employee
employee
employee
Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences (Junior Researcher)
employee
employee
Russian Federation
employee
Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences
employee
National Research Tomsk State University
employee
employee
Siberian State Medical University (Professor)
employee
student
employee
Siberian State Medical University (Professor)
employee
GRNTI 76.03 Медико-биологические дисциплины
GRNTI 76.33 Гигиена и эпидемиология
OKSO 14.04.02 Ядерные физика и технологии
OKSO 31.06.2001 Клиническая медицина
OKSO 31.08.08 Радиология
OKSO 32.08.12 Эпидемиология
BBK 51 Социальная гигиена и организация здравоохранения. Гигиена. Эпидемиология
BBK 534 Общая диагностика
TBK 5708 Гигиена и санитария. Эпидемиология. Медицинская экология
TBK 5712 Медицинская биология. Гистология
TBK 5734 Медицинская радиология и рентгенология
TBK 6212 Радиоактивные элементы и изотопы. Радиохимия
Purpose: To conduct genome wide association study of the association of 750,000 SNPs and an increased frequency of different types of chromosomal aberrations, induced by chronic irradiation in the dose range of 100–300 mSv. Material and methods: The study was conducted among Siberian Group of Chemical Enterprises healthy employees (n = 37) exposed to professional external γ-radiation in a dose range of 100–300 mSv. The de novo induced CNVs were previously detected in these persons. Mean dose – 188.8 ± 8.3 mSv, median – 185 mSv, interquartile range – 147.8–218.7 mSv, min – 103.4 mSv, max – 295.8 mSv. Genotyping of DNA samples from 37 employees was carried out by microarray CytoScan™ HD Array (Affymetrix, USA), containing 750,000 SNP-markers of 36,000 genes. The standard cytogenetic analysis was performed in the entire examined group. Results: We analyzed the association of these SNPs with the frequencies of aberrant cells and following chromosomal aberrations: single chromatid fragments, chromatid exchanges, paired fragments, dicentrics, rings, and translocations. We have found that 8 SNPs (rs10779468, rs158735, rs158710, rs158712, rs11131536, rs528170, rs9533572, rs10512439) are associated with the frequency of aberrant cells. Conclusion: We have discovered polymorphic variants that are associated with an increased frequency of aberrant cells in workers of Siberian Group of Chemical Enterprises exposed to irradiation at a dose of 100–300 mSv. This polymorphic variants can be considered as potential markers of individual radiosensitivity. To confirm identified associations, further validation studies on an extended sample of people exposed to radiation are needed.
individual radiosensitivity, external γ-radiation, long-term radiation exposure, chromosomal aberrations, single nucleotide polymorphism
Введение
За последние годы было проведено множество научных исследований генома в рамках проектов GWAS (genome-wide association studies – полногеномный поиск ассоциаций). Основная цель GWAS состоит в поиске различных генетических маркеров, прежде всего SNPs (single-nucleotide polymorphisms – однонуклеотидных полиморфизмов), определяющих генетическую индивидуальность человека, ассоциированных с риском развития различных патологических состояний, с помощью которых можно предиктивно оценить вероятность развития того или иного заболевания, спрогнозировать течение болезни, а также разработать новые стратегии профилактики и лечения [1]. Поиск связей между SNPs и различными заболеваниями человека, такими как злокачественные новообразования, болезни сердечно-сосудистой системы, диабет, аутоиммунные заболевания и психические расстройства, находит широкое применение в современной науке [1]. GWAS может использоваться также с целью изучения сложных фенотипических признаков в популяции, в том числе, таких как индивидуальная чувствительность к факторам окружающей среды.
1. Bush WS, Moore JH. Genome-wide association studies. PLoS computational biology. 2012;8(12):e1002822. DOI:https://doi.org/10.1371/journal.pcbi.1002822.
2. Freidin MB, Vasilyeva YeO, Skobelskaya YeV, Goncharova IA, Karpov AB, Takhauov RM. The prevalence and spectrum of chromosomal aberrations in workers of the Siberian Group of Chemical Enterprises. Bulletin of Siberian Medicine. 2005;(2):75-81. (Russian).
