POLYMORPHISMS WITHIN INNATE IMMUNE RESPONSE, CALCIUM METABOLISM AND LIPID METABOLISM ARE PREDICTORS OF INFECTIVE ENDOCARDITIS

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Abstract

Infective endocarditis (IE) is a septic inflammation of the endocardium generally caused by bacteria. Despite certain advances in treatment, case fatality rate and mortality of IE are still relatively high, particularly in high-risk groups. This requires the development of novel efficient preventive approaches; one of them is a personalized medicine. Recognition of microbial patterns, cytokine and acute phase responses, hemostasis features and alterations in plasma lipid and calcium profile all have been reported to affect pathogenesis and clinical course of IE. We hypothesized that inherited genomic variation in the abovementioned pathways may determine individual susceptibility to IE. Having recruited 124 patients with IE and 300 age-, sex-, and ethnicity-matched healthy controls, we profiled their genomic DNA for 35 functionally significant polymorphisms within the 22 selected genes involved in pathways mentioned above, with the further genetic association analysis. Genotyping was performed using TaqMan allelic discrimination assay while statistical analysis was carried out utilizing SNPStats, a web tool for genetic association analysis. We found that the G/A genotype of the rs1143634 polymorphism within the IL1B gene, the G/T genotype of the rs3212227 polymorphism within the IL12B gene, the A/G genotype of the rs1130864 polymorphism within the CRP gene, and the G allele of the rs1801197 polymorphism within the CALCR gene are associated with a decreased risk of IE whereas the T/T genotype of the rs1205 polymorphism within the CRP gene is associated with a higher risk of IE. Furthermore, heterozygous genotypes of the rs1143634 and rs3212227 polymorphisms were associated with the higher plasma levels of IL-1β and IL-12, respectively, suggesting their possible importance for IE development. Our results indicate that inherited variation in the cytokine, acute phase response, and calcium metabolism pathways may be linked to IE. However, further molecular epidemiology studies are needed to thoroughly uncover the genetic basis of IE.

About the authors

A. V. Ponasenko

Research Institute for Complex Issues of Cardiovascular Diseases

Author for correspondence.
Email: avapanass@mail.ru

PhD (Medicine), Head of the Laboratory of Genomic Medicine, Division of Experimental and Clinical Cardiology,

650002, Kemerovo, Sosnovy avenue, 6

Russian Federation

A. G. Kutikhin

Research Institute for Complex Issues of Cardiovascular Diseases

Email: fake@neicon.ru

PhD (Medicine), Senior Researcher, Laboratory of Genomic Medicine, Division of Experimental and Clinical Cardiology, 

650002, Kemerovo, Sosnovy avenue, 6

Russian Federation

M. V. Khutornaya

Research Institute for Complex Issues of Cardiovascular Diseases

Email: fake@neicon.ru

Junior Researcher, Laboratory of Genomic Medicine, Division of Experimental and Clinical Cardiology,

650002, Kemerovo, Sosnovy avenue, 6

Russian Federation

N. V. Rutkovskaya

Research Institute for Complex Issues of Cardiovascular Diseases

Email: fake@neicon.ru

PhD, MD (Medicine), Senior Researcher, Laboratory of Bioprosthetic Heart Valves, Division of Experimental and Clinical Cardiology,

650002, Kemerovo, Sosnovy avenue, 6

Russian Federation

N. V. Kondyukova

Research Institute for Complex Issues of Cardiovascular Diseases

Email: fake@neicon.ru

Junior Researcher, Laboratory of Cardiovascular Prostheses, Division of Experimental and Clinical Cardiology,

650002, Kemerovo, Sosnovy avenue, 6

Russian Federation

Yu. N. Odarenko

Research Institute for Complex Issues of Cardiovascular Diseases

Email: fake@neicon.ru

PhD, MD (Medicine), Head of the Laboratory of Cardiovascular Prostheses, Division of Experimental and Clinical Cardiology,

