vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-24-87vavilov-4352Research ArticleБИОТЕХНОЛОГИЯ В ПОСТГЕНОМНУЮ ЭРУMEDICAL GENETICSПолиморфные варианты генов ферментов антиоксидантной системы, апоптоза и воспаления как потенциальные предикторы инфаркта миокардаPolymorphic variants of the genes for enzymes of the antioxidant system, apoptosis and inflammation as potential predictors of myocardial infarctionhttps://orcid.org/0000-0001-8823-8678НасибуллинТ. Р.NasibullinT. R.

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Ufa

nasibullintr@yandex.ruhttps://orcid.org/0000-0002-1219-3458ЭрдманВ. В.ErdmanV. V.

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Ufa

https://orcid.org/0000-0002-9918-6962ТимашеваЯ. Р.TimashevaY. R.

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https://orcid.org/0000-0001-6928-648XТуктароваИ. А.TuktarovaI. A.

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https://orcid.org/0009-0003-3526-9691ПетинцеваА. А.PetinsevaA. A.

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Ufa

https://orcid.org/0000-0002-1695-5173КорытинаГ. Ф.KorytinaG. F.

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Институт биохимии и генетики - обособленное структурное подразделение Уфимского федерального исследовательского центра Российской академии наукРоссияInstitute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of SciencesRussian FederationИнститут биохимии и генетики - обособленное структурное подразделение Уфимского федерального исследовательского центра Российской академии наук; Уфимский университет науки и технологийРоссияInstitute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences; Ufa University of Science and TechnologyRussian Federation202422112024287792800Copyright © Насибуллин Т.Р., Эрдман В.В., Тимашева Я.Р., Туктарова И.А., Петинцева А.А., Корытина Г.Ф., 20242024Насибуллин Т.Р., Эрдман В.В., Тимашева Я.Р., Туктарова И.А., Петинцева А.А., Корытина Г.Ф.Nasibullin T.R., Erdman V.V., Timasheva Y.R., Tuktarova I.A., Petinseva A.A., Korytina G.F.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4352

Инфаркт миокарда (ИМ) - многофакторное полигенное заболевание, развивающееся в результате сложного взаимодействия многочисленных генетических факторов и внешней среды. Соответственно, вклад каждого из них по отдельности, как правило, невелик и может существенно зависеть от состояния других сопут­ ствующих факторов. Цель исследования - поиск информативных предикторов развития ИМ на основе полигенного анализа полиморфных вариантов генов ферментов антиоксидантной защиты - PON1 (rs662), PON2  (rs7493), CAT (rs1001179), MSRA (rs10098474), GSTP1 (rs1695); апоптоза - CASP8 (rs3834129), TP53 (rs1042522), BCL2 (rs12454712); воспаления CRP  (rs1205), CX3CR1 (rs3732378), IL6 (rs1800795), CCL2 (rs1024611). В работе использованы образцы: 591 - ДНК (280 больных, перенесших ИМ в возрасте от 30 до 60 лет, средний возраст 46.02 ± 6.17; 311 - контроль, возраст от 30 до 62 лет, средний возраст 44.65 ± 7.07). Все участники исследования -мужчины, татары по этнической принадлежности. С помощью логистического регрессионного анализа с учетом различных моделей выявлены ассоциации с ИМ полиморфных вариантов генов CX3CR1 (rs3732378) (сверхдоминантная модель – G/G+A/A vs A/G Р = 0.0002, OR = 1.9), MSRA (rs10098474) (доминантная модель - T/T vs T/C+C/C Р = 0.015, OR = 1.51), CCL2 (rs1024611) (рецессивная модель - P = 0.0007 - A/A+A/G vs G/G OR = 2.63), BCL2 (rs12454712) (лог-аддитивная модель - аллель *C, P  =  0.005, OR  =  1.38). C применением метода Монте-Карло и цепей Маркова (APSampler) получены сочетания аллелей/генотипов изученных полиморфных локусов, ассоциированных с высоким риском ИМ, в составе которых, помимо обнаруженных в ходе анализа ассоциаций ИМ и отдельных полиморфных вариантов, присутствуют полиморфные варианты генов CASP8, TP53, CAT, PON2, CRP, IL6, GSTP1. Среди этих сочетаний проведен попарный анализ возможного нелинейного взаимодействия между выявленными комбинациями аллелей/генотипов, который показал синергетические взаимодействия полиморфных вариантов CX3CR1*A/G и CASP8*I/I, MSRA*C и CRP*C, CAT*С/T и MSRA*C, CAT*C/T и CX3CR1*A, способствующие развитию ИМ. На основе полученных результатов с использованием многофакторного логистического регрессионного анализа построена предиктивная модель для оценки риска развития ИМ, предсказательная способность которой достигла значения AUC = 0.71 (AUC (area under curve) - площадь под кривой при ROC-анализе).

Myocardial infarction (MI) is a multifactorial polygenic disease that develops as a result of a complex interaction of numerous genetic factors and the external environment. Accordingly, the contribution of each of them separately is usually not large and may significantly depend on the state of other accompanying factors. The purpose of the study was to search for informative predictors of MI risk based on polygenic analysis of polymorphic variants of (1) the antioxidant defense enzyme genes PON1 (rs662), PON2 (rs7493), CAT (rs1001179), MSRA (rs10098474) and GSTP1 (rs1695); (2) the apoptosis genes CASP8 (rs3834129), TP53 (rs1042522) and BCL2 (rs12454712); and (3) the inflammation genes CRP (rs1205), CX3CR1 (rs3732378), IL6 (rs1800795) and CCL2 (rs1024611). 591 DNA samples were used in the study (280 patients with the onset at 30 to 60 years, with an average age of 46.02 ± 6.17, and 311 control subjects aged 30 to 62, with an average age of 44.65 ± 7.07). All the participants were male and Tatars by ethnicity. The logistic regression analysis with various models demonstrated associations with MI of polymorphic variants of the genes CX3CR1 (rs3732378) (overdominant model – G/G + A/A vs A/G P = 0.0002, OR = 1.9), MSRA (rs10098474) (dominant model – T/T vs T/C + C/C P = 0.015, OR = 1.51), CCL2 (rs1024611) (recessive model – P = 0.0007 – A/A + A/G vs G/G OR = 2.63), BCL2 (rs12454712) (log-additive model – *C allele, P = 0.005, OR = 1.38). Using the Monte Carlo method and Markov chains (APSampler), combinations of alleles/ genotypes of the studied polymorphic loci associated with a high risk of MI were obtained, which, in addition to those identified during single-locus analysis, contained polymorphic variants of the genes CASP8, TP53, CAT, PON2, CRP, IL6, GSTP1. Among the combinations obtained, a pairwise analysis of possible non-linear interactions between the identified combinations of alleles/genotypes was carried out, which showed synergistic interactions of the polymorphic variants CX3CR1*A/G and CASP8*I/I, MSRA*C and CRP*C, CAT*C/T and MSRA*C, CAT*C/T and CX3CR1*A contributing to the development of MI. Based on the results obtained using multivariate logistic regression analysis, a predictive model was built to assess the risk of developing MI, the predictive ability of which reached the value AUC = 0.71 (AUC – area under the curve in ROC analysis).

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The authors declare that there are no conflicts of interest present.