3. Sal’nikova LE, Chumachenko AG, Vesnina IN, Lapteva NSh, Kuznetsova GI, Abilev SK, Rubanovich AV. Polymorphism of Repair Genes and Cytogenetic Radiation Effects. Radiat. Biol. Radioecol. 2010;50(6):29-38. (Russian).
4. Abilev SK, Sal’nikova LE, Rubanovich AV Candidate gene association study of the radiosensitivity of human chromosomes with candidate gene polymorphisms upon exposure to gamma-irradiation in vitro and in vitro. Gig. Sanit. 2011;(5):14-8. (Russian).
5. Salnikova L, Chumachenko A, Belopolskaya O, Rubanovich A. Correlations between DNA polymorphism and frequencies of gamma-radiation induced and spontaneous cytogenetic damage. Health Phys. 2012;103(1):37-41. DOI:https://doi.org/10.1097/HP.0b013e3182231a9d.
6. Minina VI. Genetic Polymorphism and Chromosome Aberrations Induced by Radiation. Siberian Medical Journal. 2012;(3):5-7. (Russian).
7. Zhang X, Zhang X, Zhang L, Chen Q, Yang Z, Yu J, et al. XRCC1 Arg399Gln was associated with repair capacity for DNA damage induced by occupational chromium exposure. BMC research notes. 2012;5(1):263. DOI:https://doi.org/10.1186/1756-0500-5-263.
8. Hornhardt S, Rößler U, Sauter W, Rosenberger A, Illig T, Bickeböller H, et al. Genetic factors in individual radiation sensitivity. DNA repair. 2014;16:54-65. DOI:https://doi.org/10.1016/j.dnarep.2014.02.001.
9. Rosenstein BS, West CM, Bentzen SM, Alsner J, Andreassen CN, Azria D, et al. Zenhausern F. Radiogenomics: radiobiology enters the era of big data and team science. Int J Radiat Oncol Biol Phys. 2014;89(4):709-13. DOI:https://doi.org/10.1016/j.ijrobp.2014.03.009.
10. Barnett GC, Coles CE, Elliott RM, Baynes C, Luccarini C, Conroy D, et al. Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study. The Lancet Oncol. 2012.13(1):65-77. DOI: https://doi.org/10.1016/S1470-2045(11)70302-3.
11. Andreassen CN, Rosenstein BS, Kerns SL, Ostrer H, De Ruysscher D, Cesaretti JA, et al. Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients. Radiother Oncol. 2016;121(3):431-9. DOI:https://doi.org/10.1016/j.radonc.2016.06.017.
12. Kerns SL, Ostrer H, Stock R, Li W, Moore J, Pearlman A, et al. Genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2010;78(5):1292-300. DOI:https://doi.org/10.1016/j.ijrobp.2010.07.036.
13. Kerns SL, Stock R, Stone N, Buckstein M, Shao Y, Campbell C, et al. A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2013;85(1):e21-28. DOI:https://doi.org/10.1016/j.ijrobp.2012.08.003.
14. Kerns SL, Stone NN, Stock RG, Rath L, Ostrer H, Rosenstein BS. A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of urinary symptoms following radiotherapy for prostate cancer. J Urol. 2013;190(1):102-8. DOI:https://doi.org/10.1016/j.juro.2013.01.096.
15. Kerns SL, Stock RG, Stone NN, Blacksburg SR, Rath L, Vega A, et al. Genome-wide association study identifies a region on chromosome 11q14.3 associated with rectal bleeding following radiation therapy for prostate cancer. Radiother Oncol. 2013;107(1):372-76. DOI:https://doi.org/10.1016/j.radonc.2013.05.001.
16. Fachal L, Gómez-Caamaño A, Barnett GC, Peleteiro P, Carballo AM, Calvo-Crespo P, et al. A three-stage genome-wide association study identifies a susceptibility locus for late radiotherapy toxicity at 2q24.1. Nat Genet. 2014;46(8):891-4. DOI:https://doi.org/10.1038/ng.3020.
