sibmedСибирский научный медицинский журналСибирский научный медицинский журнал2410-25122410-2520ИЦиГ СО РАН10.18699/SSMJ20230410sibmed-1165Research ArticleМЕДИКО-БИОЛОГИЧЕСКИЕ НАУКИBIOMEDICINEАнализ полиморфизма генов рецепторов врожденного иммунитета у пациентов с коронарным атеросклерозом и в популяционной выборке г. НовосибирскаAnalysis of polymorphism of innate immunity receptor genes in patients with coronary atherosclerosis and in a population sample from Novosibirskhttps://orcid.org/0000-0002-0897-5473МихайловаС. В.MikhailovaS. V.

Михайлова Светлана Владимировна, к.б.н.

630090, г. Новосибирск, просп. Академика Лаврентьева, 10

Svetlana V. Mikhailova, candidate of biological sciences

630090, Novosibirsk, Akademika Lavrentieva ave., 10

mikhail@bionet.nsc.ruhttps://orcid.org/0000-0002-0403-545XИванощукД. Е.IvanoshchukD. E.

Иванощук Динара Евгеньевна

630090, г. Новосибирск, просп. Академика Лаврентьева, 10

Dinara E. Ivanoshchuk

630090, Novosibirsk, Akademika Lavrentieva ave., 10

dinara2084@mail.ruhttps://orcid.org/0000-0001-9371-2178ОрловП. С.OrlovP. S.

Орлов Павел Сергеевич

630090, г. Новосибирск, просп. Академика Лаврентьева, 10

Pavel S. Orlov

630090, Novosibirsk, Akademika Lavrentieva ave., 10

ops86@bionet.nsc.ruhttps://orcid.org/0000-0003-1913-5231ЛатынцеваЛ. Д.LatyntsevaL. D.

Латынцева Людмила Дмитриевна, к.м.н.

630089, г. Новосибирск, ул. Бориса Богаткова, 175/1

Lyudmila D. Latyntseva, candidate of medical sciences

630089, Novosibirsk, Borisa Bogatkova st., 175/1

latyntsevald@bionet.nsc.ruhttps://orcid.org/0000-0003-2268-4186КаштановаЕ. В.KashtanovaE. V.

Каштанова Елена Владимировна, д.б.н.

630089, г. Новосибирск, ул. Бориса Богаткова, 175/1

Elena V. Kashtanova, doctor of biological sciences

630089, Novosibirsk, Borisa Bogatkova st., 175/1

elekastanova@yandex.ruhttps://orcid.org/0000-0002-3538-0280ПолонскаяЯ. В.PolonskayaYa. V.

Полонская Яна Владимировна, д.б.н.

630089, г. Новосибирск, ул. Бориса Богаткова, 175/1

Yana V. Polonskaya, doctor of biological sciences

630089, Novosibirsk, Borisa Bogatkova st., 175/1

yana-polonskaya@yandex.ruhttps://orcid.org/0000-0002-4936-8362РагиноЮ. И.RaginoYu. I.

Рагино Юлия Игоревна, д.м.н., проф., чл.-корр. РАН

630089, г. Новосибирск, ул. Бориса Богаткова, 175/1

Yuliya I. Ragino, doctor of medical sciences, professor, corresponding member of RAS

630089, Novosibirsk, Borisa Bogatkova st., 175/1

raginoyi@bionet.nsc.ruhttps://orcid.org/0000-0001-6108-1025ШахтшнейдерЕ. В.ShakhtshneiderE. V.

