Analysis of HLA Variants and Graves’ Disease and Its Comorbidities Using a High Resolution Imputation System to Examine Electronic Medical Health Records

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.