Association of Human Leukocyte Antigen Genotypes with Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine-Induced Subacute Thyroiditis

Abstract

Background:

Despite mass vaccination, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced subacute thyroiditis (SAT) is rarely seen as a complication. The reason why some individuals are susceptible to developing vaccine-induced SAT is not known. SAT develops in genetically predisposed individuals who carry specific human leukocyte antigen (HLA) haplotypes. It is unknown whether specific HLA alleles are associated with SARS-CoV-2 vaccine-induced SAT.

Objective:

This study compared the HLA profiles of patients with SARS-CoV-2 vaccine-induced SAT to controls, to assess whether there is an association between specific HLA genotypes and development of SAT. The relationship between HLA genotypes and the clinical course of SARS-CoV-2 vaccine-induced SAT was also evaluated.

Methods:

A case–control study was conducted in a Turkish tertiary care center. Fourteen patients with SARS-CoV-2 vaccine-induced SAT and 100 healthy controls were included. HLA-A, HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 frequencies were analyzed by next-generation sequencing.

Results:

The frequencies of HLA-B*35 and HLA-C*04 alleles were significantly higher in SARS-CoV-2 vaccine-induced SAT cohort when compared with controls (HLA-B*35: 13 [93%] vs. 40 [40%], p < 0.001; HLA-C*04: 13 [93%] vs. 43 [43%], p < 0.001, respectively). More severe thyrotoxicosis was seen in patients having HLA-B*35 and HLA-C*04 homozygous alleles (free thyroxine: 4.47 ng/dL [3.77–5.18] vs. 1.41 ng/dL [1.22–2.63], p = 0.048). Inflammation tended to be more severe in homozygous patients (C-reactive protein: 28.2 mg/dL [13.6–42.9] vs. 4.8 [1.2–10.5], p = 0.07).

Conclusions:

The frequencies of HLA-B*35 and HLA-C*04 alleles were higher in SARS-CoV-2 vaccine-induced SAT compared with controls. Homozygosity for HLA-B*35 and HLA-C*04 was associated with thyrotoxicosis and a greater inflammatory reaction. Our findings should be confirmed in studies of other populations.

Introduction

The new coronavirus disease 2019 (COVID-19), which is caused by the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a major detrimental impact on health. Various vaccines have been developed within a short time while the catastrophic pandemic of the recent century continues (1). Some examples of currently used vaccines include the following: mRNA-based SARS-CoV-2 vaccines (BNT162b2 from Pfizer-BioNTech; mRNA-1273 from Moderna), inactivated SARS-CoV-2 vaccine (CoronaVac from Sinovac Life Sciences), and the viral vector vaccine (ChAdOx1 nCoV-19 from Oxford-AstraZeneca) (2 –5). Widespread vaccination programs have been launched worldwide to control the pandemic. Billions of people have been vaccinated, and mass vaccination continues.

Several inflammatory/autoimmune diseases associated with the SARS-CoV-2 vaccine, which have not been observed in phase III studies, have been described after mass vaccination (6). Subacute thyroiditis (SAT) cases following SARS-CoV-2 vaccination have been reported (7). However, despite mass vaccination, the rarity of SARS-CoV-2 vaccine-induced SAT and other autoimmune diseases suggests there may be individual predisposition. Although the pathogenesis of SAT is not fully understood, genetic predisposition in individuals carrying specific human leukocyte antigen (HLA) haplotypes has been reported (8). However, there are no prior studies explaining individual susceptibility to the SARS-CoV-2 vaccine-induced SAT.

In this study, we compared the HLA profiles of patients with SARS-CoV-2 vaccine-induced SAT with that of historical control subjects. A secondary objective was to explore for a potential relationship between HLA genotypes and the clinical course of SARS-CoV-2 vaccine-induced SAT (including severity of thyrotoxicosis and inflammation).

Materials and Methods

Study design and study population

The study was designed as case–control study. It was conducted in the Division of Endocrinology and Metabolism outpatient clinic, Department of Internal Medicine of Hacettepe University Hospital, a Turkish tertiary care center. The study was performed between January 2021 and January 2022. During the study period, 41 potentially eligible patients with SAT were identified. Sixteen patients with SAT who developed symptoms within 4 weeks of receiving the SARS-CoV-2 vaccinations and had negative polymerase chain reaction (PCR) for SARS-CoV-2 and had no recent history of any viral infections were diagnosed as SARS-CoV-2 vaccine-related SAT. Two of 16 patients declined to participate in the study. Final analyses were performed using the data from 14 consenting patients (Fig. 1).

