Romatizmal Kalp Kapak Hastalığı Olan Türk Hastalarda IL-1Ra VNTR Gen Polimorfizminin İlişkisi Üzerine Bir Çalışma
Abstract
Amaç: Romatizmal kalp kapak hastalığının (RKKH)’da dahil olduğu çeşitli otoimmün ve kronik enflamatuvar hastalıklarda, IL-1 resep-tör antagonisti (IL-1Ra) A2 allelinin uzun süreli ve şiddetli proenflamatuvar bağışıklık cevabıyla ilişkili olabileceği yönünde çalışmalar bulunmaktadır. Ancak, RKKH patogenezinde IL-1Ra varyantının ilişkisi ile ilgili çalışmalar oldukça sınırlıdır. Bu çalışmanın amacı, Türk hastalarda IL-1Ra rs2234663 değişken sayıda ardışık yineleme (VNTR) varyantları ile RKKH duyarlılığı ve/veya hastalığın şiddeti arasında bir ilişki olup olmadığını araştırmaktır.
Gereç ve Yöntem: Bu vaka-kontrol çalışmasında (165 RKKH/300 kontrol) IL-1Ra VNTR için polimeraz zincir reaksiyonu (PZR) yöntemi ile genotipleme yapılmıştır.
Bulgular: Hastalar ve kontroller arasında genotip ve allel frekanslarında istatistiksel olarak anlamlı fark tespit edilmiştir (p<0,001). A1 allel frekansı, RKKH hastalarında kontrol grubuyla karşılaştırıldığında, anlamlı olarak daha yüksek bulunmuştur (p=0,004; OR=3,821; %95 GA=1,459-10,005). A3 allel frekansı hasta grubunda kontrol grubuna kıyasla istatistiksel olarak anlamlı şekilde artış göstermiştir (p=0,034; OR=2,536; %95 GA=1,045-6,152). Şiddetli ve hafif kapak hasarı olan hastalar arasında genotip dağılımları istatistiksel olarak anlamlı şekilde farklı bulunmuştur (p=0,031). A2 alleli şid-detli kapak hasarı olan hastalarda hafif kapak hasarı olan hastalara göre istatistiksel olarak yüksek olarak tespit edilmiştir (p=0,003).
Sonuç:IL-1Ra VNTR rs2234663 varyantlarının Türk toplumunda RKKH açısından duyarlı bireylerin tanımlanmasında kullanılabilecek uygun bir biyobelirteç olabileceği önerilmektedir.
Supporting Institution
Giresun Üniversitesi BAP
Project Number
(SAĞ-BAP-A-270220-04)
References
- 1. Cunningham MW. Rheumatic fever, autoimmunity, and molecu-lar mimicry: the streptococcal connection. Int Rev Immunol 2014; 33(4): 314-9. [CrossRef] google scholar
- 2. Guilherme L, Kalil J, Cunningham M. Molecular mimicry in the au-toimmune pathogenesis of rheumatic heart disease. Autoimmu-nity 2006; 39(1): 31-9. [CrossRef] google scholar
- 3. Poomarimuthu M, Elango S, Solomon PR, Soundarapandian S, Mariakuttikan J. Lack of Association Between TNF-a, IFN-y, IL-10 Gene Polymorphisms and Rheumatic Heart Disease in South In-dian Population. Fetal and Pediatric Pathology 2018; 37: 309-8. [CrossRef] google scholar
- 4. Marijon E, Mirabel M, Celermajer DS, Jouven X. Rheumatic heart disease. Lancet 2012; 10: 953-4. [CrossRef] google scholar
- 5. Guilherme L, Kalil J. Rheumatic fever: from sore throat to autoim-mune heart lesions. Int Arch Allergy Immunol 2004; 134: 56-64. [CrossRef] google scholar
- 6. Carapetis JR, Currie BJ, Mathews JD. Cumulative incidence of rheumatic fever in an endemic region: a guide to the suscep-tibility of the population? Epidemiol Infect 2000; 124: 239-44. [CrossRef] google scholar
- 7. Guilherme L, Ramasawmy R, Kalil J. Rheumatic fever and rheuma-tic heart disease: genetics and pathogenesis. Scand J Immunol 2007; 66: 199-207. [CrossRef] google scholar
- 8. Engel ME, Stander R, Vogel J, Adeyemo AA, Mayosi BM. Gene-tic susceptibility to acute rheumatic fever: a systematic review and meta-analysis of twin studies. PLoS One 2011; 6 (9): e25326. [CrossRef] google scholar
- 9. Toor D, Vohra H. Immune responsiveness during disease progres-sion from acute rheumatic fever to chronic rheumatic heart dise-ase. Microbes Infect 2012; 14: 1111-7. [CrossRef] google scholar
- 10. Guilherme L, Kalil J. Rheumatic fever and rheumatic heart disease: cellular mechanisms leading autoimmune reactivity and disease. J Clin Immunol 2010; 30: 17-23. [CrossRef] google scholar
- 11. Col-Araz N, Pehlivan S, Baspinar O, Oguzkan-Balci S, Sever T, Balat A. Role of cytokine gene (IFN-c, TNF-a, TGF-b1, IL-6, and IL-10) pol-ymorphisms in pathogenesis of acute rheumatic fever in Turkish children. Eur J Pediatr 2012; 171: 1103-8. [CrossRef] google scholar
- 12. Van Deventer SJ. Cytokine and cytokine receptor polymorphisms in infectious disease. Intensive Care Med 2000; 26: 98-102. [CrossRef] google scholar
