Dataset Information

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

ABSTRACT: BACKGROUND:The 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. METHODS:We 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. RESULTS:The strongest finding across the HLA genes was the association with HLA-DP?1 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-DP?1 residue Met11 (OR=1.90, Pbinary=1.76×10-31). Applying stepwise conditional analysis, we identified amino acid position 205 in HLA-DP?1, position 66 and 99 in HLA-B and position 28 in HLA-DR?1 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-DP?1 position 205, HLA-B position 69 and 199 and HLA-DR?1 position 28 drive pTRAb+ GD?risk. The risk heterogeneity between pTRAb+ and?pTRAb- GD might be driven by HLA-DP?1 Met11. CONCLUSIONS:Four 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.

SUBMITTER: Chu X

PROVIDER: S-EPMC6161647 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Chu Xun X Yang Minjun M Song Zhen-Ju ZJ Dong Yan Y Li Chong C Shen Min M Zhu Yong-Qiang YQ Song Huai-Dong HD Chen Sai-Juan SJ Chen Zhu Z Huang Wei W

Journal of medical genetics 20180709 10

<h4>Background</h4>The 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.<h4>Methods</h4>We 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 <i>HLA</i> genes in 1468 patients with GD and 1490 controls of Han Chinese.<h4>Result ...[more]

PMID: 29987165

Similar Datasets

Project description:ImportanceThyrotoxic periodic paralysis (TPP) is a potentially lethal complication of hyperthyroidism. However, only 1 specific susceptibility locus for TPP has been identified. Additional genetic determinants should be detected so that a prediction model can be constructed.ObjectiveTo investigate the genetic architecture of TPP and distinguish TPP from Graves disease cohorts.Design, setting, and participantsThis population-based case-control study used a 2-stage genome-wide association study to investigate the risk loci of TPP and weighted genetic risk score to construct a TPP prediction model with data from a Chinese Han population recruited in hospitals in China from March 2003 to December 2015. The analysis was conducted from November 2014 to August 2016.Main outcomes and measuresLoci specifically associated with TPP risk and those shared with Graves disease and prediction model of joint effects of TPP-specific loci.ResultsA total of 537 patients with TPP (mean [SD] age, 35 [11] years; 458 male) 1519 patients with Graves disease and no history of TPP (mean [SD] age, 38 [13] years; 366 male), and 3249 healthy participants (mean [SD] age, 46 [10] years; 1648 male) were recruited from the Han population by hospitals throughout China. Two new TPP-specific susceptibility loci were identified: DCHS2 on 4q31.3 (rs1352714: odds ratio [OR], 1.58; 95% CI, 1.35-1.85; P = 1.24 × 10-8) and C11orf67 on 11q14.1 (rs2186564: OR, 1.50; 95% CI, 1.29-1.74; P = 2.80 × 10-7). One previously reported specific locus was confirmed on 17q24.3 near KCNJ2 (rs312729: OR, 2.08; 95% CI, 1.83-2.38; P = 8.02 × 10-29). Meanwhile, 2 risk loci (MHC and Xq21.1) were shared by Graves disease and TPP. After 2 years of treatment, the ratio of persistent thyrotropin receptor antibody positivity was higher in patients with TPP than in patients with Graves disease and no history of TPP (OR, 3.82; 95% CI, 2.04-7.16; P = 7.05 × 10-6). The prediction model using a weighted genetic risk score and 11 candidate TPP-specific single-nucleotide polymorphisms had an area under the curve of 0.80.Conclusions and relevanceThese findings provide evidence that TPP is a novel molecular subtype of Graves disease. The newly identified loci, along with other previously reported loci, demonstrate the growing complexity of the heritable contribution to TPP pathogenesis. A complete genetic architecture will be helpful to understand the pathophysiology of TPP, and a useful prediction model could prevent the onset of TPP.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets