sibmedСибирский научный медицинский журналСибирский научный медицинский журнал2410-25122410-2520ИЦиГ СО РАН10.15372/SSMJ20190607sibmed-312Research ArticleКЛИНИЧЕСКАЯ МЕДИЦИНАCLINICAL MEDICINEГаплотипический анализ генов CAT, TLR4 и IL10 у больных бронхиальной астмой с сопутствующей артериальной гипертензиейAnalysis of haplotypes of CAT, TLR4, and IL10 genes in bronchial asthma patients comorbid with arterial hypertensionhttps://orcid.org/0000-0002-1103-3073БрагинаЕ. Ю.BraginaE. Y.

Елена Юрьевна Брагина – кандидат биологических наук.

634050, Томск, ул. Набережная реки Ушайки, 10

Elena Yurjevna Bragina - candidate of biological sciences.

634050, Tomsk, Naberezhnaya reki Ushayky str., 10

elena.bragina72@gmail.comhttps://orcid.org/0000-0002-9527-7015ГончароваИ. А.GoncharovaI. A.

Ирина Александровна Гончарова - кандидат биологических наук.

634050, Томск, ул. Набережная реки Ушайки, 10

Irina Alexandrovna Goncharova

634050, Tomsk, Naberezhnaya reki Ushayky str., 10

irina.goncharova@medgenetics.ruhttps://orcid.org/0000-0002-1439-6259ФрейдинМ. Б.FreidinM. B.

Максим Борисович Фрейдин – доктор биологических наук.

634050, Томск, ул. Набережная реки Ушайки, 10

Maxim Borisovich Freidin - doctor of biological sciences.

634050, Tomsk, Naberezhnaya reki Ushayky str., 10

mfreidin@medgenetics.ruhttps://orcid.org/0000-0001-6848-7749ЖалсановаИ. Ж.ZhalsanovaI. Zh.

Ирина Жаргаловна Жалсанова

634050, Томск, ул. Набережная реки Ушайки, 10

Irina Zhargalovna Zhalsanova

634050, Tomsk, Naberezhnaya reki Ushayky str., 10

irina.zhalsanova@medgenetics.ruhttps://orcid.org/0000-0002-7882-2093ГомбоеваД. Е.GomboevaD. E.

Дэнсэма Евгеньевна Гомбоева

634050, Томск, ул. Набережная реки Ушайки, 10

Densema Evgenjevna Gomboeva - candidate of biological sciences.

634050, Tomsk, Naberezhnaya reki Ushayky str., 10

gomboeva.densema@medgenetics.ruНемеровЕ. В.NemerovE. V.

Евгений Владимирович Немеров  – кандидат медицинских наук.

634050, Томск, Московский тракт, 2

Siberian State Medical University of Minzdrav of Russia

nemerevg@mail.ruhttps://orcid.org/0000-0002-2113-4556ПузыревВ. П.PuzyrevV. P.

Валерий Павлович Пузырев – академик РАН, профессор.

634050, Томск, ул. Набережная реки Ушайки, 10; 634050, Томск, Московский тракт, 2

Valeriy Pavlovich Puzyrev - academician of RAS, professor.

634050, Tomsk, Naberezhnaya reki Ushayky str., 10; 634050, Tomsk, Moskovsky path, 2

p.valery@medgenetics.ruНИИ медицинской генетики Томского национального исследовательского медицинского центра, РАНРоссияResearch Institute of Medical Genetics of Tomsk National Research Medical Center of RASRussian FederationEvgeniy Vladimirovich Nemerov - candidate of medical sciences. 634050, Tomsk, Moskovsky path, 2Russian FederationНИИ медицинской генетики Томского национального исследовательского медицинского центра, РАН; Сибирский государственный медицинский университет Минздрава РоссииРоссияResearch Institute of Medical Genetics of Tomsk National Research Medical Center of RAS; Siberian State Medical University of Minzdrav of RussiaRussian Federation2019040120203965564Copyright © Брагина Е.Ю., Гончарова И.А., Фрейдин М.Б., Жалсанова И.Ж., Гомбоева Д.Е., Немеров Е.В., Пузырев В.П., 20202020Брагина Е.Ю., Гончарова И.А., Фрейдин М.Б., Жалсанова И.Ж., Гомбоева Д.Е., Немеров Е.В., Пузырев В.П.Bragina E.Y., Goncharova I.A., Freidin M.B., Zhalsanova I.Z., Gomboeva D.E., Nemerov E.V., Puzyrev V.P.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/312

