In this study, we hypothesized that the changes localized at angiopoietin-2 (ANGPT2), granulocyte-macrophage colony-stimulating factor (CSF2), fms-related tyrosine kinase 1 (FLT1) and toll-like receptor (TLR) 2, TLR6 and TLR9 genes were associated with spontaneous preterm labor (PTL), as well as with possible genetic alterations on PTL-related coagulation. This case-control genetic association study aimed to identify single nucleotide polymorphisms (SNPs) for the aforementioned genes, which are correlated with genetic risk or protection against PTL in Polish women. The study was conducted in 320 patients treated between 2016 and 2020, including 160 women with PTL and 160 term controls in labor. We found that ANGPT2 rs3020221 AA homozygotes were significantly less common in PTL cases than in controls, especially after adjusting for activated partial thromboplastin time (APTT) and platelet (PLT) parameters. TC heterozygotes for TLR2 rs3804099 were associated with PTL after correcting for anemia, vaginal bleeding, and history of threatened miscarriage or PTL. TC and CC genotypes in TLR9 rs187084 were significantly less common in women with PTL, compared to the controls, after adjusting for bleeding and gestational diabetes. For the first time, it was shown that three polymorphisms-ANGPT2 rs3020221, TLR2 rs3804099 and TLR9 rs187084 -were significantly associated with PTL, adjusted by pregnancy development influencing factors.

Biomedical Research Center University Hospital Hradec Kralove 500 03 Hradec Kralove Czech Republic

Department of Gynecology and Obstetrics Medical University of Lodz 93 338 Lodz Poland

Department of Gynecology Reproduction and Fetal Therapy and Diagnostics and Treatment of Infertility Polish Mother's Memorial Hospital Research Institute 93 338 Lodz Poland

Department of Obstetrics and Gynecology Polish Mother's Memorial Hospital Research Institute 93 338 Lodz Poland

Department of Obstetrics and Gynecology University Hospital Hradec Kralove Charles University 500 03 Hradec Kralove Czech Republic

Department of Perinatology Obstetrics and Gynecology Polish Mother's Memorial Hospital Research Institute 93 338 Lodz Poland

Laboratory of Molecular Diagnostics and Pharmacogenomics Department of Pharmaceutical Biochemistry and Molecular Diagnostics Medical University of Lodz 90 151 Lodz Poland

Scientific Laboratory of the Center of Medical Laboratory Diagnostics and Screening Polish Mother's Memorial Hospital Research Institute 93 338 Lodz Poland

Zobrazit více v PubMed

Merced C., Goya M., Pratcorona L., Rodó C., Llurba E., Higueras T., Cabero L., Carreras E. Cervical pessary for preventing preterm birth in twin pregnancies with maternal short cervix after an episode of threatened preterm labor: Randomised controlled trial. Am. J. Obstet. Gynecol. 2019;221:55.e1–55.e14. doi: 10.1016/j.ajog.2019.02.035. PubMed DOI

Bomba-Opoń D.A., Wielgoś M. Nowoczesna terapia porodu przedwczesnego. In: Wielgoś M., editor. Diagnostyka Prenatalna z Elementami Perinatologii. Via Medica; Gdańsk, Poland: 2009. pp. 218–227.

Hamilton B.E., Martin J.A., Osterman M.J., Curtin S.C., Matthews T.J. Births: Final data for 2014. Natl. Vital Stat. Rep. 2015;64:1–64. PubMed

Treyvaud K. Parent and family outcomes following very preterm or very low birth weight birth: A review. Semin. Fetal Neonatal Med. 2014;19:131–135. doi: 10.1016/j.siny.2013.10.008. PubMed DOI

Leijnse J.E., de Heus R., de Jager W., Rodenburg W., Peeters L.L., Franx A., Eijkelkamp N. First trimester placental vascularization and angiogenetic factors are associated with adverse pregnancy outcome. Pregnancy Hypertens. 2018;13:87–94. doi: 10.1016/j.preghy.2018.04.008. PubMed DOI

Patni S., Bryant A.H., Wynen L.P., Seager A.L., Morgan G., Thornton C.A. Functional activity but not gene expression of toll-like receptors is decreased in the preterm versus term human placenta. Placenta. 2015;36:1031–1038. doi: 10.1016/j.placenta.2015.06.017. PubMed DOI

Umapathy A., Chamley L.W., James J.L. Reconciling the distinct roles of angiogenic/anti-angiogenic factors in the placenta and maternal circulation of normal and pathological pregnancies. Angiogenesis. 2020;23:105–117. doi: 10.1007/s10456-019-09694-w. PubMed DOI