FIG. 1.

Flow diagram of participants. HLA, human leukocyte antigen; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SAT, subacute thyroiditis.

The American Thyroid Association Guidelines of 2016 and the local expertise were used to diagnose SAT (9). Patients were assessed according to (i) symptoms and physical examination findings; (ii) thyroid function tests and serum thyroglobulin levels; (iii) inflammatory markers; (iv) ultrasonography examination findings; and (v) radioactive iodine uptake (RAIU) values (if available). Patients who exhibited symptoms consistent with SAT such as neck pain, tenderness on thyroid palpation, elevated inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, or white blood cell count), and who had thyroid ultrasonography/color flow Doppler ultrasonography findings compatible with SAT (i.e., hypoechoic ill-defined area(s) with decreased blood flow and pain sensation with ultrasonography probe during a sonographic examination of the thyroid lesions), and decreased RAIU, were diagnosed as SAT. Patients with SAT and had a temporal relationship with vaccine exposure were diagnosed with SARS-CoV-2 vaccine-induced SAT.

Disease management of SAT was informed by current clinical practice guidelines (9), evidence from the medical literature (10,11), and local experience. No medication was initiated in the absence of neck pain. NSAIDs were initiated in case of mild symptoms; the treatment was replaced with glucocorticoids if the symptoms were not relieved over several days. Glucocorticoids were initially commenced in patients with moderate to severe neck pain and then tapered gradually to a minimum dose that controlled the pain. Beta-adrenergic blockers were prescribed for patients who experienced palpitations or tremors.

Chemiluminescent immunometric assays were used to measure thyrotropin (TSH) and free thyroxine (fT4) levels (Unicell DxI-800 Access Immunoassay Systems; Beckman Coulter GmbH, Krefeld, Germany). TSH measurements had a 0.003 mU/L analytical sensitivity. The Siemens Immulite 2000/2000XPi assay was used to measure thyroglobulin (Siemens Healthcare Diagnostics, Inc.). Antithyroglobulin antibody and antithyroid peroxidase antibody titers were measured by the Unicel Dxl-800 Thyroglobulin Antibody II and Access TPO Antibody assays, respectively (Beckman Coulter GmbH). TSH receptor antibody titers were analyzed using Roche Elecsys Anti-TSHR assay.

The historical control group consisted of healthy Turkish donor candidates recruited from the Department of Basic Oncology, Hacettepe University Cancer Institute from 2010 until 2015 (12), and all had predetermined HLA profiles for hematopoietic stem cell transplantation. Control group participants were unrelated persons from all geographical areas of Turkey. The same control group was used in our previously published studies (12). Details of the selection of controls are given in Figure 1. The control group was matched with patients according to age and sex.

Hacettepe University Non-Interventional Clinical Research Ethics Board approved the protocol with the project number GO 21/1298. All subjects gave their written informed consent, and the study was conducted according to the Declaration of Helsinki and its later amendments.

HLA typing

We collected 5–10 mL peripheral venous blood for HLA typing. Genomic DNA was extracted using a DNA isolation kit (QIAamp DNA Blood Mini Kit; Qiagen, CA), and samples were quantified with Qubit™ 4 Fluorometer. HLA typing for HLA-A, -B, -C, -DRB1, -DQB1 was performed by next-generation sequencing in patients with SAT. First, related HLA loci were amplified with PCR (NGSgo^®-MX6-1; GenDX, Utrecht, The Netherlands). The library was prepared with NGSgo^®-LibrX kit (GenDX), and the library consisted of fragmentation, adaptor ligation, and index PCR steps. The HLA typing was conducted with the MiniSeq NGS platform (Illumina, San Diego), and readings were analyzed with NGSengine software (version 3.43). All HLA typing results have been reported as high resolution in SAT cohort. Sequence-specific oligonucleotide-based HLA genotyping was carried out in the control group.

WHO Nomenclature Committee for Factors of the HLA System Guidelines were followed to describe HLA alleles. Correspondingly, HLA prefix expresses the MHC gene complex preceded by the capital letters that show a specific gene. Each HLA antigen was specified beginning with the locus, antigenic specificity, and molecularly typed allele group. IMGT/HLA version 3.38 was used for the patient's HLA typing (13).

