MN) in carriers of the His/His genotype of the XpG gene Asp1104His polymorphism in comparison to heterozygous and homozygous carriers of the Asp allele. In addition, the Ala/Ala genotype for the ADPRT gene Val762Ala polymorphism and the Glu/Gln genotype for the NBS1 gene Glu185Gln polymorphism were associated with the elevated frequency of binucleated lymphocytes with nucleoplasmic bridges (NPB). Conclusions: As a result of this study, the elevated frequency of cytogenetic damage in people with particular DNA-repair gene polymorphisms in response to chronic exposure to radon was demonstrated. It was shown that the genes and corresponding polymorphisms (the XpG gene Asp1104His polymorphism, the ADPRT gene Val762Ala polymorphism and the NBS1 gene Glu185Gln polymorphism) can be used as molecular genetic markers of increased individual radiosensitivity in long-term residents of areas with high concentrations of radon.

Assessing the level of chromosome aberrations in peripheral blood lymphocytes in long-term resident children under conditions of high exposure to radon and its decay products.

In this study, the frequency and spectrum of chromosomal aberrations were analysed in samples of peripheral blood from 372 (mean age = 12.24 ± 2.60 years old) long-term resident children in a boarding school (Tashtagol city, Kemerovo Region, Russian Federation) under conditions of high exposure to radon and its decay products. As a control group, we used blood samples from people living in Zarubino village (Kemerovo Region, Russian Federation). We discovered that the average frequencies of single and double fragments, chromosomal exchanges, total number of aberrations, chromatid type, chromosome type and all types of aberrations were significantly increased in the exposed group. This is evidence of considerable genotoxicity to children living under conditions of high exposure to radon compared to children living under ecological conditions without increased radon radiation.

Association of DNA Repair Gene Polymorphism with Chromosomal Aberrations Frequency in Human Lymphocytes

Analysis of the association between several DNA repair gene polymorphisms and the level of chromosomal aberrations (CAs) in lymphocytes of two groups of adolescents was carried out: in a group of 256 donors exposed to indoor radon and a control group of 94 donors. In a group of children with living conditions exposing them to high doses of radon (>200 Bq/m3), the level of CAs was significantly higher among carriers of genotypes hOGG1 Cys/Cys, hOGG1 Ser/Cys, ADPRT Ala/Ala, and ADPRT Val/Ala. No significant association between the level of CA and XRCC1 Arg194Trp, XRCC1 Arg280His, XRCC1 Arg399Gln, and APE1 Asp148Glu polymorphisms was found.

DNA excision repair and double-strand break repair gene polymorphisms and the level of chromosome aberration in children with long-term exposure to radon

Abstract Purpose: To study polymorphic variants of repair genes in people affected by long-term exposure to radon. The chromosome aberration frequency in peripheral blood lymphocytes was used as the biological marker of genotoxicity. Materials and methods: Genotyping of 12 single nucleotide polymorphisms in DNA repair genes (APE, XRCC1, OGG1, ADPRT, XpC, XpD, XpG, Lig4 and NBS1) was performed in children with long-term resident exposure to radon. Quantification of the aberrations was performed using light microscopy. Results: The total frequency of aberrations was increased in carriers of the G/G genotype for the XpD gene (rs13181) polymorphism in recessive model confirmed by the results of ROC-analysis (‘satisfactory predictor’, AUC = 0.609). Single chromosome fragments frequency was increased in carriers of the G/G genotype in comparison with the T/T genotype. In respect to the total frequency of aberrations, the G/G genotype for the XpG gene (rs17655) polymorphism was also identified as a ‘satisfactory predictor’ (AUC = 0.605). Carriers of the T/C genotype for the ADPRT gene (rs1136410) polymorphism were characterized by an increased level of single fragments relative to the T/T genotype. Conclusion: The relationships with several types of cytogenetic damage suggest these three SNP (rs13181, rs17655 and rs1136410) may be considered radiosensitivity markers.

Research of the Influence of the LIG4 Gene Polymorphism on the Chromosomal Aberration Level in Human Lymphocytes, with Background And Excessive Exposure to a Radon

The effects of LIG4 gene polymorphisms rs1805388 (Thr9lle) and rs1805389 (Ala3Val) on the level of chromosomal aberrations in the lymphocytes of peripheral blood was estimated for children that live and study in conditions of normal and supernormal radon exposure in several locations in Kemerovskaya oblast. A statistically significant difference of the cytogenetic values among genotypic groups with the use of marker rs1805388 was not shown. At the same time, in the group of Val carriers (marker rs1805389) from the second cohort of our analysis revealed a significant increase of the amount of paired fragments in comparison to homozygotes Ala/Ala.

Associations of polymorphisms in the cytokine genes IL1β (rs16944), IL6 (rs1800795), IL12b (rs3212227) and growth factor VEGFA (rs2010963) with anthracosilicosis in coal miners in Russia and related genotoxic effects

Anthracosilicosis (AS), a prevalent form of pneumoconiosis among coal miners, results from the accumulation of carbon and silica in the lungs from inhaled coal dust. This study investigated genotoxic effects and certain cytokine genes polymorphic variants in Russian coal miners with АS. Peripheral leukocytes were sampled from 129 patients with AS confirmed by X-ray and tissue biopsy and from 164 asymptomatic coal miners. Four single-nucleotide polymorphisms were genotyped in the extracted DNA samples: IL1β T-511C (rs16944), IL6 C-174G (rs1800795), IL12b A1188C (rs3212227) and VEGFA C634G (rs2010963). Genotoxic effects were assessed by the analysis of chromosome aberrations in cultured peripheral lymphocytes. The mean frequency of chromatid-type aberrations and chromosome-type aberrations, namely, chromatid-type breaks and dicentric chromosomes, was found to be higher in AS patients [3.70 (95% confidence interval {CI}, 3.29-4.10) and 0.28 (95% CI, 0.17-0.38)] compared to the control group [2.41 (95% CI, 2.00-2.82) and 0.09 (95% CI, 0.03-0.15)], respectively. IL1β gene T/T genotype (rs16944) was associated with AS [17.83% in AS patients against 4.35% in healthy donors, odds ratio = 4.77 (1.88-12.15), P < 0.01]. A significant increase in the level of certain chromosome interchanges among AS donors is of interest because such effects are typical for radiation damage and caused by acute oxidative stress. IL1β T allele probably may be considered as an AS susceptibility factor among coal miners.

Genotoxic effects of the combined influence of radon and heavy metals depending on polymorphism of genes of monooxygenase system enzymes

The correlation between the level of chromosomal aberrations and CYP1A genotypes in adolescents of the Tashtagol boarding school (Kemerovo region) exposed to a combined effect of high doses of radon and heavy metals has been studied. It was found that the level of chromosomal aberrations shows a statistically significantly increase in carriers of at least one CYP1A1*2A (A2455G) allele. The frequency of ring chromosomes shows a statistically significant increase in carriers of the CYP1A1 *1A*1A (T3801C) genotype. The frequency of multiple chromosomal aberrations was higher in carriers of the CYP1A2*1A*1A genotype. A conclusion on the important role of polymorphic CYP1A loci in genotoxic effects of radon and heavy metals is made.