Horm Metab Res
DOI: 10.1055/a-2298-4366
Original Article: Endocrine Care
Wenyi Li
1
Endocrinology Department, Kunming Medical University Second Affiliated
Hospital, Kunming, China
,
1
Endocrinology Department, Kunming Medical University Second Affiliated
Hospital, Kunming, China
,
Jia Wang
1
Endocrinology Department, Kunming Medical University Second Affiliated
Hospital, Kunming, China
,
Fangling Zhu
1
Endocrinology Department, Kunming Medical University Second Affiliated
Hospital, Kunming, China
,
Yan Chi
1
Endocrinology Department, Kunming Medical University Second Affiliated
Hospital, Kunming, China
› Author Affiliations
Funding Information
Applied Basic Research Key Project of Yunnan —
http://dx.doi.org/10.13039/501100005147; 202201AY070001-127
Candidate Talents Training Fund of Yunnan Province —
http://dx.doi.org/10.13039/100012544; No.L-2019014
› Further Information
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Abstract
Graves’ disease (GD) is an autoimmune disease that primarily affects the thyroid
gland. It is the most common cause of hyperthyroidism. Genetic studies have
shown that human leukocyte antigen (HLA) plays an important role in the
development of GD. In this article, we performed a meta-analysis determined to
evaluate the relationship between HLA-DRB1 alleles and GD. This meta-analysis
included 9 studies (3582 cases in the case group and 23070 cases in the control
group) and 27 alleles was performed. The combined results showed that, compared
with the control group, GD patients have a significant increase in the frequency
of DRB1*1403 (OR=2.50, 95% CI=1.78–3.51, pc<0.0001) and have a significant
decrease in frequencies of DRB1* 0101 (OR=0.45, 95% CI=0.34–0.59, pc<0.0001)
and DRB1*0701 (OR=0.44, 95% CI=0.35–0.55, pc<0.0001). The meta-analysis
indicated that, in Asian populations, DRB1*1403 is a risk allele for GD, and
DRB1*0101 and DRB1*0701 are protective against the occurrence of GD. We
surprisingly discovered that the susceptibility alleles for GD in Asian
populations are completely different from Caucasians and the protective alleles
for GD in Asians are quite similar to those of Caucasians. The results of our
study may provide new opportunities for gene-targeted therapy for GD in Asian
populations.
Keywords
Gravesʼ disease -
HLA-DRB1 alleles -
Asians -
meta-analysis
Publication History
Received: 03 March 2024
Accepted after revision: 24 March 2024
Article published online:
02 May 2024
© 2024. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart,
Germany
References
1
Davies TF,
Andersen S,
Latif R.
et al.
Graves' disease. Nat Rev Dis Primers 2020; 6: 52
2
Smith TJ,
Hegedüs L.
Graves' disease. N Engl J Med 2016; 375: 1552-1565
3
Tomer Y.
Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics. Annu Rev of Pathol Mech Dis 2014; 9: 147-156
4
Dvornikova KA,
Bystrova EY,
Platonova ON.
et al.
Polymorphism of toll-like receptor genes and autoimmune endocrine diseases. Autoimm Rev 2020; 19: 102496
5
Brix TH,
Kyvik KO,
Christensen K.
et al.
Evidence for a major role of heredity in Graves' disease: a
population-based study of two Danish twin cohorts. J Clin Endocrinol Metab 2001; 86: 930-934
6
McLeod DSA,
Caturegli P,
Cooper DS.
et al.
Variation in rates of autoimmune thyroid disease by race/ethnicity in US
military personnel. JAMA 2014; 311: 1563-1565
7
Shapira Y,
Agmon-Levin N,
Shoenfeld Y.
Defining and analyzing geoepidemiology and human autoimmunity. J Autoimm 2010; 34: J168-J177
8
Shin D-H,
Baek I-C,
Kim HJ.
et al.
HLA alleles, especially amino-acid signatures of HLA-DPB1, might contribute to
the molecular pathogenesis of early-onset autoimmune thyroid disease. PloS One 2019; 14: e0216941
9
Zawadzka-Starczewska K,
Tymoniuk B,
Stasiak B.
et al.
