Article Text
Abstract
Objective The strong genetic contribution of the major histocompatibility complex (MHC) region to rheumatoid arthritis (RA) has been generally attributed to human leukocyte antigen (HLA)-DRB1. However, due to the high polymorphisms and linkage disequilibrium within MHC, it is difficult to define novel and/or independent genetic risks using conventional HLA genotyping or chip-based microarray technology. This study aimed to identify novel RA risk variants by performing deep sequencing for MHC.
Methods We first conducted target sequencing for the entire MHC region in 357 anticitrullinated protein antibodies (ACPA)-positive patients with RA and 1001 healthy controls, and then performed HLA typing in an independent case–control cohort consisting of 1415 samples for validation. All study subjects were Han Chinese. Genetic associations for RA susceptibility and severity were analysed. Comparative modelling was constructed to predict potential functions for the newly discovered RA association variants.
Results HLA-DQα1:160D conferred the strongest and independent susceptibility to ACPA-positive RA (p=6.16×10−36, OR=2.29). DRβ1:37N had an independent protective effect (p=5.81×10−16, OR=0.49). As predicted by comparative modelling, the negatively charged DQα1:160D stabilises the dimer of dimers, thus may lead to an increased T cell activation. The negatively charged DRβ1:37N encoding alleles preferentially bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.
Conclusions We provide the first evidence that HLA-DQα1:160D, instead of HLA-DRB1*0405, is the strongest and independent genetic risk for ACPA-positive RA in Han Chinese. Our study also illustrates the value of deep sequencing for fine-mapping disease risk variants in the MHC region.
- rheumatoid arthritis
- gene polymorphism
- ant-ccp
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Footnotes
JG, TZ, HC, XL and HL contributed equally.
Handling editor Josef S Smolen
Contributors JG, XX and ZL conceptualised and designed the study. XJZ and LK participated in the study design and supervised manuscript writing. JG, TZ and HC coordinated and supervised the study teams. JG, XWL, TZ, HL and HC conducted data management and manuscript preparation. TZ, XWL, YWZ, XM and HJY conducted the statistical analyses. HMY, HJJ, JW, LS, LP, LHL, LL and KY participated in data interpretation and manuscript writing. ML, YDZ, YW, XS, FH, YD, MZ, HJ, XuL, YH, XiL, YY, XW, XZ and YS conducted sample selection and participated in data management. All coauthors edited and reviewed the final version of the manuscript.
Funding This work was supported in part by the National Key Basic Research Program of China (973 Program) (No 2014CB541901), the National Natural Science Foundation of China (No 81120108020, No 31711530023, No 31670915, No 31870913, No 31470875, No 31270914, No 31530020, No 31700794, No 81401329, No 81771678, No 81471601, No 81671604), the National Key Research and Development Program of China (No 2016YFA05022300), Beijing Natural Science Foundation (No 7162192), and Shenzhen Municipal of Government of China (No CXB201108250094A).
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval The study was approved by the Medical Ethics Committee of Peking University People’s Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as online supplementary information.