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 Federation10.15825/1995-1191-2016-3-22-30vtio-668Research ArticleКлиническая трансплантологияClinical TransplantologyРИСК РАННЕЙ ДИСФУНКЦИИ ТРАНСПЛАНТАТА ПЕЧЕНИ АССОЦИИРОВАН С ГЕНОТИПОМ ГЕНА TLR-4 В ПОСЛЕДОВАТЕЛЬНОСТИ RS913930 И РЕАЛИЗУЕТСЯ ЧЕРЕЗ АКТИВАЦИЮ ЯДЕРНОГО БЕЛКА HMGB1, КЛЕТОК КУПФЕРА И IL-23THE RISK OF EARLY LIVER ALLOGRAFT DYSFUNCTION IS ASSOCIATED WITH THE TLR-4 GENE GENOTYPE IN THE RS913930 SEQUENCE AND IS IMPLEMENTED VIA HMGB1 NUCLEAR PROTEIN, KUPFFER CELLS AND IL-23 ACTIVATIONЩербаА. Е.ShcherbaA. E.

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aleina@tut.byКустановичА. М.KustanovichA. M.КирееваА. И.KireyevaA. I.ЕфимовД. Ю.EfimovD. Yu.КоротковС. В.KorotkovS. V.МиновА. Ф.MinovA. F.ЛебедьО. А.LebedzO. A.КориткоА. А.KoritkoA. A.ФедорукД. А.FedorukD. A.СантоцкийЕ. О.SantotskyE. O.ДзядзькоА. М.DzyadzkoA. M.РуммоО. О.RummoO. O.РНПЦ трансплантации органов и тканей, МинскБеларусьRepublican Scientifi c and Practical Center for Organ and Tissue Transplantation, MinskBelarusРНПЦ детской онкологии, гематологии и иммунологии, МинскБеларусьBelarusian Research Center for Pediatric Oncology, Hematology and Immunology, MinskBelarusИнститут генетики и цитологии НАН Республики Беларусь, МинскБеларусьInstitute of Genetics and Cytology, National Academy of Sciences of Belarus, MinskBelarusРНПЦ морфологии, МинскБеларусьRepublican Scientific and Practical Center of Morphology, MinskBelarus2016181120161832238Copyright © Щерба А.Е., Кустанович А.М., Киреева А.И., Ефимов Д.Ю., Коротков С.В., Минов А.Ф., Лебедь О.А., Коритко А.А., Федорук Д.А., Сантоцкий Е.О., Дзядзько А.М., Руммо О.О., 20162016Щерба А.Е., Кустанович А.М., Киреева А.И., Ефимов Д.Ю., Коротков С.В., Минов А.Ф., Лебедь О.А., Коритко А.А., Федорук Д.А., Сантоцкий Е.О., Дзядзько А.М., Руммо О.О.Shcherba A.E., Kustanovich A.M., Kireyeva A.I., Efimov D.Y., Korotkov S.V., Minov A.F., Lebedz O.A., Koritko A.A., Fedoruk D.A., Santotsky E.O., Dzyadzko A.M., Rummo O.O.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/668

