The role of human leukocyte antigens in patients with heart failure

Öz

Despite advances in drug therapies and invasive procedures in cardiology, heart failure (HF) remains one of the leading causes of mortality and morbidity worldwide. Given the high mortality and morbidity rates associated with HF, understanding its etiology—particularly its genetic basis—is crucial. Elucidating these mechanisms can expand therapeutic options, thereby improving patient life expectancy, enhancing quality of life, and reducing healthcare costs. This review discusses the human genome in the context of HF pathophysiology, its classifications, their genetic basis, and the specific role of Human Leukocyte Antigens (HLA) in HF. The HLA system is one of the most polymorphic regions of the human genome. Its main function is to regulate the human immune system. The most important characteristic of HLA mole-cules is that they allow for a wide variety of peptide presentations, contributing to inter-individual varia-bility in immune responses. This polymorphism is associated with numerous autoimmune and inflamma-tory diseases. In particular, HLA-DQ2 and HLA-DQ8 haplotypes are considered genetic risk factors for celiac disease and type 1 diabetes mellitus due to abnormal antigen presentation. Transgenic animal mod-els expressing human HLA-DQ alleles have demonstrated the development of autoimmune myocarditis progressing to dilated cardiomyopathy. HLA haplotypes should not currently be regarded as standalone diagnostic or prognostic markers for HF. Rather, they may represent one component of a broader immuno-genetic and inflammatory network, particularly in selected phenotypes such as myocarditis-related or idiopathic dilated cardiomyopathy.

Anahtar Kelimeler

• Human leukocyte antigen
• Heart failure
• Genetics

Destekleyen Kurum

This study was funded by the Scientific Research Coordination Unit of Canakkale Onsekiz Mart University (Project No. TSA-2022- 3876).

Etik Beyan

none

Teşekkür

This study was funded by the Scientific Research Coordination Unit of Canakkale Onsekiz Mart University (Project No. TSA-2022- 3876).

Kalp yetersizliği olan hastalarda insan lökosit antijenlerinin rolü

Öz

İlaç tedavilerindeki ve kardiyolojideki invaziv prosedürlerdeki ilerlemelere rağmen, kalp yetersizliği (KY) dünya çapında ölüm ve sakatlığın önde gelen nedenlerinden biri olmaya devam etmektedir. KY ilişkili yüksek ölüm ve hastalık oranları göz önüne alındığında, etiyolojisini -özellikle genetik temelini- anlamak çok önemlidir. Bu mekanizmaların aydınlatılması, tedavi seçeneklerini genişleterek hastaların yaşam beklentisini artırabilir, yaşam kalitesini iyileştirebilir ve sağlık hizmeti maliyetlerini düşürebilir. Bu incelemede, KY patofizyolojisi, tipleri, genetik temeli ve son olarak İnsan Lökosit Antijenlerinin (İLA) KY'deki rolü ele alındı. İLA sistemi, insan genomunun en polimorfik bölgelerinden biridir. Ana işlevi insan bağışıklık sistemini düzenlemektir. İLA moleküllerinin en önemli özelliği, çok çeşitli peptit sunumlarına izin vermeleri ve bağışıklık yanıtlarında bireyler arası değişkenliğe katkıda bulunmalarıdır. Bu polimorfizm, çok sayıda otoimmün ve inflamatuar hastalıkla ilişkilidir. Özellikle İLA-DQ2 ve İLA-DQ8 haplotipleri, anormal antijen sunumu nedeniyle çölyak hastalığı ve tip 1 diyabet mellitus için ge-netik risk faktörleri olarak kabul edilir. İnsan İLA-DQ alellerini ifade eden transgenik hayvan modelleri, otoimmün miyokardit ve ardından dilate kardiyomiyopati gelişimini göstermiştir. İLA haplotipleri şu anda KY için tek başına tanısal veya prognostik belirteçler olarak değerlendirilmemelidir. Bunun yerine, özellikle miyokardit ilişkili veya idiyopatik dilate kardiyomiyopati gibi seçilmiş fenotiplerde, daha geniş bir immünogenetik ve inflamatuar ağın bir bileşenini temsil edebilirler.

Anahtar Kelimeler

• İnsan lökosit antijeni
• Kalp yetersizliği
• Genetik

Destekleyen Kurum

Bu çalışma Çanakkale Onsekiz Mart Üniversitesi Bilimsel Araştırma Koordinasyon Birimi tarafından finanse edilmiştir (Proje No. TSA-2022-3876).

Etik Beyan

yok

Teşekkür

Bu çalışma Çanakkale Onsekiz Mart Üniversitesi Bilimsel Araştırma Koordinasyon Birimi tarafından finanse edilmiştir (Proje No. TSA-2022-3876).