17. Barnett GC, Thompson D, Fachal L, Kerns S, Talbot C, Elliott RM, et al. A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity. Radiother Oncol. 2014;111(2):178-85. DOI:https://doi.org/10.1016/j.radonc.2014.02.012.
18. Litviakov NV, Freidin MB, Khalyuzova MV, Sazonov AJ, Vasilyeva EO, Albakh EN, et al. The frequency and spectrum of cytogenetic anomalies in employees of Siberian Group of Chemical Enterprises. Radiat Biol Radioecol. 2014;54(3):283-96. DOI:https://doi.org/10.7868/S0869803114030084. (Russian).
19. Litviakov NV, Goncharik OO, Freidin MB, Sazonov AE, Vasil’eva EO, Mezheritskiĭ SA, et al. The Estimate of Association Between Gene Polymorphisms and the Frequency and Spectrum of Cytogenetic Abnormalities in the Cohort of Siberian Group of Chemical Enterprises Employees Exposed to Professional Irradiation (Microarray Studies). Radiat Biol Radioecol. 2013;53(23):137-50. DOI:https://doi.org/10.7868/S0869803113020069. (Russian).
20. Khalyuzova MV, Litviakov NV, Isubakova DS, Bronikovskaya EV, Usova TV, Al’bakh EN et al. Validation of Association between Gene Polymorphisms and the Frequency of Cytogenetic Abnormalities in the Cohort of Employees of Radiation Facilities. Radiat Biol Radioecol. 2017;57(4):365-83. DOI:https://doi.org/10.7868/S0869803117040038. (Russian).
21. Takhauov RM, Karpov AB, Albach EN, Khalyuzova MV, Freidin MB, Litviakov NV, et al. The bank of biological samples representing individuals exposed to long-term ionizing radiation at various doses. Biopreserv Biobank. 2015;13(2):72-8. DOI:https://doi.org/10.1089/bio.2014.0035.
22. Powell SN, Kachnic LA. Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene. 2003;22:5784-91.
23. West AB, Lockhart PJ, O’Farell C, Farrer MJ. Identification of a novel gene linked to parkin via a bi-directional promoter. J Mol Biol. 2003;326(1):11-9.
24. Taylor JM, Song YJ, Huang Y, Farrer MJ, Delatycki MB, Halliday GM, Lockhart PJ. Parkin Co-regulated Gene (PACRG) is regulated by the ubiquitin-proteasomal system and is present in the pathological features of parkinsonian diseases. Neurobiol Dis. 2007;27(2):238-47.
25. Schurr E, Alcaïs A, de Léséleuc L, Abel L. Genetic predisposition to leprosy: a major gene reveals novel pathways of immunity to Mycobacterium leprae. Semin Immunol. 2006;18(6):404-10.
26. Imai Y, Soda M, Murakami T, Shoji M, Abe K, Takahashi R. A product of the human gene adjacent to parkin is a component of Lewy bodies and suppresses Pael receptor-induced cell death. J Biol Chem. 2003;278(51):51901-10.
27. Wilson GR, Sim ML, Brody KM, Taylor JM, McLachlan RI, O’Bryan MK, et al. Molecular analysis of the parkin co-regulated gene and association with male infertility. Fertil Steril. 2010;93(7):2262-68. DOI:https://doi.org/10.1016/j.fertnstert.2009.01.079.
28. Entrez Gene: Ecto-NOX disulfide-thiol exchanger 1. Available from: https://www.ncbi.nlm.nih.gov/gene/55068.
29. Landouré G, Knight MA, Stanescu H, Taye AA, Shi Y, Diallo O, et al. NIH Intramural Sequencing Center. A candidate gene for autoimmune myasthenia gravis. Neurology. 2012;79(4):342-47.
30. Benesh AE, Fleming JT, Chiang C, Carter BD, Tyska MJ. Expression and localization of myosin-1d in the developing nervous system. Brain Res. 2012;1440:9-22. DOI:https://doi.org/10.1016/j.brainres.2011.12.054.
31. Stone JL, Merriman B, Cantor RM, Geschwind DH, Nelson SF. High density SNP association study of a major autism linkage region on chromosome 17. Hum Mol Genet. 2007;16(6):704-15.
