vtioВестник трансплантологии и искусственных органовRussian Journal of Transplantology and Artificial Organs1995-1191Academician V.I.Shumakov National Medical Research Center of Transplantology and Artificial Organs", Ministry of Health of the Russian Federation10.15825/1995-1191-2024-3-168-175vtio-1840Research ArticleТрансплантомикаTransplantomicsУ детей с билиарной атрезией высокая встречаемость редких гаплотипов гена профиброгенного цитокина TGFB1High incidence of rare TGFB1 haplotypes in children with biliary atresiaКурабековаР. М.KurabekovaR. M.

Курабекова Ривада Мусабековна

123182, Москва, ул. Щукинская, д. 1

Rivada М. Kurabekova

1, Shchukinskaya str., Moscow, 123182

kourabr@yandex.ruГичкунО. Е.GichkunO. E.

Москва

Moscow

ЦирульниковаО. М.TsirulnikovaO. M.

Москва

Moscow

ПашковаИ. Е.PashkovaI. E.

Москва

Moscow

ВакуроваЕ. А.VakurovaE. A.

Москва

Moscow

ШевченкоО. П.ShevchenkoO. P.

Москва

Moscow

ГотьеС. В.GautierS. V.

Москва

Moscow

ФГБУ «Национальный медицинский исследовательский центр трансплантологии и искусственных органов имени академика В.И. Шумакова» Минздрава РоссииРоссияShumakov National Medical Research Center of Transplantology and Artificial OrgansRussian FederationФГБУ «Национальный медицинский исследовательский центр трансплантологии и искусственных органов имени академика В.И. Шумакова» Минздрава России; ФГАОУ ВО Первый Московский государственный медицинский университет имени И.М. Сеченова Минздрава России (Сеченовский университет)РоссияShumakov National Medical Research Center of Transplantology and Artificial Organs; Sechenov UniversityRussian FederationФГАОУ ВО Первый Московский государственный медицинский университет имени И.М. Сеченова Минздрава России (Сеченовский университет)РоссияSechenov UniversityRussian Federation202419072024263168175Copyright © Курабекова Р.М., Гичкун О.Е., Цирульникова О.М., Пашкова И.Е., Вакурова Е.А., Шевченко О.П., Готье С.В., 20242024Курабекова Р.М., Гичкун О.Е., Цирульникова О.М., Пашкова И.Е., Вакурова Е.А., Шевченко О.П., Готье С.В.Kurabekova R.M., Gichkun O.E., Tsirulnikova O.M., Pashkova I.E., Vakurova E.A., Shevchenko O.P., Gautier S.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.transpl.ru/vtio/article/view/1840Цель

Цель: оценить встречаемость однонуклеотидных полиморфизмов (ОНП) гена TGFB1 – rs1800469, rs1800470, rs1800471 и их гаплотипов у детей с атрезией желчевыводящих путей (АЖВП).

Материалы и методы

Материалы и методы. Исследовано 106 детей – реципиентов печени в возрасте от 4 до 150 месяцев (медиана – 8), из них 44 мальчика, и 199 здоровых лиц в возрасте 32,7 ± 9,6 года, из них 79 мужчин. Показанием к трансплантации печени детям была АЖВП. Геномную ДНК выделяли из периферической крови с помощью коммерческого набора QIAamp DNA Blood Mini Kit на автоматическом анализаторе QIAcube. ОНП rs1800469, rs1800470, rs1800471 гена TGFB1 определяли методом полимеразной цепной реакции в режиме реального времени с помощью зондов TaqMan на амплификаторе CFX96.