The study's primary research question measure was to assess whether there is an association between specific HLA genotypes and SARS-CoV-2 vaccine-induced SAT. A secondary research question was to explore for a potential relationship between the clinical course of SARS-CoV-2 vaccine-induced SAT and HLA genotype (including severity of thyrotoxicosis and inflammation). We estimated 99% statistical power to detect a difference of 93% versus 36% in HLA-B*35 allele frequency between vaccine-induced SAT cases (N = 14) and controls (N = 56). The power analysis was conducted using a two-tailed hypothesis with an alpha level of 0.05 testing design in the G*Power software.

Statistical analysis

The distributions of continuous variables were tested for normality using histograms and probability plots, and the Kolmogorov–Smirnov/Shapiro–Wilk's test. Normally distributed data were presented as the mean ± standard deviation, whereas the median and interquartile range (IQR) were used to describe continuous data with a skewed distribution. Categorical variables were expressed as frequencies and/or percentages. Student's t-test and Mann–Whitney U-test were used to compare differences in normally distributed and non-normally distributed continuous variables, respectively. The differences in categorical variables were assessed by the chi-square or Fisher's exact test. A value of p ≤ 0.05 was considered statistically significant. Statistical Package for Social Sciences (SPSS) version 21.0 was used for the statistical analyses.

Results

Four of 14 patients had nodular thyroid disease, and 1 patient had a past subtotal thyroidectomy for treatment of goiter. One of our cases had a recent SAT diagnosis (only 2 months before vaccination), and vaccination might have exacerbated the first attack or precipitated a new episode [detailed clinical characteristics, medical history, and follow-up results of these patients have been published recently (14)]. None of the patients took thyroid medication and no history of other thyroid disorders such as autoimmune thyroid disease or cancer was noted. Other than SARS-CoV-2 vaccine-induced SAT and a local reaction at the injection site (pain, redness, and swelling), none of the patients reported any other adverse vaccine effects.

The data of 14 patients who developed SARS-CoV-2 vaccine-induced SAT and 100 healthy controls were analyzed. Demographic, clinical, and genotype characteristics of patients are given in Table 1. While 12 patients were women, 2 patients were men. The mean age of the SAT cohort was 43.1 ± 9.3 years. The control group consisted of 47 (47%) women and 53 (53%) men with a mean age of 45.9 ± 14.4 years. SARS-CoV-2 vaccine-induced SAT was developed following BNT162b2 in 8 (57%) patients and CoronaVac in 6 (43%). Eleven (79%) patients needed medical treatment; 5 of 11 required glucocorticoids, whereas the remaining were controlled with nonsteroidal anti-inflammatory drugs.

Table 1.

