Research Article

Association of Toll-like receptor 2, 4, and 9 gene polymorphism with high altitude induced thrombosis patients in Indian population

Swati Sharma#, Iti Garg*#, Gauri Mishra, Babita Kumari, Lilly Ganju and Bhuvnesh Kumar

Published: 02/08/2019 | Volume 3 - Issue 1 | Pages: 006-015

Abstract

Venous Thromboembolism (VTE) is a multifactorial disease that is influenced by individual genetic background and various environmental factors, high altitude (HA) being the one. HA exposure may cause release of several damage associated molecular patterns (DAMPs), which act as ligand for various immune receptors. Previous studies on western population involving SNPs analysis of TLRs demonstrated that TLRs are involved in development and progression of several cardiovascular diseases. But, no such study has been done in Indian population in context of HA exposure. TLRs, being receptors play a significant role in manifestation and elimination of diseases by recognition of specific ligands and downstream signal transduction therefore; the genetic variation in TLRs could be implicated for imparting varying response of individuals to discrete diseases.

Therefore, in accordance with it, in present study changes in protein structures of TLR2 and TLR4 due to presence of SNP were accessed by in-silico tools to observe whether the mutation has effect on protein structure and integrity which further influencing its function. The results showed that SNP harbouring protein has decreased functional pockets, thus may be protective for disease. Taking this lead further to genotypic level, first time association between Toll-like receptor genes polymorphism and risk of high altitude induced venous thrombosis is analyzed in Indian population by PCR RFLP method. Though the result showed initial trend that TLR2 and TLR9 SNP are monomrphic in distribution and for TLR4 there was no significant difference in distribution of SNP between healthy and HA-DVT group, these SNPs have potential to be used as susceptibility markers if studied in large population size. 

