Medical Radiology and radiation safety Medical Radiology and radiation safety Медицинская радиология и радиационная безопасность 1024-6177 2618-9615 29406 10.12737/article_5d1103efefe893.65968050 Радиационная медицина Radiation medicine Радиационная медицина Genome Wide Association Study of an Association between Gene Polymorphisms and the Increased Frequency of Cytogenetic Abnormalities in the Persons Exposed to Long-Term Irradiation Полногеномное ассоциативное исследование связи полиморфных локусов с повышенной частотой хромосомных аберраций у лиц, подвергавшихся длительному радиационному воздействию Халюзова М. В. Khalyuzova M. V. Цыганов М. М. Tsyganov M. M. Исубакова Д. С. Isubakova D. S. Брониковская Е. В. Bronikovskaya E. V. Усова Т. В. Usova T. V. Литвяков Н. В. Litviakov N. V.

доктор биологических наук;

doctor of sciences in biology;

 Карпов А. Б. Karpov A. B.

доктор медицинских наук;

doctor of medical sciences;

 Тахауова Л. Р. Takhauova L. R. Тахауов Р. М. Takhauova T. M.

доктор медицинских наук;

doctor of medical sciences;

 Северский биофизический научный центр ФМБА России Северск Россия Seversk Biophysical Research Center Seversk Russian Federation Научно-исследовательский институт онкологии Томского национального исследовательского медицинского центра РАН Томск Россия Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences Tomsk Russian Federation Северский биофизический научный центр ФМБА России Северск Россия Seversk Biophysical Research Center Seversk Russian Federation Научно-исследовательский институт онкологии Томского национального исследовательского медицинского центра РАН Северск Россия Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences Seversk Russian Federation Северский биофизический научный центр ФМБА России Северск Россия Seversk Biophysical Research Center Seversk Russian Federation Северский биофизический научный центр ФМБА России Северск Россия Seversk Biophysical Research Center Seversk Russian Federation Северский биофизический научный центр ФМБА России Северск Россия Seversk Biophysical Research Center Seversk Russian Federation Научно-исследовательский институт онкологии Томского национального исследовательского медицинского центра РАН Томск Россия Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences Tomsk Russian Federation Национальный исследовательский Томский государственный университет Томск Россия National Research Tomsk State University Tomsk Russian Federation Северский биофизический научный центр ФМБА России Северск Россия Seversk Biophysical Research Center Seversk Russian Federation Сибирский государственный медицинский университет Томск Россия Siberian State Medical University Tomsk Russian Federation Сибирский государственный медицинский университет Томск Россия Siberian State Medical University Tomsk Russian Federation Северский биофизический научный центр ФМБА России Северск Россия Seversk Biophysical Research Center Seversk Russian Federation Сибирский государственный медицинский университет Томск Россия Siberian State Medical University Tomsk Russian Federation 64 4 32 40 https://naukaru.ru/en/nauka/article/29406/view

Цель: Полногеномное исследование связи 750 тыс. однонуклеотидных полиморфизмов (SNPs) с повышенной частотой различных типов хромосомных аберраций, возникших у работников радиационно-опасного производства, под действием хронического облучения в диапазоне доз 100–300 мЗв. Материал и методы: Объектом исследования служили пробы крови 37 работников Сибирского химического комбината. Средняя суммарная доза внешнего облучения обследованных лиц составила 188,8 ± 8,3 мЗв, медиана – 185 мЗв, интерквартильный размах – 147,8–218,7 мЗв, мин. – 103,4 мЗв, макс. – 295,8 мЗв. Генотипирование образцов ДНК лейкоцитов крови работников проводили на микроматрицах высокой плотности CytoScan™ HD Array (фирма Affymetrix, США), содержащих более 750 тыс. SNPs всех генов OMIM и межгенных областей. У всех обследованных был проведен стандартный цитогенетический анализ и определена частота аберрантных клеток, парных фрагментов, кольцевых и дицентрических хромосом, хроматидных фрагментов и хроматидных обменов. Результаты: Установлено, что с учетом поправки Бонферрони имеются только статистически значимые связи SNPs с частотой аберрантных клеток, все остальные типы хромосомных аберраций не показали статистической значимости. С повышенной частотой аберрантных клеток, возникающих под действием хронического облучения, ассоциировано 8 SNPs (rs10779468, rs158735, rs158710, rs158712, rs11131536, rs528170, rs9533572, rs10512439). Четыре межгенных SNPs (rs10779468, rs158735, rs158710, rs158712) в длинном плече 1-й хромосомы, по-видимому, находятся в важном регуляторном регионе (1:222282882–1:222402787). Интронные полиморфизмы (rs528170, rs9533572, rs10512439) принадлежат генам PACRG, ENOX1, MYO1D, и на эти гены следует обратить пристальное внимание как на новых участников генетической детерминации индивидуальной радиочувствительности. Заключение: Обнаруженные полиморфные варианты, минорные генотипы которых ассоциированы с повышенной частотой аберрантных клеток у работников Сибирского химического комбината, подвергавшихся радиационному воздействию в дозе 100–300 мЗв, можно рассматривать в качестве потенциальных маркеров индивидуальной радиочувствительности. Для подтверждения выявленных ассоциаций необходимы дальнейшие валидационные исследования на расширенной выборке людей, подвергавшихся радиационному воздействию.

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.

 индивидуальная радиочувствительность внешнее γ-облучение длительное радиационное воздействие полиморфизм генов хромосомные аберрации individual radiosensitivity external γ-radiation long-term radiation exposure chromosomal aberrations single nucleotide polymorphism

ВведениеЗа 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. 

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