Kaynakça

1. 1. Mensah GA, Prabhakaran D, Mbakwem AC, Narula J. Closing the prevention gap in heart failu-re: World Heart Federation. Lancet 2026; 407(10525): 221-2.
2. 2. Chioncel O, Parissis J, Mebazaa A, et al. Epide-miology, pathophysiology and contemporary management of cardiogenic shock - a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2020; 22(8): 1315-41.
3. 3. Tokcan M, Hoevelmann J, Markwirth P, Haring B. What's new in heart failure? November 2025. Eur J Heart Fail 2025; 27(11): 1947-9.
4. 4. Skouri H, Girerd N, Monzo L, et al. Clinical management and therapeutic optimization of pa-tients with heart failure with reduced ejection fraction and low blood pressure. A clinical con-sensus statement of the Heart Failure Associa-tion (HFA) of the ESC. Eur J Heart Fail 2025; 27(4): 707-22.
5. 5. Seferovi´c PM, Vardas P, Jankowska EA, et al. National Heart Failure Societies of the ESC member countries. The Heart Failure Associa-tion Atlas: Heart Failure Epidemiology and Management Statistics 2019. Eur J Heart Fail 2021; 23: 906–14.
6. 6. Heidenreich PA, Fonarow GC, Opsha Y, et al. Economic issues in heart failure in the United States. J Card Fail 2022; 28(3): 453-66.
7. 7. Virani SS, Alonso A, Benjamin EJ, et al. Ameri-can Heart Association Council on Epidemio-logy and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circula-tion 2020; 141(9): e139–e596.
8. 8. Heidenreich PA, Albert NM, Allen LA, et al. American Heart Association Advocacy Coordi-nating Committee; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Stroke Council. Forecasting the impact of heart failure in the United States: a policy statement from the Ame-rican Heart Association. Circ Heart Fail 2013; 6: 606–19.