Read Full Article HTMLDOI: 10.29328/journal.icci.1001008Cite this Article

References

  1. Homans J. Thrombosis of the deep leg veins due to prolonged sitting. N Engl J Med. 1954; 250: 148-149. Ref.: https://goo.gl/za8FH9
  2. Gibbs NM. Venous thrombosis of the lower limbs with particular to bed rest. Br J Surg. 1957; 45: 209-236. Ref.: https://goo.gl/t2j1EN
  3. Hull RD, Raskob GE. Prophylaxis of venous thromboembolic disease following hip and knee surgery. J Bone Joint Surg Am.1986; 68: 146-150. Ref.: https://goo.gl/RN48ra
  4. Ward M. Mountain Medicine: A Clinical Study of Cold and High Altitude. 1975; Ref.: https://goo.gl/dDt4Ab
  5. Zangari M, Fink L, Tolomelli G, Lee JC, Stein BL, et al. Could hypoxia increase the prevalence of thrombotic complications in polycythemia vera? Blood Coagul Fibrinolysis. 2013; 24: 311-316. Ref.: https://goo.gl/8UkEK6
  6. Anand AC, Saha A, Kumar R, Sharma V, Jha SK. Portal system thrombosis: a new dimension of high altitude illnesses. Trop Gastroenterol. 2000; 21: 172-173. Ref.: https://goo.gl/FrQesU
  7. Cheng S, Chng SM, Singh R. Cerebral venous infarction during a high altitude expedition. Singapore Med J. 2009; 50: e306-308. Ref.: https://goo.gl/Txhhdz
  8. Gupta N, Ashraf MZ. Exposure to high altitude: a risk factor for venous thromboembolism? Semin Thromb Hemost. 2012; 38: 156-163. Ref.: https://goo.gl/MdT1w6
  9. Anand AC, Jha SK, Saha A, Sharma V, Adya CM. Thrombosis as a complication of extended stay at high altitude. Natl Med J India. 2001; 14: 197-201 Ref.: https://goo.gl/3pLNJg
  10. White RH, Zhou H, Romano PS. Incidence of idiopathic deep vein thrombosis and secondary thromboembolism among ethnic groups in California. Ann Inter Med. 1998; 128: 737-740. Ref.: https://goo.gl/vuUKa1
  11. Kapoor VK. Venous thromboembolism in India. Editorials. Natl Med J India. 2010; 23: 93-95.
  12. Griffin JH, Evatt B, Zimmerman TS. Deficiency of protein C in congenital thrombotic disease. J Clin Invest. 1981; 68: 1370-1373. Ref.: https://goo.gl/FxEHjB
  13. Koster T, Rosendaal FR, Briët E, van der Meer FJ, Colly LP, et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood. 1995; 85: 2756-2761. Ref.: https://goo.gl/fFLbzx
  14. Bezemer ID, Rosendaal FR. Predictive genetic variants for venous thrombosis: what’s new? Semin Hematol. 2007; 44: 85-92. Ref.: https://goo.gl/khg4Q2
  15. Heit JA, Armasu SM, Asmann YW, Cunningham JM, Matsumoto ME, et al. A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q. J Thromb Haemost. 2012; 10: 1521-1531. Ref.: https://goo.gl/Qswtwx
  16. Mannucci PM, Gringeri A, Peyvandi F, Di Paolantonio T, Mariani G. Short-term exposure to high altitude causes coagulation activation and inhibits fibrinolysis. Thromb Haemost. 2002; 87: 342-343. Ref.: https://goo.gl/Asrhok
  17. Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med. 2011; 364: 656-665. Ref.: https://goo.gl/ea8Ncw
  18. Frantz S, Ertl G, Bauersachs J. Mechanism of disease: Toll Like Receptors in cardiovascular diseases. Nat Clin Pract Cardiovasc Med. 2007; 4: 444–454. Ref.: https://goo.gl/JfJP2m
  19. Hamann L, Gomma A, Schröder NW, Stamme C, Glaeser C, et al. A frequent Toll like receptor (TLR) 2 polymorphism is a risk factor for coronary restenosis. J Mol Med. 2005; 83: 478–485. Ref.: https://goo.gl/LLYXTW
  20. Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, et al. Toll-like receptor 4 polymorphism and atherogenesis. N Engl J Med. 2002; 347:185–192. Ref.: https://goo.gl/o3xEaa
  21. Hodgkinson CP1, Ye S. Toll-like receptors, their ligands, and atherosclerosis. Sci World J. 2011; 11: 437–453. Ref.: https://goo.gl/K62h2M
  22. Hamann L, Glaeser C, Hamprecht A, Gross M, Gomma A, et al. Toll-like receptor (TLR)-9 promotor polymorphisms and atherosclerosis. Clin Chim Acta. 2006; 364: 303–307. Ref.: https://goo.gl/LorUDw
  23. Källberg M, Wang H, Wang S, Peng J, Wang Z, et al. Template-based protein structure modeling using the RaptorX web server. Nature Protocols. 2012; 7: 1511–1522. Ref.: https://goo.gl/GLBAzG
  24. Källberg M, Wang H, Wang S, Peng J, Wang Z, et al. Template-based protein structure modeling using the RaptorX web server. Nature Protocols. 2012; 7: 1511–1522. Ref.: https://goo.gl/fuefUb
