Angiotensin-converting enzyme genotypes and sarcoidosis: Correlation with susceptibility, progression and treatment response
Keywords:
sarcoidosis, angiotensin-converting enzyme, gene polymorphism, prognosis, treatment outcomeAbstract
Introduction: Previous research has yielded conflicting results regarding the association between ACE genotypes and both susceptibility to sarcoidosis and disease prognosis. While some studies have found no significant impact of the ACE genotype on sarcoidosis susceptibility, others have suggested that the DD genotype may be associated with an increased risk of developing the disease and a poor prognosis.
This study aimed to evaluate the influence of ACE genotypes on the susceptibility to sarcoidosis, prognosis and treatment response in patients with pulmonary sarcoidosis in Denmark.
Methods: Patients with sarcoidosis were consecutively enrolled and genotyped using allele-specific PCR and high-resolution melting methods. The distribution of ACE genotypes was then compared with that of 400 healthy Danish individuals. To assess the impact of ACE genotypes on sarcoidosis prognosis, their association with changes in pulmonary function tests, radiological staging over 24 months, the frequency of Löfgren’s syndrome, and treatment response were analyzed.
Results: Among 148 patients with sarcoidosis, the frequency of the II, ID, and DD genotypes was 25%, 52%, and 23%, respectively. No significant difference was observed in the distribution of ACE genotypes between patients and controls. Prognostic factors and treatment response also did not vary among the genotypes.
Conclusion: Our findings do not support an association between the ACE I/D genotypes and sarcoidosis susceptibility, prognosis or response to treatment in a Danish cohort.
References
1. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86(4):1343–6. doi: 10.1172/JCI114844.
2. Sayed-Tabatabaei FA, Oostra BA, Isaacs A, Van Duijn CM, Witteman JCM. ACE polymorphisms. Circ Res. 2006 May;98(9):1123–33. doi: 10.1161/01.RES.0000223145.74217.e7.
3. Yang H, Mo T, Nie W, Li B. Angiotensin converting enzyme I/D polymorphism and sarcoidosis risk. Sarcoidosis, Vasculitis and Diffuse Lung Diseases. 2015;32(4):284–8. PMID: 26847094.
4. Gilbert S, Steinbrech DS, Landas SK, Hunninghake GW. Amounts of angiotensin-converting enzyme mRNA reflect the burden of granulomas in granulomatous lung disease. Am Rev Respir Dis. 1993;148(2):483–6. doi: 10.1164/ajrccm/148.2.483.
5. Fløe A, Hoffmann HJ, Nissen PH, Møller HJ, Hilberg O. Genotyping increases the yield of angiotensinconverting enzyme in sarcoidosis - A systematic review. Dan Med J. 2014;61(5):1–6. PMID: 24814734.
6. Grunewald J, Brynedal B, Darlington P, et al. Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients. Respir Res. 2010 Feb 26;11(1). PMID: 20187937.
7. Møller J, Hilberg O, Bendstrup E. Fatigue in Patients with Sarcoidosis in Denmark. Lung. 2023 Feb 1;201(1):103–10. doi: 10.1007/s00408-023-00602-0.
8. Grunewald J. HLA associations and Löfgren’s syndrome. Vol. 8, Expert Review of Clinical Immunology. 2012. p. 55–62. doi: 10.1586/eci.11.76.
9. Nissen PH, Campbell NB, Højskov CS, et al. Development of a high-resolution melting genotyping assay for the angiotensin I converting enzyme insertion/deletion polymorphism and establishment of genotype-specific reference intervals in a Danish population. Ann Clin Biochem. 2015;52(1):105–12. doi: 10.1177/0004563214529261.
10. Crouser ED, Maier LA, Baughman RP, et al. Diagnosis and Detection of Sarcoidosis An Official American Thoracic Society Clinical Practice Guideline. Vol. 201, American Journal of Respiratory and Critical Care Medicine. American Thoracic Society; 2020. p. E26–51. doi: 10.1164/rccm.202002-0251ST.
11. Møller J, Hilberg O, Bendstrup E. Design and rationale of ProSar, the first Danish sarcoidosis registry. Sarcoidosis Vasc Diffuse Lung Dis. 2022;38,4. doi: 10.36141/svdld.v38i4.11605.
12. Grunewald J, Brynedal B, Darlington P, et al. Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients. Respir Res. 2010 Feb 26;11(1). doi: 10.1186/1465-9921-11-25.
13. McGrath DS, Foley PJ, Petrek M, et al. ACE Gene I/D Polymorphism and Sarcoidosis Pulmonary Disease Severity. 2012 Dec 14;164(2):197–201. doi: 10.1164/ajrccm.164.2.2011009.
14. Planck A, Eklund A, Yamaguchi E, Grunewald J. Angiotensin-converting enzyme gene polymorphism in relation to HLA-DR in sarcoidosis. J Intern Med. 2002 Mar 3 ;251(3):217–22. doi: 10.1046/j.1365-2796.2002.00946.x.
15. Lahtela E, Wennerström A, Pietinalho A, et al. ACE gene variants and sarcoidosis in a Finnish population. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases. 2017;34(2):104. PMID: 32476831
16. Maliarik MJ, Rybicki BA, Malvitz E, et al. Angiotensin-converting enzyme gene polymorphism and risk of sarcoidosis. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1566–70. doi: 10.1164/ajrccm.158.5.9804123.
17. Javadi A, Shamaei M, Zarei M, Rezaeian L, Kiani A, Abedini A. Insertion/Deletion Polymorphisms and Serum Angiotensin-converting Enzyme Levels in Iranian Patients with Sarcoidosis. Iran J Public Health. 2016 Nov 26 ;45(11):1473. PMID: 28032065.
18. Yilmaz D, Karkucak M, Coşkun F, Yakut T, Kunt Uzaslan E. ACE gene I/D polymorphism and risk of sarcoidosis development in Turkish patients. Tuberk Toraks. 2012;60(3):201–6. doi: 10.5578/tt.3935.
19. Alía P, Mañá J, Capdevila O, Álvarez A, Navarro MÁ. Association between ACE gene I/D polymorphism and clinical presentation and prognosis of sarcoidosis. Scand J Clin Lab Invest. 2005; 65(8):691–8. doi: 10.1080/00365510500354128.
20. Pietinalho A, Furuya K, Yamaguchi E, Kawakami Y, Selroos O. The angiotensin-converting enzyme DD gene is associated with poor prognosis in Finnish sarcoidosis patients. European Respiratory Journal. 1999 Apr 1;13(4):723–6. doi: 10.1034/j.1399-3003.1999.13d04.x.
21. Papadopoulos KI, Melander O, Orho-Melander M, Groop LC, Carlsson M, Hallengren B. Angiotensin converting enzyme (ACE) gene polymorphism in sarcoidosis in relation to associated autoimmune diseases. J Intern Med. 2000 Jan 1;247(1):71–7. doi: 10.1046/j.1365-2796.2000.00575.x.
22. Sikjær MG, Hilberg O, Ibsen R, Løkke A. Sarcoidosis: A nationwide registry-based study of incidence, prevalence and diagnostic work-up. Respir Med. 2021 Oct 1;187. doi: 10.1016/j.rmed.2021.106548.
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