Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population.
Ann Rheum Dis
; 78(6): 773-780, 2019 06.
Article
em En
| MEDLINE
| ID: mdl-30936065
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-DQα1160D conferred the strongest and independent susceptibility to ACPA-positive RA (p=6.16×10-36, OR=2.29). DRß137N had an independent protective effect (p=5.81×10-16, OR=0.49). As predicted by comparative modelling, the negatively charged DQα1160D stabilises the dimer of dimers, thus may lead to an increased T cell activation. The negatively charged DRß137N encoding alleles preferentially bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.CONCLUSIONS:
We provide the first evidence that HLA-DQα1160D, 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artrite Reumatoide
/
Cadeias alfa de HLA-DQ
Tipo de estudo:
Etiology_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Ann Rheum Dis
Ano de publicação:
2019
Tipo de documento:
Article