- 13. Teker E, Akadam-Teker AB, Ozturk O, Eronat AP, Yalin K, Golcuk SE, et al. Association Between the Interferon Gamma 874 T/A Polymorphism and the Severity of Valvular Damage in Patients with Rheumatic Heart Disease. Biochem Genet 2018; 56: 225-34. [CrossRef] google scholar
- 14. Hirsch E, Irikura VM, Paul SM, Hirsh D. Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc Natl Acad Sci USA 1996; 93 (20): 11008-13. [CrossRef] google scholar
- 15. Tarlow JK, Blakemore AI, Lennard A, Solari R, Hughes HN, Stein-kasserer A, et al. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet 1993; 91(4): 403-4. [CrossRef] google scholar
- 16. Vamvakopoulos JE, Taylor CJ, Morris-Stiff CJ, Green C, Metcalfe S. The interleukin-1 receptor antagonist gene: a single-copy variant of the intron 2 variable number tandem repeat (VNTR) polymorp-hism. Eur J Immunogenet 2002; 29(4): 337-40. [CrossRef] google scholar
- 17. Settin A, El-Baz HA, Saber I. Gene polymorphisms of TNF-a-308, IL-10-1082, IL-6-174 and IL-RaVNTR related to susceptibility and severity of rheumatic heart disease. Pediatr Cardiol 2007; 28: 36371. [CrossRef] google scholar
- 18. Witkin SS, Gerber S, Ledger WJ. Influence of Interleukin-1 re-ceptor antagonist gene polymorphism on disease. Clin Infect Dis 2002; 34: 204-9. [CrossRef] google scholar
- 19. Gewitz MH, Baltimore RS, Tani LY, Sable C A, Shulman ST, Cara-petis J, et al. Revision of the Jones Criteria for the Diagnosis of Acute Rheumatic Fever in the Era of Doppler Echocardiography: A Scientific Statement From the American Heart Association. Cir-culation 2015; 131: 1806-18. [CrossRef] google scholar
- 20. World Medical Association. World Medical Association Declara-tion of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013; 310(20): 2191-4. [CrossRef] google scholar
- 21. Excoffier L, Laval G, Schneider S. Arlequin ver. 3.0: an integrated software package for population genetics data analysis. Evol Bio-inform Online 2005; 1: 47-50. [CrossRef] google scholar
- 22. Patterson D, Jones C, Hart I, Bleskan J, Berger R, Geyer D, et al. The human interleukin-1 receptor antagonist (IL1RN) gene is lo-cated in the chromosome 2q14 region. Genomics 1993; 15: 173-6. [CrossRef] google scholar
- 23. Carapetis J, Beaton A, Cunningham MW, Guilherme L, Karthi-keyan G, Mayosi BM et al. Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers 2016; 2: 15084. [CrossRef] google scholar
- 24. Tarlow JK, Blakemore AI, Lennard A, Solari R, Hughes HN, Stein-kasserer A et al. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genetic 1993; 91(4): 403-4. [CrossRef] google scholar
- 25. Al-Tahhan M, Etewa RL, El Behery MM. Association between cir-culating interleukin-1 beta (IL-10) levels and IL-10 C-511 T poly-morphism with cervical cancer risk in Egyptian women. Mol Cell Biochem 2011; 353: 159-65. [CrossRef] google scholar
- 26. Azevedo PM, Bauer R, Caparbo F, Silva CA, Bonfa E, Pereira RM. Interleukin-1 receptor antagonist gene (IL1RN) polymorphism possibly associated to severity of rheumatic carditis in a Brazilian cohort. Cytokine 2010; 49: 109-13. [CrossRef] google scholar
- 27. Rehman S, Akhtar N, Saba N, Munir S, Ahmed W, Mohyuddin A, et al. A study on the association of TNF-a-308, IL-6-174, IL-10-1082 and IL-1RaVNTR gene polymorphisms with rheumatic heart di-sease in Pakistani patients. Cytokine 2013; 61: 527-31. [CrossRef] google scholar
- 28. Chou HT, Tsai CH, Chen WC, Tsai FJ. Lack of association of genetic polymorphisms in the interleukin-1beta, interleukin-1 receptor antagonist,interleukin-4, and interleukin-10 genes with risk of rheumatic heart disease in Taiwan Chinese. Int Heart J 2005; 46: 397-406. [CrossRef] google scholar
A Study on the Relationship of IL-1Ra VNTR Gene Polymorphism in Turkish Patients with Rheumatic Heart Disease
Abstract
Objective: There are studies that suggest that the IL-1 receptor antagonist (IL-1Ra) A2 allele may be associated with a long-term and severe proinflammatory immune response in various autoimmune and chronic inflammatory diseases, including rheumatic valvular heart disease (RVHD). However, studies on the relationship of the IL-1Ra variant in the pathogenesis of RVHD are very limited. The aim of this study was to investigate whether there is a relationship between IL-1Ra rs2234663 variable number tandem repeat (VNTR) variants and RVHD susceptibility and/or disease severity in Turkish patients.