Среди пациентов с бронхиальной астмой значительно распространены сопутствующие сердечно-сосудистые заболевания. Предполагается, что генетические факторы могут оказывать значительное влияние на развитие артериальной гипертензии у пациентов с астмой. Цель исследования - изучить ассоциации полиморфных вариантов, затрагивающих количественные изменения профиля экспрессии (ExpressionQuantitativeTraitLoci (eQTL)) генов CAT, TLR4 и IL10, с развитием бронхиальной астмы в сочетании с артериальной гипертензией.

Материал и методы

Материал и методы. Генотипирование 48 eQTL вариантов генов CAT, TLR4 и IL10 выполнено с помощью масс-спектрометрии MALDI-TOF у пациентов с «изолированными» астмой (n = 145) и артериальной гипертензией (n = 144) и их сочетанием (n = 146), а также в контрольной группе здоровых индивидов (n = 152). С помощью логистической регрессии проведен анализ ассоциаций гаплотипов с исследуемыми болезнями.

Результаты

Результаты. Развитие бронхиальной астмы в сочетании с артериальной гипертензией ассоциировано с гаплотипами, образованными eQTL полиморфизмами генов CAT и TLR4. «Изолированная» астма и коморбидная форма патологии различаются по спектру гаплотипов, ассоциированных с изученными заболеваниями.

Заключение

Заключение. Полученные результаты демонстрируют, что молекулярные связи астмы и гипертензии могут быть опосредованы вариантами, контролирующими экспрессию генов TLR4 и CAT.

Co-occurrence of cardiovascular diseases is significantly common among patients with bronchial asthma. Genetic factors can have a significant effect on the development of hypertension in patients with asthma. Objective of the study was to investigate the associations of polymorphic variants relating to quantitative changes in the expression profile (eQTL) of the CAT, TLR4, and IL10 genes with the development of bronchial asthma co-morbid with arterial hypertension.

Material and methods

Material and methods. Genotyping of 48 eQTL SNPs of the CAT, TLR4, and IL10 genes was performed using MALDI-TOF mass spectrometry in patients with «isolated» asthma (n = 145) and arterial hypertension (n = 144) and their combination (n = 146), as well as in the control group of healthy individuals (n = 152). Using logistic regression, an analysis of the associations of haplotypes with the studied diseases was carried out.

Results

Results. An association of bronchial asthma in combination with arterial hypertension with haplotypes formed by eQTL SNPs of the CAT and TLR4 genes was established. The spectrum of haplotypes associated with comorbidity of asthma and hypertension differs from the haplotypes associated with “isolated” asthma.

Conclusion

Conclusion. The molecular base of asthma and hypertension comorbidity can be associated with variants that control the expression of TLR4 and CAT genes.

