The Role of Low-Resolution Classical HLA Class I and Class II Alleles in the Diagnosis, Clinical Features, and MRI Lesion Count of Multiple Sclerosis Patients
Year 2026,
Volume: 7 Issue: 1, 24 - 33, 24.02.2026
Background:
Genetic susceptibility plays a central role in multiple sclerosis (MS), and combined evaluation of HLA class I and class II alleles may contribute to a better understanding of disease heterogeneity.
Methods:
This case–control study included 40 MS patients diagnosed according to the 2010 McDonald criteria and 40 healthy controls recruited from the Department of Neurology, Atatürk University Faculty of Medicine. Clinical parameters (disease duration, relapse characteristics, and EDSS scores) and MRI findings were recorded. HLA class I and class II typing was performed using the sequence-specific oligonucleotide (SSO) method, and statistical analyses were conducted using IBM SPSS Statistics (version 26.0). Frequencies of HLA class I and class II alleles and their combined genotypes were compared between groups.
Results:
The frequencies of HLA-A*03, HLA-A*32, and HLA-B*08 alleles were significantly higher in MS patients than in controls (p=0.0022). Significant differences were observed for several HLA class I–class II allele combinations, including B*52DR*15, B*08DQ*03, B*35DQ*02, C*03DR*04, C*07DR*11, and C*03DQ*03 (p=0.005). Carriers of HLA-C*03DR*04 and HLA-C*03DQ*03 exhibited a significantly higher number of cortical and juxtacortical lesions on MRI (p=0.0012 and p=0.0008, respectively). HLA-A*03 positivity was associated with increased infratentorial plaque burden (p=0.0040). Moreover, individuals carrying the combined HLA-C*03DR*04DQ*03 genotype demonstrated a significantly greater infratentorial lesion load (p=0.0012).
Conclusion:
Specific combinations of HLA class I and class II alleles are associated with MS susceptibility and distinct radiological phenotypes. HLA-based genetic profiling may therefore serve as a complementary tool for risk stratification and disease monitoring in MS.
This study was approved by the Ethics Committee of Atatürk University Faculty of Medicine (Approval No: 62, Meeting No: 07, Date: 07 November 2019). All procedures were conducted in accordance with the principles of the Declaration of Helsinki.
Supporting Institution
This study was supported by Atatürk University Scientific Research Projects Coordination Unit (BAP) (Project Code: TSA-2020-8237).
Project Number
TSA-2020-8237
Thanks
The authors gratefully acknowledge Atatürk University for the institutional facilities and support that enabled the completion of this research.
References
1. Corboy JR, Weinshenker BG, Wingerchuk DM. Comment on 2018 American Academy of Neurology guidelines on disease-modifying therapies in MS. Neurology.2018;90:1106-112
2. Alroughani R, Al Hashel J, Lamdhade S, Ahmed SF. Predictors of conversion to multiple sclerosis in patients with clinical isolated syndrome using the 2010 revised McDonald criteria. Int Sch Res Notices. 2012;2012(1):792192.
3. Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA, et al. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Multiple Sclerosis Journal. 2020 Dec 11;26(14):1816-21.
4. Lane J, Ng HS, Poyser C, Lucas RM, Tremlett H. Multiple sclerosis incidence: A systematic review of change over time by geographical region. Mult Scler Relat Disord. 2022;63:103932.
5. Sezer E, Can Demirdöğen B, Demirkaya Ş, et al. Association of cholesterol 7α-hydroxylase (CYP7A1) promoter polymorphism (rs3808607) and cholesterol 24S-hydroxylase (CYP46A1) intron 2 polymorphism (rs754203) with serum lipids, vitamin D levels, and multiple sclerosis risk in the Turkish population. Neurological Sciences. 2022;43(4):2611-20.
6. Beltrami S, Rizzo S, Strazzabosco G, et al. Non-classical HLA class I molecules and their potential role in viral infections. Hum Immunol. 2023;84(8):384-92.
7. Altundaş N, Balkan E, Kızılkaya M, et al. Impact of HLA Alleles on COVID-19 Severity in Kidney Transplant Recipients: A Single-Center Study. Cureus. 2024; 6(8):e67881.