Material and Method: In this case-control study (165 RVHD/300 controls), we genotyped IL-1Ra VNTR using the polymerase chain reaction (PCR) method.
Results: There was a statistically significant difference in genotype and allele frequencies between patients and controls (p<0.001). The A1 allele frequency was found to be significantly higher in RVHD patients compared to the control group (p=0.004; OR=3.821; 95% CI=1.459-10.005). The A3 allele showed a statistically significant increase in the patient group compared to the control group (p=0.034; OR=2.536; 95% CI=1.045-6.152). Genotype distributions were statistically significantly different between patients with severe and mild valve damage (p=0.031). The A2 allele was statis-tically higher in patients with severe valve damage compared to patients with mild valve damage (p=0.003).
Conclusion:IL-1Ra VNTR can be recommended as a suitable biomarker that can be used to identify susceptible individuals in terms of RVHD susceptibility in the Turkish population.
Project Number
(SAĞ-BAP-A-270220-04)
References
- 1. Cunningham MW. Rheumatic fever, autoimmunity, and molecu-lar mimicry: the streptococcal connection. Int Rev Immunol 2014; 33(4): 314-9. [CrossRef] google scholar
- 2. Guilherme L, Kalil J, Cunningham M. Molecular mimicry in the au-toimmune pathogenesis of rheumatic heart disease. Autoimmu-nity 2006; 39(1): 31-9. [CrossRef] google scholar
- 3. Poomarimuthu M, Elango S, Solomon PR, Soundarapandian S, Mariakuttikan J. Lack of Association Between TNF-a, IFN-y, IL-10 Gene Polymorphisms and Rheumatic Heart Disease in South In-dian Population. Fetal and Pediatric Pathology 2018; 37: 309-8. [CrossRef] google scholar
- 4. Marijon E, Mirabel M, Celermajer DS, Jouven X. Rheumatic heart disease. Lancet 2012; 10: 953-4. [CrossRef] google scholar
- 5. Guilherme L, Kalil J. Rheumatic fever: from sore throat to autoim-mune heart lesions. Int Arch Allergy Immunol 2004; 134: 56-64. [CrossRef] google scholar
- 6. Carapetis JR, Currie BJ, Mathews JD. Cumulative incidence of rheumatic fever in an endemic region: a guide to the suscep-tibility of the population? Epidemiol Infect 2000; 124: 239-44. [CrossRef] google scholar
- 7. Guilherme L, Ramasawmy R, Kalil J. Rheumatic fever and rheuma-tic heart disease: genetics and pathogenesis. Scand J Immunol 2007; 66: 199-207. [CrossRef] google scholar
- 8. Engel ME, Stander R, Vogel J, Adeyemo AA, Mayosi BM. Gene-tic susceptibility to acute rheumatic fever: a systematic review and meta-analysis of twin studies. PLoS One 2011; 6 (9): e25326. [CrossRef] google scholar
- 9. Toor D, Vohra H. Immune responsiveness during disease progres-sion from acute rheumatic fever to chronic rheumatic heart dise-ase. Microbes Infect 2012; 14: 1111-7. [CrossRef] google scholar
- 10. Guilherme L, Kalil J. Rheumatic fever and rheumatic heart disease: cellular mechanisms leading autoimmune reactivity and disease. J Clin Immunol 2010; 30: 17-23. [CrossRef] google scholar
- 11. Col-Araz N, Pehlivan S, Baspinar O, Oguzkan-Balci S, Sever T, Balat A. Role of cytokine gene (IFN-c, TNF-a, TGF-b1, IL-6, and IL-10) pol-ymorphisms in pathogenesis of acute rheumatic fever in Turkish children. Eur J Pediatr 2012; 171: 1103-8. [CrossRef] google scholar
- 12. Van Deventer SJ. Cytokine and cytokine receptor polymorphisms in infectious disease. Intensive Care Med 2000; 26: 98-102. [CrossRef] google scholar
- 13. Teker E, Akadam-Teker AB, Ozturk O, Eronat AP, Yalin K, Golcuk SE, et al. Association Between the Interferon Gamma 874 T/A Polymorphism and the Severity of Valvular Damage in Patients with Rheumatic Heart Disease. Biochem Genet 2018; 56: 225-34. [CrossRef] google scholar