  25. Wiederstein M, Sippl MJ. ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Research. 2007; 35: W407-W410. Ref.: https://goo.gl/57YcWa
  26. Sippl MJ. Recognition of Errors in Three-Dimensional Structures of Proteins. Proteins. 1993; 17: 355-362. Ref.: https://goo.gl/EuZEie
  27. Laskowski RA, Moss DS, Thornton JM. Main-chain bond lengths and bondangles in protein structures. J Mol Biol. 1993; 231: 1049–1067. Ref.: https://goo.gl/csfJh2
  28. Dundas J, Ouyang Z, Tseng J, Binkowski A, Turpaz Y, et al. CASTp:computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues. Nucleic Acids Res 2006, 34(Web Server issue): W116–W118. Ref.: https://goo.gl/F8n6Qn
  29. Laskowski RA, Watson JD, Thornton JM. ProFunc: a server for predicting protein function from 3D structure. Nucleic Acids Res. 2005; 33 (Web Server issue): W89–W93. Ref.: https://goo.gl/q6AzY5
  30. Capriotti E, Calabrese R, Casadio R. Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information. Bioinformatics. 2006; 22: 2729–2734. Ref.: https://goo.gl/SU8AC5
  31. Kim JK, Cho Y, Lee M, Laskowski RA, Ryu SE, et al. BetaCavityWeb: a webserver for molecular voids and channels. Nucleic Acids Res. 2015; W413-418. Ref.: https://goo.gl/hthiKx
  32. Libby P, Simon DI. Inflammation and Thrombosis. The Clot Thickens. Circulation. 2001; 103: 1718-1720. Ref.: https://goo.gl/pWiZgg
  33. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002; 105: 1135–1143. Ref.: https://goo.gl/j5Ym2X
  34. Zebrack JS, Anderson JL. The role of inflammation and infection in the pathogenesis and evolution of coronary artery disease. Current Cardiology Reports. 2002; 4: 278–288. Ref.: https://goo.gl/pcjdUZ
  35. Liu F, Lu W, Qian Q, Qi W, Hu J, et al. Frequency of TLR 2, 4, and 9 Gene Polymorphisms in Chinese Population and Their Susceptibility to Type 2 Diabetes and Coronary Artery Disease. J Biomed Biotechnol. 2012; 2012: Article ID 373945. Ref.: https://goo.gl/CHHgq3
  36. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila toll protein signals activation of adaptive immunity. Nature. 1997; 388: 394–397. Ref.: https://goo.gl/8FS3AK
  37. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006; 124: 783–801. Ref.: https://goo.gl/eyckzd
  38. Uematsu S, Akira S. Toll-like receptors and innate immunity. J Mol Med (Berl). 2006; 84: 712–725. Ref.: https://goo.gl/2gN9rC
  39. Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, et al. Toll-like receptor 4 polymorphisms and atherogenesis. The New England Journal of Medicinel. 2002; 347: 185–192. Ref.: https://goo.gl/hujrpw
  40. Hollestelle SC, De Vries MR, Van Keulen JK, Schoneveld AH, Vink A, et al. Toll-like receptor 4 is involved in outward arterial remodeling. Circulation. 2004; 109: 393–398. Ref.: https://goo.gl/NcqXx1
  41. Boekholdt SM, Agema WR, Peters RJ, Zwinderman AH, van der Wall EE, et al. Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events. Circulation. 2003; 107: 2416–2421. Ref.: https://goo.gl/RLGTh4
  42. Kolek MJ, Carlquist JF, Muhlestein JB, Whiting BM, Horne BD, et al. Toll-like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes. Am Heart J. 2004; 148: 1034–1040. Ref.: https://goo.gl/vqUa9r
  43. Hang J, Zhou W, Zhang H, Sun B, Dai H, et al. TLR4 Asp299Gly and Thr399Ile polymorphims are very rare in the Chinese population. J Endotoxin Res. 2004; 10: 238–240. Ref.: https://goo.gl/jiwGNY
  44. Lin YC, Chang YM, Yu JM, Yen JH, Chang JG, et al. Toll-like receptor 4 gene C119A but not Asp299Gly polymorphism is associated with ischemic stroke among ethnic Chinese in Taiwan. Atherosclerosis. 2005; 180: 305–309. Ref.: https://goo.gl/TTi92x
  45. Hur JW, Shin HD, Park BL, Kim LH, Kim SY, et al. Association study of Toll-like receptor 9 gene polymorphism in Korean patients with systemic lupus erythematosus. Tissue Antigens. 2005; 65: 266–270. Ref.: https://goo.gl/nD33Eq
  46. Tao K, Fujii M, Tsukumo SI, Maekawa Y, Kishihara K, et al. Genetic variations of Toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population. Annals of the Rheumatic Diseases. 2007; 66: 905–909. Ref.: https://goo.gl/gkwdsb
  47. Ng MW, Lau CS, Chan TM, Wong WH, Lau YL. Polymorphisms of the toll-like receptor 9 (TLR9) gene with systemic lupus erythematosus in Chinese. Rheumatology. 2005; 44: 1456–1457. Ref.: https://goo.gl/NoayCf