Demographic, Clinical and Genotype Characteristics of the Cases

	Age, years	Gender	Type of vaccine^a	TSH^b	fT4^b	CRP^c	ESR^c	Thyroid antibodies	History of autoimmune/inflammatory disease	HLA subtypes
Case 1	42	Female	BNT162b2	0.005	5.1	4.4	74	TPOAb: 0.3 IU/mL TgAb: 2 IU/mL	None	HLA-B^35:08; HLA-C^04:01
Case 2	47	Female	BNT162b2	0.54	1.34	4.8	55	TPOAb: 5.8 IU/mL TgAb: <0.9 IU/mL	None	HLA-B^35:03; HLA-C^04:01
Case 3	50	Male	CoronaVac	0.13	1.14	1.02	41	TPOAb: 2.9 IU/mL TgAb: 7.9 IU/mL TRAb: 0.9 IU/mL	Subacute thyroiditis	None
Case 4	61	Female	CoronaVac	4.4	1.09	1.16	34	TPOAb: 1.2 IU/mL TgAb: <0.9 IU/mL	None	HLA-B^35:03; HLA-C^04:01 DRB1^01:01*
Case 5	36	Female	CoronaVac	0.47	1.91	10.5	53	TPOAb: 1.2 IU/mL TgAb: 10.9 IU/mL TRAb: <1.5 IU/mL	None	HLA-B^35:03; HLA-C^04:01 DRB1^01:01*
Case 6	38	Female	CoronaVac	0.018	2.61	0.3	44	TPOAb: 4.1 IU/mL TgAb: <0.9 IU/mL TRAb: <1.5 IU/mL	None	HLA-B^35:03; HLA-C^04:01
Case 7	38	Female	BNT162b2	<0.010	5.18	13.6	55	TPOAb: 6.11 IU/mL TgAb: <0.9 IU/mL TRAb: 0.45 IU/mL	None	HLA-B^35:03* HLA-B^35:08* HLA-C^04:01* Homozygous DRB1^12:01*
Case 8	38	Female	CoronaVac	0.032	1.22	1.9	42	TPOAb: 1.2 IU/mL TgAb: <0.9 IU/mL	None	HLA-B^35:01; HLA-C^04:01
Case 9	43	Female	BNT162b2	0.01	3.77	42.9	NA	TPOAb: 28 IU/mL (N < 34) TgAb: 26 IU/mL (N < 115) TRAb: 0.8 IU/mL	None	HLA-B^35:01* Homozygous HLA-C^04:01* Homozygous DRB1^01:01*
Case 10	60	Female	BNT162b20	0.6	1.4	5.2	33	NA	None	HLA-B^35:01; HLA-C^04:01
Case 11	46	Female	BNT162b2	0.43	1.4	1.7	60	TPOAb: 0.7 IU/mL TgAb <0.9 IU/mL	None	HLA-B^35:02; HLA-C^04:01
Case 12	41	Male	CoronaVac	<0.005	2.63	18.8	54	TPOAb: 0.6 IU/mL TgAb: <0.9 IU/mL	None	HLA-B^35:03; HLA-C^04:01
Case 13	36	Female	BNT162b2	<0.005	3.18	6.2	46	TPOAb: 1.5 IU/mL TgAb: <0.9 IU/mL	None	HLA-B^35:01; HLA-C^04:01
Case 14	27	Female	BNT162b2	0.005	6.83 (N 0.93–1.7)	2.05	NA	TPOAb <0.25 IU/mL TgAb: <0.9 IU/mL	None	HLA-B^35:08; HLA-C^04:01

Type of vaccine-associated with subacute thyroiditis.

Thyroid function test data regarding the highest fT4 levels obtained during the follow-up of the patients are given.

The highest CRP and ESR levels obtained during the follow-up of the patients are given. TSH normal range: 0.38–5.33 mIU/L. fT4 normal range: 0.78–1.44 ng/dL (unless specified otherwise in the table). CRP normal range: 0–0.8 mg/dL. ESR normal range: 0–25 mm/h. TgAb normal range, 0–4 IU/mL (unless specified otherwise in the table). TPOAb normal range, 0–9 IU/mL (unless specified otherwise in the table). TRAb normal range, <1.5 IU/mL.

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; fT4, free thyroxine; HLA, human leukocyte antigen; NA, not available; TgAb, antithyroglobulin antibody; TPOAb, antithyroid peroxidase antibody; TRAb, TSH receptor antibody; TSH, thyrotropin.

Results of HLA genotype analyses

Among 14 patients diagnosed with SARS-CoV-2 vaccine-induced SAT, 93% (n = 13) were identified as having at least one allele of HLA-B*35, 93% (n = 13) had HLA-C*04, 86% (n = 12) had HLA-DQ*03, and none had HLA-B*18. Two patients (14%) were homozygous for both HLA-B*35 and HLA-C*04.

The comparison of HLA allele frequency between patients with vaccine-induced SAT and controls is given in Table 2. In the SARS-CoV-2 vaccine-induced SAT cases, the frequency of HLA-B*35 and HLA-C*04 alleles were higher than controls. HLA profiles of patients were compared with that of the age- and sex-matched control group, and similar results were found (Table 2). The frequency of remaining HLA genotypes, including those previously suggested as risk factors for SAT, were not different between SARS-CoV-2 vaccine-induced SAT cases and controls (Table 2). All HLA genotyping results are provided in Supplementary Table S1.

Table 2.

