Significance of HLA in the Development of Graves' Orbitopathy

Overview

Journal Genes Immun

Date 2023 Jan 13

PMID 36639701

Authors

Magdalena Stasiak

Katarzyna Zawadzka-Starczewska

Boguslaw Tymoniuk

Bartlomiej Stasiak

Andrzej Lewinski

Affiliations

Soon will be listed here.

Abstract

Graves' disease (GD), similarly to most autoimmune disease, is triggered by environmental factors in genetically predisposed individuals. Particular HLA alleles increase or decrease GD risk. No such correlation was demonstrated for Graves' orbitopathy (GO) in Caucasian population. HLA-A, -B, -C, -DQB1 and -DRB1 genotyping was performed using a high-resolution method in a total number of 2378 persons including 70 patients with GO, 91 patients with non-GO GD and 2217 healthy controls to compare allele frequencies between GO, non-GO and controls. Significant associations between GO and HLA profile were demonstrated, with HLA-A*01:01, -A*32:01, -B*37:01, -B*39:01, -B*42:01, -C*08:02, C*03:02, DRB1*03:01, DRB1*14:01 and DQB1*02:01 being genetic markers of increased risk of GO, and HLA-C*04:01, -C*03:04, -C*07:02 and -DRB1*15:02 being protective alleles. Moreover, correlations between HLA alleles and increased or decreased risk of non-GO GD, but with no impact on risk of GO development, were revealed. Identification of these groups of GO-related and GO-protective alleles, as well as the alleles strongly related to non-GO GD, constitutes an important step in a development of personalized medicine, with individual risk assessment and patient-tailored treatment.

Citing Articles

Associations Between Clinical Manifestations of SARS-CoV-2 Infection and HLA Alleles in a Caucasian Population: A Molecular HLA Typing Study.

Tymoniuk B, Borowiec M, Makowska J, Holwek E, Sarnik J, Styrzynski F J Clin Med. 2025; 13(24.

PMID: 39768617 PMC: 11676434. DOI: 10.3390/jcm13247695.

Uncommon P1 Anchor-featured Viral T Cell Epitope Preference within HLA-A*2601 and HLA-A*0101 Individuals.

Zhang J, Yue C, Lin Y, Tian J, Guo Y, Zhang D Immunohorizons. 2024; 8(6):415-430.

PMID: 38885041 PMC: 11220742. DOI: 10.4049/immunohorizons.2400026.

Fibrocyte Participation in Thyroid-Associated Ophthalmopathy Suggests New Approaches to Therapy.

Smith T Ophthalmic Plast Reconstr Surg. 2023; 39(6S):S9-S18.

PMID: 38054981 PMC: 10703002. DOI: 10.1097/IOP.0000000000002509.

Significance of HLA in Graves' disease and Graves' orbitopathy in Asian and Caucasian populations - a systematic review.

Stasiak M, Stasiak B, Zawadzka-Starczewska K, Lewinski A Front Immunol. 2023; 14:1256922.

PMID: 37841270 PMC: 10568027. DOI: 10.3389/fimmu.2023.1256922.

Associations between Lipid Profiles and Graves' Orbitopathy can Be HLA-Dependent.

Stasiak M, Zawadzka-Starczewska K, Tymoniuk B, Stasiak B, Lewinski A Genes (Basel). 2023; 14(6).

PMID: 37372389 PMC: 10298599. DOI: 10.3390/genes14061209.

References

Heward J, Allahabadia A, Daykin J, Carr-Smith J, Daly A, Armitage M . Linkage disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves' disease: replication using a population case control and family-based study. J Clin Endocrinol Metab. 1998; 83(10):3394-7. DOI: 10.1210/jcem.83.10.5137. View

Khong J, Burdon K, Lu Y, Leonardos L, Laurie K, Walsh J . Association of Polymorphisms in MACRO Domain Containing 2 With Thyroid-Associated Orbitopathy. Invest Ophthalmol Vis Sci. 2016; 57(7):3129-37. DOI: 10.1167/iovs.15-18797. View

Nestorowicz K, Bogacz A, Bukowska A, Chraplak M, Czerwinski J, Goralski M . High-resolution allele frequencies for NGS based HLA-A, B, C, DQB1 and DRB1 typing of 23,595 bone marrow donors recruited for the Polish central potential unrelated bone marrow donor registry. Hum Immunol. 2020; 81(2-3):49-51. DOI: 10.1016/j.humimm.2019.12.005. View

Maciejewski A, Kowalczyk M, Gasinska T, Szeliga A, Prendecki M, Dorszewska J . The Role of Vitamin D Receptor Gene Polymorphisms in Thyroid-Associated Orbitopathy. Ocul Immunol Inflamm. 2019; 28(3):354-361. DOI: 10.1080/09273948.2019.1629605. View