Шахтшнейдер Елена Владимировна, к.м.н

630090, г. Новосибирск, просп. Академика Лаврентьева, 10

630089, г. Новосибирск, ул. Бориса Богаткова, 175/1

Elena V. Shakhtshneider, candidate of medical sciences

630090, Novosibirsk, Akademika Lavrentieva ave., 10

630089, Novosibirsk, Borisa Bogatkova st., 175/1

2117409@mail.ruФИЦ Институт цитологии и генетики СО РАНРоссияFederal Research Center Institute of Cytology and Genetics SB RASRussian FederationНИИ терапии и профилактической медицины – филиал ФИЦ Институт цитологии и генетики СО РАНРоссияResearch Institute of Internal and Preventive Medicine – Branch of the Federal Research Center Institute of Cytology and Genetics SB RASRussian FederationФИЦ Институт цитологии и генетики СО РАН; НИИ терапии и профилактической медицины – филиал ФИЦ Институт цитологии и генетики СО РАНРоссияFederal Research Center Institute of Cytology and Genetics SB RAS; Research Institute of Internal and Preventive Medicine – Branch of the Federal Research Center Institute of Cytology and Genetics SB RASRussian Federation20233008202343497109Copyright © Михайлова С.В., Иванощук Д.Е., Орлов П.С., Латынцева Л.Д., Каштанова Е.В., Полонская Я.В., Рагино Ю.И., Шахтшнейдер Е.В., 20232023Михайлова С.В., Иванощук Д.Е., Орлов П.С., Латынцева Л.Д., Каштанова Е.В., Полонская Я.В., Рагино Ю.И., Шахтшнейдер Е.В.Mikhailova S.V., Ivanoshchuk D.E., Orlov P.S., Latyntseva L.D., Kashtanova E.V., Polonskaya Y.V., Ragino Y.I., Shakhtshneider E.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://sibmed.elpub.ru/jour/article/view/1165

Понимание молекулярных механизмов атеросклеротического повреждения сосудов необходимо как для оценки рисков сердечно-сосудистых заболеваний, так и для поиска подходов к их терапии. Задача остается актуальной несмотря на большое число проведенных исследований, так как существуют различия в факторах генетической предрасположенности к атеросклерозу и его осложнениям между представителями различных этнотерриториальных групп. Целью данного исследования был поиск генетических вариантов паттерн-распознающих рецепторов, ассоциированных с нарушениями липидного обмена, которые могут приводить к развитию коронарного атеросклероза.Материал и методы. Выполнен анализ последовательностей экзонов и прилежащих сайтов сплайсинга генов паттерн-распознающих рецепторов у пациентов с коронарным атеросклерозом (30 мужчин), а затем генотипирование популяционной выборки г. Новосибирска (n = 1441) методом ПЦР в реальном времени по отобранному rs113706342 гена TLR1 и анализ ассоциации его носительства с показателями липидного обмена.Результаты и их обсуждение. Частота минорного аллеля rs113706342 С гена TLR1 в выборке жителей г. Новосибирска составила 0,0114 ± 0,0062, носительство этого варианта было ассоциировано с повышенным уровнем холестерина липопротеинов низкой плотности как у женщин, так и у мужчин (p = 0,009 и p = 0,019 соответственно). Носительницы минорного аллеля C rs113706342 имели также статистически значимое увеличение содержания общего холестерина сыворотки (p = 0,013) по сравнению с гомозиготами ТТ. Для проверки роли этого варианта в развитии коронарного атеросклероза необходимо генотипирование расширенной выборки пациентов. У одного из обследованных с коронарным атеросклерозом найден ранее не описанный однонуклеотидный вариант chr16:3614637 G/C, приводящий к замене Leu101Val в гене NLRC3, для оценки его функциональной значимости необходим сегрегационный анализ.Заключение. Показана ассоциация rs113706342 С гена TLR1 с нарушением липидного обмена в российской популяции.

Understanding the molecular mechanisms of atherosclerotic vascular lesions formation is necessary both for assessing the risks of cardiovascular diseases and for finding approaches to their therapy. The task remains relevant, despite the large number of studies carried out, because there are differences in the factors of genetic predisposition to atherosclerosis and its complications between different ethno-territorial groups. The aim of this study was to search for genetic variants of pattern recognition receptors associated with lipid metabolism disorders that can lead to the development of coronary atherosclerosis (CA).Material and methods. Analysis of exons and adjacent splicing sites of pattern recognition receptors genes in patients with CA (30 men), and then genotyping of a population sample from Novosibirsk (n = 1441) by real-time PCR for selected rs113706342 of the TLR1 gene and analysis of associations of its carriage with lipid metabolism were performed.Results and discussion. The frequency of the minor allele rs113706342 C of the TLR1 gene in the sample of residents of Novosibirsk was 0.0114 ± 0.0062, the carriage of this variant was associated with an increased level of low-density lipoprotein cholesterol in both women and men (p = 0.009 and p = 0.019, respectively). Women carriers of the minor allele C for rs113706342 also had a statistically significant increase in total serum cholesterol (p = 0.013) compared with TT homozygotes. To test the role of this variant in the development of CA, genotyping of an extended sample of patients is required. In one of the patients with CA, a previously undescribed single nucleotide variant chr16:3614637 G/C was found, leading to the Leu101Val substitution in the NLRC3 gene; segregation analysis is required to assess its functional significance.Conclusions. The association of rs113706342 C of the TLR1 gene with lipid metabolism disorders in the Russian population is shown.