Результаты

Результаты. У детей с АЖВП встречаемость изученных ОНП гена TGFB1 составила: для rs1800469 – 38% гомозигот GG, 50% гетерозигот АG и 12% гомозигот АА; rs1800470 – 39% АА, 44% АG, 17% GG; rs1800471 – 88% CC, 12% GC, 0% GG. Распределение всех 3 ОНП соответствовало закону Харди–Вайнберга. Для rs1800469 и rs1800470 частоты генотипов и аллелей у детей с АЖВП не отличались от такового у здоровых лиц, тогда как для rs1800471 гетерозиготный генотип GC встречался в 3 раза чаще у детей с АЖВП, чем у здоровых. Анализ гаплотипов показал наличие 6 основных сочетаний; 2 наиболее частых суммарно имели около 66% пациентов и 91% здоровых лиц, каждая из частот практически не различалась в группах сравнения. Достоверные различия выявлены в частоте 3 более редких гаплотипов – A-A-C, G-G-C и G-A-G в положении rs1800469, rs1800470, rs1800471, которые у пациентов с АЖВП наблюдались чаще, соответственно в 3,10 (ДИ 1,59–6,04; р = 0,001), 3,10 (ДИ 1,55–6,17; р = 0,0015) и 17,02 (ДИ 1,94–149,30; р = 0,011) раза, чем у здоровых лиц.

Заключение

Заключение. У детей с АЖВП встречаемость гетерозиготного варианта CG rs1800471, а также распределение трех редких гаплотипов A-A-C, G-G-C и G-A-G ОНП rs1800469, rs1800470 и rs1800471 гена TGFB1 значительно отличается от такового у здоровых лиц. Возможно, что носительство редких генотипов и гаплотипов гена TGFB1 может предрасполагать к развитию билиарной атрезии у детей.

Objective

Objective: to evaluate the occurrence of single nucleotide polymorphisms (SNPs) in transforming growth factor beta 1 (TGFB1) – rs1800469, rs1800470, rs1800471 – and their haplotypes in children with biliary atresia (BA).

Materials and methods

Materials and methods. We studied 106 pediatric liver recipients aged 4 to 150 (median 8) months, of whom 44 were boys, and 199 healthy individuals aged 32.7 ± 9.6 years, of whom 79 were boys. The indication for pediatric liver transplantation was BA. Genomic DNA was isolated from peripheral blood using a commercial QIAamp DNA Blood Mini Kit on a QIAcube automated analyzer. SNPs rs1800469, rs1800470, and rs1800471 in the TGFB1 gene were determined by real-time polymerase chain reaction using TaqMan probes on a CFX96 amplifier.

Results

Results. In children with BA, the occurrence of the investigated SNPs in TGFB1 was as follows: rs1800469 – 38% GG homozygotes, 50% AG heterozygotes and 12% AA homozygotes; rs1800470 – 39% AA, 44% AG, 17% GG; rs1800471 – 88% CC, 12% GC, 0% GG. The distributions of all the three SNPs followed the Hardy–Weinberg principle. For rs1800469 and rs1800470, the genotype and allele frequencies in children with BA did not differ from those in healthy individuals, whereas for rs1800471, the heterozygous GC genotype was three-fold more frequent in children with BA than in healthy individuals. Haplotype analysis showed the presence of 6 major combinations: 2 most frequent were present in a total of about 66% of patients and 91% of healthy individuals, each of the frequencies practically did not differ between the comparison groups. Significant differences were found in the frequency of 3 rarer haplotypes, A-A-C, G-G-C and G-A-G at position rs1800469, rs1800470, rs1800471, which were observed more frequently in patients with BA by 3.10 (CI 1.59 to 6.04) (p = 0.001), 3.10 (CI 1.55 to 6.17) (p = 0.0015), and 17.02 (CI 1.94 to 149.30) (p = 0.011) times, respectively, than in healthy individuals.

Conclusion

Conclusion. In children with BA, the occurrence of CG heterozygotes in rs1800471 and the distribution of three rare haplotypes A-A-C, G-G-C and G-A-G of the rs1800469, rs1800470 and rs1800471 SNPs in the TGFB1 gene significantly differs from that in healthy individuals. It is possible that carriage of rare genotypes and haplotypes of TGFB1 may predispose to BA in children.

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