бронхиальная астмаартериальная гипертензиякоморбидностьполиморфизм геновга-плотипCATTLR4IL10bronchial asthmahypertensioncomorbiditypolymorphism of geneshaplotypeCATTLR4IL10Исследование выполнено при финансовой поддержке фонда Volkswagen Stiftung (# 90335) и Комплексной программы фундаментальных научных исследований СО РАН (№ 0550-2018-0003)This study was supported by the Volkswagen Stiftung (# 90335) and project of the integrated basic research program of the SB RAS (# 0550-2018-0003)ReferencesБушуева О.Ю., Иванов В.П., Рыжаева В.Н., Пономаренко И.В., Чурносов М.И., Полоников А.В. Ассоциация полиморфизма -844G>A гена каталазы с повышенным риском развития артериальной гипертонии у курильщиков. Терапевт. арх. 2016; 88 (9): 50-54. doi: 10.17116/terarkh201688950-54Bushueva O.Yu., Ivanov V.P., Ryzhaeva V.N., Ponomarenko I.V., Churnosov M.I., Polonikov A.V Association of the -844G>A polymorphism in the catalase gene with the increased risk of essential hypertension in smokers. Terapevticheskiy arkhiv = Therapeutic archive. 2016; 88 (9): 50-54. [In Russian]. doi: 10.17116/terarkh201688950-54Ганковская Л.В., Намазова-Баранова Л.С., Хорева М.В., Брагвадзе Б.Г., Огурцова А.Д., Алексеева А.А., Ганковский В.А., Свитич О.А. Особенности экспрессии ton-подобного рецептора 2 и ton-подобного рецептора 4 у детей с бронхиальной астмой. Мед. иммунология. 2017; 19 (4): 431-440. doi: 10.15789/1563-0625-2017-4-431-440Gankovskaya L.V., Namazova-Baranova L.S., Khoreva M.V., Bragvadze B.G., Ogurtsova A.D., Alekseeva A.A., Gankovskii V.A., Svitich O.A. Expression features of Toll-like receptor 2 and Toll-like receptor 4 in children with asthma. Meditsinskaya immunolo-giya = Medical Immunology. 2017; 19 (4): 431-440. doi: 10.15789/1563-0625-2017-4-431-44Национальная программа «Бронхиальная астма у детей. Стратегия лечения и профилактика». 5-е изд., перераб. и доп. М.: Оригинал-макет, 2017. 160 с.National program «Bronchial asthma in children. Strategy of treatment and prevention. 5th ed., revised and supplemented. Moscow: Original-maket, 2017. 160 p. [In Russian].Фрейдин М.Б., Брагина Е.Ю., Салтыкова И.В., Деева Е.В., Огородова Л.М., Пузырев В.П. Влияние дополнительной болезни (коморбидности) на ассоциацию аллергического ринита с вариантом rs12621643 гена KCNE4. Генетика. 2013; 49 (4): 541-544. doi: 10.7868/S001667581304005XFreidin M.B., Bragina E.Yu., Saltykova I.V., Deeva E.V., Ogorodova L.M., Puzyrev V.P. Effect of additional disease (comorbidity) on association of allergic rhinitis with KCNE4 gene rs12621643 variant. Russ. J. Genet. 2013; 4 (4): 473-475. [In Russian].Чистяков Д.А., Туракулов Р.И., Щербаче-ва Л.Н., Мамаева Г.Г., Балаболкин М.И., Носиков В.В. Анализ полиморфизма локуса D11S2008 рядом с геном каталазы у больных гипертонией и ишемической болезнью сердца при инсулиннезависимом сахарном диабете в Московской популяции. Генетика. 2000; 36 (3): 423-426.Chistyakov D.A., Turakulov R.I., Shcherbache-va L.N., Mamaeva G.G., Balabolkin M.I., Nosikov V.V. Analysis of polymorphism of the D11S2008 locus of the catalase gene in patients with hypertension and ischemic heart disease in non-insulin-dependent diabetes mellitus in the Muscovite population. Russ. J. Genet. 2000; 36 (3): 340-342. [In Russian].Asea A., Rehli M., Kabingu E., Boch J.A., Bare O., Auron P.E., Stevenson M.A., Calderwood S.K. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J. Biol. Chem. 2002; 277 (17): 15028-15034. doi: 10.1074/jbc.M200497200Asea A., Rehli M., Kabingu E., Boch J.A., Bare O., Auron P.E., Stevenson M.A., Calderwood S.K. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J. Biol. Chem. 2002; 277 (17): 15028-15034. doi: 10.1074/jbc.M200497200Barrett J.C., Fry B., Maller J., Daly M.J. Hap-loview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21 (2): 263-265.Barrett J.C., Fry B., Maller J., Daly M.J. Hap-loview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21 (2): 263-265.Bomfim G.F., Dos Santos R.A., Oliveira M.A., Giachini F.R., Akamine E.H., Tostes R.C., Fortes Z.B., Webb R.C., Carvalho M.H. Toll-like receptor 4 contributes to blood pressure regulation and vascular contraction in spontaneously hypertensive rats. Clin. Sci. (Lond). 2012; 122 (11): 535-543. doi: 10.1042/CS20110523Bomfim G.F., Dos Santos R.A., Oliveira M.A., Giachini F.R., Akamine E.H., Tostes R.C., Fortes Z.B., Webb R.C., Carvalho M.H. Toll-like receptor 4 contributes to blood pressure regulation and vascular contraction in spontaneously hypertensive rats. Clin. Sci. (Lond). 2012; 122 (11): 535-543. doi: 10.1042/CS20110523Bragina E.Y., Goncharova I.A., Garaeva A.F., Nemerov E.V., Babovskaya A.A., Karpov A.B., Semenova Y.V., Zhalsanova I.Z., Gomboeva D.E., Saik O.V., Zolotareva O.I., Ivanisenko V.A., Dosenko V.E., Hofes-taedt R., Freidin M.B. Molecular relationships between bronchial asthma and hypertension as comorbid diseases. J. Integr. Bioinform. 2018; 15 (4). doi: 10.1515/jib-2018-0052Bragina E.Y., Goncharova I.A., Garaeva A.F., Nemerov E.V., Babovskaya A.A., Karpov A.B., Semenova Y.V., Zhalsanova I.Z., Gomboeva D.E., Saik O.V., Zolotareva O.I., Ivanisenko V.A., Dosenko V.E., Hofes-taedt R., Freidin M.B. Molecular relationships between bronchial asthma and hypertension as comorbid diseases. J. Integr. Bioinform. 2018; 15 (4). doi: 10.1515/jib-2018-0052Branum A.M., Lukacs S.L. Food allergy among children in the United States. Pediatrics. 2009; 124 (6): 1549-1555. doi: 10.1542/peds.2009-1210Branum A.M., Lukacs S.L. Food allergy among children in the United States. Pediatrics. 2009; 124 (6): 1549-1555. doi: 10.1542/peds.2009-1210Christiansen S.C., Zuraw B.L. Treatment of hypertension in patients with asthma. N. Engl. J. Med. 2019; 381 (11): 1046-1057. doi: 10.1056/NEJM-ra1800345Christiansen S.C., Zuraw B.L. Treatment of hypertension in patients with asthma. N. Engl. J. Med. 2019; 381 (11): 1046-1057. doi: 10.1056/NEJM-ra1800345Ferguson S., Teodorescu M.C., Gangnon R.E., Peterson A.G., Consens F.B., Chervin R.D., Teodores-cu M. Factors associated with systemic hypertension in asthma. Lung. 2014; 192 (5): 675-683. doi: 10.1007/s00408-014-9600-yFerguson S., Teodorescu M.C., Gangnon R.E., Peterson A.G., Consens F.B., Chervin R.D., Teodorescu M. Factors associated with systemic hypertension in asthma. Lung. 2014; 192 (5): 675-683. doi: 10.1007/s00408-014-9600-yFrantz S., Kobzik L., Kim Y.D., Fukazawa R., Medzhitov R., Lee R.T., Kelly R.A. Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J. Clin. Invest. 1999; 104 (3): 271-280.Frantz S., Kobzik L., Kim Y.D., Fukazawa R., Medzhitov R., Lee R.T., Kelly R.A. Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J. Clin. Invest. 