Alfaidy N., Hoffmann P., Boufettal H., Samouh N., Aboussaouira T., Benharouga M., Feige J.J., Brouillet S. The multiple roles of EG-VEGF/PROK1 in normal and pathological placental angiogenesis. Biomed. Res. Int. 2014;2014:451906. doi: 10.1155/2014/451906. PubMed DOI PMC

Pereira R.D., De Long N.E., Wang R.C., Yazdi F.T., Holloway A.C., Raha S. Angiogenesis in the placenta: The role of reactive oxygen species signaling. Biomed. Res. Int. 2015;2015:814543. doi: 10.1155/2015/814543. PubMed DOI PMC

Brosens I., Pijnenborg R., Vercruysse L., Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am. J. Obstet. Gynecol. 2011;204:193–201. doi: 10.1016/j.ajog.2010.08.009. PubMed DOI PMC

Witzenbichler B., Maisonpierre P.C., Jones P., Yancopoulos G.D., Isner J.M. Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. J. Biol. Chem. 1998;273:18514–18521. doi: 10.1074/jbc.273.29.18514. PubMed DOI

Tzepi I.-M., Giamarellos-Bourboulis E.J., Carrer D.-P., Tsaganos T., Claus R.A., Vaki I., Pelekanou A., Kotsaki A., Tziortzioti V., Topouzis S., et al. Angiopoietin-2 enhances survival in experimental sepsis induced by multidrug-resistant Pseudomonas aeruginosa. J. Pharmacol. Exp. Ther. 2012;343:278–287. doi: 10.1124/jpet.112.195180. PubMed DOI

Polyzou E.N., Evangelinakis N., Pistiki A., Kotsaki A., Siristatidis C.S., Chrelias C.G., Salamalekis E., Kassanos D.P., Giamarellos-Bourboulis E.J. Angiopoietin-2 primes infection-induced preterm delivery. PLoS ONE. 2014;9:e86523. doi: 10.1371/journal.pone.0086523. PubMed DOI PMC

Abrahams V.M., Mor G. Toll-like receptors and their role in the trophoblast. Placenta. 2005;26:540–547. doi: 10.1016/j.placenta.2004.08.010. PubMed DOI

Patni S., Wynen L.P., Seager A.L., Morgan G., White J.O., Thornton C.A. Expression and activity of Toll-like receptors 1-9 in the human term placenta and changes associated with labor at term. Biol. Reprod. 2009;80:243–248. doi: 10.1095/biolreprod.108.069252. PubMed DOI

Aplin A.C., Ligresti G., Fogel E., Zorzi P., Smith K., Nicosia R.F. Regulation of angiogenesis, mural cell recruitment and adventitial macrophage behavior by Toll-like receptors. Angiogenesis. 2014;17:147–161. doi: 10.1007/s10456-013-9384-3. PubMed DOI

Grote K., Schuett H., Salguero G., Grothusen C., Jagielska J., Drexler H., Mühlradt P.F., Schieffer B. Toll-like receptor 2/6 stimulation promotes angiogenesis via GM-CSF as a potential strategy for immune defense and tissue regeneration. Blood. 2010;115:2543–2552. doi: 10.1182/blood-2009-05-224402. PubMed DOI

Grote K., Petri M., Liu C., Jehn P., Spalthoff S., Kokemüller H., Luchtefeld M., Tschernig T., Krettek C., Haasper C., et al. Toll-like receptor 2/6-dependent stimulation of mesenchymal stem cells promotes angiogenesis by paracrine factors. Eur. Cell Mater. 2013;26:66–79. doi: 10.22203/eCM.v026a05. PubMed DOI

Hilbert T., Dornbusch K., Baumgarten G., Hoeft A., Frede S., Klaschik S. Pulmonary vascular inflammation: Effect of TLR signalling on angiopoietin/TIE regulation. Clin. Exp. Pharmacol. Physiol. 2017;44:123–131. doi: 10.1111/1440-1681.12680. PubMed DOI

Wu J., Su W., Powner M.B., Liu J., Copland D.A., Fruttiger M., Madeddu P., Dick A.D., Liu L. Pleiotropic action of CpG-ODN on endothelium and macrophages attenuates angiogenesis through distinct pathways. Sci. Rep. 2016;6:31873. doi: 10.1038/srep31873. PubMed DOI PMC

Srinivas S.K., Morrison A.C., Andrela C.M., Elovitz M.A. Allelic variations in angiogenic pathway genes are associated with preeclampsia. Am. J. Obstet. Gynecol. 2010;202:445.e1–445.e11. doi: 10.1016/j.ajog.2010.01.040. PubMed DOI