коронарный атеросклерозишемическая болезнь сердцасеквенирование нового поколенияпаттерн-распознающие рецепторыоднонуклеотидный вариантген TLR1ген NLRC3rs113706342.coronary atherosclerosisischemic heart diseasenext generation sequencingpattern recognition receptorssingle nucleotide variantTLR1 geneNLRC3 geners113706342Секвенирование ДНК выполняли с использованием оборудования ЦКП и «Протеомный анализ», поддержанного финансированием Минобрнауки России (соглашение № 075-15-2021-691).This study was supported by Russian State Budjet program FWNR-2022-0021.ReferencesBaker R.G., Hayden M.S., Ghosh S. NF-κB, inflammation, and metabolic disease. Cell. Metab. 2011;13(1):11–22. doi: 10.1016/j.cmet.2010.12.008Baker R.G., Hayden M.S., Ghosh S. NF-κB, inflammation, and metabolic disease. Cell. Metab. 2011;13(1):11–22. doi: 10.1016/j.cmet.2010.12.008Tibaut M., Caprnda M., Kubatka P., Sinkovič A., Valentova V., Filipova S., Gazdikova K., Gaspar L., Mozos I., Egom E.E., … Petrovic D. Markers of atherosclerosis: Part 2 – Genetic and imaging markers. Heart. Lung. Circ. 2019;28(5):678–689. doi: 10.1016/j.hlc.2018.09.006Tibaut M., Caprnda M., Kubatka P., Sinkovič A., Valentova V., Filipova S., Gazdikova K., Gaspar L., Mozos I., Egom E.E., … Petrovic D. Markers of atherosclerosis: Part 2 – Genetic and imaging markers. Heart. Lung. Circ. 2019;28(5):678–689. doi: 10.1016/j.hlc.2018.09.006Forgo B., Medda E., Hernyes A., Szalontai L., Tarnoki D.L., Tarnoki A.D. Carotid artery atherosclerosis: a review on heritability and genetics. Twin Res. Hum. Genet. 2018;21(5):333–346. doi: 10.1017/thg.2018.45Forgo B., Medda E., Hernyes A., Szalontai L., Tarnoki D.L., Tarnoki A.D. Carotid artery atherosclerosis: a review on heritability and genetics. Twin Res. Hum. Genet. 2018;21(5):333–346. doi: 10.1017/thg.2018.45Posadas-Sánchez R., Vargas-Alarcón G. Innate immunity in coronary disease. The role of Interleukin-12 cytokine family in atherosclerosis. Rev. Invest. Clin. 2018;70(1):5–17. doi: 10.24875/RIC.17002335Posadas-Sánchez R., Vargas-Alarcón G. Innate immunity in coronary disease. The role of Interleukin-12 cytokine family in atherosclerosis. Rev. Invest. Clin. 2018;70(1):5–17. doi: 10.24875/RIC.17002335Chyu K.Y., Dimayuga P.C., Shah P.K. Immunogenetics of atherosclerosis-link between lipids, immunity, and genes. Curr. Atheroscler. Rep. 2020;22(10):53. doi: 10.1007/s11883-020-00874-4Chyu K.Y., Dimayuga P.C., Shah P.K. Immunogenetics of atherosclerosis-link between lipids, immunity, and genes. Curr. Atheroscler. Rep. 2020;22(10):53. doi: 10.1007/s11883-020-00874-4Jaén R.I., Val-Blasco A., Prieto P., Gil-Fernández M., Smani T., López-Sendón J.L., Delgado C., Boscá L., Fernández-Velasco M. Innate immune receptors, key actors in cardiovascular diseases. JACC Basic Transl. Sci. 2020;5(7):735–749. doi: 10.1016/j.jacbts.2020.03.015Jaén R.I., Val-Blasco A., Prieto P., Gil-Fernández M., Smani T., López-Sendón J.L., Delgado C., Boscá L., Fernández-Velasco M. Innate immune receptors, key actors in cardiovascular diseases. JACC Basic Transl. Sci. 2020;5(7):735–749. doi: 10.1016/j.jacbts.2020.03.015Fiordelisi A., Iaccarino G., Morisco C., Coscioni E., Sorriento D. NFkappaB is a key player in the crosstalk between inflammation and cardiovascular diseases. Int. J. Mol. Sci. 2019;20(7):1599. doi: 