650002, Kemerovo, Sosnovy avenue, 6

Russian Federation

Ya. V. Kazachek

Research Institute for Complex Issues of Cardiovascular Diseases

Email: fake@neicon.ru

PhD (Medicine), Scientific Secretary,

650002, Kemerovo, Sosnovy avenue, 6

Russian Federation

A. V. Tsepokina

Research Institute for Complex Issues of Cardiovascular Diseases

Email: fake@neicon.ru

Junior Researcher, Laboratory of Genomic Medicine, Division of Experimental and Clinical Cardiology,

650002, Kemerovo, Sosnovy avenue, 6

Russian Federation

A. E. Yuzhalin

Department of Oncology, Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford

Email: fake@neicon.ru

PhD Student,

Oxford

United Kingdom

L. S. Barbarash

Research Institute for Complex Issues of Cardiovascular Diseases

Email: fake@neicon.ru

RAS Full Member, PhD, MD (Medicine), Professor, Head Researcher,

650002, Kemerovo, Sosnovy avenue, 6

Russian Federation

O. L. Barbarash

Research Institute for Complex Issues of Cardiovascular Diseases

Email: fake@neicon.ru

RAS Corresponding Member, PhD, MD (Medicine), Professor, Director,

650002, Kemerovo, Sosnovy avenue, 6

Russian Federation

References

  1. Araújo I.R., Ferrari T.C., Teixeira-Carvalho A., Campi-Azevedo A.C., Rodrigues L.V., uimarães Júnior M.H., Barros T.L., Gelape C.L., Sousa G.R., Nunes M.C. Cytokine signature in infective endocarditis. PLoS One, 2015, vol. 10, iss. 7, e0133631. doi: 10.1371/journal.pone.0133631
  2. Bakhtiar S.M., Ali A., Baig S.M., Barh D., Miyoshi A., Azevedo V. Identifying human disease genes: advances in molecular genetics and computational approaches. Genet. Mol. Res., 2014, vol. 13, iss. 3, pp. 5073–5087. doi: 10.4238/2014.July.4.23
  3. Bin Abdulhak A.A., Baddour L.M., Erwin P.J., Hoen B., Chu V.H., Mensah G.A., Tleyjeh I.M. Global and regional burden of infective endocarditis, 1990-2010: a systematic review of the literature. Glob. Heart, 2014, vol. 9, iss. 1, pp. 131–143. doi: 10.1016/j.gheart.2014.01.002
  4. Bustamante J., Tamayo E., Flórez S., Telleria J.J., Bustamante E., López J., San Román J.A., Alvarez F.J. Toll-like receptor 2 R753Q polymorphisms are associated with an increased risk of infective endocarditis. Rev. Esp. Cardiol., 2011, vol. 64, iss. 11, pp. 1056–1059. doi: 10.1016/j.rec.2011.02.027
  5. Buyukasýk N.S., Ileri M., Alper A., Senen K., Atak R., Hisar I., Yetkin E., Turhan H., Demirkan D. Increased blood coagulation and platelet activation in patients with infective endocarditis and embolic events. Clin. Cardiol., 2004, vol. 27, iss. 3, pp. 154–158. doi: 10.1002/clc.4960270312
  6. Cahill T.J., Prendergast B.D. Infective endocarditis. Lancet, 2016, vol. 387, iss. 10021, pp. 882–893. doi: 10.1016/S0140-6736(15)00067-7
  7. Chu V.H., Cabell C.H., Benjamin D.K. Jr., Kuniholm E.F., Fowler V.G. Jr., Engemann J., Sexton D.J., Corey G.R., Wang A. Early predictors of in-hospital death in infective endocarditis. Circulation, 2004, vol. 109, iss. 14, pp. 1745–1749. doi: 10.1161/01.CIR.0000124719.61827.7F
  8. Daga S., Shepherd J.G., Callaghan J.G., Hung R.K., Dawson D.K., Padfield G.J., Hey S.Y., Cartwright R.A., Newby D.E., Fitzgerald J.R. Platelet receptor polymorphisms do not influence Staphylococcus aureus-platelet interactions or infective endocarditis. Microbes Infect., 2011, vol. 13, iss. 3, pp. 216–225. doi: 10.1016/j.micinf.2010.10.016