Valenzuela F.J., Perez-Sepulveda A., Torres M.J., Correa P., Repetto G.M., Illanes S.E. Pathogenesis of preeclampsia: The genetic component. J. Pregnancy. 2012;2012:632732. doi: 10.1155/2012/632732. PubMed DOI PMC

Ajabi N., Mashayekhi F., Osalou M.A. Angiopoietin-2 1087G > A rs3020221 gene polymorphism is associated with in vitro fertilization and embryo transfer outcome. Middle East Fertil. Soc. J. 2017;22:336–339. doi: 10.1016/j.mefs.2017.05.010. DOI

Konac E., Onen H.I., Metindir J., Alp E., Biri A.A., Ekmekci A. Lack of association between −460 C/T and 936 C/T of the vascular endothelial growth factor and angiopoietin-2 exon 4 G/A polymorphisms and ovarian, cervical, and endometrial cancers. DNA Cell Biol. 2007;26:453–463. doi: 10.1089/dna.2007.0585. PubMed DOI

Pietrowski D., Tempfer C., Bettendorf H., Bürkle B., Nagele F., Unfried G., Keck C. Angiopoietin-2 polymorphism in women with idiopathic recurrent miscarriage. Fertil. Steril. 2003;80:1026–1029. doi: 10.1016/S0015-0282(03)01011-2. PubMed DOI

Mirkamandar E., Nemati M., Hayatbakhsh M.M., Bassagh A., Khosravimashizi A., Jafarzadeh A. Association of a single nucleotide polymorphism in the TLR2 gene (rs3804099), but not in the TLR4 gene (rs4986790), with Helicobacter pylori infection and peptic ulcer. Turk. J. Gastroenterol. 2018;29:283–291. doi: 10.5152/tjg.2018.17484. PubMed DOI PMC

Zhang P., Zhang N., Liu L., Zheng K., Zhu L., Zhu J., Cao L., Jiang Y., Liu G., He Q. Polymorphisms of toll-like receptors 2 and 9 and severity and prognosis of bacterial meningitis in Chinese children. Sci. Rep. 2017;7:42796. doi: 10.1038/srep42796. PubMed DOI PMC

Randhawa A.K., Shey M., Keyser A., Peixoto B., Wells R.D., De Kock M., Lerumo L., Hughes J., Hussey G., Hawkridge A., et al. South African Tuberculosis Vaccine Initiative Team. Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants. PLoS Pathog. 2011;7:e1002174. doi: 10.1371/journal.ppat.1002174. PubMed DOI PMC

Schurz H., Daya M., Moller M., Hoal E.G., Salie M. TLR1, 2, 4, 6 and 9 Variants Associated with Tuberculosis Susceptibility: A Systematic Review and Meta-Analysis. PLoS ONE. 2015;10:e0139711. doi: 10.1371/journal.pone.0139711. PubMed DOI PMC

Shey M., Randhawa A.K., Bowmaker M., Smith E., Scriba T., De Kock M., Mahomed H., Hussey G., Hawn T.R., Hanekom W.A. Single nucleotide polymorphisms in toll-like receptor 6 are associated with altered lipopeptide- and mycobacteria-induced interleukin-6 secretion. Genes Immun. 2010;11:561–572. doi: 10.1038/gene.2010.14. PubMed DOI PMC

Wang M.G., Zhang M.M., Wang Y., Wu S.Q., Zhang M., He J.Q. Association of TLR8 and TLR9 polymorphisms with tuberculosis in a Chinese Han population: A case-control study. BMC Infect. Dis. 2018;18:561. doi: 10.1186/s12879-018-3485-y. PubMed DOI PMC

Fischer J., Weber A., Böhm S., Dickhöfer S., El Maadidi S., Deichsel D., Knop V., Klinker H., Möller B., Rasenack J., et al. Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection. Gut. 2017;66:1829–1837. doi: 10.1136/gutjnl-2015-310239. PubMed DOI

Ambrocio-Ortiz E., Pérez-Rubio G., Abarca-Rojano E., Montaño M., Ramos C., Hernández-Zenteno R.D., Del Angel-Pablo A.D., Reséndiz-Hernández J.M., Ramírez-Venegas A., Falfán-Valencia R. Influence of proinflammatory cytokine gene polymorphisms on the risk of COPD and the levels of plasma protein. Cytokine. 2018;111:364–370. doi: 10.1016/j.cyto.2018.09.017. PubMed DOI