10.3390/ijms20071599Fiordelisi A., Iaccarino G., Morisco C., Coscioni E., Sorriento D. NFkappaB is a key player in the crosstalk between inflammation and cardiovascular diseases. Int. J. Mol. Sci. 2019;20(7):1599. doi: 10.3390/ijms20071599Cheng W., Cui C., Liu G., Ye C., Shao F., Bagchi A.K., Mehta J.L., Wang X. NF-κB, a potential therapeutic target in cardiovascular diseases. Cardiovasc. Drugs Ther. 2022. doi: 10.1007/s10557-022-07362-8Cheng W., Cui C., Liu G., Ye C., Shao F., Bagchi A.K., Mehta J.L., Wang X. NF-κB, a potential therapeutic target in cardiovascular diseases. Cardiovasc. Drugs Ther. 2022. doi: 10.1007/s10557-022-07362-8Hernandez R., Zhou C. Recent advances in understanding the role of IKKβ in cardiometabolic diseases. Front. Cardiovasc. Med. 2021;8:752337. doi: 10.3389/fcvm.2021.752337Hernandez R., Zhou C. Recent advances in understanding the role of IKKβ in cardiometabolic diseases. Front. Cardiovasc. Med. 2021;8:752337. doi: 10.3389/fcvm.2021.752337Mikhailova S.V., Ivanoshchuk D.E. Innate-immunity genes in obesity. J. Pers. Med. 2021;11(11):1201. doi: 10.3390/jpm11111201Mikhailova S.V., Ivanoshchuk D.E. Innate-immunity genes in obesity. J. Pers. Med. 2021;11(11):1201. doi: 10.3390/jpm11111201Hotamisligil G.S. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017;542(7640):177–185. doi: 10.1038/nature21363Hotamisligil G.S. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017;542(7640):177–185. doi: 10.1038/nature21363Kawai T., Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 2010;11(5):373–384. doi: 10.1038/ni.1863Kawai T., Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 2010;11(5):373–384. doi: 10.1038/ni.1863Fore F., Budipranama M., Destiawan R.A. TLR10 and its role in immunity. Handb. Exp. Pharmacol. 2022;276:161–174. doi: 10.1007/164_2021_541Fore F., Budipranama M., Destiawan R.A. TLR10 and its role in immunity. Handb. Exp. Pharmacol. 2022;276:161–174. doi: 10.1007/164_2021_541Coutermarsh-Ott S., Eden K., Allen I.C. Beyond the inflammasome: Regulatory NOD-like receptor modulation of the host immune response following virus exposure. J. Gen. Virol. 2016;97:825–838. doi: 10.1099/jgv.0.000401Coutermarsh-Ott S., Eden K., Allen I.C. Beyond the inflammasome: Regulatory NOD-like receptor modulation of the host immune response following virus exposure. J. Gen. Virol. 2016;97:825–838. doi: 10.1099/jgv.0.000401Barra N.G., Henriksbo B.D., Anhê F.F., Schertzer J.D. The NLRP3 inflammasome regulates adipose tissue metabolism. Biochem. J. 2020;477(6):1089–1107. doi: 10.1042/BCJ20190472Barra N.G., Henriksbo B.D., Anhê F.F., Schertzer J.D. The NLRP3 inflammasome regulates adipose tissue metabolism. Biochem. J. 2020;477(6):1089–1107. doi: 10.1042/BCJ20190472Lupfer C., Kanneganti T.D. Unsolved mysteries in NLR biology. Front. Immunol. 2013;4:285. doi: 10.3389/fimmu.2013.00285Lupfer C., Kanneganti T.D. Unsolved mysteries in NLR biology. Front. Immunol. 2013;4:285. doi: 10.3389/fimmu.2013.00285Takimoto M. Multidisciplinary roles of LRRFIP1/GCF2 in human biological systems and diseases. Cells. 2019;8:108. doi: 10.3390/cells8020108Takimoto M. Multidisciplinary roles of LRRFIP1/GCF2 in human biological systems and diseases. Cells. 