Inoue D, Sato K, Maeda M, Inoko H, Tsuji K, Mori T . Genetic differences shown by HLA typing among Japanese patients with euthyroid Graves' ophthalmopathy, Graves' disease and Hashimoto's thyroiditis: genetic characteristics of euthyroid Graves' ophthalmopathy. Clin Endocrinol (Oxf). 1991; 34(1):57-62. DOI: 10.1111/j.1365-2265.1991.tb01736.x. View

Stasiak M, Tymoniuk B, Stasiak B, Lewinski A . The Risk of Recurrence of Subacute Thyroiditis Is HLA-Dependent. Int J Mol Sci. 2019; 20(5). PMC: 6429176. DOI: 10.3390/ijms20051089. View

Mangklabruks A, Cox N, DeGroot L . Genetic factors in autoimmune thyroid disease analyzed by restriction fragment length polymorphisms of candidate genes. J Clin Endocrinol Metab. 1991; 73(2):236-44. DOI: 10.1210/jcem-73-2-236. View

Ross D, Burch H, Cooper D, Greenlee M, Laurberg P, Maia A . 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016; 26(10):1343-1421. DOI: 10.1089/thy.2016.0229. View

Zawadzka-Starczewska K, Tymoniuk B, Stasiak B, Lewinski A, Stasiak M . Actual Associations between HLA Haplotype and Graves' Disease Development. J Clin Med. 2022; 11(9). PMC: 9099647. DOI: 10.3390/jcm11092492. View

10.

Barlow A, Wheatcroft N, Watson P, Weetman A . Association of HLA-DQA1*0501 with Graves' disease in English Caucasian men and women. Clin Endocrinol (Oxf). 1996; 44(1):73-7. DOI: 10.1046/j.1365-2265.1996.634454.x. View

11.

Inoue D, Sato K, Enomoto T, Sugawa H, Maeda M, Inoko H . Correlation of HLA types and clinical findings in Japanese patients with hyperthyroid Graves' disease: evidence indicating the existence of four subpopulations. Clin Endocrinol (Oxf). 1992; 36(1):75-82. DOI: 10.1111/j.1365-2265.1992.tb02905.x. View

12.

Zamani M, Spaepen M, Bex M, Bouillon R, Cassiman J . Primary role of the HLA class II DRB1*0301 allele in Graves disease. Am J Med Genet. 2001; 95(5):432-7. DOI: 10.1002/1096-8628(20001218)95:5<432::aid-ajmg5>3.0.co;2-7. View

13.

Stasiak M, Lewinski A . Strong Correlation between HLA and Clinical Course of Subacute Thyroiditis-A Report of the Three Siblings. Genes (Basel). 2020; 11(11). PMC: 7693567. DOI: 10.3390/genes11111282. View

14.

Simmonds M, Howson J, Heward J, Carr-Smith J, Franklyn J, Todd J . A novel and major association of HLA-C in Graves' disease that eclipses the classical HLA-DRB1 effect. Hum Mol Genet. 2007; 16(18):2149-53. DOI: 10.1093/hmg/ddm165. View

15.

Wang P, Chen I, Juo S, Hsi E, Liu R, Hsieh C . Genotype and phenotype predictors of relapse of graves' disease after antithyroid drug withdrawal. Eur Thyroid J. 2014; 1(4):251-8. PMC: 3821483. DOI: 10.1159/000342621. View

16.

Kus A, Szymanski K, Peeters R, Miskiewicz P, Porcu E, Pistis G . The association of thyroid peroxidase antibody risk loci with susceptibility to and phenotype of Graves' disease. Clin Endocrinol (Oxf). 2014; 83(4):556-62. DOI: 10.1111/cen.12640. View

17.

Kus A, Szymanski K, Jurecka-Lubieniecka B, Pawlak-Adamska E, Kula D, Miskiewicz P . Gender-dependent and age-of-onset-specific association of the rs11675434 single-nucleotide polymorphism near TPO with susceptibility to Graves' ophthalmopathy. J Hum Genet. 2016; 62(3):373-377. DOI: 10.1038/jhg.2016.135. View

18.

Mehraji Z, Farazmand A, Esteghamati A, Noshad S, Sadr M, Amirzargar S . Association of Human Leukocyte Antigens Class I and II with Graves' Disease in Iranian Population. Iran J Immunol. 2017; 14(3):223-230. DOI: IJIv14i3A5. View

19.

Chen W, Chen X, Zhang M, Huang Z . The association of human leukocyte antigen class II (HLA II) haplotypes with the risk of Latent autoimmune diabetes of adults (LADA): Evidence based on available data. Gene. 2020; 767:145177. DOI: 10.1016/j.gene.2020.145177. View

20.

Yin X, Latif R, Bahn R, Davies T . Genetic profiling in Graves' disease: further evidence for lack of a distinct genetic contribution to Graves' ophthalmopathy. Thyroid. 2012; 22(7):730-6. PMC: 3387758. DOI: 10.1089/thy.2012.0007. View