1999; 104 (3): 271-280.GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 19902016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017; 390 (10100): 1211— 1259. doi: 10.1016/S0140-6736(17)32154-2GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 19902016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017; 390 (10100): 1211— 1259. doi: 10.1016/S0140-6736(17)32154-2Ji Y., Liu J., Wang Z., Liu N. Angiotensin II induces inflammatory response partly via toll-like receptor 4-dependent signaling pathway in vascular smooth muscle cells. Cell Physiol. Biochem. 2009; 23 (4-6): 265-276. doi: 10.1159/000218173Ji Y., Liu J., Wang Z., Liu N. Angiotensin II induces inflammatory response partly via toll-like receptor 4-dependent signaling pathway in vascular smooth muscle cells. Cell Physiol. Biochem. 2009; 23 (4-6): 265-276. doi: 10.1159/000218173Jiang Z., Akey J.M., Shi J., Xiong M., Wang Y., Shen Y., Xu X., Chen H., Wu H., Xiao J., Lu D., Huang W., Jin L. A polymorphism in the promoter region of catalase is associated with blood pressure levels. Hum. Genet. 2001; 109 (1): 95-98. doi: 10.1007/s004390100553Jiang Z., Akey J.M., Shi J., Xiong M., Wang Y., Shen Y., Xu X., Chen H., Wu H., Xiao J., Lu D., Huang W., Jin L. A polymorphism in the promoter region of catalase is associated with blood pressure levels. Hum. Genet. 2001; 109 (1): 95-98. doi: 10.1007/s004390100553Kodydkova J., Vavrova L., Kocik M., Zak A. Human catalase, its polymorphisms, regulation and changes of its activity in different diseases. Folia Biol. (Praha). 2014; 60 (4): 153-167.Kodydkova J., Vavrova L., Kocik M., Zak A. Human catalase, its polymorphisms, regulation and changes of its activity in different diseases. Folia Biol. (Praha). 2014; 60 (4): 153-167.Lafferty E.I., Qureshi S.T., Schnare M. The role of toll-like receptors in acute and chronic lung inflammation. J. Inflamm. (Lond.). 2010; 7: 57. doi: 10.1186/1476-9255-7-57Lafferty E.I., Qureshi S.T., Schnare M. The role of toll-like receptors in acute and chronic lung inflammation. J. Inflamm. (Lond.). 2010; 7: 57. doi: 10.1186/1476-9255-7-57Lau M.Y., Dharmage S.C., Burgess J.A., Win A.K., Lowe A.J., Lodge C., Perret J., Hui J., Thomas P.S., Morrison S., Giles G.G., Hopper J., Abramson M.J., Walters E.H., Matheson M.C. The interaction between farming/rural environment and TLR2, TLR4, TLR6 and CD14 genetic polymorphisms in relation to early- and late-onset asthma. Sci. Rep. 2017; 7: 43681. doi: 10.1038/srep43681Lau M.Y., Dharmage S.C., Burgess J.A., Win A.K., Lowe A.J., Lodge C., Perret J., Hui J., Thomas P.S., Morrison S., Giles G.G., Hopper J., Abramson M.J., Walters E.H., Matheson M.C. The interaction between farming/rural environment and TLR2, TLR4, TLR6 and CD14 genetic polymorphisms in relation to early- and late-onset asthma. Sci. Rep. 2017; 7: 43681. doi: 10.1038/srep43681Liu N., Liu J.T., Ji Y.Y., Lu P.P. C-reactive protein triggers inflammatory responses partly via TLR4/ IRF3/NF-kB signaling pathway in rat vascular smooth muscle cells. Life Sci. 2010; 87 (11-12): 367-374. doi: 10.1016/j.lfs.2010.07.012Liu N., Liu J.T., Ji Y.Y., Lu P.P. C-reactive protein triggers inflammatory responses partly via TLR4/ IRF3/NF-kB signaling pathway in rat vascular smooth muscle cells. Life Sci. 2010; 87 (11-12): 367-374. doi: 10.1016/j.lfs.2010.07.012Makeeva O.A., Sleptsov A.A., Kulish E.V., Barbarash O.L., Mazur A.M., Prokhorchuk E.B., Chekanov N.N., Stepanov V.A., Puzyrev V.P. Genomic study of cardiovascular continuum comorbidity. Acta Naturae. 2015; 7 (3): 89-99.Makeeva O.A., Sleptsov A.A., Kulish E.V., Barbarash O.L., Mazur A.M., Prokhorchuk E.B., Chekanov N.N., Stepanov V.A., Puzyrev V.P. Genomic study of cardiovascular continuum comorbidity. Acta Naturae. 