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

doi:10.1371/journal.pone.0150283

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

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

20 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 language	English
Article number	e0150283
Journal	PLoS ONE
Volume	11
Issue number	2
DOIs	https://doi.org/10.1371/journal.pone.0150283
State	Published - Feb 2016

Bibliographical note

Funding Information:
This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2015R1C1A1A02036527 to Dr. Kwangwoo Kim), the US National Institutes of Health (R01MD007909 and R01AR060366 to Dr. Swapan K. Nath), and the Korea Healthcare Technology R&D Project of the Ministry for Health & Welfare (HI13C2124 to Dr. Sang-Cheol Bae). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2016 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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10.1371/journal.pone.0150283

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Kim, K., Bang, S. Y., Yoo, D. H., Cho, S. K., Choi, C. B., Sung, Y. K., Kim, T. H., Jun, J. B., Kang, Y. M., Suh, C. H., Shim, S. C., Lee, S. S., Lee, J., Chung, W. T., Kim, S. K., Choe, J. Y., Nath, S. K., Lee, H. S., & Bae, S. C. (2016). Imputing variants in HLA-DR beta genes reveals that HLA-DRB1 is solely associated with rheumatoid arthritis and systemic lupus erythematosus. PLoS ONE, 11(2), Article e0150283. https://doi.org/10.1371/journal.pone.0150283

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

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.",

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

note = "Funding Information: This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2015R1C1A1A02036527 to Dr. Kwangwoo Kim), the US National Institutes of Health (R01MD007909 and R01AR060366 to Dr. Swapan K. Nath), and the Korea Healthcare Technology R&D Project of the Ministry for Health & Welfare (HI13C2124 to Dr. Sang-Cheol Bae). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2016 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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Kim, K, Bang, SY, Yoo, DH, Cho, SK, Choi, CB, Sung, YK, Kim, TH, Jun, JB, Kang, YM, Suh, CH, Shim, SC, Lee, SS, Lee, J, Chung, WT, Kim, SK, Choe, JY, Nath, SK, Lee, HS & Bae, SC 2016, 'Imputing variants in HLA-DR beta genes reveals that HLA-DRB1 is solely associated with rheumatoid arthritis and systemic lupus erythematosus', PLoS ONE, vol. 11, no. 2, e0150283. https://doi.org/10.1371/journal.pone.0150283

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AU - Kim, Kwangwoo

AU - Bang, So Young

AU - Yoo, Dae Hyun

AU - Cho, Soo Kyung

AU - Choi, Chan Bum

AU - Sung, Yoon Kyoung

AU - Kim, Tae Hwan

AU - Jun, Jae Bum

AU - Kang, Young Mo

AU - Suh, Chang Hee

AU - Shim, Seung Cheol

AU - Lee, Shin Seok

AU - Lee, Jisoo

AU - Chung, Won Tae

AU - Kim, Seong Kyu

AU - Choe, Jung Yoon

AU - Nath, Swapan K.

AU - Lee, Hye Soon

AU - Bae, Sang Cheol

N1 - Funding Information: This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2015R1C1A1A02036527 to Dr. Kwangwoo Kim), the US National Institutes of Health (R01MD007909 and R01AR060366 to Dr. Swapan K. Nath), and the Korea Healthcare Technology R&D Project of the Ministry for Health & Welfare (HI13C2124 to Dr. Sang-Cheol Bae). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2016 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2016/2

Y1 - 2016/2

N2 - 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.

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

Abstract

Bibliographical note

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