9. 9. Tran DT, Ohinmaa A, Thanh NX, et al. The cur-rent and future financial burden of hospital ad-missions for heart failure in Canada: a cost analysis. CMAJ Open 2016; 4(3): E365–E70.
10. 10. Khan SU, Khan MZ, Alkhouli M. Trends of Cli-nical Outcomes and Health Care Resource Use in Heart Failure in the United States. J Am He-art Assoc 2020; 9(14): e016782.
11. 11. Yoon J, Fonarow GC, Groeneveld PW, et al. Pa-tient and Facility Variation in Costs of VA He-art Failure Patients. JACC Heart Fail 2016; 4: 551–8.
12. 12. Lesyuk W, Kriza C, Kolominsky-Rabas P. Cost-of-illness studies in heart failure: a systematic review 2004–2016. BMC Cardiovasc Disord 2018; 18(1): 74.
13. 13. Beghini A, Sammartino AM, Papp Z, et al. 2024 update in heart failure. ESC Heart Fail 2025; 12(1): 8-42.
14. 14. McDonagh TA, Metra M, Adamo M, et al. ESC Scientific Document Group. 2023 Focused Up-date of the 2021 ESC Guidelines for the diag-nosis and treatment of acute and chronic heart failure. Eur. Heart J 2023; 44(37): 3627-39.
15. 15. Schwinger RHG. Pathophysiology of heart fai-lure. Cardiovasc Diagn Ther 2021; 11(1): 263-76.
16. 16. Fonseka O, Gare R, Chen X, et al. Molecular Mechanisms Underlying Heart Failure and Their Therapeutic Potential. Cells 2025; 14(5): 324.
17. 17. Amara M, Stoler O, Birati EY. The Role of Inf-lammation in the Pathophysiology of Heart Fai-lure. Cells 2025; 14(14): 1117.
18. 18. Pah AM, Serban S, Mateescu DM, et al. Systemic Inflammatory Biomarkers (Interleukin-6, High-Sensitivity C-Reactive Protein, and Neutrophil-to-Lymphocyte Ratio) and Prognosis in Heart Failure: A Meta-Analysis of Prospective Cohort Studies. J Clin Med 2025; 14(23): 8610.
19. 19. Roman-Pepine D, Serban AM, Capras RD, Cis-maru CM, Filip AG. A Comprehensive Review: Unraveling the Role of Inflammation in the Eti-ology of Heart Failure. Heart Fail Rev 2025; 30(5): 931-54.
20. 20. Simmonds SJ, Cuijpers I, Heymans S, Jones EAV. Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding. Cells 2020; 9(1): 242.
21. 21. Van Tassell BW, Raleigh JM, Abbate A. Targe-ting interleukin-1 in heart failure and inflamma-tory heart disease. Curr Heart Fail Rep 2015; 12(1): 33-41.
22. 22. Shah S, Henry A, Roselli C, et al. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nat Commun 2020; 11(1): 163.
23. 23. Arbelo E, Protonotarios A, Gimeno JR, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J 2023; 44(37): 3503-626.
24. 24. El-Osta A. Current opinion in cardiology, epi-genetics of heart failure. Curr Opin Cardiol 2026; 41(3): 129-37.
25. 25. Richards S, Aziz N, Bale S, et al.. Standards and guidelines for the interpretation of sequence va-riants: a joint consensus recommendation of the American College of Medical Genetics and Ge-nomics and the Association for Molecular Pat-hology. Genet Med 2015; 17: 405–23.
26. 26. Morales A, Kinnamon DD, Jordan E, et al. Vari-ant Interpretation for Dilated Cardiomyopathy: Refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study. Circ Genomic Precis Med 2020; 13: e002480.
27. 27. Garnier S, Harakalova M, Weiss S, et al. Geno-me-wide association analysis in dilated cardi-omyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23. Eur Heart J 2021; 42: 2000–11.
28. 28. Trowsdale J, Knight JC. Major histocompatibi-lity complex genomics and human disease. An-nu Rev Genomics Hum Genet 2013; 14: 301-23.
29. 29. Norman PJ; Norberg SJ; Guethlein LA, et al. Sequences of 95 human MHC haplotypes reveal extreme coding variation in genes other than highly polymorphic HLA class I and II. Geno-me Res 2017; 27: 813–23.
30. 30. Trowsdale J. Genomic structure and function in the MHC. Trends Genet 1993; 9; 117–22.
31. 31. Horton R, Wilming L, Rand V, et al. Gene map of the extended human MHC. Nat Rev Genet 2004; 5: 889–99.
32. 32. Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium. Nature 1999 ; 401: 921–3.
33. 33. Milner CM, Campbell RD. Genetic organization of the human MHC class III region. Front Biosci 2001; 6: 914–6.
34. 34. Neefjes J, Jongsma MLM, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol 2011; 11: 823–36.
35. 35. Lechler RI. Structure-function relationships of MHC class II molecules. Immunol Suppl 1988; 1: 25–6.
36. 36. Stern LJ, Potolicchio I, Santambrogio L. MHC class II compartment subtypes: Structure and function. Curr Opin Immunol 2006; 18: 64–9.
37. 37. Rock KL, Reits E, Neefjes J. Present Yourself! By MHC Class I and MHC Class II Molecules. Trends Immunol 2016; 37: 724–37.
38. 38. Gruen JR, Weissman SM. Human MHC class III and IV genes and disease associations. Front Biosci 2001; 6: 960–72.
39. 39. Deakin JE, Papenfuss AT, Belov K, et al. Evolu-tion and comparative analysis of the MHC Class III inflammatory region. BMC Genom 2006; 7: 281.
40. 40. Xie T, Rowen L, Aguado B, et al. Analysis of the gene-dense major histocompatibility comp-lex class III region and its comparison to mouse. Genome Res 2003; 13: 2621–36.
41. 41. Caforio AL, Mahon NJ, Tona F, McKenna WJ. Circulating cardiac autoantibodies in dilated cardiomyopathy and myocarditis: pathogenetic and clinical significance. Eur J Heart Fail 2002 ;4(4): 411-17.
42. 42. Rose NR. Myocarditis: infection versus auto-immunity. J Clin Immunol 2009; 29(6): 730-37.
43. 43. Blum JS, Wearsch PA, Cresswell P. Pathways of antigen processing. Annu Rev Immunol 2013; 31: 443–73.
44. 44. Hengstenberg C, Hufnagel G, Haverich A, et al. De novo expression of MHC class I and class II antigens on endomyocardial biopsies from pati-ents with inflammatory heart disease and rejec-tion following heart transplantation. Eur Heart J 1993; 14(6): 758–63.
45. 45. Yajima T, Knowlton KU. Viral myocarditis: from the perspective of the virus. Circulation 2009; 119(19): 2615–24.
46. 46. Taneja V, David CS. Spontaneous autoimmune myocarditis and cardiomyopathy in HLA-DQ8. NODAbo transgenic mice. J Autoimmun 2009; 33(3-4): 260-9.
47. 47. Taylor JA, Havari E, McInerney MF, Bronson R, Wucherpfennig KW, Lipes MA. A spontaneous model for autoimmune myocarditis using the human MHC molecule HLA-DQ8. J Immunol 2004; 172(4): 2651-8.
48. 48. McKenna CJ, Codd MB, McCann HA, Sugrue DD. Idiopathic dilated cardiomyopathy: fami-lial prevalence and HLA distribution. Heart 1997; 77(6): 549–52.
49. 49. Anderson JL, Carlquist JF, Lutz JR, DeWitt CW, Hammond EH. HLA A, B and DR typing in idiopathic dilated cardiomyopathy: a search for immune response factors. Am J Cardiol 1984; 53(9): 1326–30.
50. 50. Elliott JF, Liu J, Yuan ZN, et al. Autoimmune cardiomyopathy and heart block develop spon-taneously in HLA-DQ8 transgenic IAbeta knockout NOD mice. Proc Natl Acad Sci U S A 2003; 100(23): 13447–52.
51. 51. Goli N, Wilcox J, Barnard J, Tang WHW. Hu-man Leukocyte Antigen Determinants in Myo-carditis and Dilated Cardiomyopathy. Curr He-art Fail Rep 2026; 23(1): 18.
52. 52. Küçük U, Sılan F, Gazi E, et al. HLA-DQ2 and HLA-DQ8 Haplotypes in Heart Failure Patients with Reduced Ejection Fraction. Oman Med J 2025; 40(4): e779.