  9. Daga S., Shepherd J.G., Hung R.K., Callaghan J.G., Dawson D.K., Padfield G.J., Fitzgerald J.R., Newby D.E. GPIb VNTR C/C genotype may predict embolic events in infective endocarditis. J. Heart Valve Dis., 2013, vol. 22, iss. 1, pp. 133–141.
  10. Dayem Ullah A.Z., Lemoine N.R., Chelala C. SNPnexus: a web server for functional annotation of novel and publicly known genetic variants (2012 update). Nucleic Acids Res., 2012, vol. 40 (Web Server issue), pp. W65–70. doi: 10.1093/nar/gks364
  11. Durante-Mangoni E., Iossa D., Molaro R., Andini R., Mattucci I., Malgeri U., Albisinni R., Utili R. Prevalence and significance of two major inherited thrombophilias in infective endocarditis. Intern. Emerg. Med., 2015, vol. 10, iss. 5, pp. 587–594. doi: 10.1007/s11739-015-1214-8
  12. Elbey M.A., Akdağ S., Kalkan M.E., Kaya M.G., Sayın M.R., Karapınar H., Bulur S., Ulus T., Akıl M.A., Elbey H.K., Akyüz A. A multicenter study on experience of 13 tertiary hospitals in Turkey in patients with infective endocarditis. Anadolu Kardiyol. Derg., 2013, vol. 13, iss. 6, pp. 523–527. doi: 10.5152/akd.2013.172
  13. Elkhatib W.F., Hair P.S., Nyalwidhe J.O., Cunnion K.M. New potential role of serum apolipoprotein E mediated by its binding to clumping factor A during Staphylococcus aureus invasive infections to humans. J. Med. Microbiol. 2015, vol. 64 (pt. 4), pp. 335–343. doi: 10.1099/jmm.0.000010
  14. Giannitsioti E., Damoraki G., Rokkas C., Tsaganos T., Fragou A., Kannelaki S., Athanasia S., Giamarellos-Bourboulis E.J. Impact of haplotypes of TNF in the natural course of infective endocarditis. Clin. Microbiol. Infect., 2014, vol. 20, iss. 5, pp. 459–464. doi: 10.1111/1469-0691.12370
  15. 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, vol. 550, iss. 1, pp. 101–109. doi: 10.1016/j.gene.2014.08.022
  16. Golovkin A.S., Ponasenko A.V., Yuzhalin A.E., Salakhov R.R., Khutornaya M.V., Kutikhin A.G., Rutkovskaya N.V., Savostyanova Y.Y., Barbarash L.S. An association between single nucleotide polymorphisms within TLR and TREM-1 genes and infective endocarditis. Cytokine, 2015, vol. 71, iss. 1, pp. 16–21. doi: 10.1016/j.cyto.2014.08.001
  17. Gupta K., Jagadeesan N., Agrawal N., Bhat P., Nanjappa M.C. Clinical, echocardiographic and microbiological study, and analysis of outcomes of infective endocarditis in tropical countries: a prospective analysis from India. J. Heart Valve Dis., 2014, vol. 23, iss. 5, pp. 624–632.
  18. Habib G., Hoen B., Tornos P., Thuny F., Prendergast B., Vilacosta I., Moreillon P., De Jesus Antunes M., Thilen U., Lekakis J., Lengyel M., Müller L., Naber C.K., Nihoyannopoulos P., Moritz A., Zamorano J.L., ESC Committee for Practice Guidelines. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the task force on the prevention, diagnosis, and treatment of infective endocarditis of the European Society of Cardiology (ESC). Eur. Heart J., 2009, vol. 30, iss. 19, pp. 2369–2413. doi: 10.1093/eurheartj/ehp285
