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

Introduction: Graves' disease (GD) and Graves' orbitopathy (GO) development were suspected to be HLA-related in both Asian and Caucasian populations. However, most studies were performed with application of serological methods or low resolution genetic typing, which led to inconsistent results even among the same population. The present review is intended to summarize the state-of-art knowledge on the HLA significance in GD and GO in Asians and Caucasians, as well as to find the most significant alleles for each of the populations. Methods: PubMed was searched for relevant articles using the following search terms: HLA plus thyroid-associated ophthalmopathy or Graves' disease or Graves' orbitopathy or thyroid eye disease or thyroid-associated orbitopathy. Results: In Asian population GD was found to be associated mostly with B*46:01, DPB1*05:01, DRB1*08:02/03, DRB1*16:02, DRB1*14:03, DRB1*04:05, DQB1*05:02 and DQB1*03:03, while DRB1*07:01, DRB1*01:01, DRB1*13:02, DRB1*12:02 are potentially protective. HLA-B*38:02, DRB1*16:02, DQA1*01:02, DQB1*05:02 can be considered associated with increased risk of GO in Asians, while HLA-B*54:01 may play protective role. In Caucasians, C*07:01, DQA1*05:01, DRB1*03, DQB1*02:01 are associated with GD risk while DRB1*07:01, DQA1*02:01 may be protective. Significance of HLA in the course of GD and novel aspects of HLA amino acid variants and potential HLA-based treatment modalities were also discussed.

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

The risk of Graves' orbitopathy (GO) is related to the human leukocyte antigen (HLA) profile and was demonstrated to be increased in patients with elevated total cholesterol (TC) and/or low-density lipoprotein (LDL) cholesterol. We hypothesized that there were some HLA alleles that were related to both GO and TC and/or LDL levels. Therefore, the aim of the study was to compare the TC/LDL results in patients in whom GO-related HLA alleles were present to those in whom they did not occur. HLA classes were genotyped using a next-generation sequencing method in 118 patients with Graves' disease (GD), including 63 and 55 patients with and without GO, respectively. Lipid profiles were assessed at the time of the GD diagnosis. A significant correlation between the presence of GO high-risk alleles (HLA-B*37:01 and C*03:02) and higher TC/LDL levels was found. Additionally, the presence of alleles associated with non-GO GD (HLA-C*17:01 and B*08:01), as well as alleles in linkage disequilibrium with B*08:01 (i.e., HLA-DRB1*03:01 and DQB1*02:01), was correlated with lower TC levels. These results further confirm the significance of TC/LDL in the risk of GO development and provide evidence that associations between TC/LDL and GO can be HLA-dependent.

Significance of HLA in the development of Graves' orbitopathy.

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.

Novel Insight into Non-Genetic Risk Factors of Graves' Orbitopathy.

An assessment of the risk of Graves' orbitopathy (GO) is an important challenge in Graves' disease (GD) management. The purpose of this study was to compare non-genetic parameters in GD patients with and without GO in order to find novel risk factors and to verify the factors already reported. A total number of 161 people, 70 with GO and 91 non-GO patients were included in this study. GO was confirmed to be associated with smoking, older age, higher TSH receptor antibodies (TRAb) and lower thyroglobulin antibody (TgAb) levels and hypercholesterolemia. We demonstrated the latter correlation even for only a mild increase in LDL cholesterol. Importantly, our study provides novel potential GO risk factors, including higher serum creatinine levels, higher MCV and lower PLT. If further confirmed, these new, simple and easily accessible potential GO markers may constitute valuable auxiliary markers in GO risk assessments. We additionally proved that in moderate to severe GO, gender-related differences attenuate. No impact of vitamin D deficiency in GO development in patients with 25-hydroxyvitamin D [25(OH)D] > 20 ng/mL was found. The present report provides a set of GO risk factors, which can be used as a precise tool for an individual GO risk assessment.

Actual Associations between HLA Haplotype and Graves' Disease Development.

