vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJGB-22-10vavilov-3257Research ArticleБИОТЕХНОЛОГИЯ В ПОСТГЕНОМНУЮ ЭРУMEDICAL GENETICSФункциональный подход к изучению генетики сердечно-сосудистых заболеваний: post-GWAS исследованиеThe functional insight into the genetics of cardiovascular disease: results from the post-GWAS studyБрызгаловЛ. О.BryzgalovL. O.

Новосибирск

Novosibirsk

КорболинаЕ. Е.KorbolinaE. E.

Новосибирск

Novosibirsk

lungry@bionet.nsc.ruДамаровИ. С.DamarovI. S.

Новосибирск

Novosibirsk

МеркуловаТ. И.MerkulovaT. I.

Новосибирск

Novosibirsk

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State UniversityRussian Federation2022010320222616573Copyright © Брызгалов Л.О., Корболина Е.Е., Дамаров И.С., Меркулова Т.И., 20222022Брызгалов Л.О., Корболина Е.Е., Дамаров И.С., Меркулова Т.И.Bryzgalov L.O., Korbolina E.E., Damarov I.S., Merkulova T.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3257

Сердечно-сосудистые заболевания (ССЗ) занимают одно из ведущих мест по уровню смертности в развитых странах. На сегодняшний день значительное число геномных локусов продемонстрировали ассоциации с ССЗ, в основном в полногеномных исследованиях (GWAS), но лишь в немногих случаях установлены молекулярно-генетические механизмы, лежащие в основе ассоциации. Таким образом, задача определения функционально значимых для предрасположенности к ССЗ генетических вариантов остается актуальной. Ранее мы разработали биоинформатический подход, позволяющий эффективно идентифицировать регуляторные SNP (rSNP) – функциональные однонуклеотидные полиморфизмы, влияющие на экспрессию генов, путем анализа комплекса полногеномных данных. В данной работе с использованием данных проекта «1000 геномов» найден 773471 кодирующий SNP, являющийся косегрегирующим маркером для 1361 идентифицированного нами rSNP. Проанализировано расположение этих маркеров в пределах геномного окна размером 10 Кб вокруг маркеров GWAS, ассоциированных с риском развития ССЗ или потенциально связанными с этим риском фенотипическими признаками. Влияние rSNP на сайты связывания транскрипционных факторов исследовано с помощью моделей DeFine. Анализ межбелковых взаимодействий и обогащения биологических путей для соответствующих генов-мишеней проведен с использованием баз STRING и DAVID. Найдено восемнадцать rSNP, функционально связанных с риском развития ССЗ. В клеточной линии K562 выявлено значительное влияние этих rSNP на сайты связывания тринадцати транскрипционных факторов, в том числе участвующих в процессах кроветворения, функционирования макрофагов, воспаления и вазоконстрикции. Для двадцати одного соответствующего генамишени, а также пяти функционально взаимодействующих с ними генов показано обогащение биологическими категориями сплайсосомы и эндоцитоза (KEGG), комплекса сортировки эндосом и процессов сплайсинга (REACTOME), а также некоторыми терминами генетических онтологий, в том числе сплайсинга и процессинга мРНК. В целом полученные результаты расширяют имеющиеся представления о роли rSNP и связанных с ними изменений экспрессии генов в развитии ССЗ и подчеркивают важность точной регуляции процессов сплайсинга мРНК и альтернативного сплайсинга для формирования определенного фенотипа.

Cardiovascular diseases (CVDs), the leading cause of death worldwide, generally refer to a range of pathological conditions with the involvement of the heart and the blood vessels. A sizable fraction of the susceptibility loci is known, but the underlying mechanisms have been established only for a small proportion. Therefore, there is an increasing need to explore the functional relevance of trait-associated variants and, moreover, to search for novel risk genetic variation. We have reported the bioinformatic approach allowing effective identification of functional non-coding variants by integrated analysis of genome-wide data. Here, the analysis of 1361 previously identified regulatory SNPs (rSNPs) was performed to provide new insights into cardiovascular risk. We found 773,471 coding co-segregating markers for input rSNPs using the 1000 Genomes Project. The intersection of GWAS-derived SNPs with a relevance to cardiovascular traits with these markers was analyzed within a window of 10 Kbp. The effects on the transcription factor (TF) binding sites were explored by DeFine models. Functional pathway enrichment and protein– protein interaction (PPI) network analyses were performed on the targets and the extended genes by STRING and DAVID. Eighteen rSNPs were functionally linked to cardiovascular risk. A significant impact on binding sites of thirteen TFs including those involved in blood cells formation, hematopoiesis, macrophage function, inflammation, and vasoconstriction was found in K562 cells. 21 rSNP gene targets and 5 partners predicted by PPI were enriched for spliceosome and endocytosis KEGG pathways, endosome sorting complex and mRNA splicing REACTOME pathways. Related Gene Ontology terms included mRNA splicing and processing, endosome transport and protein catabolic processes. Together, the findings provide further insight into the biological basis of CVDs and highlight the importance of the precise regulation of splicing and alternative splicing.

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