Keren-Politansky A., Breizman T., Brenner B., Sarig G., Drugan A. The coagulation profile of preterm delivery. Thromb. Res. 2014;133:585–589. doi: 10.1016/j.thromres.2014.01.018. PubMed DOI

Bremme K.A. Haemostatic changes in pregnancy. Best Pr. Res. Clin. Haematol. 2003;16:153–168. doi: 10.1016/S1521-6926(03)00021-5. PubMed DOI

Cerneca F., Ricci G., Simeone R., Malisano M., Alberico S., Guaschino S. Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 1997;73:31–36. doi: 10.1016/S0301-2115(97)02734-6. PubMed DOI

Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin. Thromb. Hemost. 2003;29:125–130. doi: 10.1055/s-2003-38897. PubMed DOI

Chaiworapongsa T., Espinoza J., Yoshimatsu J., Kim Y.M., Bujold E., Edwin S., Yoon B.H., Romero R. Activation of coagulation system in preterm labor and preterm premature rupture of membranes. J. Matern. Fetal Neonatal Med. 2002;11:368–373. doi: 10.1080/jmf.11.6.368.373. PubMed DOI

Elovitz M.A., Baron J., Phillippe M. The role of thrombin in preterm parturition. Am. J. Obstet. Gynecol. 2001;185:1059–1063. doi: 10.1067/mob.2001.117638. PubMed DOI

Magee L.A., Pels A., Helewa M., Rey E., von Dadelszen P., Canadian Hypertensive Disorders of Pregnancy Working Group Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: Executive summary. J. Obstet. Gynaecol. Can. 2014;36:416–441. doi: 10.1016/S1701-2163(15)30588-0. PubMed DOI

SNP Database (dbSNP) of the National Center for Biotechnology Information (NCBI) [(accessed on 22 February 2022)]; Available online: https://www.ncbi.nlm.nih.gov/snp/

Amin-Beidokhti M., Gholami M., Abedin-Do A., Pirjani R., Sadeghi H., Karamoddin F., Yassaee V.R., Mirfakhraie R. An intron variant in the FLT1 gene increases the risk of preeclampsia in Iranian women. Clin. Exp. Hypertens. 2019;41:697–701. doi: 10.1080/10641963.2018.1539097. PubMed DOI

Denschlag D., Bettendorf H., Watermann D., Keck C., Tempfer C., Pietrowski D. Polymorphism of the p53 tumor suppressor gene is associated with susceptibility to uterine leiomyoma. Fertil. Steril. 2005;84:162–166. doi: 10.1016/j.fertnstert.2005.01.103. PubMed DOI

Elloumi N., Fakhfakh R., Abida O., Ayadi L., Marzouk S., Hachicha H., Fourati M., Bahloul Z., Mhiri M.N., Kammoun K., et al. Relevant genetic polymorphisms and kidney expression of Toll-like receptor (TLR)-5 and TLR-9 in lupus nephritis. Clin. Exp. Immunol. 2017;190:328–339. doi: 10.1111/cei.13022. PubMed DOI PMC

Meena N.K., Ahuja V., Meena K., Paul J. Association of TLR5 gene polymorphisms in ulcerative colitis patients of north India and their role in cytokine homeostasis. PLoS ONE. 2015;10:e0120697. doi: 10.1371/journal.pone.0120697. PubMed DOI PMC

Saeki H., Tsunemi Y., Asano N., Nakamura K., Sekiya T., Hirai K., Kakinuma T., Fujita H., Kagami S., Tamaki K. Analysis of GM-CSF gene polymorphisms (3606T/C and 3928C/T) in Japanese patients with atopic dermatitis. Clin. Exp. Dermatol. 2006;31:278–280. doi: 10.1111/j.1365-2230.2005.02052.x. PubMed DOI

Zhao Y., Bu H., Hong K., Yin H., Zou Y.-L., Geng S.-J., Zheng M.-M., He J.-Y. Genetic polymorphisms of CCL1 rs2072069 G/A and TLR2 rs3804099 T/C in pulmonary or meningeal tuberculosis patients. Int. J. Clin. Exp. Pathol. 2015;8:12608–12620. PubMed PMC

SNPStats Software. [(accessed on 22 February 2022)]. Available online: https://www.snpstats.net/start.htm.