  19. Habib G., Lancellotti P., Antunes M.J., Bongiorni M.G., Casalta J.P., Del Zotti F., Dulgheru R., El Khoury G., Erba P.A., Iung B., Miro J.M., Mulder B.J., Plonska-Gosciniak E., Price S., Roos-Hesselink J., Snygg-Martin U., Thuny F., Tornos Mas P., Vilacosta I., Zamorano J.L. 2015 ESC Guidelines for the management of infective endocarditis: The task force for the management of infective endocarditis of the European Society of Cardiology (ESC). Eur. Heart J., 2015, vol. 36, iss. 44, pp. 3075–3128. doi: 10.1093/eurheartj/ehv319
  20. Hill E.E., Herijgers P., Claus P., Vanderschueren S., Herregods M.C., Peetermans W.E. Infective endocarditis: changing epidemiology and predictors of 6-month mortality: a prospective cohort study. Eur. Heart J., 2007, vol. 28, iss. 2, pp. 196–203. doi: 10.1093/eurheartj/ehl427
  21. İleri M., Kanat S., Orhan G., Bayır P.T., Gürsoy H.T., Şahin D., Çiçek G., Elalmış Ö.U., Güray Ü. Increased mean platelet volume in patients with infective endocarditis and embolic events. Cardiol. J., 2015, vol. 22, iss. 1, pp. 37–43. doi: 10.5603/CJ.a2014.0021
  22. Kahveci G., Bayrak F., Mutlu B., Gurel Y.E., Karaahmet T., Tigen K., Basaran Y. Clinical significance of high-density lipoprotein cholesterol in left-sided infective endocarditis. Am. J. Cardiol., 2008, vol. 101, iss. 8, pp. 1170–1173. doi: 10.1016/j.amjcard.2007.11.075
  23. Kutikhin A.G., Ponasenko A.V., Khutornaya M.V., Yuzhalin A.E., Zhidkova I.I., Salakhov R.R., Golovkin A.S., Barbarash O.L., Barbarash L.S. Association of TLR and TREM-1 gene polymorphisms with atherosclerosis severity in a Russian population. Meta Gene, 2016, vol. 9, pp. 76–89. doi: 10.1016/j.mgene.2016.04.001
  24. Mangoni E., Molaro R., Iossa D. The role of hemostasis in infective endocarditis. Curr. Infect. Dis. Rep., 2014, vol. 16, iss. 11: 435. doi: 10.1007/s11908-014-0435-8
  25. McNicholas S., Talento A.F., O’Gorman J., Hannan M.M., Lynch M., Greene C.M., Humphreys H., Fitzgerald-Hughes D. Cytokine responses to Staphylococcus aureus bloodstream infection differ between patient cohorts that have different clinical courses of infection. BMC Infect. Dis., 2014, vol. 14: 580. doi: 10.1186/s12879-014-0580-6
  26. Muñoz P., Kestler M., De Alarcon A., Miro J.M., Bermejo J., Rodríguez-Abella H., Fariñas M.C., Cobo Belaustegui M., Mestres C., Llinares P., Goenaga M., Navas E., Oteo J.A., Tarabini P., Bouza E., Spanish Collaboration on Endocarditis-Grupo de Apoyo al Manejo de la Endocarditis Infecciosa en España (GAMES). Current epidemiology and outcome of infective endocarditis: a multicenter, prospective, cohort study. Medicine (Baltimore), 2015, vol. 94, iss. 43, e1816. doi: 10.1097/MD.0000000000001816
  27. Murdoch D.R., Corey G.R., Hoen B., Miró J.M., Fowler V.G. Jr., Bayer A.S., Karchmer A.W., Olaison L., Pappas P.A., Moreillon P., Chambers S.T., Chu V.H., Falcó V., Holland D.J., Jones P., Klein J.L., Raymond N.J., Read K.M., Tripodi M.F., Utili R., Wang A., Woods C.W., Cabell C.H., International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS) Investigators. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the international collaboration on endocarditis-prospective cohort study. Arch. Intern. Med., 2009, vol. 169, iss. 5, pp. 463–473. doi: 10.1001/archinternmed.2008.603.
