We evaluated the associations of genetic variants at the HLA-B and HLA-DRB1 loci and 32 candidate single nucleotide polymorphisms (SNPs) with agranulocytosis in 29 patients with ATD-induced agranulocytosis and in 140 patients with Graves' disease (GD) as controls.
We found that HLA-B residues Lys66-Arg69-Val76 could drive pTRAb- GD risk alone, while HLA-DPβ1 position 205, HLA-B position 69 and 199 and HLA-DRβ1 position 28 drive pTRAb+ GD risk.
This study shows that the susceptibility to Graves' disease is inherited associated with HLA and that whereas the disease susceptibility gene for Graves' disease is in linkage disequilibrium with HLA-B8 in Caucasians, it can be randomly associated with other HLA-B antigens.
Namely, the HLA-DP allele (DPB1*0501) and the HLA-B allele (B46) are primarily involved in the pathogenesis of early-onset and late-onset Graves' disease in Japanese, respectively.
We applied HLA imputation to genome-wide association study (GWAS) data for Graves' disease in Japanese (n = 9,003) and found that amino acid polymorphisms of multiple class I and class II HLA genes independently contribute to disease risk (HLA-DPB1, HLA-A, HLA-B and HLA-DRB1; P < 2.3 × 10(-6)), with the strongest impact at HLA-DPB1 (P = 1.6 × 10(-42)).
Our results showed a trend toward an increased risk of GD in HLA-B*46-positive subjects compared to those HLA-B*46-negative (OR = 2.48; 95% CI = 1.96-3.13, P < 0.01).