Bagamery K., Landau R., Kvell K., Graham J. Different platelet activation levels in non-pregnant, normotensive pregnant, pregnancy-induced hypertensive and pre-eclamptic women. A pilot study of flow cytometric analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 2005;121:117–118. doi: 10.1016/j.ejogrb.2004.12.004. PubMed DOI

Erez O., Romero R., Hoppensteadt D., Fareed J., Chaiworapongsa T., Kusanovic J.P., Mazaki-Tovi S., Gotsch F., Than N.G., Vaisbuch E., et al. Premature labor: A state of platelet activation? J. Perinat. Med. 2008;36:377–387. doi: 10.1515/JPM.2008.082. PubMed DOI PMC

Lok C.A.R., Nieuwland R., Sturk A., Hau C.M., Boer K., Van Bavel E., Vanderpost J.A.M. Microparticle-associated P-selectin reflects platelet activation in preeclampsia. Platelets. 2007;18:68–72. doi: 10.1080/09537100600864285. PubMed DOI

Missfelder-Lobos H., Teran E., Lees C., Albaiges G., Nicolaides K.H. Platelet changes and subsequent development of pre-eclampsia and fetal growth restriction in women with abnormal uterine artery Doppler screening. Ultrasound Obstet. Gynecol. 2002;19:443–448. doi: 10.1046/j.1469-0705.2002.00672.x. PubMed DOI

Artunc Ulkumen B., Pala H.G., Calik E., Oruc Koltan S. Platelet distribution width (PDW): A putative marker for threatened preterm labour. Pak. J. Med. Sci. 2014;30:745–748. doi: 10.12669/pjms.304.4991. PubMed DOI PMC

Tygart S.G., McRoyan D.K., Spinnato J.A., McRoyan C.J., Kitay D.Z. Longitudinal study of platelet indices during normal pregnancy. Am. J. Obstet. Gynecol. 1986;154:883–887. doi: 10.1016/0002-9378(86)90476-X. PubMed DOI

Badfar G., Shohani M., Soleymani A., Azami M. Maternal anemia during pregnancy and small for gestational age: A systematic review and meta-analysis. J. Matern. Fetal Neonatal Med. 2019;32:1728–1734. doi: 10.1080/14767058.2017.1411477. PubMed DOI

Druk L., Hants Y., Farkash R., Ruchlemer R., Samueloff A., Grisaru-Granovsky S. Iron deficiency anemia at admission for labor and delivery is associated with an increased risk for Cesarean section and adverse maternal and neonatal outcomes. Transfusion. 2015;55:2799–2806. doi: 10.1111/trf.13252. PubMed DOI

Mahmood T., Rehman A.U., Tserenpil G., Siddiqui F., Ahmed M., Siraj F., Kumar B. The Association between Iron-deficiency Anemia and Adverse Pregnancy Outcomes: A Retrospective Report from Pakistan. Cureus. 2019;11:e5854. doi: 10.7759/cureus.5854. PubMed DOI PMC

Parks S., Hoffman M.K., Goudar S.S., Patel A., Saleem S., Ali S.A., Goldenberg R.L., Hibberd P.L., Moore J., Wallace D., et al. Maternal anaemia and maternal, fetal, and neonatal outcomes in a prospective cohort study in India and Pakistan. BJOG. 2019;126:737–743. doi: 10.1111/1471-0528.15585. PubMed DOI PMC

Ronkainen J., Lowry E., Heiskala A., Uusitalo I., Koivunen P., Kajantie E., Vääräsmäki M., Järvelin M.-R., Sebert S. Maternal hemoglobin associates with preterm delivery and small for gestational age in two Finnish birth cohorts. Eur. J. Obstet. Gynecol. Reprod. Biol. 2019;238:44–48. doi: 10.1016/j.ejogrb.2019.04.045. PubMed DOI

Young M.F., Oaks B.M., Tandon S., Martorell R., Dewey K.G., Wendt A.S. Maternal hemoglobin concentrations across pregnancy and maternal and child health: A systematic review and meta-analysis. Ann. N.Y. Acad. Sci. 2019;1450:47–68. doi: 10.1111/nyas.14093. PubMed DOI PMC

Jung J., Rahman M., Rahman S., Swe K.T., Islam R., Rahman O., Akter S. Effects of hemoglobin levels during pregnancy on adverse maternal and infant outcomes: A systematic review and meta-analysis. Ann. N.Y. Acad. Sci. 2019;1450:69–82. doi: 10.1111/nyas.14112. PubMed DOI

Ramaeker D.M., Simhan H.N. Sonographic cervical length, vaginal bleeding, and the risk of preterm birth. Am. J. Obstet. Gynecol. 2012;206:224.e1–224.e4. doi: 10.1016/j.ajog.2011.10.879. PubMed DOI

