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Abstract
The genetic association of HLA-DRB1 with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is well documented, but association with other HLA-DR beta genes (HLA-DRB3, HLA-DRB4 and HLA-DRB5) has not been thoroughly studied, despite their similar functions and chromosomal positions. We examined variants in all functional HLA-DR beta genes in RA and SLE patients and controls, down to the amino-acid level, to better understand disease association with the HLA-DR locus. To this end, we improved an existing HLA reference panel to impute variants in all protein-coding HLA-DR beta genes. Using the reference panel, HLA variants were inferred from high-density SNP data of 9,271 RA-control subjects and 5,342 SLE-control subjects. Disease association tests were performed by logistic regression and log-likelihood ratio tests. After imputation using the newly constructed HLA reference panel and statistical analysis, we observed that HLA-DRB1 variants better accounted for the association between MHC and susceptibility to RA and SLE than did the other three HLA-DRB variants. Moreover, there were no secondary effects in HLA-DRB3, HLA-DRB4, or HLA-DRB5 in RA or SLE. Of all the HLA-DR beta chain paralogs, those encoded by HLA-DRB1 solely or dominantly influence susceptibility to RA and SLE.
Highlights
HLA-DR is a key molecule implicated in conferring risk for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other diseases
Imputation accuracy in imputation using the new HLA reference panel was examined by cross-validation comparing the imputed and actual genotypes of classical alleles of HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DPB1, HLA-DQB1, HLA-DRB3, HLA-DRB4 and HLADRB5, as described following
The classical HLA alleles in a test group were imputed from major histocompatibility complex (MHC) SNPs in the test group using SNP2HLA and the reference panel that was constructed from the matched reference group
Summary
HLA-DR is a key molecule implicated in conferring risk for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other diseases. Genetic studies have fine-mapped the primary association within the major histocompatibility complex (MHC) locus with RA and SLE to HLA-DRB1, and further narrowed it down to specific amino-acid positions [2,3,4]. These studies did not investigate the other functional HLA-DR beta genes (HLA-DRB3, HLA-DRB4, or HLA-DRB5) due to the lack of a reference panel suitable for imputing their genetic variants, all the HLA-DRB genes are in strong linkage disequilibrium and encode beta chains functionally the same as HLA-DRβ1. It is very important to examine the associations of all the HLA-DRB genes simultaneously with HLA-DRB1-associated diseases
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