2019;8:108. doi: 10.3390/cells8020108Plourde M., Vohl M.C., Bellis C., Carless M., Dyer T., Dolley G., Marette A., Després J.P., Bouchard C., Blangero J., Pérusse L. A variant in the LRRFIP1 gene is associated with adiposity and inflammation. Obesity (Silver Spring). 2013;21(1):185–192. doi: 10.1002/oby.20242Plourde M., Vohl M.C., Bellis C., Carless M., Dyer T., Dolley G., Marette A., Després J.P., Bouchard C., Blangero J., Pérusse L. A variant in the LRRFIP1 gene is associated with adiposity and inflammation. Obesity (Silver Spring). 2013;21(1):185–192. doi: 10.1002/oby.20242Kimura I., Ichimura A., Ohue-Kitano R., Igarashi M. Free fatty acid receptors in health and disease. Physiol. Rev. 2020;100(1):171–210. doi: 10.1152/physrev.00041.2018Kimura I., Ichimura A., Ohue-Kitano R., Igarashi M. Free fatty acid receptors in health and disease. Physiol. Rev. 2020;100(1):171–210. doi: 10.1152/physrev.00041.2018Ichimura A., Hirasawa A., Poulain-Godefroy O., Bonnefond A., Hara T., Yengo L., Kimura I., Leloire A., Liu N., Iida K., … Froguel P. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature. 2012;483(7389):350–354. doi: 10.1038/nature10798Ichimura A., Hirasawa A., Poulain-Godefroy O., Bonnefond A., Hara T., Yengo L., Kimura I., Leloire A., Liu N., Iida K., … Froguel P. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature. 2012;483(7389):350–354. doi: 10.1038/nature10798Wang Z., Manichukal A., Goff D.C. Jr., Mora S., Ordovas J.M., Pajewski N.M., Post W.S., Rotter J.I., Sale M.M., Santorico S.A., … Frazier-Wood A.C. Genetic associations with lipoprotein subfraction measures differ by ethnicity in the multi-ethnic study of atherosclerosis (MESA). Hum. Genet. 2017;136(6):715–726. doi: 10.1007/s00439-017-1782-yWang Z., Manichukal A., Goff D.C. Jr., Mora S., Ordovas J.M., Pajewski N.M., Post W.S., Rotter J.I., Sale M.M., Santorico S.A., … Frazier-Wood A.C. Genetic associations with lipoprotein subfraction measures differ by ethnicity in the multi-ethnic study of atherosclerosis (MESA). Hum. Genet. 2017;136(6):715–726. doi: 10.1007/s00439-017-1782-yPeasey A., Bobak M., Kubinova R., Malyutina S., Pajak A., Tamosiunas A., Pikhart H., Nicholson A., Marmot M. Determinants of cardiovascular disease and other non-communicable diseases in Central and Eastern Europe: rationale and design of the HAPIEE study. BMC Public Health. 2006;6:255. doi: 10.1186/1471-2458-6-255Peasey A., Bobak M., Kubinova R., Malyutina S., Pajak A., Tamosiunas A., Pikhart H., Nicholson A., Marmot M. Determinants of cardiovascular disease and other non-communicable diseases in Central and Eastern Europe: rationale and design of the HAPIEE study. BMC Public Health. 2006;6:255. doi: 10.1186/1471-2458-6-255Sambrook J., Russell D.W. Purification of nucleic acids by extraction with phenol:chloroform. CSH Protoc. 2006;2006(1):pdb.prot4455. doi: 10.1101/pdb.prot4455Sambrook J., Russell D.W. Purification of nucleic acids by extraction with phenol:chloroform. CSH Protoc. 