Actual associations between HLA haplotype and Graves' disease
development. J Clin Med 2022; 11: 2492
10
Chen QY,
Huang W,
She JX.
et al.
HLA-DRB1*08, DRB1*03/DRB3*0101, and DRB3*0202 are susceptibility genes for
Graves' disease in North American Caucasians, whereas DRB1*07 is
protective. J Clin Endocrinol Metab 1999; 84: 3182-3186
11
Zeitlin AA,
Heward JM,
Newby PR.
et al.
Analysis of HLA class II genes in Hashimoto's thyroiditis reveals
differences compared to Graves' disease. Gen. Immun 2008; 9: 358-363
12
Tomer Y,
Davies TF.
Searching for the autoimmune thyroid disease susceptibility genes: from gene
mapping to gene function. Endocrine Rev 2003; 24: 694-717
13
Jang HW,
Shin HW,
Cho H-J.
et al.
Identification of HLA-DRB1 alleles associated with Graves' disease in
Koreans by sequence-based typing. Immunolog Invest 2011; 40: 172-182
14
Katahira M,
Ogata H,
Takashima H.
et al.
Critical amino acid variants in HLA-DRB1 allotypes in the development of
Graves' disease and Hashimoto's thyroiditis in the Japanese
population. Hum Immunol 2021; 82: 26-231
15
Hashimoto K,
Maruyama H,
Nishiyama M.
et al.
Susceptibility alleles and haplotypes of human leukocyte antigen DRB1, DQA1, and
DQB1 in autoimmune polyglandular syndrome type III in Japanese population. Horm Res 2005; 64: 253-260
16
Park MH,
Park YJ,
Song EY.
et al.
Association of HLA-DR and -DQ genes with Graves disease in Koreans. Hum Immunol 2005; 66: 41-47
17
Huang S-M,
Wu T-J,
Lee TD.
et al.
The association of HLA -A, -B, and -DRB1 genotypes with Graves' disease in
Taiwanese people. Tissue Antigen 2003; 61: 154-158
18
Ueda S,
Oryoji D,
Yamamoto K.
et al.
Identification of independent susceptible and protective HLA alleles in Japanese
autoimmune thyroid disease and their epistasis. J Clin Endrocrinol Metab 2014; 99: E379-E383
19
Chu X,
Yang M,
Song Z-J.
et al.
Fine mapping MHC associations in Graves' disease and its clinical subtypes
in Han Chinese. J Med Genet 2018; 55: 685-692
20
Chen P-L,
Fann CS-J,
Chu C-C.
et al
Comprehensive genotyping in two homogeneous Graves' disease samples reveals
major and novel HLA association alleles. PloS One 2011; 6: e16635
21
Wongsurawat T,
Nakkuntod J,
Charoenwongse P.
et al.
The association between HLA class II haplotype with Graves' disease in Thai
population. Tissue Antigen 2006; 67: 79-83
22
Muñoz-Ortiz J,
Sierra-Cote MC,
Zapata-Bravo E.
et al.
Prevalence of hyperthyroidism, hypothyroidism, and euthyroidism in thyroid eye
disease: a systematic review of the literature. System Rev 2020; 9: 201
23
Konno N,
Yuri K,
Taguchi H.
et al.
Screening for thyroid diseases in an iodine sufficient area with sensitive
thyrotrophin assays, and serum thyroid autoantibody and urinary iodide
determinations. Clin Endocrinol 1993; 38: 273-281
24
Sriphrapradang C,
Pavarangkoon S,
Jongjaroenprasert W.
et al.
Reference ranges of serum TSH, FT4 and thyroid autoantibodies in the Thai
population: the national health examination survey. Clin Endocrinol 2014; 80: 751-756
25
Hollowell JG,
Staehling NW,
Flanders WD.
et al.
Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to
1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002; 87: 489-499
26
Bjoro T,
Holmen J,
Krüger O.
et al.
Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase
antibodies in a large, unselected population. The Health Study of Nord-Trondelag
(HUNT). Eur J Endocrinol 2000; 143: 639-647
27
O'Leary PC,
Feddema PH,
Michelangeli VP.
et al.
