Abstract
Hyperthyroidism is a prevalent endocrine disorder, and genetics play a major role in the development of thyroid-associated diseases. In particular, the inheritance of HLA has been demonstrated to induce the highest susceptibility to Graves’ disease (GD). However, thus far, no studies have reported the contribution of HLA to the development of GD and the complications that follow. Thus, in the present study, to the best of our knowledge, for the first time, a powerful imputation method, HIBAG, was used to predict the HLA subtypes among populations with available genome-wide SNP array data from the China Medical University Hospital (CMUH). The disease status was extracted from the CMUH electronic medical records; a total of 2,998 subjects with GD were identified as the cases to be tested and 29,083 subjects without any diagnosis of thyroid disorders were randomly selected as the controls. A total of 12 HLA class I genotypes (HLA-A*02:07-*11:01, HLA-B*40:01-*46:01 and *46:01-*46:01, and HLA-C*01:02-*01:02, *01:02-*03:04, and *01:02-*07:02) and 17 HLA class II genotypes (HLA-DPA1*02:02-*02:02, HLA-DPB1*02:01-*05:01, *02:02-*05:01, and *04:01-*05:01, HLA-DQA1*03:02, HLA-DRB1*09:01-*15:01, and *09:01-*09:01) were found to be associated with GD in the Taiwanese population. Moreover, the HLA subtypes HLA-A*11:01, HLA-B*46:01, HLA-DPA1*01:03, and HLA-DPB1*05:01 were found to be associated with heart disease, stroke, diabetes, and hypertension among subjects with GD. Our data suggest that several HLA alleles are markedly associated with GD and its comorbidities, including heart disease, hypertension, and diabetes.
Highlights
Hyperthyroidism is a prevalent endocrine disorder characterized by an inappropriately high synthesis and secretion of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) [1]
All clinical information, including disease diagnoses, medical and surgical procedures, prescriptions, laboratory measurements, physiological measurements, hospitalization, and catastrophic illness status were collected from the electronic medical records (EMRs) of the China Medical University Hospital (CMUH)
A total of 2,998 subjects with Graves’ disease (GD) were identified using the EMRs of the CMUH
Summary
Hyperthyroidism is a prevalent endocrine disorder characterized by an inappropriately high synthesis and secretion of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) [1]. Graves’ disease (GD) is an organ-specific autoimmune disorder caused by thyroid-stimulatory immunoglobulins and is the most common type of hyperthyroidism [2]. The autoantibodies produced imitate the activity of the thyroid-stimulating hormone (TSH) and lead to the stimulation of thyroid function, suppressing the TSH levels, while elevating the serum free T4 and T3 levels. Thyroid disorders are associated with an abnormal elevation of the levels of serum lipids [3] and are associated with a range of clinical consequences, including an increased risk of metabolic disorders, cardiovascular mortality, and thyroid cancer [4]. Many susceptibility loci associated with autoimmunity (human leukocyte antigen [HLA], protein tyrosine phosphatase, nonreceptor type 22 [PTPN22], cytotoxic T-lymphocyte associated protein 4 [CTLA4], and interleukin 2 receptor subunit alpha [IL2RA]) or thyroid-specific genes (thyroid-stimulating hormone receptor [TSHR] and forkhead box E1 [FOXE1]) have been identified to be associated with various thyroid diseases [5]
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