Imputing variants in HLA-DR beta genes reveals that HLA-DRB1 is solely associated with rheumatoid arthritis and systemic lupus erythematosus

Kwangwoo Kim, So Young Bang, Dae Hyun Yoo, Soo Kyung Cho, Chan Bum Choi, Yoon Kyoung Sung, Tae Hwan Kim, Jae Bum Jun, Young Mo Kang, Chang Hee Suh, Seung Cheol Shim, Shin Seok Lee, Jisoo Lee, Won Tae Chung, Seong Kyu Kim, Jung Yoon Choe, Swapan K. Nath, Hye Soon Lee, Sang Cheol Bae

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18 Scopus citations

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.

Original languageEnglish
Article numbere0150283
JournalPLoS ONE
Volume11
Issue number2
DOIs
StatePublished - Feb 2016

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