Association Between Human Leukocyte Antigen Alleles and Endocrine Disorders in 895-Patient Cohort From Russian Clinical Population

Diseases of the endocrine system represent a serious public health problem and frequently can be caused by genetic factors or their combinations with environmental and lifestyle factors. Assessing relevant genetic factors is important to estimate the risk of endocrine pathologies in an individual patient before their manifestation. Identification of genetic variations in proteins of the major histocompatibility complex is important in connection with the autoimmune nature of many endocrine pathologies, including type 1 diabetes. In this study, we investigated the relationship between human leukocyte antigen (HLA) genes and 13 endocrine disorders by using experimental whole-exome sequencing profiles obtained for 895 patients from the National Medical Research Center for Endocrinology, Moscow. In addition, the linkage disequilibrium of the identified alleles in the context of the respective diagnoses was assessed. We identified totally 45 statistically significant associations between HLA alleles and specific diagnoses of endocrine pathologies. Among them, 33 were described for the first time and 12 were previously communicated for type 1 diabetes. Overall, 17 alleles were associated with type 1 diabetes and four with other forms of diabetes. Furthermore, three alleles were associated with obesity, five with adrenogenital diseases, three with hypoglycemia, and three with precocious puberty. Single alleles were found to be associated with congenital hypothyroidism without goiter, hyperfunction of pituitary gland, adrenomedullary hyperfunction, and short stature due to endocrine disorder. The study shows that early HLA typing can help detecting endocrine disorder genetic risk factors. In addition, associations with specific HLA alleles can broaden our understanding of the mechanisms of pathogenesis of relevant endocrine disorders.