vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-26-53vavilov-5118Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSРедкие варианты в генах транспортеров холестерина у пациентов с нарушениями липидного обменаRare variants in cholesterol transporter genes in patients with lipid metabolism disordersИзюмченкоА. Д.IzyumchenkoA. D.

Санкт-­Петербург, Гатчина, Ленинградская область

St. Petersburg, Gatchina, Leningrad region

artemiz98@yandex.ruГрунинаМ. Н.GruninaM. N.

Санкт-­Петербург, Гатчина, Ленинградская область

St. Petersburg, Gatchina, Leningrad region

ДрачеваК. В.DrachevaK. V.

Санкт-­Петербург

St. Petersburg

ЧумаковаЮ. А.ChumakovaO. A.

Санкт-­Петербург

St. Petersburg

ТанаянцК. О.TanayantsK. O.

Гатчина, Ленинградская область

Gatchina, Leningrad region

ЛегостаеваК. В.LegostaevaK. V.

Санкт-­Петербург

St. Petersburg

КуликовА. Н.KulikovA. N.

Санкт-­Петербург

St. Petersburg

БерковичО. А.BerkovichO. A.

Санкт-­Петербург

St. Petersburg

БарановаЕ. И.BaranovaE. I.

Санкт-­Петербург

St. Petersburg

ПчелинаС. Н.PchelinaS. N.

Санкт-­Петербург, Гатчина, Ленинградская область

St. Petersburg, Gatchina, Leningrad region

МирошниковаВ. В.MiroshnikovaV. V.

Санкт-­Петербург, Гатчина, Ленинградская область

St. Petersburg, Gatchina, Leningrad region

Первый Санкт­-Петербургский государственный медицинский университет им. академика И.П. Павлова; Петербургский институт ядерной физики им. Б.П. Константинова Национального исследовательского центра «Курчатовский институт»РоссияPavlov First St. Petersburg State Medical University; Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre “Kurchatov Institute”, Gatchina, Leningrad regionRussian FederationПервый Санкт­-Петербургский государственный медицинский университет им. академика И.П. ПавловаРоссияPavlov First St. Petersburg State Medical UniversityRussian FederationПетербургский институт ядерной физики им. Б.П. Константинова Национального исследовательского центра «Курчатовский институт»РоссияPetersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre “Kurchatov Institute”, Gatchina, Leningrad regionRussian Federation202626052026303490501Copyright © Изюмченко А.Д., Грунина М.Н., Драчева К.В., Чумакова Ю.А., Танаянц К.О., Легостаева К.В., Куликов А.Н., Беркович О.А., Баранова Е.И., Пчелина С.Н., Мирошникова В.В., 20262026Изюмченко А.Д., Грунина М.Н., Драчева К.В., Чумакова Ю.А., Танаянц К.О., Легостаева К.В., Куликов А.Н., Беркович О.А., Баранова Е.И., Пчелина С.Н., Мирошникова В.В.Izyumchenko A.D., Grunina M.N., Dracheva K.V., Chumakova O.A., Tanayants K.O., Legostaeva K.V., Kulikov A.N., Berkovich O.A., Baranova E.I., Pchelina S.N., Miroshnikova V.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/5118