Comparison of Human Leukocyte Antigen Allele Frequency Between Vaccine-Induced Subacute Thyroiditis and Controls

	Patients, n = 14	Controls, n = 100	Age- and sex-matched controls, n = 56	p	p ^a
Age, mean ± SD	43.1 ± 9.3	45.9 ± 14.4	45.5 ± 12.8	0.48	0.51
Gender, n (%)				0.007	0.87
Female	12 (86)	47 (47)	47 (84)
Male	2 (14)	53 (53)	9 (16)
	At least one allele, n (%)
HLA-B^35*				<0.001	<0.001
Present	13 (93)	40 (40)	20 (36)
Not present	1 (7)	60 (60)	36 (64)
HLA-C^04*				<0.001	<0.001
Present	13 (93)	43 (43)	22 (39)
Not present	1 (7)	57 (57)	34 (61)
HLA-DR^01*				0.46	0.47
Present	4 (29)	20 (20)	11 (20)
Not present	10 (71)	80 (80)	45 (80)
HLA-B^18*				0.31	0.25
Present	0 (0)	7 (7)	5 (9)
Not present	14 (0)	93 (93)	51 (91)
HLA-DR^04*				0.09	0.10
Present	6 (43)	22 (22)	12 (21)
Not present	8 (57)	78 (78)	44 (79)
HLA-DQ^03*				0.06	0.10
Present	12 (86)	60 (60)	35 (63)
Not present	2 (14)	40 (40)	21 (37)

Bold values indicate the statistical significance.

Significant difference from age- and sex-matched controls.

To explore for a relationship between disease severity between patients homozygous for HLA-B*35 and HLA-C*04 and those who were not, the highest fT4 and C-reactive protein levels obtained during the follow-up of the patients were compared. Although there was a limited number of cases (only two) to make a statistical interference, patients who were homozygous for HLA-B*35 and HLA-C*04 demonstrated more pronounced biochemical thyrotoxicosis compared with those who were not homozygous (fT4: 4.47 ng/dL [3.77–5.18] vs. 1.41 ng/dL [1.22–2.63], p = 0.048). The inflammatory reaction also tended to be more severe in patients who were homozygous for HLA-B*35 and HLA-C*04 (C-reactive protein: 28.2 mg/dL [13.6–42.9] vs. 4.8 [1.2–10.5], p = 0.07). All results are given as median (IQR).

There were no differences between homozygous and nonhomozygous patients regarding disease duration, glucocorticoid requirement, and the time lag between the vaccine dose and SAT symptom onset: time lag for homozygous patients, 8.5 days (7 –10) versus nonhomozygous patients, 6.5 days (4–11.5), p = 0.65; disease duration for homozygous patients, 7.5 weeks (4 –11) versus nonhomozygous homozygous patients, 12 weeks (6 –18), p = 0.30. One homozygous patient (50%) required glucocorticoid therapy, while four nonhomozygous patients (33%) required it.

Discussion

In this study, we evaluated the association between SARS-CoV-2 vaccine-induced SAT and HLA genotype. The allele frequency of the HLA-B*35 and HLA-C*04 were higher in SARS-CoV-2 vaccine-induced SAT cases compared with controls (8,15). HLA-B*18 and HLA-DRB*01, which were previously shown to be associated with SAT, were not observed in postvaccination cases (15 –17). Furthermore, patients who were homozygous for high-risk alleles were more thyrotoxic and had a higher inflammatory reaction.

Since the beginning of the pandemic, significant efforts have been expensed to develop an effective vaccine against SARS-CoV-2. After developing various vaccines against SARS-CoV-2, the phase III trials and global vaccination campaigns have documented safety and a satisfactorily high protection profile against COVID-19 (2 –5). With the onset of mass vaccination, diverse vaccine-related adverse events have been reported, including cases of SAT following the inactive SARS-CoV-2 vaccination (7). Subsequently, cases of SARS-CoV-2 vaccine-induced SAT associated with different types of vaccines have been reported (18). Although billions have been vaccinated, vaccine-induced SAT has been relatively uncommonly observed in clinical practice.

The etiology and pathogenesis of SAT are not entirely known; however, the disease commonly follows a viral infection, especially in genetically susceptible individuals (19). Previous studies have indicated that individuals carrying specific HLA haplotypes are predisposed to develop SAT. The first study has reported that the frequency of HLA-B*35 carriers was significantly higher in patients with SAT compared with the population (8). Subsequent reports have demonstrated that the presence of HLA-C*04, HLA-B*18, and HLA-DRB*01 alleles was also associated with an increased SAT risk (15 –17,20). Further research has shown that in Caucasian populations, HLA-C*04:01 and HLA-B*35 are in linkage disequilibrium, and these two alleles commonly occur together because of the close location of their loci. No linkage disequilibrium has been identified for HLA-B*18 or HLA-DRB1 (20). These studies have confirmed the existence of an individual genetic predisposition in the development of SAT after viral infections.

