Background/Purpose: 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/and additional independent genetic risks using the conventional HLA genotyping or chip-based microarray technology.

Methods: To fine map HLA region and identify novel variants contributing to RA, we performed a deep sequencing for entire MHC region for discovery and classical HLA-typing for validation in 2773 subjects of Han ancestry (961 cases and 1812 controls). We analyzed HLA alleles, amino acids, SNPs, and indels across the MHC region to define the association for anti-citrullinated protein antibodies (ACPA)-positive RA.

Results: We identified HLA-DQa1:160D as a novel and 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 DRb1:37N has an independent protective effect on ACPA–positive RA (P = 5.81 x 10⁻¹⁶, OR=0.49). The DQa1:160 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).

Conclusion: 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. DRb1:37N is an independent protective factor for ACPA-positive RA. Our study also illustrates the value of MHC deep sequencing for fine mapping disease risk variants in the MHC region.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sequencing-of-the-mhc-region-defines-hla-dqa1-as-driven-risk-for-anti-citrullinated-protein-antibodies-acpa-positive-rheumatoid-arthritis-in-han-population/