Сердечно­сосудистые заболевания являются основной причиной смерти в России и мире. Один из предрасполагающих к развитию сердечно­сосудистых заболеваний факторов – нарушения липидного обмена (дислипидемии), способствующие прогрессированию атеросклероза. На настоящий момент известны гены, ассоциированные с развитием моногенных форм нарушений липидного обмена, характеризующихся выраженным изменением уровня липидов. Однако выявление лиц с повышенным генетическим риском развития дислипидемии остается нерешенной задачей, что связано с полигенной природой большинства случаев. Целью настоящей работы было изучить спектр редких вариантов в генах транспортеров холестерина ABCA1, ABCG1, ABCG5, ABCG8 и NPC1L1, которые встречаются у пациентов с нарушениями липидного обмена в популяции Северо­-западного региона России. Проведен поиск редких вариантов (частота gnomAD менее 1 %) в генах ABCA1, ABCG1, ABCG5, ABCG8 и NPC1L1 с использованием данных таргетного секвенирования для 169 пациентов с нарушениями липидного обмена. Выявлено 14 вариантов в гене ABCA1 (17 пациентов), 4 варианта в гене ABCG1 (5 пациентов), 11 вариантов в гене ABCG5 (18 пациентов) и 7 вариантов в гене ABCG8 (11 пациентов). Частота некоторых из них, согласно базе данных RUSeq, была выше, чем в общемировой популяции. 19 пациентов (11 %) были носителями гаплотипа p.(Val177Ile)/p.(His221Tyr)/p.(Ala271Phe) гена NPC1L1, который предполо­жительно может быть специфичен для российской популяции, т. е. эти варианты являются не редкими, а полиморфными и встречаются чаще у пациентов с нарушениями липидного обмена. Для варианта p.(Val177Ile) гена NPC1L1 был проведен анализ его вклада в развитие атеросклероза с использованием дополнительных выборок (группа пациентов с атеросклерозом, контрольная группа), который не выявил достоверных различий в частотах генотипов. Таким образом, в настоящее время данных в пользу влияния гаплотипа p.(Val177Ile)/ p.(His221Tyr)/p.(Ala271Phe) гена NPC1L1 на развитие дислипидемии и атеросклероза недостаточно. Проведенное исследование заставляет обратить внимание на популяционную специфичность ряда вариантов в генах транспортеров холестерина, в частности в гене NPC1L1, для Северо­-западного региона России. Полученные данные в дальнейшем могут быть учтены в разработке шкал генетического риска развития дислипидемий.

Cardiovascular diseases are the leading cause of death both in Russia and in the world. One of the factors predisposing to the development of cardiovascular diseases is lipid metabolism disorders (dyslipidemias), which contribute to the progression of atherosclerosis. Currently, there are known genes associated with the development of monogenic forms of lipid metabolism disorders characterized by marked changes in lipid levels. However, identifying individuals with an increased genetic risk of dyslipidemia remains an unsolved problem, due to the polygenic nature of most cases. The aim of this work was to study the spectrum of rare variants in the cholesterol transporter genes ABCA1, ABCG1, ABCG5, ABCG8 and NPC1L1 that occur in patients with lipid metabolism disorders in the population of the Northwestern region of Russia. The search for rare variants (gnomAD frequency less than 1 %) in the ABCA1, ABCG1, ABCG5, ABCG8 and NPC1L1 genes was performed using targeted sequencing data for 169 patients with lipid metabolism disorders. 14 variants were identified in the ABCA1 gene (17 patients); 4 variants, in the ABCG1 gene (5 patients); 11 variants, in the ABCG5 gene (18 patients); and 7 variants, in the ABCG8 gene (11 patients). The frequency of some of them, according to the RUSeq database, is higher than in the global population. 19 patients (11 %) were carriers of the p.(Val177Ile)/p.(His221Tyr)/p.(Ala271Phe) haplotype in the NPC1L1 gene, which may be specific to the Russian population, meaning that these variants are not rare, but polymorphic, and occur more frequently in patients with impaired lipid metabolism. Influence of the p.(Val177Ile) variant of the NPC1L1 gene on the development of atherosclerosis was assessed using additional sample sets (a group of patients with atherosclerosis, a control group), but no significant differences in genotype frequencies were revealed. Thus, at present, there are insufficient data to support the role of the p.(Val177Ile)/p.(His221Tyr)/p.(Ala271Phe) haplotype of the NPC1L1 gene in the development of dyslipidemia and atherosclerosis. The study draws attention to the population specificity of a number of variants in cholesterol transporter genes, in particular in the NPC1L1 gene, for the Northwestern region of Russia. The data can be further used for design and calculation of genetic risk scores for dyslipidemia.

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