Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis
- Title
- Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis
- Author
- 배상철
- Keywords
- MAJOR HISTOCOMPATIBILITY COMPLEX; SHARED EPITOPE; JAPANESE PATIENTS; HLA-DRB1 ALLELES; ANTIBODY-LEVELS; ASSOCIATION; DISEASE; CLASSIFICATION; SUSCEPTIBILITY; IDENTIFICATION
- Issue Date
- 2016-08
- Publisher
- CELL PRESS
- Citation
- AMERICAN JOURNAL OF HUMAN GENETICS, v. 99, NO. 2, Page. 366-374
- Abstract
- Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n=7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p=1.4 x 10(-) 9), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping.
- URI
- https://www.sciencedirect.com/science/article/pii/S0002929716302233?via%3Dihubhttps://repository.hanyang.ac.kr/handle/20.500.11754/76412
- ISSN
- 0002-9297; 1537-6605
- DOI
- 10.1016/j.ajhg.2016.06.019
- Appears in Collections:
- COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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