2015; 7 (3): 89-99.Moore W.C., Hastie A.T., Li X., Li H., Busse W.W., Jarjour N.N., Wenzel S.E., Peters S.P., Meyers D.A., Bleecker E.R. National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J. Allergy Clin. Immunol. 2014; 133 (6): 1557-1563.e5. doi: 10.1016/jjaci.2013.10.011Moore W.C., Hastie A.T., Li X., Li H., Busse W.W., Jarjour N.N., Wenzel S.E., Peters S.P., Meyers D.A., Bleecker E.R. National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J. Allergy Clin. Immunol. 2014; 133 (6): 1557-1563.e5. doi: 10.1016/jjaci.2013.10.011Moore W.C., Meyers D.A., Wenzel S.E., Teague W.G., Li H., Li X., D’Agostino R., Jr., Castro M., Curran-Everett D., Fitzpatrick A.M., Gaston B., Jarjour N.N., Sorkness R., Calhoun W.J., Chung K.F., Comhair S.A., Dweik R.A., Israel E., Peters S.P., Busse W.W., Erzurum S.C., Bleecker E.R. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am. J. Respir. Crit. Care Med. 2010; 181 (4): 315-323. doi: 10.1164/rccm.200906-0896OCMoore W.C., Meyers D.A., Wenzel S.E., Teague W.G., Li H., Li X., D’Agostino R., Jr., Castro M., Curran-Everett D., Fitzpatrick A.M., Gaston B., Jarjour N.N., Sorkness R., Calhoun W.J., Chung K.F., Comhair S.A., Dweik R.A., Israel E., Peters S.P., Busse W.W., Erzurum S.C., Bleecker E.R. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am. J. Respir. Crit. Care Med. 2010; 181 (4): 315-323. doi: 10.1164/rccm.200906-0896OCNagel M., Jansen P.R., Stringer S., Watanabe K., de Leeuw C.A., Bryois J., Savage J.E., Hammerschlag A.R., Skene N.G., Munoz-Manchado A.B., White T., Tiemeier H., Linnarsson S., Hjerling-Leffler J., Polderman T.J.C., Sullivan P.F., van der Sluis S., Posthuma D. Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways. Nat. Genet. 2018; 50 (7): 920-927. doi: 10.1038/s41588-018-0151-7Nagel M., Jansen P.R., Stringer S., Watana-be K., de Leeuw C.A., Bryois J., Savage J.E., Hammerschlag A.R., Skene N.G., Munoz-Manchado A.B., White T., Tiemeier H., Linnarsson S., Hjerling-Lef-fler J., Polderman T.J.C., Sullivan P.F., van der Sluis S., Posthuma D. Metaanalysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways. Nat. Genet. 2018; 50 (7): 920-927. doi: 10.1038/s41588-018-0151-7Nenoi M., Ichimura S., Mita K., Yukawa O., Cartwright I.L. Regulation of the catalase gene promoter by Sp1, CCAAT-recognizing factors, and a WT1/Egr-related factor in hydrogen peroxide-resistant HP100 cells. Cancer Res. 2001; 61 (15): 5885-5894.Nenoi M., Ichimura S., Mita K., Yukawa O., Cartwright I.L. Regulation of the catalase gene promoter by Sp1, CCAAT-recognizing factors, and a WT1/Egrrelated factor in hydrogen peroxide-resistant HP100 cells. Cancer Res. 2001; 61 (15): 5885-5894.Ohashi K., Burkart V, Flohe S., Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol. 2000; 164 (2): 558-561. doi: 10.4049/jimmunol.164.2.558Ohashi K., Burkart V, Flohe S., Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol. 2000; 164 (2): 558-561. doi: 10.4049/jimmunol.164.2.558Pasterkamp G., van Keulen J.K., de Kleijn D.P. Role of Toll-like receptor 4 in the initiation and progression of atherosclerotic disease. Eur. J. Clin. Invest. 2004; 34 (5): 328-334. doi: 10.1111/j.1365-2362.2004.01338.xPasterkamp G., van Keulen J.K., de Kleijn D.P. Role of Toll-like receptor 4 in the initiation and progression of atherosclerotic disease. Eur. J. Clin. Invest. 