8. Altundaş N, Balkan E, Kizilkaya M, et al. Effects of de novo donor-specific Class I and II antibodies on graft outcomes after liver transplantation: A pilot cohort study. Open Life Sci. 2025;20:20251078.
9. Balkan E, İşlek A, Yaşar E, Doğan H. Prevalence of HLA-DQ02 and HLA-DQ08 in patients with celiac disease in Eastern Anatolia and the diagnostic role of HLA-DQ02 and HLA-DQ08 genotyping. Turk J Immunol. 2019;7(1):6-10.
10. De Silvestri A, Capittini C, Mallucci G, et al. The involvement of HLA class II alleles in multiple sclerosis: a systematic review with meta‐analysis. Dis Markers. 2019;2019:1409069
11. Santoro S, Clarelli F, Preziosa P, et al. Exploring the association of HLA genetic risk burden on thalamic and hippocampal atrophy in multiple sclerosis patients. Genes (Basel).02022;13:2136
12. van Luijn MM, Kreft KL, Jongsma ML, et al. Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis. Brain. 2015;138:1531-547
13. Balnyte R, Rastenyte D, Vaitkus A, et al. The importance of HLA DRB1 gene allele to clinical features and disability in patients with multiple sclerosis in Lithuania. BMC Neurol. 2013;13:77.
14. Herrera BM, Ramagopalan S V, Lincoln MR, et al. Parent-of-origin effects in MS: observations from avuncular pairs. Neurology. 2008;71:799-803.
15. Goodin DS. The epidemiology of multiple sclerosis: insights to disease pathogenesis. Handb Clin Neurol. 2014;122:231-66.
16. Ateş H, Tunalı G, Durupınar B. Multipl Sklerozda Human Lökasit Antijen Sıklığının İncelenmesi. Ondokuz Mayis Universitesi Tip Dergisi. 2002;19: (1):25-31.
17. Lassmann H, Brück W, Lucchinetti CF. The Immunopathology of Multiple Sclerosis: An Overview. Brain Pathology. 2007 Apr 2;17(2):210-18.
18. Naito S, Namerow N, Mickey MR, Terasaki PI. Multiple sclerosis: association with HL-A3. Tissue Antigens. 1972;2:1-4.
19. Kumar DR, Aslinia F, Yale SH, Mazza JJ. Charcot JM. The Father of Neurology. Clin Med Res. 2011 Mar 1;9(1):46–9.Dausset J, Hors J. Some contributions of the HL‐A complex to the genetics of human diseases. Immunol Rev. 1975;22:44-74.
20. Dausset J, Hors J. Some contributions of the HL‐A complex to the genetics of human diseases. Immunol Rev. 1975;22:44-74.
21. Engell T, Raun NE, Thomsen M, Platz P. HLA and heterogeneity of multiple sclerosis. Neurology. Neurology. 1982;32:1043.
22. Visscher BR, Myers LW, Ellison GW et al. HLA types and immunity in multiple sclerosis. Neurology. 1979;29:1561-565.
23. Abd AL-Khaliq IM (2024) The relation between human leukocyte antigen and multiple sclerosis. South Asian Res J Med Sci 6:54-55
24. Brynedal B, Duvefelt K, Jonasdottir G et al. HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS One. 2007;25;2(7):e664
25. Akel O, Zhao LP, Geraghty DE, Lind A. High‐resolution HLA class II sequencing of Swedish multiple sclerosis patients. Int J Immunogenet. 2022;49:333-39.
26. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-73.
27. Jokubaitis VG. A role for HLA in mediating long-term multiple sclerosis outcomes? Mult Scler. 2023;29:314-16.
28. Fogdell‐Hahn A, Ligers A, Grønning M, et al. Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease. Tissue Antigens. 2000;55:140-48
30. Harbo HF, Lie BA, Sawcer S, et al. Genes in the HLA class I region may contribute to the HLA class II‐associated genetic susceptibility to multiple sclerosis. Tissue Antigens. 2004;63:237-47
Bılge N, Balkan E, Aykaç M, Kızılkaya M (February 1, 2026) The Role of Low-Resolution Classical HLA Class I and Class II Alleles in the Diagnosis, Clinical Features, and MRI Lesion Count of Multiple Sclerosis Patients. New Trends in Medicine Sciences 7 1 24–33.