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Licensed Unlicensed Requires Authentication Published by De Gruyter April 9, 2014

Interleukin-6 receptor Asp358Ala gene polymorphism is associated with plasma C-reactive protein levels and severity of aortic valve stenosis

  • Ewa Wypasek EMAIL logo , Daniel P. Potaczek , Markus Lamplmayr , Jerzy Sadowski and Anetta Undas

Abstract

Background: Interleukin-6 receptor (IL-6R) gene Asp358Ala (A>C, rs2228145) polymorphism has been associated with lower circulating inflammation biomarkers in coronary artery disease (CAD), such as C-reactive protein (CRP) or fibrinogen, but its role in the pathogenesis of aortic valve stenosis (AS) remains unknown. Since the pathogenesis of AS and atherosclerosis shares several similarities, we tested the hypothesis that IL-6R Asp358Ala polymorphism is associated with the severity of AS.

Methods: A total of 284 AS patients aged 64.3±11.1 years were studied, in whom IL-6R polymorphism was determined by TaqMan genotyping.

Results: The genotype distribution was as follows: AA-43.7% (n=124); AC-37.0% (n=105); and CC-19.4% (n=55). For every copy of C allele inherited, mean concentration of CRP was reduced by 22% (95% CI 13.8–30.4; p<0.0001). Carriers of the C allele compared to the AA homozygotes were also characterized by lower mean and maximal transvalvular gradients [44.8 (30.5–60.0) vs. 52.7 (40.5–69.0) mmHg, p=0.0005; and 78.1±26.5 vs. 87.3±27.6 mmHg; p=0.008, respectively], and larger aortic valve area [0.8 (0.6–1.0) vs. 0.7 (0.5–0.9) cm2, p=0.005].

Conclusions: Our study is the first to show that the presence of the IL-6R 358Ala allele in AS patients is associated with attenuated systemic inflammatory state and less severe AS.


Corresponding author: Ewa Wypasek, Institute of Cardiology, Jagiellonian University School of Medicine, 80 Pradnicka Street, 31-202 Cracow, Poland; and John Paul II Hospital, Cracow, Poland, Phone: +48 12 6143145, Fax: +48 12 6143145, E-mail:
aEwa Wypasek and Daniel P. Potaczek contributed equally to this work.

Acknowledgments

The study has been supported by a grant of the Polish Ministry of Science (K/ZDS/002936 to A.U.).

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research support played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

References

1. Miller JD, Weiss RM, Heistad DD. Calcific aortic valve stenosis: methods, models, and mechanisms. Circ Res 2011;108:1392–412.10.1161/CIRCRESAHA.110.234138Search in Google Scholar

2. Rajamannan NM. Calcific aortic stenosis: lessons learned from experimental and clinical studies. Arterioscler Thromb Vasc Biol 2009;29:162–8.10.1161/ATVBAHA.107.156752Search in Google Scholar

3. Olszowska M. Pathogenesis and pathophysiology of aortic valve stenosis in adults. Pol Arch Med Wewn 2011;121:409–13.10.20452/pamw.1103Search in Google Scholar

4. Adamczyk T, Mizia-Stec K, Mizia M, Haberka M, Chmiel A, Chudek J, et al. Biomarkers of calcification and atherosclerosis in patients with degenerative aortic stenosis in relation to concomitant coronary artery disease. Pol Arch Med Wewn 2012;122:14–21.10.20452/pamw.1128Search in Google Scholar

5. Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther 2006;8:S3.10.1186/ar1917Search in Google Scholar

6. Van Lente F. Markers of inflammation as predictors in cardiovascular disease. Clin Chim Acta 2000;293:31–52.10.1016/S0009-8981(99)00236-3Search in Google Scholar

7. Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, et al. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 1989;58:573–81.10.1016/0092-8674(89)90438-8Search in Google Scholar

8. Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. Faseb J 2001;15:43–58.10.1096/fj.99-1003revSearch in Google Scholar PubMed

9. Kim L, Lee H, Kim Y, Jung JH, Kim JY, Park BL, et al. Identification of novel SNPs in the interleukin 6 receptor gene (IL6R). Hum Mut 2003;21:450–1.10.1002/humu.9130Search in Google Scholar PubMed

10. Marinou I, Walters K, Winfield J, Bax DE, Wilson AG. A gain of function polymorphism in the interleukin 6 receptor influences RA susceptibility. Ann Rheum Dis 2010;69:1191–4.10.1136/ard.2008.100644Search in Google Scholar PubMed

11. Ferreira MA, Matheson MC, Duffy DL, Marks GB, Hui J, Le Souëf P, et al. and the Australian Asthma Genetics Consortium. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 2011;378:1006–14.10.1016/S0140-6736(11)60874-XSearch in Google Scholar

12. Kristiansen OP, Mandrup-Poulsen T. Interleukin-6 and diabetes: the good, the bad, or the indifferent? Diabetes 2005;54:S114–24.10.2337/diabetes.54.suppl_2.S114Search in Google Scholar

13. IL6R Genetics Consortium Emerging Risk Factors Collaboration, Sarwar N, Butterworth AS, Freitag DF, Gregson J, Willeit P, et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies IL6R. Lancet 2012;379:1205–13.10.1016/S0140-6736(11)61931-4Search in Google Scholar

14. Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, Hingorani AD, Casas JP. The interleukin-6 receptor as a target for prevention of coronary heart disease: a Mendelian randomization analysis. Lancet 2012;379:1214–24.10.1016/S0140-6736(12)60110-XSearch in Google Scholar

15. Chester AH, Taylor PM. Molecular and functional characteristics of heart-valve interstitial cells. Philos Trans R Soc Lond B Biol Sci 2007;362:1437–43.10.1098/rstb.2007.2126Search in Google Scholar

16. Erices A, Conget P, Rojas C, Minguell JJ. Gp130 activation by soluble interleukin-6 receptor/interleukin-6 enhances osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells. Exp Cell Res 2002;280:24–32.10.1006/excr.2002.5627Search in Google Scholar

17. Okraska-Bylica A, Wilkosz T, Słowik L, Bazanek M, Konieczyńska M, Undas A. Altered fibrin clot properties in patients with premature peripheral artery disease. Pol Arch Med Wewn 2012;122:608–15.10.20452/pamw.1535Search in Google Scholar

18. Galante A, Pietroiusti A, Vellini M, Piccolo P, Possati G, De Bonis M, et al. C-reactive protein is increased in patients with degenerative aortic valvular stenosis. J Am Coll Cardiol 2001;38:1078–82.10.1016/S0735-1097(01)01484-XSearch in Google Scholar

19. Skowasch D, Schrempf S, Preusse CJ, Likungu JA, Welz A, Lüderitz B, et al. Tissue resident C reactive protein in degenerative aortic valves: correlation with serum C reactive protein concentrations and modification by statins. Heart 2006;92:495–8.10.1136/hrt.2005.069815Search in Google Scholar

20. Teirstein P, Yeager M, Yock PG, Popp RL. Doppler echocardiographic measurement of aortic valve area in aortic stenosis: a noninvasive application of the Gorlin formula. J Am Coll Cardiol 1986;8:1059–65.10.1016/S0735-1097(86)80382-5Search in Google Scholar

21. Bonow RO, Carabello BA, Kanu C, de Leon AC Jr, Faxon DP, Freed MD, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006;114:e84–231.10.1161/CIRCULATIONAHA.106.177303Search in Google Scholar

22. Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. [Rapid physiological coagulation method in determination of fibrinogen.]. Acta Haematol 1957;17:237–46.10.1159/000205234Search in Google Scholar PubMed

23. Esser C, Tomluk J. Reporting Hardy-Weinberg tests in case-control studies: reasons for caution but not for panic reactions. J Invest Dermatol 2005;124:1082–3.10.1111/j.0022-202X.2005.23709.xSearch in Google Scholar PubMed

24. Stephens OW, Zhang Q, Qu P, Zhou Y, Chavan S, Tian E, et al. An intermediate-risk multiple myeloma subgroup is defined by sIL-6r: levels synergistically increase with incidence of SNP rs2228145 and 1q21 amplification. Blood 2012;119:503–12.10.1182/blood-2011-07-367052Search in Google Scholar PubMed PubMed Central

25. Gerber IL, Stewart RA, Hammett CJ, Legget ME, Oxenham H, West TM, et al. Effect of aortic valve replacement on C-reactive protein in nonrheumatic aortic stenosis. Am J Cardiol 2003;92:1129–32.10.1016/j.amjcard.2003.07.012Search in Google Scholar PubMed

26. Sanchez PL, Santos JL, Kaski JC, Cruz I, Arribas A, Villacorta E, et al. Relation of circulating C-reactive protein to progression of aortic valve stenosis. Am J Cardiol 2006;97:90–3.10.1016/j.amjcard.2005.07.113Search in Google Scholar PubMed

27. Chan KL, Dumesnil JG, Tam J, Ni A, Teo K. Effect of rosuvastatin on C-reactive protein and progression of aortic stenosis. Am Heart J 2011;161:1133–9.10.1016/j.ahj.2011.03.016Search in Google Scholar PubMed

28. Novaro GM, Katz R, Aviles RJ, Gottdiener JS, Cushman M, Psaty BM, et al.Clinical factors, but not C-reactive protein, predict progression of calcific aortic-valve disease: the Cardiovascular Health Study. J Am Coll Cardiol 2007;20:1992–8.10.1016/j.jacc.2007.07.064Search in Google Scholar PubMed

29. Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation 2005;111:3316–26.10.1161/CIRCULATIONAHA.104.486738Search in Google Scholar PubMed

30. Novo G, Fazio G, Visconti C, Carità P, Maira E, Fattouch K, et al. Atherosclerosis, de generative aortic stenosis and statins. Curr Drug Targets 2011;12:115–21.10.2174/138945011793591545Search in Google Scholar PubMed

31. Natorska J, Marek G, Hlawaty M, Sadowski J, Tracz W, Undas A. Fibrin presence within aortic valves in patients with aortic stenosis: association with in vivo thrombin generation and fibrin clot properties. Thromb Haemost 2011;105:254–60.10.1160/TH10-09-0612Search in Google Scholar PubMed

Received: 2013-7-30
Accepted: 2014-3-13
Published Online: 2014-4-9
Published in Print: 2014-7-1

©2014 by Walter de Gruyter Berlin/Boston

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