Expert Panel on GYN and OB Imaging. Shipp T.D., Poder L., Feldstein V.A., Oliver E.R., Promes S.B., Strachowski L.M., Sussman B.L., Wang E.Y., Weber T.M., et al. ACR Appropriateness Criteria® Second and Third Trimester Vaginal Bleeding. J. Am. Coll. Radiol. 2020;17:S497–S504. doi: 10.1016/j.jacr.2020.09.004. PubMed DOI

Petriglia G., Palaia I., Musella A., Marchetti C., Antonilli M., Brunelli R., Ostuni R. Threatened abortion and late-pregnancy complications: A case-control study and review of literature. Minerva Ginecol. 2015;67:491–497. PubMed

Saraswat L., Bhattacharya S., Maheshwari A., Bhattacharya S. Maternal and perinatal outcome in women with threatened miscarriage in the first trimester: A systematic review. BJOG. 2010;117:245–257. doi: 10.1111/j.1471-0528.2009.02427.x. PubMed DOI

Saber T., Veale D.J., Balogh E., McCormick J., NicAnUltaigh S., Connolly M., Fearon U. Toll-like receptor 2 induced angiogenesis and invasion is mediated through the Tie2 signalling pathway in rheumatoid arthritis. PLoS ONE. 2011;6:e23540. doi: 10.1371/journal.pone.0023540. PubMed DOI PMC

Chen K.-H., Gu W., Zeng L., Jiang D.-P., Zhang L.-Y., Zhou J., Du D.-Y., Hu P., Liu Q., Huang S.-N., et al. Identification of haplotype tag SNPs within the entire TLR2 gene and their clinical relevance in patients with major trauma. Shock. 2011;35:35–41. doi: 10.1097/SHK.0b013e3181eb45b3. PubMed DOI

Varzari A., Deyneko I.V., Vladei I., Grallert H., Schieck M., Tudor E., Illig T. Genetic variation in TLR pathway and the risk of pulmonary tuberculosis in a Moldavian population. Infect. Genet. Evol. 2018;68:84–90. doi: 10.1016/j.meegid.2018.12.005. PubMed DOI

Ma X., Liu Y., Gowen B.B., Graviss E.A., Clark A.G., Musser J.M. Full-exon resequencing reveals toll-like receptor variants contribute to human susceptibility to tuberculosis disease. PLoS ONE. 2007;2:e1318. doi: 10.1371/journal.pone.0001318. PubMed DOI PMC

Naderi M., Hashemi M., Hazire-Yazdi L., Taheri M., Moazeni-Roodi A., Eskandari E., Bahari G. Association between toll-like receptor2 Arg677Trp and 597T/C gene polymorphisms and pulmonary tuberculosis in Zahedan, Southeast Iran. Braz. J. Infect. Dis. 2013;17:516–520. doi: 10.1016/j.bjid.2012.12.009. PubMed DOI PMC

Xue X., Qiu Y., Jiang D., Jin T., Yan M., Zhu X., Chu Y. The association analysis of TLR2 and TLR4 gene with tuberculosis in the Tibetan Chinese population. Oncotarget. 2017;8:113082–113089. doi: 10.18632/oncotarget.22996. PubMed DOI PMC

Junjie X., Songyao J., Minmin S., Yanyan S., Baiyong S., Xiaxing D., Jiabin J., Xi Z., Hao C. The association between Toll-like receptor 2 single-nucleotide polymorphisms and hepatocellular carcinoma susceptibility. BMC Cancer. 2012;12:57. doi: 10.1186/1471-2407-12-57. PubMed DOI PMC

Kim M.K., Park S.W., Kim S.K., Park H.J., Eun Y.G., Kwon K.H., Kim J. Association of Toll-like receptor 2 polymorphisms with papillary thyroid cancer and clinicopathologic features in a Korean population. J. Korean Med. Sci. 2012;27:1333–1338. doi: 10.3346/jkms.2012.27.11.1333. PubMed DOI PMC

Zeng H.-M., Pan K.-F., Zhang Y., Zhang L., Ma J.-L., Zhou T., Su H.-J., Li W.-Q., Li J.-Y., You W.-C. The correlation between polymorphisms of Toll-like receptor 2 and Toll-like receptor 9 and susceptibility to gastric cancer. Zhonghua Yu Fang Yi Xue Za Zhi. 2011;45:588–592. doi: 10.3760/cma.j.issn.0253-9624.2011.07.004. PubMed DOI

Semlali A., Parine N.R., Al-Numair N.S., Almutairi M., Hawsawi Y.M., Al Amri A., Aljebreen A.M., Arafah M., Almadi M.A., Azzam N.A., et al. Potential role of Toll-like receptor 2 expression and polymorphisms in colon cancer susceptibility in the Saudi Arabian population. OncoTargets Ther. 2018;11:8127–8141. doi: 10.2147/OTT.S168478. PubMed DOI PMC