The association between HLA and the risk of Graves' disease (GD) has been analyzed for many years. However, the results were often inconsistent and mostly regarded Asian populations. The purpose of our study was to perform HLA genotyping using a next-generation sequencing (NGS) method in Caucasians, to find out which alleles are eventually correlated with GD morbidity as well as which of them can be considered protective. HLA-A, -B, -C, -DQB1, -DRB1 were genotyped using a next-generation sequencing method in 2376 persons, including 159 GD patients and 2217 healthy controls. We have demonstrated a significant association between the risk of GD and the following alleles: HLA-B*08:01, -B*39:06, -B*37:01, -C*07:01, -C*14:02, -C*03:02, -C*17:01, -DRB1*03:01, -DRB1*11:01, -DRB1*13:03, -DRB1*01:03, -DRB1*14:01, -DQB1*03:01, DQB1*02:01. The alleles HLA-B*39:06, -B*37:01, -C*14:02, -C*03:02, -C*17:01, -DRB1*14:01 are novel GD-associated, previously not-reported independent ones with no linkage disequilibrium with other high-risk alleles. On the other hand, the frequencies of HLA-B*07:02, -C*07:02, -C*03:04, DRB1*07:01, -DQB1*02:02, -DQB1*03:03 were significantly lower in GD compared to controls. This study demonstrated the actual relationships between HLA and GD based on the NGS method and provided a novel set of alleles as a reliable tool for an individual personalized risk assessment.

Significance of HLA Haplotypes in Two Patients with Subacute Thyroiditis Triggered by mRNA-Based COVID-19 Vaccine.

Subacute thyroiditis (SAT) can be triggered by several viral factors in genetically predisposed individuals. In the case of COVID-19, SAT can be induced by SARS-CoV-2 infection as well as COVID-19 vaccination. The aim of this study was to present two cases of SAT triggered by mRNA-based COVID-19 vaccines, with special attention paid to the possible significance of HLA-related SAT susceptibility. In our patients, a strong similarity of HLA profiles with regard not only to SAT high-risk alleles but also to other SAT-unrelated ones was observed. The rare phenomenon of SAT occurrence after COVID-19 vaccination can be HLA-dependent and related to a co-presence of HLA-B*35:03 and -C*04:01. Taking into account the similarity of HLA profiles in both our patients, the co-presence of other alleles, such as HLA-A*03:01, -DQA1:01, DQB1*05:01 as well as some of HLA-DRB1, can also play a role. This hypothesis is strongly consistent with autoimmune/inflammatory syndrome induced by adjuvants (ASIA) being the postulated mechanism of this post-vaccine reaction, as ASIA-related immune reactions are directly associated with HLA-based genetic susceptibility. Further research is necessary to confirm these findings.

Clinical Manifestation of Subacute Thyroiditis Triggered by SARS-CoV-2 Infection Can Be HLA-Dependent.

In the last two years, we have been struggling with the pandemic of SARS-CoV-2, the virus causing COVID-19. Several cases of subacute thyroiditis (SAT) have already been described as directly related to SARS-CoV-2 infection. The clinical course of SAT induced by SARS-CoV-2 can be entirely different from the classic SAT course, and one of the most important differences is a very rapid SAT onset observed in some patients, especially a phenomenon of the simultaneous presence of both diseases. The aim of this report is to compare HLA profile and clinical course of SAT in four patients, in whom SAT was considered as triggered by COVID-19, with special attention paid to the differences between a patient with rare simultaneous presence of SAT and COVID-19, and patients with longer time lag between the diseases. The unusual phenomenon of simultaneous occurrence of COVID-19 and SAT induced by SARS-CoV-2 infection can be HLA-dependent and related to the presence of homozygosity at HLA-B*35. Additionally, the clinical course of SAT triggered by COVID-19 can be HLA-related in regard to the risk of recurrence, and to a variety of other aspects, including severity of thyrotoxicosis.

Novel Germline c.105_107dupGCT MEN1 Mutation in a Family with Newly Diagnosed Multiple Endocrine Neoplasia Type 1.

In multiple endocrine neoplasia type 1 (MEN1), the causative MEN1 gene mutations lead to the reduced expression of menin, which is a tumor suppressor protein. In this study, we present a case of a 16-year-old woman with severe primary hyperparathyroidism and a non-functioning pituitary microadenoma. Genetic testing demonstrated a novel germline heterozygote variant c.105_107dupGCT of MEN1, leading to Leu duplication in position 37 of the menin polypeptide chain. As such a mutation was not reported before as a causative one, confirmation of its pathogenicity required showing the same mutation in a symptomatic first-degree relative. An identical mutation was found in the patient's father, who was further diagnosed with hyperparathyroidism and a pituitary microadenoma. We observed the presence of the same MEN1-related tumors but an entirely different symptom severity. To the best of our knowledge, this is the first report of MEN1 syndrome caused by the c.105_107dupGCT MEN1 mutation. This case report demonstrates the importance of genetic evaluation towards MEN1. Genetic testing for MEN1 mutations should be performed in all patients with MEN1-related tumors, and in the young patients even with only one such tumor, despite the supposedly negative family history.