Various viral vaccines may also trigger SAT. Several hypotheses have been proposed to explain the mechanism behind the development of vaccine-induced SAT. Among them, the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) attracts more attention (7,21). ASIA has originally been suggested as an umbrella term for autoimmune/inflammatory diseases induced by “exposure to an external stimulus before clinical manifestations” in genetically susceptible subjects, involving postvaccination autoimmune phenomena (22). Adjuvants are used in vaccines to enhance immune responses against pathogens. Immunological responses generated by adjuvants should ideally be pathogen specific, with no immune reaction against the adjuvants themselves (23,24). However, some adjuvants can induce autoimmunity and autoimmune disorders, as evidenced in animal models (25). Several SAT cases have been reported as a component of ASIA syndrome with various vaccines (HPV, HBV, influenza, H1N1) (26). Among them, HLA-B*35 was reported in two patients who developed SAT after influenza vaccination to date (27,28).

Moreover, Stasiak et al. recently reported that HLA-B*35:03 and HLA-C*04:01 were found together in two SARS-CoV-2 vaccine-induced SAT cases (29). However, detailed haplotype analyses of those postvaccination cases in larger cohorts are lacking. This study has evaluated detailed HLA haplotype analyses and demonstrated an association between postvaccination SAT cases and HLA-B*35 and HLA-C*04. Our results support the role of specific HLA genotypes in developing postvaccination SAT.

As previously stated, HLA-B*35 and HLA-C*04 are in linkage disequilibrium, making these particular alleles occur together more frequently (20). However, the impact of the presence of these alleles as SAT risk factors is high not only when they occur together, but also when any of them was proved to be a strong risk factor for SAT (15). Accordingly, Stasiak et al. have speculated that the co-presence of HLA-B*35 and HLA-C*04 may be associated with an increased risk of SAT induced by COVID-19 vaccination (29). Consistently, HLA-B*35 and HLA-C*04 were concurrently found in almost all patients in our cohort, which may have resulted in a significant increase in SAT risk. Considering the ongoing pandemic and the need for booster doses of vaccines against COVID-19, subjects with high-risk HLA genotypes or populations with a high frequency of risky HLA haplotypes such as HLA-B*35 and HLA-C*04 may be predisposed to developing postvaccination SAT.

Roles of specific HLA haplotypes in the clinical course of SAT have also been studied. These studies have reported that thyroid gland involvement patterns, the risk of recurrence, and the dependence on steroids were associated with the HLA genotypes (30 –32). In support of these reports, a secondary analysis in this study has suggested more severe thyrotoxicosis and inflammation in HLA-B*35 and HLA-C*04 homozygous patients. However, only two patients were homozygous for HLA-B*35 and HLA-C*04. The course of the disease may be more severe in homozygous patients, but it is difficult to reach a definite conclusion owing to a limited number of patients.

There were some limitations of our study. First, the total number of cases was low, and the case group was a mix of various vaccine brands. We had no detailed information in the control group regarding COVID-19 status, vaccine status, and other risk factors related to SAT (smoking, alcohol, and body mass index). Therefore, there could be other factors that could inflate the observed differences. Moreover, the size of our control group was too small to detect differences in alleles of low frequency. In addition, HLA typing with next-generation sequencing was performed only in SAT cases. Sequence-specific oligonucleotide-based HLA genotyping was used in the control group.

However, despite the small size of the case group, based on the HLA-B*35 allele frequency difference, the power of the study was 99%. In addition, this study was the second one comparing HLA haplotype patterns in SAT patients with healthy controls based on the high-resolution method (15). Moreover, this is the largest cohort of patients with SARS-CoV-2 vaccine-induced SAT published so far.

In conclusion, our results support the role of HLA-B*35 and HLA-C*04 genotypes in susceptibility to postvaccination SAT. Homozygosity for high-risk alleles was also associated with worse thyrotoxicosis and greater inflammation in secondary analyses. Further studies in various populations are needed to confirm these results.

Footnotes

Authors' Contributions

S.N.Ş. and U.Ü. designed the study, collected and interpreted the data, performed the statistical analyses, and drafted the article. F.Ö. and Ü.Y.M. performed the experiments, interpreted the data, provided the HLA data of controls, read and approved the final version of the article. S.H.O., B.G.İ., A.G., and T.E. contributed to the coordination of the patients' care; collected and interpreted the data, read and approved the final version of the article.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Supplementary Material

Supplementary Table S1

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