Цель исследования. Оценить ассоциации генотипов клинически значимых последовательностей нуклеотидов rs11536865, rs913930 и rs5030717 гена TLR-4 с риском возникновения и выраженностью ранней дисфункции трансплантатов печени. Материалы и методы. Для достижения поставленной цели было организованно исследование «случай–контроль», включавшее 71 пациента. Критерии включения: трансплантация печени от умершего донора. Критерии исключения: трансплантация от родственного донора, редуцированный графт, возраст реципиента менее 18 лет. Результаты. В пределах rs5030717 были выявлены три генотипа: AA (81,6%) и два генотипа с минорной аллелью G – AG (12,6%) и GG (5,6%). В пределах rs913930 были выявлены 3 генотипа: TT (59,1%) и два генотипа с минорной аллелью С – TC (29,5%), CC (11,2%). Изучение rs11536865 не выявило полиморфизма (генотип – GG). Ранняя дисфункция трансплантата печени развилась у 19,7% пациентов, тяжелая ранняя дисфункция трансплантата – 11,2%, септические осложнения – 14%, острое клеточное отторжение – 23,9%. Генотип C/T гена TLR-4 в последовательности SNP rs913930 имеет сильную связь с развитием ранней дисфункции трансплантата (Отношение шансов 4,8:1; p = 0,047; 95% ДИ 1–23,4). Пациенты с генотипом донорской печени С/T имели достоверно большую пропорцию HMGB1 (%) положительных гепатоцитов в донорском биоптате, 21 (17–29)%, по сравнению с генотипами СС+TT, 16 (10–19)% (Mann–Whitney p = 0,01). Экспрессии CD68 в биоптате печени на этапе донорского забора достоверно выше у носителей гетерозигот по SNP rs913930 (генотип C/T) и SNP rs5030717 (генотип AG), (Mann–Whitney test, p = 0,03). Получена достоверная корреляция между экспрессией CD68 в биоптатах печени доноров и уровнем IL-23 в печеночных венах трансплантата через 1 час после реперфузии (ρ = 0,62; p = 0,04) и между экспрессией HMGB1 в биоптатах печени доноров и уровнем АСТ через 24 часа после реперфузии (r = 0,4; p = 0,02). Экспрессия HMGB1 в биоптатах печени доноров была больше у пациентов с РДТ, 21 (20; 29) кл/мм2 , по сравнению с пациента- ми без РДТ 16 (12; 18) (Mann–Whitney test, p = 0,0036). Заключение. Ранняя дисфункция трансплантата имеет генетические предпосылки, обусловленные полиморфизмом гена TLR-4 и реализующиеся через активацию HMGB1, клеток Купфера и IL-23. 

Aim. To evaluate the associations of genotypes of clinically relevant nucleotides rs11536865, rs913930 and rs5030717 of the TLR-4 gene with the risk of development and severity of early allograft dysfunction after liver transplantation. Materials and methods. A case-control study enrolling 71 patients was organized. Inclusion criteria: DBD liver transplantation. Exclusion criteria: living related liver transplantation, reduced graft transplantation, recipient’s age fewer than 18. Results. Within rs5030717 there were identifi ed three genotypes: AA (81.6%) and two genotypes with the minor G-allele: AG (12.6%) and GG (5.6%). Within rs913930 there identi- fi ed three genotypes: TT (59.1%) and two genotypes with the minor C-allele: C/T (29.5%) and CC (11.2%). The rs11536865 studying revealed no polymorphism (GG genotype). The early allograft liver dysfunction (EAD) developed in 19.7% of patients, the severe EAD in 11.2% of patients, septic complications in 14%, acute cellular rejection in 23.9% of cases. The C/T genotype of the TLR-4 gene in the SNP rs913930 sequence was closely associated with the EAD development (OR 4.8 to 1; p = 0.047; 95% CI 1–23.4). Рatients with the donor’s liver C/T genotype had a reliably higher proportion (%) of the HMGB1 positive hepatocytes in the donor’s bioptate, 21 (17–29%) vs the СС+TT genotypes, 16 (10–19%) (Mann–Whitney test, p = 0.01). The CD68 expression in the liver bioptate at the donor’s stage was reliably higher in the carriers of heterozygotes in the SNP rs913930 (C/T genotype) and in the SNP rs5030717 (AG genotype), (Mann–Whitney test, p = 0.03). Signifi cant positive correlation between the CD68 expression in the donor’s liver bioptates and the IL-23 level in the hepatic vein has been determined in an hour after the portal reperfusion (ρ = 0.62; p = 0.04) as well as between the HMGB1 expression in the donor’s liver bioptates and the АSТ level in 24 hours after the reperfusion (r = 0.4; p = 0.02). The HMGB1 staining in the donor’s liver bioptates was higher in the EAD patients, 21 (20; 29) cells/mm2 in comparison with the patients without EAD, 16 (12; 18) (Mann–Whitney test, p = 0.0036). Conclusion. The early allograft liver dysfunction is associated with the genetic predisposition caused by the TLR-4 gene polymorphism and is implemented via the HMGB1, Kupffer cells and IL-23 activation. 

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