The effects of NLRP3 rs10754558 and rs4612666 polymorphisms on preeclampsia susceptibility, onset, and severity: a case-control study and in silico analysis

Document Type : Original article

Authors

1 Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran

2 Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran

3 Department of Obstetrics and Gynecology, Pregnancy Health Research Center, Zahedan University of Medical Sciences, Zahedan, Iran

4 Pregnancy Health Research Center, Zahedan University of Medical Sciences, Zahedan, Iran

5 Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Abstract

Preeclampsia (PE) is one of the serious complications of pregnancy and its exact etiology is unknown. Inflammasomes are multiportion complexes whose relation with PE has been described. Evidence showed the effect of NLRP3 inflammasome in PE pathogenesis. In the current study, we investigated the possible impacts of NLRP3 polymorphisms on PE.  A total of 252 PE and 258 control pregnant women were selected for the study. The PCR-RFLP method was employed to genotype rs10754558 and rs4612666 polymorphisms. The RNAsnp and SpliceAid 2 software were used for in silico analysis. There was no relationship between NLRP3 polymorphisms and PE. In comparison to control women, the NLRP3 rs10754558 could increase the risk of severe PE in codominant and dominant models (OR=1.89, 95% CI=1.19-3.01, P=0.012, OR=1.95, 95% CI=1.24-3.06, P=0.0037, respectively). The findings of the in silico analysis revealed the effects of rs10754558 C to G and rs4612666 C to T substitutions on protein binding sites and rs10754558 C to G substitution on secondary RNA structure. These findings could confirm the finding those studies reported the impacts of these variants on various diseases. In conclusion, the NLRP3 rs10754558 variant was associated with an increased risk of EOPE and severe PE.

