Endocrine Abstracts

Introduction: 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. We have recently demonstrated novel, previously not reported association between a presence of alleles HLA-B*39:06, -B*37:01, -C*14:02, -C*03:02, -C*17:01, -DRB1*14:01 and GD. These alleles are independent risk factors, with no linkage disequilibrium with other, already reported, high-risk alleles. Up to 2022, no such correlation was demonstrated for Graves’ orbitopathy (GO) in Caucasian population.

Material and Methods: We performed HLA-A, -B, -C, -DQB1 and -DRB1 genotyping using a high-resolution next generation sequencing 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 in GO, non-GO and control groups.

Results: The risk of GO was significantly associated with a presence of 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. The highest risk of GO was associated with the presence of HLA-C*08:02 (OR 6.9), -C*03:02 (8.3), -DRB1*14:01 (6.2) and -B*37:01 (OR 4.5). On the other hand, HLA-C*04:01, -C*03:04, -C*07:02 and -DRB1*15:02 were demonstrated to be 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. The presence of HLA-B*08:01, -B*39:06, -B*51:01, -C*07:01, -C*14:02, -C*16:02, -C*17:01, -DRB1*01:03, -DRB1*15:02, -DQB1*03:01 was associated with increased risk of non-GO GD, while HLA-B*07:02, -C*07:02, -A*32:01 were demonstrated to be protective against non-GO GD. The highest risk of non-GO was associated with the presence of HLA-DRB1*01:03 (OR 8.4), -B*39:06 (OR 5.6), -C*17:01 (OR 4.6) and -C*16:02 (OR 4.2). Additionally, correlations between HLA and clinical risk of GO were found.

Conclusions: These results complemented our previous study, which demonstrated GD high risk alleles, by precise identification and distinction of the groups of GO-related and GO-protective alleles, as well as the alleles strongly related to non-GO GD. The knowledge on HLA-related genetic background of GO and non-GO GD constitutes an important step in a development of personalized medicine, with new possibilities of individual risk assessment and patient-tailored treatment.