Oyarzún C.P.M., Glembotsky A.C., Goette N.P., Lev P.R., De Luca G., Pietto M.C.B., Moiraghi B., Ríos M.A.C., Vicente A., Marta R.F., et al. Platelet Toll-Like Receptors Mediate Thromboinflammatory Responses in Patients with Essential Thrombocythemia. Front. Immunol. 2020;11:705. doi: 10.3389/fimmu.2020.00705. PubMed DOI PMC

Oluboyo A., Chukwu S.I., O Oluboyo B., Odewusi O.O. Evaluation of Angiopoietins 1 and 2 in Malaria-Infested Children. J. Environ. Public Health. 2020;2020:2169763. doi: 10.1155/2020/2169763. PubMed DOI PMC

Jäckel S., Kiouptsi K., Lillich M., Hendrikx T., Khandagale A., Kollar B., Hörmann N., Reiss C., Subramaniam S., Wilms E., et al. Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2. Blood. 2017;130:542–553. doi: 10.1182/blood-2016-11-754416. PubMed DOI

Biswas S., Zimman A., Gao D., Byzova T.V., Podrez E.A. TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated With Hyperlipidemia. Circ. Res. 2017;121:951–962. doi: 10.1161/CIRCRESAHA.117.311069. PubMed DOI PMC

Allam R., Anders H.J. The role of innate immunity in autoimmune tissue injury. Curr. Opin. Rheumatol. 2008;20:538–544. doi: 10.1097/BOR.0b013e3283025ed4. PubMed DOI

Brentano F., Kyburz D., Gay S. Toll-like receptors and rheumatoid arthritis. Methods Mol. Biol. 2009;517:329–343. doi: 10.1007/978-1-59745-541-1_20. PubMed DOI

Lampropoulou V., Hoehlig K., Roch T., Neves P., Calderón-Gómez E., Sweenie C.H., Hao Y., Freitas A.A., Steinhoff U., Anderton S.M., et al. TLR-activated B cells suppress T cell-mediated autoimmunity. J. Immunol. 2008;180:4763–4773. doi: 10.4049/jimmunol.180.7.4763. PubMed DOI

Lien E., Zipris D. The role of Toll-like receptor pathways in the mechanism of type 1 diabetes. Curr. Mol. Med. 2009;9:52–68. doi: 10.2174/156652409787314453. PubMed DOI

Papadimitraki E.D., Bertsias G.K., Boumpas D.T. Toll like receptors and autoimmunity: A critical appraisal. J. Autoimmun. 2007;29:310–318. doi: 10.1016/j.jaut.2007.09.001. PubMed DOI

Wen L., Ley R.E., Volchkov P.Y., Stranges P.B., Avanesyan L., Stonebraker A.C., Hu C., Wong F.S., Szot G.L., Bluestone J.A., et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008;455:1109–1113. doi: 10.1038/nature07336. PubMed DOI PMC

Tai N., Wong F.S., Wen L. TLR9 deficiency promotes CD73 expression in T cells and diabetes protection in nonobese diabetic mice. J. Immunol. 2013;191:2926–2937. doi: 10.4049/jimmunol.1300547. PubMed DOI PMC

Wong F.S., Hu C., Zhang L., Du W., Alexopoulou L., Flavell R.A., Wen L. The role of Toll-like receptors 3 and 9 in the development of autoimmune diabetes in NOD mice. Ann. N.Y. Acad. Sci. 2008;1150:146–148. doi: 10.1196/annals.1447.039. PubMed DOI

Zhang Y., Lee A.S., Shameli A., Geng X., Finegood D., Santamaria P., Dutz J.P. TLR9 blockade inhibits activation of diabetogenic CD8+ T cells and delays autoimmune diabetes. J. Immunol. 2010;184:5645–5653. doi: 10.4049/jimmunol.0901814. PubMed DOI

Liu M., Peng J., Tai N., Pearson J.A., Hu C., Guo J., Hou L., Zhao H., Wong F.S., Wen L. Toll-like receptor 9 negatively regulates pancreatic islet beta cell growth and function in a mouse model of type 1 diabetes. Diabetologia. 2018;61:2333–2343. doi: 10.1007/s00125-018-4705-0. PubMed DOI PMC

Wifi M.-N.A., Assem M., Elsherif R.H., El-Azab H.A.-F., Saif A. Toll-like receptors-2 and -9 (TLR2 and TLR9) gene polymorphism in patients with type 2 diabetes and diabetic foot. Med. Balt. 2017;96:e6760. doi: 10.1097/MD.0000000000006760. PubMed DOI PMC

