vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ21.099vavilov-3204Research ArticleБИОТЕХНОЛОГИЯ В ПОСТГЕНОМНУЮ ЭРУMEDICAL GENETICSРегуляторный потенциал SNP-маркеров генов, ассоциированных с бронхиальной астмой, артериальной гипертензией и их коморбидным фенотипомPutative regulatory functions of SNPs associated with bronchial asthma, arterial hypertension and their comorbid phenotypehttps://orcid.org/0000-0002-9527-7015ГончароваИ. А.GoncharovaI. A.

Томск, Россия

Tomsk, Russia

irina.goncharova@medgenetics.ruhttps://orcid.org/0000-0002-1103-3073БрагинаЕ. Ю.BraginaE. Yu.

Томск, Россия

Tomsk, Russia

https://orcid.org/0000-0001-6848-7749ЖалсановаИ. Ж.ZhalsanovaI. Zh.

Томск, Россия

Tomsk, Russia

https://orcid.org/0000-0002-1439-6259ФрейдинМ. Б.FreidinM. B.

Томск, Россия

Tomsk, Russia

https://orcid.org/0000-0002-0673-4094НазаренкоМ. С.NazarenkoM. S.

Томск, Россия

Tomsk, Russia

Научно-исследовательский институт медицинской генетики Томского национального исследовательского медицинского центра Российской академии наукРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesRussian Federation202101012022258855863Copyright © Гончарова И.А., Брагина Е.Ю., Жалсанова И.Ж., Фрейдин М.Б., Назаренко М.С., 20222022Гончарова И.А., Брагина Е.Ю., Жалсанова И.Ж., Фрейдин М.Б., Назаренко М.С.Goncharova I.A., Bragina E.Y., Zhalsanova I.Z., Freidin M.B., Nazarenko M.S.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3204

В работе оценено неравновесие по сцеплению однонуклеотидных вариантов (SNP) генов TLR4/AL160272.2 (rs1927914, rs1928298, rs7038716, rs7026297, rs7025144) у славян-жителей Западной Сибири. Проведен анализ ассоциаций SNP в области генов TLR4/AL160272.2 (rs1927914, rs7038716, rs7025144), SERPINA1 (rs1980616), ATXN2/BRAP (rs11065987), IL2RB (rs2284033), NT5C2 (rs11191582), CARD8 (rs11669386), ANG/RNASE4 (rs1010461) и ABTB2/САТ (rs2022318) при бронхиальной астме (БА), артериальной гипертензии (АГ) и их сочетании. Выполнено in silico аннотирование SNP, ассоциированных с данными заболеваниями, в отношении их регуляторного потенциала. В результате у славян-жителей Западной Сибири выявлено сильное неравновесие по сцеплению rs1928298 и rs1927914, а также rs7026297 и rs7038716. Установлено, что к развитию БА предрасполагают аллель G rs1927914 гена TLR4 и аллель С rs1980616 гена SERPINA1. Данные SNP влияют на изменение аффинности транскрипционных факторов семейств Pou и Klf4, а также на экспрессию генов TLR4 и SERPINA1 в клетках крови соответственно. Аллель А rs11065987 генов ATXN2/BRAP, аллель А rs11669386 гена CARD8, аллель G rs2284033 гена IL2RB и аллель G rs11191582 гена NT5C2 ассоциированы с риском развития артериальной гипертензии. Данные варианты изменяют аффинность транскрипционных факторов Hoxa9, Irf, RORalpha1 и HMG-IY, а также экспрессию генов ALDH2, CARD8, NT5C2, ARL3 и SFXN2 в клетках крови, сосудах и сердце. Риск развития коморбидного фенотипа БА и АГ ассоциирован с аллелем А rs7038716 и аллелем Т rs7025144 генов TLR4/AL160272.2, аллелем А – rs1010461 гена ANG и аллелем С – rs2022318 генов ABTB2/САТ. Варианты rs7038716 и rs7025144 изменяют экспрессию гена TLR4 в клетках крови, а rs1010461 и rs2022318 – генов ANG и RNASE4, CAT и ABTB2 в клетках крови, легких, сосудов и сердца.

Linkage disequilibrium (LD) of single nucleotide polymorphisms (SNPs) of TLR4/AL160272.2 (rs1927914, rs1928298, rs7038716, rs7026297, rs7025144) was estimated in the Slavs of West Siberia. We further investigated an association of SNPs in TLR4/AL160272.2 (rs1927914, rs7038716, rs7025144), SERPINA1 (rs1980616), ATXN2/BRAP (rs11065987), IL2RB (rs2284033), NT5C2 (rs11191582), CARD8 (rs11669386), ANG/RNASE4 (rs1010461), and ABTB2/ САТ (rs2022318) genes with bronchial asthma (BA), arterial hypertension (AH) and their comorbidity. Then, the disease-associated SNPs were annotated in silico in relation to their potential regulatory functions. Strong LD was detected between rs1928298 and rs1927914, as well as rs7026297 and rs7038716 in the Slavs of West Siberia. It was found that the rs1927914 G allele of the TLR4 gene and the rs1980616 C allele of the SERPINA1 gene are associated with the predisposition to BA. These SNPs can affect binding affinity of transcription factors of the Pou and Klf4 families, as well as the expression levels of the TLR4 and SERPINA1 genes. The rs11065987 allele A of the ATXN2/BRAP genes, the rs11669386 A allele of the CARD8 gene, the rs2284033 allele G of the IL2RB gene, and the rs11191582 allele G of the NT5C2 gene were associated with the risk of AH. These variants can alter binding affinity of the Hoxa9, Irf, RORalpha1 and HMG-IY transcription factors, as well as the expression levels of the ALDH2, CARD8, NT5C2, ARL3, and SFXN2 genes in blood cells/vessels/heart, respectively. The risk of developing a comorbid phenotype of AD and AH is associated with the A allele of rs7038716 and the T allele of rs7025144 of the TLR4/AL160272.2 genes, the A allele of rs1010461 of the ANG gene and the C allele of rs2022318 of the ABTB2/CAT genes. Variants rs7038716 and rs7025144 can change the expression levels of the TLR4 gene in blood cells, while rs1010461 and rs2022318 influence the expression levels of the ANG and RNASE4 genes as well as the CAT and ABTB2 genes in blood cells, lungs/vessels/heart.

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