Keywords


  1. Hod T, Cerdeira AS, Karumanchi SA. Molecular mechanisms of preeclampsia. Cold Spring Harb Perspect Med 2015;5:a023473.
  2. Kharaghani R, Cheraghi Z, Okhovat Esfahani B, Mohammadian Z, Nooreldinc RS. Prevalence of Preeclampsia and Eclampsia in Iran. Arch Iran Med 2016;19:64-71.
  3. Cunningham FG, Leveno KJ, Dashe JS, Hoffman BL, Spong CY, Casey BM. Williams Obstetrics, 26e. Editors New York, NY: McGraw Hill; 2022.
  4. Vitoratos N, Hassiakos D, Iavazzo C. Molecular mechanisms of preeclampsia. J Pregnancy 2012;2012:298343.
  5. Miller D, Motomura K, Galaz J, Gershater M, Lee ED, Romero R, Gomez-Lopez N. Cellular immune responses in the pathophysiology of preeclampsia. J Leukoc Biol 2022;111:237-260.
  6. Fu J, Wu H. Structural mechanisms of NLRP3 inflammasome assembly and activation. Annu Rev Immunol 2023;41:301-316.
  7. Shirasuna K, Karasawa T, Takahashi M. Role of the NLRP3 inflammasome in preeclampsia. Front Endocrinol (Lausanne) 2020;11:80.
  8. Gomez-Lopez N, Motomura K, Miller D, Garcia-Flores V, Galaz J, Romero R. Inflammasomes: their role in normal and complicated pregnancies. J Immunol 2019;203: 2757-2769.
  9. Franchi L, Eigenbrod T, Núñez G. Cutting edge: TNF-α mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol 2009;183:792-796.
  10. Swanson KV, Deng M, Ting JPY. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 2019;19:477-489.
  11. Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ, Wang C, Morozova-Roche LA, Herzog RI, Iwasaki A, Dixit VD. β-Hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep 2017;18:2077-2087.
  12. Mulla MJ, Myrtolli K, Potter J, Boeras C, Kavathas PB, Sfakianaki AK, Tadesse S, Norwitz ER, Guller S, Abrahams VM. Uric acid induces trophoblast IL‐1β production via the inflammasome: implications for the pathogenesis of preeclampsia. Ame J Reprod Immunol 2011;65:542-548.
  13. Xie F, Hu Y, Turvey SE, Magee LA, Brunham RM, Choi KC, Krajden M, Leung PCK, Money DM, Patrick DM, Thomas E, Dadelszen P. Toll‐like receptors 2 and 4 and the cryopyrin inflammasome in normal pregnancy and pre‐eclampsia. BJOG 2010;117:99-108.
  14. Stødle GS, Silva GB, Tangerås LH, Gierman LM, Nervik I, Dahlberg UE, Sun C, Aune MH, Thomsen LCV, Bjørge L, Iversen AC. Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP) 3 inflammasome activation in trophoblasts. Clin Exp Immunol 2018;193:84-94.
  15. Xu L, Li S, Liu Z, Jiang S, Wang J, Guo M, Zhao X, Song W, Liu S. The NLRP3 rs10754558 polymorphism is a risk factor for preeclampsia in a Chinese Han population. J Matern Fetal Neonatal Med 2019;32:1792-1799.
  16. Chen A, Zhao H, Wang J, Zhang R, Liu J, Zhao X, Li C, Jia X, Li X, Lin Y, Guo M, Li S, Liu C, Li Y, Liu S. Haplotype analysis of candidate genes involved in inflammation and oxidative stress and the susceptibility to preeclampsia. J Immunol Res 2020;2020:4683798.
  17. Rezaei M, Eskandari F, Mohammadpour-Gharehbagh A, Teimoori B, Yaghmaei M, Mokhtari M, Salimi S. The Drosha rs10719 T>C polymorphism is associated with preeclampsia susceptibility. Clin Exp Hypertens 2018;40:440-445.
  18. Cheng L, Yin R, Yang S, Pan X, Ma A. Rs4612666 polymorphism of the NLRP3 gene is associated with the occurrence of large artery atherosclerotic ischemic strokes and microembolic signals. BioMed Res Int 2018;2018:6345805.
  19. Abolfathi M, Bagheri N, Iranparast S, Soltani A, Sanaei A, Rahimian G, Kheiri S, Shirzad H. Associations of a NLRP3 rs10754558 polymorphism with Helicobacter pylori-infected patients with gastritis and peptic ulcer disease. Jundishapur J Microb 2019;12:e88231.
  20. Piva F, Giulietti M, Burini AB, Principato G. SpliceAid 2: a database of human splicing factors expression data and RNA target motifs. Hum Mutat 2012;33:81-85.
  21. Sabarinathan R, Tafer H, Seemann SE, Hofacker IL, Stadler PF, Gorodkin J. RNA snp: efficient detection of local RNA secondary structure changes induced by SNP s. Hum Mutat 2013;34:546-556.
  22. Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: pathophysiology, challenges, and perspectives. Circ Res 2019;124:1094-1112.