- 14. Hirsch E, Irikura VM, Paul SM, Hirsh D. Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc Natl Acad Sci USA 1996; 93 (20): 11008-13. [CrossRef] google scholar
- 15. Tarlow JK, Blakemore AI, Lennard A, Solari R, Hughes HN, Stein-kasserer A, et al. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet 1993; 91(4): 403-4. [CrossRef] google scholar
- 16. Vamvakopoulos JE, Taylor CJ, Morris-Stiff CJ, Green C, Metcalfe S. The interleukin-1 receptor antagonist gene: a single-copy variant of the intron 2 variable number tandem repeat (VNTR) polymorp-hism. Eur J Immunogenet 2002; 29(4): 337-40. [CrossRef] google scholar
- 17. Settin A, El-Baz HA, Saber I. Gene polymorphisms of TNF-a-308, IL-10-1082, IL-6-174 and IL-RaVNTR related to susceptibility and severity of rheumatic heart disease. Pediatr Cardiol 2007; 28: 36371. [CrossRef] google scholar
- 18. Witkin SS, Gerber S, Ledger WJ. Influence of Interleukin-1 re-ceptor antagonist gene polymorphism on disease. Clin Infect Dis 2002; 34: 204-9. [CrossRef] google scholar
- 19. Gewitz MH, Baltimore RS, Tani LY, Sable C A, Shulman ST, Cara-petis J, et al. Revision of the Jones Criteria for the Diagnosis of Acute Rheumatic Fever in the Era of Doppler Echocardiography: A Scientific Statement From the American Heart Association. Cir-culation 2015; 131: 1806-18. [CrossRef] google scholar
- 20. World Medical Association. World Medical Association Declara-tion of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013; 310(20): 2191-4. [CrossRef] google scholar
- 21. Excoffier L, Laval G, Schneider S. Arlequin ver. 3.0: an integrated software package for population genetics data analysis. Evol Bio-inform Online 2005; 1: 47-50. [CrossRef] google scholar
- 22. Patterson D, Jones C, Hart I, Bleskan J, Berger R, Geyer D, et al. The human interleukin-1 receptor antagonist (IL1RN) gene is lo-cated in the chromosome 2q14 region. Genomics 1993; 15: 173-6. [CrossRef] google scholar
- 23. Carapetis J, Beaton A, Cunningham MW, Guilherme L, Karthi-keyan G, Mayosi BM et al. Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers 2016; 2: 15084. [CrossRef] google scholar
- 24. Tarlow JK, Blakemore AI, Lennard A, Solari R, Hughes HN, Stein-kasserer A et al. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genetic 1993; 91(4): 403-4. [CrossRef] google scholar
- 25. Al-Tahhan M, Etewa RL, El Behery MM. Association between cir-culating interleukin-1 beta (IL-10) levels and IL-10 C-511 T poly-morphism with cervical cancer risk in Egyptian women. Mol Cell Biochem 2011; 353: 159-65. [CrossRef] google scholar
- 26. Azevedo PM, Bauer R, Caparbo F, Silva CA, Bonfa E, Pereira RM. Interleukin-1 receptor antagonist gene (IL1RN) polymorphism possibly associated to severity of rheumatic carditis in a Brazilian cohort. Cytokine 2010; 49: 109-13. [CrossRef] google scholar
- 27. Rehman S, Akhtar N, Saba N, Munir S, Ahmed W, Mohyuddin A, et al. A study on the association of TNF-a-308, IL-6-174, IL-10-1082 and IL-1RaVNTR gene polymorphisms with rheumatic heart di-sease in Pakistani patients. Cytokine 2013; 61: 527-31. [CrossRef] google scholar
- 28. Chou HT, Tsai CH, Chen WC, Tsai FJ. Lack of association of genetic polymorphisms in the interleukin-1beta, interleukin-1 receptor antagonist,interleukin-4, and interleukin-10 genes with risk of rheumatic heart disease in Taiwan Chinese. Int Heart J 2005; 46: 397-406. [CrossRef] google scholar
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Clinical Sciences |
| Journal Section | Research Article |
| Authors | |
| Project Number | (SAĞ-BAP-A-270220-04) |
| Publication Date | December 8, 2021 |
| Submission Date | May 6, 2021 |
| Published in Issue | Year 2021 Volume: 11 Issue: 3 |