2004; 34 (5): 328-334. doi: 10.1111/j.1365-2362.2004.01338.xPolonikov A.V., Ivanov V.P., Bogomazov A.D., Freidin M.B., Illig T., Solodilova M.A. Antioxidant defense enzyme genes and asthma susceptibility: gender-specific effects and heterogeneity in gene-gene interactions between pathogenetic variants of the disease. Biomed. Res. Int. 2014; 2014: 708903. doi: 10.1155/2014/708903Polonikov A.V., Ivanov V.P., Bogomazov A.D., Freidin M.B., Illig T., Solodilova M.A. Antioxidant defense enzyme genes and asthma susceptibility: gender-specific effects and heterogeneity in gene-gene interactions between pathogenetic variants of the disease. Biomed. Res. Int. 2014; 2014: 708903. doi: 10.1155/2014/708903Pouladi N., Achour I., Li H., Berghout J., Kenost C., Gonzalez-Garay M.L., Lussier Y.A. Biomechanisms of Comorbidity: Reviewing Integrative Analyses of Multi-omics Datasets and Electronic Health Records. Yearb Med Inform. 2016; (1): 194-206.Pouladi N., Achour I., Li H., Berghout J., Kenost C., Gonzalez-Garay M.L., Lussier Y.A. Biomechanisms of Comorbidity: Reviewing Integrative Analyses of Multi-omics Datasets and Electronic Health Records. Yearb Med Inform. 2016; (1): 194-206.Saik O.V., Demenkov P.S., Ivanisenko T.V., Bragina E.Y., Freidin M.B., Goncharova I.A., Dosen-ko V.E., Zolotareva O.I., Hofestaedt R., Lavrik I.N., Rogaev E.I., Ivanisenko V.A. Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks. BMC Med. Genomics. 2018; 11 (Suppl. 1): 15. doi: 10.1186/s12920-018-0331-4Saik O.V., Demenkov P.S., Ivanisenko T.V., Bragina E.Y., Freidin M.B., Goncharova I.A., Dosen-ko V.E., Zolotareva O.I., Hofestaedt R., Lavrik I.N., Rogaev E.I., Ivanisenko V.A. Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks. BMC Med. Genomics. 2018; 11 (Suppl. 1): 15. doi: 10.1186/s12920-018-0331-4Saltykova I.V., Ogorodova L.M., Bragina E.Y., Puzyrev V.P., Freidin M.B. Opisthorchis felineus liver fluke invasion is an environmental factor modifying genetic risk of atopic bronchial asthma. Acta Trop. 2014; 139: 53-56. doi: 10.1016/j.actatropica.2014.07.004Saltykova I.V., Ogorodova L.M., Bragina E.Y., Puzyrev V.P., Freidin M.B. Opisthorchis felineus liver fluke invasion is an environmental factor modifying genetic risk of atopic bronchial asthma. Acta Trop. 2014; 139: 53-56. doi: 10.1016/j.actatropica.2014.07.004Schneider S., Hoppmann P., Koch W., Kemmner S., Schmaderer C., Renders L., Kastrati A., Laug-witz K.L., Heemann U., Baumann M. Obesity-associated hypertension is ameliorated in patients with TLR4 single nucleotide polymorphism (SNP) rs4986790. J. Inflamm. (Lond). 2015; 12: 57. doi: 10.1186/s12950-015-0100-5Schneider S., Hoppmann P., Koch W., Kemmn-er S., Schmaderer C., Renders L., Kastrati A., Laug-witz K.L., Heemann U., Baumann M. Obesity-associated hypertension is ameliorated in patients with TLR4 single nucleotide polymorphism (SNP) rs4986790. J. Inflamm. (Lond). 2015; 12: 57. doi: 10.1186/s12950-015-0100-5Schneider S., Koch W., Hoppmann P., Ubrich R., Kemmner S., Steinlechner E., Heemann U., Laugwitz K.L., Kastrati A., Baumann M. Association of Toll-like receptor 4 polymorphism with age-dependent systolic blood pressure increase in patients with coronary artery disease. Immun. Ageing. 2015; 12: 4. doi: 10.1186/s12979-015-0031-2Schneider S., Koch W., Hoppmann P., Ubrich R., Kemmner S., Steinlechner E., Heemann U., Laugwitz K.L., Kastrati A., Baumann M. Association of Toll-like receptor 4 polymorphism with age-dependent systolic blood pressure increase in patients with coronary artery disease. Immun. Ageing. 