  23. El-Sayed AA. Preeclampsia: A review of the pathogenesis and possible management strategies based on its pathophysiological derangements. Taiwan J Obstet Gynecol 2017;56: 593-598.
  24. Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int J Mol Sci 2019;20:3328.
  25. Zhang Y, Yang W, Li W, Zhao Y. NLRP3 inflammasome: checkpoint connecting innate and adaptive immunity in autoimmune diseases. Front Immunol 2021;12:732933.
  26. Sutterwala FS, Haasken S, Cassel SL. Mechanism of NLRP3 inflammasome activation. Ann N Y Acad Sci 2014;1319:82-95.
  27. Xu J, Núñez G. The NLRP3 inflammasome: activation and regulation. Trends Biochem Sci 2023;48:331-344.
  28. Weel IC, Romão-Veiga M, Matias ML, Fioratti EG, Peraçoli JC, Borges VT, Araujo Jr JP, Peracoli MT. Increased expression of NLRP3 inflammasome in placentas from pregnant women with severe preeclampsia. J Reprod Immunol 2017;123:40-47.
  29. Zeng H, Han X, Zhu Z, Yu S, Mei S, Cheng X, Zhang W, Zhang G, Fang D. Increased uterine NLRP3 inflammasome and leucocyte infiltration in a rat model of preeclampsia. Am J Reprod Immunol 2021;86:e13493.
  30. Pontillo A, Reis EC, Bricher PN, Vianna P, Diniz S, Fernandes KS, Chies JA, Sandrim V. NLRP1 L155H polymorphism is a risk factor for preeclampsia development. Am J Reprod Immunol 2015;73:577-581.
  31. Wu Z, Wu S, Liang T. Association of NLRP3 rs35829419 and rs10754558 polymorphisms with risks of autoimmune diseases: a systematic review and meta-analysis. Front Genet 2021;12:690860.
  32. Lee YH, Song GG. The role of NLRP3 and CARD8 polymorphisms in the risk of rheumatoid arthritis: A meta‐analysis of genetic association studies. Int J Rheum Dis 2023; 26:2214-2222.
  33. Lee YH, Bae SC. Association between functional NLRP3 polymorphisms and susceptibility to autoimmune and inflammatory diseases: a meta-analysis. Lupus 2016;25:1558-1566.
  34. Zhou 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.
  35. Zheng Y, Zhang D, Zhang L, Fu M, Zeng Y, Russell R. Variants of NLRP3 gene are associated with insulin resistance in Chinese Han population with type-2 diabetes. Gene 2013;530:151-154.
  36. Bala K, Kumar V, Singh J, Singh J. Association of nod-like receptor pyrin domain containing 3 (rs10754558) and protein kinase C zeta (rs2503706) gene polymorphisms with the risk of type 2 diabetes mellitus in Indian population. Gene Rep 2021;23:101093.
  37. Xu G, Huang R, Xia W, Jiang B, Xiao G, Li Y. Associations between inflammasome‐related gene NLRP3 polymorphisms (rs10754558 and rs35829419) and risk of bladder cancer in a Chinese population. J Clin Lab Anal 2021;35:e23973.
  38. Barreau C, Paillard L, Mereau A, Osborne HB. Mammalian CELF/Bruno-like RNA-binding proteins: molecular characteristics and biological functions. Biochimie 2006;88:515-525.
  39. Chen-Plotkin AS, Lee VMY, Trojanowski JQ. TAR DNA-binding protein 43 in neurodeg-enerative disease. Nat Rev Neurol 2010;6:211-220.
  40. Yoshino H, Enokida H, Chiyomaru T, Tatarano S, Hidaka H, Yamasaki T, Gotannda T, Tachiwada T, Nohata N, Yamane T, Seki N, Nakagawa M. Tumor suppressive microRNA-1 mediated novel apoptosis pathways through direct inhibition of splicing factor serine/ arginine-rich 9 (SRSF9/SRp30c) in bladder cancer. Biochem Biophys Res Commun 2012; 417:588-593.
  41. Oiwa K, Watanabe S, Onodera K, Iguchi Y, Kinoshita Y, Komine O, Sobue A, Okada Y, Katsuno M, Yamanaka K. Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis. Sci Adv 2023;9:eadf6895.
  42. Guan YC, Jiang L, Ma LL, Sun XN, Yu DD, Liu J, Qu DX, Fang MY. Expression of glucocorticoid receptor isoforms and associations with serine/arginine-rich protein 30c and 40 in patients with systemic lupus erythematosus. Clin Exp Rheumatol 2015;33:225-233.
  43. Guo Q, Wu Y, Guo X, Cao L, Xu F, Zhao H, Zhu J, Wen H, Ju X, Wu X. The RNA-binding protein CELF2 inhibits ovarian cancer progression by stabilizing FAM198B. Mol Ther Nucleic Acids 2020;23:169-184.
  44. Pique L, Martinez de Paz A, Pineyro D, Martinez-Cardus A, Castro de Moura M, Llinas-Arias P, Setien F, Gomez-Miragaya J, Gonzalez-Suarez E, Sigurdsson S, Jonasson JG, Villanueva A, Vidal A, Davalos V, Esteller M. Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer. Oncogene 2019;38:7106-7112.