2006;2006(1):pdb.prot4455. doi: 10.1101/pdb.prot4455Weyrich P., Staiger H., Stančáková A., Machicao F., Machann J., Schick F., Stefan N., Kuusisto J., Laakso M., Schäfer S., Fritsche A., Häring H.U. The D299G/T399I Toll-like receptor 4 variant associates with body and liver fat: results from the TULIP and METSIM Studies. PLoS One. 2010;5(11):e13980. doi: 10.1371/journal.pone.0013980Weyrich P., Staiger H., Stančáková A., Machicao F., Machann J., Schick F., Stefan N., Kuusisto J., Laakso M., Schäfer S., Fritsche A., Häring H.U. The D299G/T399I Toll-like receptor 4 variant associates with body and liver fat: results from the TULIP and METSIM Studies. PLoS One. 2010;5(11):e13980. doi: 10.1371/journal.pone.0013980Soydas T., Karaman O., Arkan H., Yenmis G., Ilhan M.M., Tombulturk K., Tasan E., Kanigur Sultuybek G. The correlation of increased CRP levels with NFKB1 and TLR2 polymorphisms in the case of morbid obesity. Scand. J. Immunol. 2016;84(5):278–283. doi: 10.1111/sji.12471Soydas T., Karaman O., Arkan H., Yenmis G., Ilhan M.M., Tombulturk K., Tasan E., Kanigur Sultuybek G. The correlation of increased CRP levels with NFKB1 and TLR2 polymorphisms in the case of morbid obesity. Scand. J. Immunol. 2016;84(5):278–283. doi: 10.1111/sji.12471Goodall A.H., Burns P., Salles I., Macaulay I.C., Jones C.I., Ardissino D., de Bono B., Bray S.L., Deckmyn H., Dudbridge F., … Bloodomics Consortium. Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function. Blood. 2010;116(22):4646–4656. doi: 10.1182/blood-2010-04-280925Goodall A.H., Burns P., Salles I., Macaulay I.C., Jones C.I., Ardissino D., de Bono B., Bray S.L., Deckmyn H., Dudbridge F., … Bloodomics Consortium. Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function. Blood. 2010;116(22):4646–4656. doi: 10.1182/blood-2010-04-280925Zhou D., Wang X., Chen T., Wen W., Liu Y., Wu Y., Yuan Z. The NLRP3 rs10754558 polymorphism is associated with the occurrence and prognosis of coronary artery disease in the Chinese han population. Biomed. Res. Int. 2016;2016:3185397. doi: 10.1155/2016/3185397Zhou D., Wang X., Chen T., Wen W., Liu Y., Wu Y., Yuan Z. The NLRP3 rs10754558 polymorphism is associated with the occurrence and prognosis of coronary artery disease in the Chinese han population. Biomed. Res. Int. 2016;2016:3185397. doi: 10.1155/2016/3185397Al-Daghri N.M., Clerici M., Al-Attas O., Forni D., Alokail M.S., Alkharfy K.M., Sabico S., Mohammed A.K., Cagliani R., Sironi M. A nonsense polymorphism (R392X) in TLR5 protects from obesity but predisposes to diabetes. J. Immunol. 2013;190(7):3716–3720. doi: 10.4049/jimmunol.1202936Al-Daghri N.M., Clerici M., Al-Attas O., Forni D., Alokail M.S., Alkharfy K.M., Sabico S., Mohammed A.K., Cagliani R., Sironi M. A nonsense polymorphism (R392X) in TLR5 protects from obesity but predisposes to diabetes. J. Immunol. 2013;190(7):3716–3720. doi: 10.4049/jimmunol.1202936Ben-Ali M., Corre B., Manry J., Barreiro L.B., Quach H., Boniotto M., Pellegrini S., Quintana-Murci L. Functional characterization of naturally occurring genetic variants in the human TLR1-2-6 gene family. Hum. Mutat. 2011;32(6):643–652. doi: 10.1002/humu.21486Ben-Ali M., Corre B., Manry J., Barreiro L.B., Quach H., Boniotto M., Pellegrini S., Quintana-Murci L. Functional characterization of naturally occurring genetic variants in the human TLR1-2-6 gene family. Hum. Mutat. 2011;32(6):643–652. doi: 10.1002/humu.21486Smith L.M., Weissenburger-Moser L.A., Heires A.J., Bailey K.L., Romberger D.J., LeVan T.D. Epistatic effect of TLR-1, -6 and -10 polymorphisms on organic dust-mediated cytokine response. Genes Immun. 