2015; 12: 4. doi: 10.1186/s12979-015-0031-2Simpson J.L., Grissell T.V., Douwes J., Scott R.J., Boyle M.J., Gibson P.G. Innate immune activation in neutrophilic asthma and bronchiectasis. Thorax. 2007; 62 (3): 211-218. doi: 10.1136/thx.2006.061358Simpson J.L., Grissell T.V., Douwes J., Scott R.J., Boyle M.J., Gibson P.G. Innate immune activation in neutrophilic asthma and bronchiectasis. Thorax. 2007; 62 (3): 211-218. doi: 10.1136/thx.2006.061358Sinnwell J.P., Schaid D.J. Haplo.stats: Statistical analysis of haplotypes with traits and covariates when linkage phase is ambiguous. R package version 1.7.9. 2018; https://CRAN.R-project.org/package=haplo.stats.Sinnwell J.P., Schaid D.J. Haplo.stats: Statistical analysis of haplotypes with traits and covariates when linkage phase is ambiguous. R package version 1.7.9. 2018; https://CRAN.R-project.org/package=haplo.stats.Sprague A.H., Khalil R.A. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem. Pharmacol. 2009; 78 (6): 539-552. doi: 10.1016/j.bcp.2009.04.029Sprague A.H., Khalil R.A. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem. Pharmacol. 2009; 78 (6): 539-552. doi: 10.1016/j.bcp.2009.04.029Su X., Ren Y, Li M., Zhao X., Kong L., Kang J. Prevalence of comorbidities in asthma and nonasthma patients: a meta-analysis. Medicine (Baltimore). 2016; 95 (22): e3459. doi: 10.1097/MD.0000000000003459Su X., Ren Y, Li M., Zhao X., Kong L., Kang J. Prevalence of comorbidities in asthma and nonasthma patients: a meta-analysis. Medicine (Baltimore). 2016; 95 (22): e3459. doi: 10.1097/MD.0000000000003459Wang N., Akey J.M., Zhang K., Chakraborty R., Jin L. Distribution of recombination crossovers and the origin of haplotype blocks: the interplay of population history, recombination, and mutation. Am. J. Hum. Genet. 2002; 71 (5): 1227-1234. doi: 10.1086/344398Wang N., Akey J.M., Zhang K., Chakraborty R., Jin L. Distribution of recombination crossovers and the origin of haplotype blocks: the interplay of population history, recombination, and mutation. Am. J. Hum. Genet. 2002; 71 (5): 1227-1234. doi: 10.1086/344398Weatherburn C.J., Guthrie B., Mercer S.W., Morales D.R. Comorbidities in adults with asthma: Population-based cross-sectional analysis of 1.4 million adults in Scotland. Clin. Exp. Allergy. 2017; 47 (10): 1246-1252. doi: 10.1111/cea.12971Weatherburn C.J., Guthrie B., Mercer S.W., Morales D.R. Comorbidities in adults with asthma: Population-based cross-sectional analysis of 1.4 million adults in Scotland. Clin. Exp. Allergy. 2017; 47 (10): 1246-1252. doi: 10.1111/cea.12971Wenzel S.E. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat. Med. 2012; 18 (5): 716-725. doi: 10.1038/nm.2678Wenzel S.E. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat. Med. 2012; 18 (5): 716-725. doi: 10.1038/nm.2678Zhang Q., Qian F.H., Zhou L.F., Wei G.Z., Jin G.F., Bai J.L., Yin K.S. Polymorphisms in tolllike receptor 4 gene are associated with asthma severity but not susceptibility in a Chinese Han population. J. Investig. Allergol. Clin. Immunol. 2011; 21 (5): 370-377.Zhang Q., Qian F.H., Zhou L.F., Wei G.Z., Jin G.F., Bai J.L., Yin K.S. Polymorphisms in tolllike receptor 4 gene are associated with asthma severity but not susceptibility in a Chinese Han population. J. Investig. Allergol. Clin. Immunol. 2011; 21 (5): 370-377.

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