Alvarez A.E., Marson F.A.L., Bertuzzo C.S., Bastos J.C.S., Baracat E.C.E., Brandao M.B., Tresoldi A.T., das Neves Romaneli M.T., Almeida C.C.B., de Oliveira T., et al. Association between single nucleotide polymorphisms in TLR4, TLR2, TLR9, VDR, NOS2 and CCL5 genes with acute viral bronchiolitis. Gene. 2018;645:7–17. doi: 10.1016/j.gene.2017.12.022. PubMed DOI PMC

Chen X., Wang S., Liu L., Chen Z., Qiang F., Kan Y., Shen Y., Wu J., Shen H., Hu Z. A genetic variant in the promoter region of Toll-like receptor 9 and cervical cancer susceptibility. DNA Cell Biol. 2012;31:766–771. doi: 10.1089/dna.2011.1427. PubMed DOI

Tian S., Zhang L., Yang T., Wei X., Zhang L., Yu Y., Li Y., Cao D., Yang X. The Associations between Toll-Like Receptor 9 Gene Polymorphisms and Cervical Cancer Susceptibility. Mediat. Inflamm. 2018;2018:9127146. doi: 10.1155/2018/9127146. PubMed DOI PMC

Gębura K., Świerkot J., Wysoczańska B., Korman L., Nowak B., Wiland P., Bogunia-Kubik K. Polymorphisms within Genes Involved in Regulation of the NF-κB Pathway in Patients with Rheumatoid Arthritis. Int. J. Mol. Sci. 2017;18:1432. doi: 10.3390/ijms18071432. PubMed DOI PMC

Chauhan A., Pandey N., Desai A., Raithatha N., Patel P., Choxi Y., Kapadia R., Khandelwal R., Jain N. Association of TLR4 and TLR9 gene polymorphisms and haplotypes with cervicitis susceptibility. PLoS ONE. 2019;14:e0220330. doi: 10.1371/journal.pone.0220330. PubMed DOI PMC

Hamann L., Hamprecht A., Gomma A., Schumann R.R. Rapid and inexpensive real-time PCR for genotyping functional polymorphisms within the Toll-like receptor -2, -4, and -9 genes. J. Immunol. Methods. 2004;285:281–291. doi: 10.1016/j.jim.2003.12.005. PubMed DOI

Bharti D., Kumar A., Mahla R., Kumar S., Ingle H., Shankar H., Joshi B., Raut A.A., Kumar H. The role of TLR9 polymorphism in susceptibility to pulmonary tuberculosis. Immunogenetics. 2014;66:675–681. doi: 10.1007/s00251-014-0806-1. PubMed DOI

Heger L.A., Hortmann M., Albrecht M., Colberg C., Peter K., Witsch T., Stallmann D., Zirlik A., Bode C., Duerschmied D., et al. Inflammation in acute coronary syndrome: Expression of TLR2 mRNA is increased in platelets of patients with ACS. PLoS ONE. 2019;14:e0224181. doi: 10.1371/journal.pone.0224181. PubMed DOI PMC

Panigrahi S., Ma Y., Hong L., Gao D., West X.Z., Salomon R.G., Byzova T.V., Podrez E.A. Engagement of platelet toll-like receptor 9 by novel endogenous ligands promotes platelet hyperreactivity and thrombosis. Circ. Res. 2013;112:103–112. doi: 10.1161/CIRCRESAHA.112.274241. PubMed DOI PMC

Aslam R., Speck E.R., Kim M., Crow A.R., Bang K.W.A., Nestel F.P., Ni H., Lazarus A., Freedman J., Semple J.W. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood. 2006;107:637–641. doi: 10.1182/blood-2005-06-2202. PubMed DOI

Wujcicka W.I., Kacerovsky M., Krekora M., Kaczmarek P., Grzesiak M. Single Nucleotide Polymorphisms from CSF2, FLT1, TFPI and TLR9 Genes Are Associated with Prelabor Rupture of Membranes. Genes. 2021;12:1725. doi: 10.3390/genes12111725. PubMed DOI PMC

Liu Y., Ke Z., Liao W., Chen H., Wei S., Lai X., Chen X. Pregnancy outcomes and superiorities of prophylactic cervical cerclage and therapeutic cervical cerclage in cervical insufficiency pregnant women. Arch. Gynecol. Obstet. 2018;297:1503–1508. doi: 10.1007/s00404-018-4766-9. PubMed DOI