Investigations of thyroid hormones and antibodies based on a community health
survey: the Busselton thyroid study. Clin Endocrinol 2006; 64: 97-104
28
Martin S,
Dutescu MI,
Sirbu A.
et al.
The clinical value of human leukocyte antigen HLA-DRB1 subtypes associated to
Graves' disease in Romanian population. Immunol Invest 2014; 43: 479-490
29
Ban Y,
Davies TF,
Greenberg DA.
et al.
Arginine at position 74 of the HLA-DR beta1 chain is associated with
Graves' disease Gene. Immun 2004; 5: 203-2088
30
Simmonds MJ,
Howson JMM,
Heward JM.
et al
Regression mapping of association between the human leukocyte antigen region and
Graves disease. Am J Hum Genet 2005; 76: 157-163
31
Morris DL,
Taylor KE,
Fernando MMA.
et al.
Unraveling multiple MHC gene associations with systemic lupus erythematosus:
model choice indicates a role for HLA alleles and non-HLA genes in
Europeans. Am J Hum Genet 2012; 91: 778-793
32
Huang R,
Yin J,
Chen Y.
et al.
The amino acid variation within the binding pocket 7 and 9 of HLA-DRB1 molecules
are associated with primary Sjögren's syndrome. J Autoimmun 2015; 57: 53-59
33
Ji C,
Liu S,
Zhu K.
et al.
HLA-DRB1 polymorphisms and alopecia areata disease risk: A systematic review and
meta-analysis. Medicine 2018; 97: e11790
34
Zamani M,
Spaepen M,
Bex M.
et al.
Primary role of the HLA class II DRB1*0301 allele in Graves disease. Am J Med Genet 2000; 95: 432-437
35
Jacobson EM,
Huber A,
Tomer Y.
The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology. J Autoimmun 2008; 30: 58-62
36
Gonzalez-Galarza FF,
McCabe A,
Santos Melo Dos EJ.
et al.
Allele frequency net database (AFND) 2020 update: gold-standard data
classification, open access genotype data and new query tools. Nucl Acid Res 2020; 48: D783-D788
37
Barkia BS,
Flesch BK,
Hansen MP.
et al.
HLA class II differentiates between thyroid and polyglandular autoimmunity. Horm Meatb Res 2016; 48: 232-237
38
Okada Y,
Momozawa Y,
Ashikawa K.
et al.
Construction of a population-specific HLA imputation reference panel and its
application to Graves' disease risk in Japanese. Nat Genet 2015; 47: 798-802
39
Menconi F,
Monti MC,
Greenberg DA.
et al.
Molecular amino acid signatures in the MHC class II peptide-binding pocket
predispose to autoimmune thyroiditis in humans and in mice. Proc Natl Acad Sci U S A 2008; 105: 14034-14039
40
Hu X,
Deutsch AJ,
Lenz TL.
et al.
Additive and interaction effects at three amino acid positions in HLA-DQ and
HLA-DR molecules drive type 1 diabetes risk. Nat Genet 2015; 47: 898-905
41
Gentil CA,
Gammill HS,
Luu CT.
et al.
Characterization of the HLA-DRβ1 third hypervariable region amino acid sequence
according to charge and parental inheritance in systemic sclerosis. Arthr Res Ther 2017; 19: 46
42
Seo GH,
Kim TH,
Chung JH.
Antithyroid drugs and congenital malformations: a nationwide Korean cohort
study. Ann Intern Med 2018; 168: 405-413
43
Watanabe N,
Narimatsu H,
Noh JY.
et al.
Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of
agranulocytosis and pancytopenia involving 50, 385 patients with Graves'
disease. J Clin Endocrinol Metab 2012; 97: E49-E53
44
Struja T,
Fehlberg H,
Kutz A.
et al.
Can we predict relapse in Graves' disease? Results from a systematic review
and meta-analysis. Eur J Endocrinol 2017; 176: 87-97
45
Li CW,
Osman R,
Menconi F.
et al.
Cepharanthine blocks TSH receptor peptide presentation by HLA-DR3: Therapeutic
implications to Graves' disease. J Autoimmun 2020; 108: 102402
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