The HLA-DRβ1 amino acid positions 11-13-26 explain the majority of SLE-MHC associations

Kwangwoo Kim; So Young Bang; Hye Soon Lee; Yukinori Okada; Buhm Han; Woei Yuh Saw; Yik Ying Teo; Sang Cheol Bae

doi:10.1038/ncomms6902

The HLA-DRβ1 amino acid positions 11-13-26 explain the majority of SLE-MHC associations

Kwangwoo Kim, So Young Bang, Hye Soon Lee, Yukinori Okada, Buhm Han, Woei Yuh Saw, Yik Ying Teo, Sang Cheol Bae

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Abstract

Genetic association of the major histocompatibility complex (MHC) locus is well established in systemic lupus erythematosus (SLE), but the causal functional variants in this region have not yet been discovered. Here we conduct the first fine-mapping study, which thoroughly investigates the SLE-MHC associations down to the amino acid level of major HLA genes in 5,342 unrelated Korean case-control subjects, taking advantages of HLA imputation with a newly constructed Asian HLA reference panel. The most significant association is mapped to amino acid position 13 of HLA-DRβ1 (P=2.48 × 10(-17)) and its proxy position 11 (P=4.15 × 10(-17)), followed by position 26 in a stepwise conditional analysis (P=2.42 × 10(-9)). Haplotypes defined by amino acid positions 11-13-26 support the reported effects of most classical HLA-DRB1 alleles in Asian and European populations. In conclusion, our study identifies the three amino acid positions at the epitope-binding groove of HLA-DRβ1 that are responsible for most of the association between SLE and MHC.

Original language	English
Article number	5902
Pages (from-to)	5902
Number of pages	1
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms6902
State	Published - 2014
Externally published	Yes

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@article{2edcf33ec4b5415c81fbc429b6e8765a,

title = "The HLA-DRβ1 amino acid positions 11-13-26 explain the majority of SLE-MHC associations",

abstract = "Genetic association of the major histocompatibility complex (MHC) locus is well established in systemic lupus erythematosus (SLE), but the causal functional variants in this region have not yet been discovered. Here we conduct the first fine-mapping study, which thoroughly investigates the SLE-MHC associations down to the amino acid level of major HLA genes in 5,342 unrelated Korean case-control subjects, taking advantages of HLA imputation with a newly constructed Asian HLA reference panel. The most significant association is mapped to amino acid position 13 of HLA-DRβ1 (P=2.48 × 10(-17)) and its proxy position 11 (P=4.15 × 10(-17)), followed by position 26 in a stepwise conditional analysis (P=2.42 × 10(-9)). Haplotypes defined by amino acid positions 11-13-26 support the reported effects of most classical HLA-DRB1 alleles in Asian and European populations. In conclusion, our study identifies the three amino acid positions at the epitope-binding groove of HLA-DRβ1 that are responsible for most of the association between SLE and MHC. ",

author = "Kwangwoo Kim and Bang, {So Young} and Lee, {Hye Soon} and Yukinori Okada and Buhm Han and Saw, {Woei Yuh} and Teo, {Yik Ying} and Bae, {Sang Cheol}",

note = "Funding Information: We are grateful to the study participants who donated DNA samples. We also thank to Dr Soumya Raychaudhuri at Brigham and Women{\textquoteright}s Hospital for the valuable feedback over the manuscript. This work was supported by grants from the Korea Healthcare Technology R&D Project of the Ministry for Health & Welfare (HI13C2124). W.-Y.S. and Y.-Y.T. acknowledge the support from the Life Science Institute, the Office of the Deputy President (Research and Technology) from the National University of Singapore and from the Singapore National Research Foundation (NRF-RF-2010-05). A part of the Korean control data was provided from Korean Biobank Project supported by the Korea Center for Disease Control and Prevention at the Korea National Institute of Health.",

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doi = "10.1038/ncomms6902",

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pages = "5902",

journal = "Nature Communications",

issn = "2041-1723",

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T1 - The HLA-DRβ1 amino acid positions 11-13-26 explain the majority of SLE-MHC associations

AU - Kim, Kwangwoo

AU - Bang, So Young

AU - Lee, Hye Soon

AU - Okada, Yukinori

AU - Han, Buhm

AU - Saw, Woei Yuh

AU - Teo, Yik Ying

AU - Bae, Sang Cheol

N1 - Funding Information: We are grateful to the study participants who donated DNA samples. We also thank to Dr Soumya Raychaudhuri at Brigham and Women’s Hospital for the valuable feedback over the manuscript. This work was supported by grants from the Korea Healthcare Technology R&D Project of the Ministry for Health & Welfare (HI13C2124). W.-Y.S. and Y.-Y.T. acknowledge the support from the Life Science Institute, the Office of the Deputy President (Research and Technology) from the National University of Singapore and from the Singapore National Research Foundation (NRF-RF-2010-05). A part of the Korean control data was provided from Korean Biobank Project supported by the Korea Center for Disease Control and Prevention at the Korea National Institute of Health.

PY - 2014

Y1 - 2014

N2 - Genetic association of the major histocompatibility complex (MHC) locus is well established in systemic lupus erythematosus (SLE), but the causal functional variants in this region have not yet been discovered. Here we conduct the first fine-mapping study, which thoroughly investigates the SLE-MHC associations down to the amino acid level of major HLA genes in 5,342 unrelated Korean case-control subjects, taking advantages of HLA imputation with a newly constructed Asian HLA reference panel. The most significant association is mapped to amino acid position 13 of HLA-DRβ1 (P=2.48 × 10(-17)) and its proxy position 11 (P=4.15 × 10(-17)), followed by position 26 in a stepwise conditional analysis (P=2.42 × 10(-9)). Haplotypes defined by amino acid positions 11-13-26 support the reported effects of most classical HLA-DRB1 alleles in Asian and European populations. In conclusion, our study identifies the three amino acid positions at the epitope-binding groove of HLA-DRβ1 that are responsible for most of the association between SLE and MHC.

AB - Genetic association of the major histocompatibility complex (MHC) locus is well established in systemic lupus erythematosus (SLE), but the causal functional variants in this region have not yet been discovered. Here we conduct the first fine-mapping study, which thoroughly investigates the SLE-MHC associations down to the amino acid level of major HLA genes in 5,342 unrelated Korean case-control subjects, taking advantages of HLA imputation with a newly constructed Asian HLA reference panel. The most significant association is mapped to amino acid position 13 of HLA-DRβ1 (P=2.48 × 10(-17)) and its proxy position 11 (P=4.15 × 10(-17)), followed by position 26 in a stepwise conditional analysis (P=2.42 × 10(-9)). Haplotypes defined by amino acid positions 11-13-26 support the reported effects of most classical HLA-DRB1 alleles in Asian and European populations. In conclusion, our study identifies the three amino acid positions at the epitope-binding groove of HLA-DRβ1 that are responsible for most of the association between SLE and MHC.

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The HLA-DRβ1 amino acid positions 11-13-26 explain the majority of SLE-MHC associations

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