  28. Ponasenko A.V., Khutornaya M.V., Kutikhin A.G., Rutkovskaya N.V., Tsepokina A.V., Kondyukova N.V., Yuzhalin A.E., Barbarash L.S. A genomics-based model for prediction of severe bioprosthetic mitral valve calcification. Int. J. Mol. Sci., 2016, vol. 17, iss. 9, p. E1385. doi: 10.3390/ijms17091385.
  29. San Román J.A., López J., Vilacosta I., Luaces M., Sarriá C., Revilla A., Ronderos R., Stoermann W., Gómez I., FernándezAvilés F. Prognostic stratification of patients with left-sided endocarditis determined at admission. Am. J. Med., 2007, vol. 120, iss. 4, e1–7. doi: 10.1186/1471-2334-10-17
  30. Snipsøyr M.G., Ludvigsen M., Petersen E., Wiggers H., Honoré B. A systematic review of biomarkers in the diagnosis of infective endocarditis. Int. J. Cardiol., 2016, vol. 202, pp. 564–570. doi: 10.1016/j.ijcard.2015.09.028
  31. Solé X., Guinó E., Valls J., Iniesta R., Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics, 2006, vol. 22, iss. 15, pp. 1928–1929. doi: 10.1093/bioinformatics/btl268
  32. Thuny F., Textoris J., Amara A.B., Filali A.E., Capo C., Habib G., Raoult D., Mege J.L. The gene expression analysis of blood reveals S100A11 and AQP9 as potential biomarkers of infective endocarditis. PLoS One, 2012, vol. 7, iss. 2, e31490. doi: 10.1371/journal.pone.0031490
  33. Vollmer T., Kleesiek K., Dreier J. Lipopolysaccharide-binding protein (LBP) gene polymorphisms: rapid genotyping by real-time PCR and association with infective endocarditis. Clin. Biochem., 2009, vol. 42, iss. 13–14, pp. 1413–1419. doi: 10.1016/j.clinbiochem.2009.06.010
  34. Wang A., Athan E., Pappas P.A., Fowler V.G. Jr., Olaison L., Paré C., Almirante B., Muñoz P., Rizzi M., Naber C., Logar M., Tattevin P., Iarussi D.L., Selton-Suty C., Jones S.B., Casabé J., Morris A., Corey G.R., Cabell C.H., International Collaboration on Endocarditis-Prospective Cohort Study Investigators. Contemporary clinical profile and outcome of prosthetic valve endocarditis. JAMA, 2007, vol. 297, iss. 12, pp. 1354–1361. doi: 10.1001/jama.297.12.1354
  35. Watkin R.W., Harper L.V., Vernallis A.B., Lang S., Lambert P.A., Ranasinghe A.M., Elliott T.S. Pro-inflammatory cytokines IL6, TNF-alpha, IL1beta, procalcitonin, lipopolysaccharide binding protein and C-reactive protein in infective endocarditis. J. Infect., 2007, vol. 55, iss. 3, pp. 220–225. doi: 10.1016/j.jinf.2007.05.174
  36. Weinstock M., Grimm I., Dreier J., Knabbe C., Vollmer T. Genetic variants in genes of the inflammatory response in association with infective endocarditis. PLoS One, 2014, vol. 9, iss. 10, e110151. doi: 10.1371/journal.pone.0110151
  37. Xu Z., Taylor J.A. SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic Acids Res., 2009, vol. 37 (Web Server issue), pp. W600–605. doi: 10.1093/nar/gkp290
  38. Yuzhalin A.E., Kutikhin A.G. Integrative systems of genomic risk markers for cancer and other diseases: future of predictive medicine. Cancer Manag. Res., 2012, vol. 4, pp. 131–135. doi: 10.2147/CMAR.S30855

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Copyright (c) 2017 Ponasenko A.V., Kutikhin A.G., Khutornaya M.V., Rutkovskaya N.V., Kondyukova N.V., Odarenko Y.N., Kazachek Y.V., Tsepokina A.V., Yuzhalin A.E., Barbarash L.S., Barbarash O.L.

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