2017;18(2):67–74. doi: 10.1038/gene.2016.51Smith L.M., Weissenburger-Moser L.A., Heires A.J., Bailey K.L., Romberger D.J., LeVan T.D. Epistatic effect of TLR-1, -6 and -10 polymorphisms on organic dust-mediated cytokine response. Genes Immun. 2017;18(2):67–74. doi: 10.1038/gene.2016.51Long H., O’Connor B.P., Zemans R.L., Zhou X., Yang I.V., Schwartz D.A. The Toll-like receptor 4 polymorphism Asp299Gly but not Thr399Ile influences TLR4 signaling and function. PLoS One. 2014;9(4):e93550. doi: 10.1371/journal.pone.0093550Long H., O’Connor B.P., Zemans R.L., Zhou X., Yang I.V., Schwartz D.A. The Toll-like receptor 4 polymorphism Asp299Gly but not Thr399Ile influences TLR4 signaling and function. PLoS One. 2014;9(4):e93550. doi: 10.1371/journal.pone.0093550Balistreri C.R., Candore G., Colonna-Romano G., Lio D., Caruso M., Hoffmann E., Franceschi C., Caruso C. Role of Toll-like receptor 4 in acute myocardial infarction and longevity. JAMA. 2004;292(19):2339– 2340. doi: 10.1001/jama.292.19.2339Balistreri C.R., Candore G., Colonna-Romano G., Lio D., Caruso M., Hoffmann E., Franceschi C., Caruso C. Role of Toll-like receptor 4 in acute myocardial infarction and longevity. JAMA. 2004;292(19):2339– 2340. doi: 10.1001/jama.292.19.2339Yin Y.W., Sun Q.Q., Hu A.M., Liu H.L., Wang Q., Zhang B.B. Toll-like receptor 4 gene Asp299Gly polymorphism in myocardial infarction: a meta-analysis of 15,148 subjects. Hum. Immunol. 2014;75(2):163–169. doi: 10.1016/j.humimm.2013.11.005Yin Y.W., Sun Q.Q., Hu A.M., Liu H.L., Wang Q., Zhang B.B. Toll-like receptor 4 gene Asp299Gly polymorphism in myocardial infarction: a meta-analysis of 15,148 subjects. Hum. Immunol. 2014;75(2):163–169. doi: 10.1016/j.humimm.2013.11.005Netea M.G., Hijmans A., van Wissen S., Smilde T.J., Trip M.D., Kullberg B.J., de Boo T., van der Meer J.W., Kastelein J.J., Stalenhoef A.F. Toll-like receptor-4 Asp299Gly polymorphism does not influence progression of atherosclerosis in patients with familial hypercholesterolaemia Eur. J. Clin. Invest. 2004 Feb;34(2):94–99. doi: 10.1111/j.1365-2362.2004.01303.xNetea M.G., Hijmans A., van Wissen S., Smilde T.J., Trip M.D., Kullberg B.J., de Boo T., van der Meer J.W., Kastelein J.J., Stalenhoef A.F. Toll-like receptor-4 Asp299Gly polymorphism does not influence progression of atherosclerosis in patients with familial hypercholesterolaemia Eur. J. Clin. Invest. 2004 Feb;34(2):94–99. doi: 10.1111/j.1365-2362.2004.01303.xKiechl S., Lorenz E., Reindl M., Wiedermann C.J., Oberhollenzer F., Bonora E., Willeit J., Schwartz D.A. Toll-like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med. 2002;347(3):185–192. doi: 10.1056/NEJMoa012673Kiechl S., Lorenz E., Reindl M., Wiedermann C.J., Oberhollenzer F., Bonora E., Willeit J., Schwartz D.A. Toll-like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med. 2002;347(3):185–192. doi: 10.1056/NEJMoa012673Peng W., Chen H., Zhao Z., Hu X., Zhou Y., Li Y., Yang L., Wang X., Song J., Liu T., … Ying B. TLR1 polymorphisms are significantly associated with the occurrence, presentation and drug-adverse reactions of tuberculosis in Western Chinese adults. Oncotarget. 2017;9(2):1691–1704. doi: 10.18632/oncotarget.23067Peng W., Chen H., Zhao Z., Hu X., Zhou Y., Li Y., Yang L., Wang X., Song J., Liu T., … Ying B. TLR1 polymorphisms are significantly associated with the occurrence, presentation and drug-adverse reactions of tuberculosis in Western Chinese adults. Oncotarget. 