Abstract
The HLA-DQB1* region exhibits complex associations with autoimmune thyroid disease (AITD). AITD patients (Hashimoto’s thyroiditis, HT = 180; Graves’ disease, GD = 55) and age/sex matched controls (n = 235) were genotyped for DQB1* alleles by PCR-SSP. Alleles DQB1*02:02, *06:03, *06:09, *03:02, and *03:03 showed an increased risk and *02:01, *05:02, and *06:02 showed a protection toward AITD. Multiple sequence alignment was used to find out the amino acid variations within the peptide-binding pockets of susceptible and/or protective DQB1* alleles. We observed susceptible associations for amino acids ‘Glu86(P < 0.0007)’ and ‘Leu87(P < 3.8 × 10−4)’ in P1, ‘Leu26(P < 4.0 × 10−12)’ in P4, ‘His9(P < 5.0 × 10−4)’ and ‘Ala57(P < 3.6 × 10−4)’ in P9 toward HT; and ‘Gly86(P < 0.0004)’ in P1 and ‘Asp57(P < 1.9 × 10−4)’ in P9 towards GD. Protective associations were observed for amino acids ‘Ala86(P < 8.2 × 10−6)’ and ‘Tyr87(P < 0.0003)’ in P1, ‘Gly26(P < 4.9 × 10−5)’ and ‘Ser74(P < 4.9 × 10−5)’ in P4, ‘Phe9(P < 0.0007)’ and ‘Ser57(P < 0.0016)’ in P9 towards HT. Thus, the present study revealed that DQB1* alleles and putative amino acid residues play an important role in susceptibility toward AITD in south India.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 digital issues and online access to articles
$119.00 per year
only $19.83 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Prabhakar BS, Bahn RS, Smith TJ. Current perspective on the pathogenesis of Graves’ disease and ophthalmopathy. Endocr Rev. 2003;24:802–35.
Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med. 1996;335:99–107.
Unnikrishnan AG, Menon UV, Thyroid disorders in India: an epidemiological perspective. Indian J Endocrinol Metab. 2011;15:S78–S81.(Suppl2).
Tomer Y, Davies TF. Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function. Endocr Rev. 2003;24:694–717.
Babbitt BP, Allen PM, Matsueda G, Haber E, Unanue ER. Binding of immunogenic peptides to Ia histocompatibility molecules. J Immunol. 2005;175:4163–5.
Jacobson EM, Huber A, Tomer Y. The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology. J Autoimmun. 2008;30:58–62.
Ban Y, Davies TF, Greenberg DA, Concepcion ES, Osman R, Oashi T, et al. Arginine at position 74 of the HLA-DRb1 chain is associated with Graves’ disease. Genes Immun. 2004;5:203–8.
Morel PA, Dorman JS, Todd JA, McDevitt HO, Trucco M. Aspartic acid at position 57 of the HLA DQ beta-chain protects against type I diabetes: a family study. Proc Natl Acad Sci USA. 1988;85:8111–5.
Straumfors A, Johansen BH, Vartdal F, Sollid LM, Thorsby E, Buus S. A peptide-binding assay for the disease-associated HLA-DQ8 molecule. Scand J Immunol. 1998;47:561–7.
Hanafusa T, Pujol BR, Chiovato L, Russell RC, Doniach D, Bottazzo GF. Aberrant expression of HLA-DR antigen on thyrocytes in Graves’ disease: relevance for autoimmunity. Lancet. 1983;2:1111–5.
Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, et al. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature. 1994;368:215–21.
Wu Z, Stephens HA, Sachs JA, Biro PA, Cutbush S, Magzoub MM, et al. Molecular analysis of HLA-DQ and -DP genes in caucasoid patients with Hashimoto’s thyroiditis. Tissue Antigens. 1994;43:116–9.
Zantut-Wittmann DE, Persoli L, Tambascia MA, Fischer E, Maldonado DF, Costa AM, et al. HLA-DRB1*04 and HLA-DQB1*03 association with the atrophic but not with the goitrous form of chronic autoimmune thyroiditis in a Brazilian population. Horm Metab Res. 2004;36:492–500.
Orhan Y, Azezli A, Carin M, Aral F, Sencer E, Molvalilar S. Human lymphocyte antigens (HLA) and Graves’ disease in Turkey. J Clin Immunol. 1993;13:339–43.
Santamaria P, Barbosa JJ, Lindstrom AL, Lemke TA, Goetz FC, Rich SS. HLA-DQB1-associated susceptibility that distinguishes Hashimoto’s thyroiditis from Graves’ disease in type I diabetic patients. J Clin Endocrinol Metab. 1994;78:878–83.
Giza S, Galli-Tsinopoulou A, Lazidou P, Trachana M, Goulis D, HLA-DQB1*05 association with Hashimoto’s thyroiditis in children of Northern Greek origin. Indian Pediatr. 2008;45:493–6.
Tamai H, Kimura A, Dong RP, Matsubayashi S, Kuma K, Nagataki S, Sasazuki T. Resistance to autoimmune thyroid disease is associated with HLA-DQ. J Clin Endocrinol Metab. 1994;78:94–7.
Heward JM, 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;83:3394–7.
Ghosh P, Amaya M, Mellins E, Wiley DC. The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3. Nature. 1995;378:457–62.
Rammensee HG, Friede T, Stevanoviíc S. MHC ligands and peptide motifs: first listing. Immunogenetics. 1995;41:178–228.
Aitman TJ, Todd JA. Molecular genetics of diabetes mellitus. Baillière’s Clin Endocrinol Metab. 1995;9:631–56.
Van den Driessche A, Eenkhoorn V, Van Gaal L, De Block C. Type 1 diabetes and autoimmune polyglandular syndrome: a clinical review. Neth J Med. 2009;67:376–87.
Heuck CC, Kallner A, Kanagasabapathy AS, Riesen W. Diagnosis and monitoring of the disease of the thyroid. WHO Document 2000; WHO/DIL/00.4: 8-9.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.
Scola L, Lio D, Candore G, Forte GI, Crivello A, Colonna-Romano G, et al. Analysis of HLA-DRB1, DQA1, DQB1 haplotypes in Sardinian centenarians. Exp Gerontol. 2008;43:114–8.
Acknowledgements
We are thankful to the various central facilities such as NRCBS, DBT-IPLS and Tissue Typing Service (KB) at Madurai Kamaraj University. We sincerely thank all the patients and paramedical staffs of hospitals from where we collected blood samples.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Ramgopal, S., Rathika, C., Padma Malini, R. et al. Critical amino acid variations in HLA-DQB1* molecules confers susceptibility to Autoimmune Thyroid Disease in south India. Genes Immun 20, 32–38 (2019). https://doi.org/10.1038/s41435-017-0008-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41435-017-0008-6
This article is cited by
-
Associations of CTLA4 +49 A/G Dimorphism and HLA-DRB1*/DQB1* Alleles With Type 1 Diabetes from South India
Biochemical Genetics (2018)