Sequencing of the MHC region defines HLA-DQA1 as the major independent risk for anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis in Han population
Posted 27 Aug 2018
bioRxiv DOI: 10.1101/400937
Posted 27 Aug 2018
The strong genetic contribution of the major histocompatibility complex (MHC) to rheumatoid arthritis (RA) susceptibility has been generally attributed to HLA-DRB1. However, due to the high linkage disequilibrium in the MHC region, it is difficult to define the real or additional independent genetic risks using the conventional HLA genotyping or chip-based microarray technology. By the capture sequencing of entire MHC region for discovery and HLA-typing for validation in 2,773 subjects of Han ancestry, we identified HLA-DQα1:160D as the strongest independent genetic risk for anti-citrullinated protein antibodies (ACPA)-positive RA in Han population (P = 6.16 x 10-36, OR=2.29). Further stepwise conditional analysis revealed that DRβ1:37N has an independent protective effect on ACPA-positive RA (P=5.81 x 10-16, OR=0.49). The DQα1:160 coding allele DQA1*0303 displayed high impact on joint radiographic severity, especially in patients with early disease and smoking (P = 3.02 x 10-5). Interaction analysis by comparative molecular modeling revealed that the negative charge of DQα1:160D stabilizes the dimer of dimers, leading to an increased T cell activation. The electrostatic potential surface analysis indicated that the negative charged DRβ1:37N encoding alleles could bind with epitope P9 arginine, thus may result in a decreased RA susceptibility. In this study, we provide the first evidence that HLA-DQA1, instead of HLA-DRB1, is the strongest and independent genetic risk for ACPA-positive RA in Chinese Han population. Our study also illustrates the value of MHC deep sequencing for fine mapping disease risk variants in the MHC region.
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