2017;9(2):1691–1704. doi: 10.18632/oncotarget.23067Li B., Xia Y., Hu B. Infection and atherosclerosis: TLR-dependent pathways. Cell. Mol. Life Sci. 2020;77(14):2751–2769. doi: 10.1007/s00018-020-03453-7Li B., Xia Y., Hu B. Infection and atherosclerosis: TLR-dependent pathways. Cell. Mol. Life Sci. 2020;77(14):2751–2769. doi: 10.1007/s00018-020-03453-7Gregor M.F., Hotamisligil G.S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 2011;29:415-445. doi: 10.1146/annurev-immunol-031210-101322Gregor M.F., Hotamisligil G.S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 2011;29:415-445. doi: 10.1146/annurev-immunol-031210-101322Kim S.J., Choi Y., Choi Y.H., Park T. Obesity activates toll-like receptor-mediated proinflammatory signaling cascades in the adipose tissue of mice. J. Nutr. Biochem. 2012;23(2):113–122. doi: 10.1016/j.jnutbio.2010.10.012Kim S.J., Choi Y., Choi Y.H., Park T. Obesity activates toll-like receptor-mediated proinflammatory signaling cascades in the adipose tissue of mice. J. Nutr. Biochem. 2012;23(2):113–122. doi: 10.1016/j.jnutbio.2010.10.012Edfeldt K., Swedenborg J., Hansson G.K., Yan Z.Q. Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation. 20022;105(10):1158–1161.Edfeldt K., Swedenborg J., Hansson G.K., Yan Z.Q. Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation. 20022;105(10):1158–1161.Golovkin A.S., Ponasenko A.V., Khutornaya M.V., Kutikhin A.G., Salakhov R.R., Yuzhalin A.E., Zhidkova I.I., Barbarash O.L., Barbarash L.S. Association of TLR and TREM-1 gene polymorphisms with risk of coronary artery disease in a Russian population. Gene. 2014;550(1):101–109. doi: 10.1016/j.gene.2014.08.022Golovkin A.S., Ponasenko A.V., Khutornaya M.V., Kutikhin A.G., Salakhov R.R., Yuzhalin A.E., Zhidkova I.I., Barbarash O.L., Barbarash L.S. Association of TLR and TREM-1 gene polymorphisms with risk of coronary artery disease in a Russian population. Gene. 2014;550(1):101–109. doi: 10.1016/j.gene.2014.08.022Zhang M., Tang X., Wang Y., Wu S., Wang M., Liu Q., Sandford A.J., He J.Q. Variants of TLR1 associated with tuberculosis susceptibility in the Chinese Tibetan population but not in Han Chinese. Infect. Genet. Evol. 2018;61:53–59. doi: 10.1016/j.meegid.2018.02.021Zhang M., Tang X., Wang Y., Wu S., Wang M., Liu Q., Sandford A.J., He J.Q. Variants of TLR1 associated with tuberculosis susceptibility in the Chinese Tibetan population but not in Han Chinese. Infect. Genet. Evol. 2018;61:53–59. doi: 10.1016/j.meegid.2018.02.021Wright S.W., Emond M.J., Lovelace-Macon L., Ducken D., Kashima J., Hantrakun V., Chierakul W., Teparrukkul P., Chantratita N., Limmathurotsakul D., West T.E. Exonic sequencing identifies TLR1 genetic variation associated with mortality in Thais with melioidosis. Emerg. Microbes Infect. 2019;8(1):282–290. doi: 10.1080/22221751.2019.1575172Wright S.W., Emond M.J., Lovelace-Macon L., Ducken D., Kashima J., Hantrakun V., Chierakul W., Teparrukkul P., Chantratita N., Limmathurotsakul D., West T.E. Exonic sequencing identifies TLR1 genetic variation associated with mortality in Thais with melioidosis. Emerg. Microbes Infect. 2019;8(1):282–290. doi: 10.1080/22221751.2019.1575172

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