Fine mapping MHC associations in Graves’ disease and its clinical subtypes in Han Chinese

Abstract

BackgroundThe classical human leucocyte antigen (HLA) genes were the most important genetic determinant for Graves’ disease (GD). The aim of the study was to fine map causal variants of the HLA genes.MethodsWe applied imputation with a Pan-Asian HLA reference panel to thoroughly investigate themajor histocompatibility complex (MHC) associations with GD down to the amino acid level of classical HLA genes in 1468 patients with GD and 1490 controls of Han Chinese.ResultsThe strongest finding across the HLA genes was the association with HLA-DPβ1 position 205 (Pomnibus=2.48×10−33). HLA-DPA1*02:02 was the strongest association among the classical HLA alleles, which was in perfect linkage disequilibrium with HLA-DPα1 residue Met11 (OR=1.90, Pbinary=1.76×10−31). Applying stepwise conditional analysis, we identified amino acid position 205 in HLA-DPβ1, position 66 and 99 in HLA-B and position 28 in HLA-DRβ1 explain majority of the MHC association to GD risk. We further evaluated risk of two clinical subtypes of GD, namely persistent thyroid stimulating hormone receptor antibody -positive (pTRAb+) group and ‘non-persistent TRAb positive’ (pTRAb−) group after antithyroid drug therapy. 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. The risk heterogeneity between pTRAb+ and pTRAb− GD might be driven by HLA-DPα1 Met11.ConclusionsFour amino acid positions could account for the associations of MHC with GD in Han Chinese. These distinct HLA association patterns indicated the two subtypes have distinct molecular mechanisms of pathogenesis.

HLA alleles, especially amino-acid signatures of HLA-DPB1, might contribute to the molecular pathogenesis of early-onset autoimmune thyroid disease

“…In Chinese patients with GD, Lys66, Arg69, and Val76 of HLA-B were identified, which were present in HLA-B*46:01 in our data. Tyr116 of HLA-C, which was present in HLA-C*01:02 in our data, was also proven to be associated with GD in Chinese [24]. Ser57 of HLA-DRB1, which was associated with GD in our data, has been reported to be associated with Primary Sjogren's syndrome in a Chinese study [25].…”

Genome‐wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis

“…(10) Several GWA studies in different autoimmune diseases have identified significant associations of different ANAs with specific polymorphisms and classical HLA alleles. (28)(29)(30) Previously, two studies investigated the association of specific HLA class I and II alleles with ANAs in PBC, but these studies have been confined to small sample sets and limited HLA alleles. (31,32) The results presented in this report also have merits over previous reported imputations in other HLA fine-mapping studies.…”

Peptides of H. sapiens and P. falciparum that are predicted to bind strongly to HLA-A*24:02 and homologous to a SARS-CoV-2 peptide

“…In the mentioned COVID-19 study ( Warren and Birol, 2020 ), HLA class II alleles DPA1*02:02 and DPB1*05:01 were found to be frequent as well. Those alleles are common in Han Chinese and associated with autoimmune diseases Graves' ( Chu et al., 2018 ) and narcolepsy ( Ollila et al., 2015 ). The latter one, DPB1*05:01, is associated with chronic hepatitis B in Asians, in addition to being a risk factor effecting viral infection clearance ability (( Kamatani et al., 2009 ; Ollila et al., 2015 ) cited in ( Middleton et al., 2003 )).…”