MHC associations of ankylosing spondylitis in East Asians are complex and involve non-HLA-B27 HLA contributions
Abstract Background The association of HLA-B*27 with AS is amongst the strongest of any known association of a common variant with any human disease. Nonetheless, there is strong evidence indicating that other HLA-B alleles are involved in the disease. European ethnicity studies have demonstrated ri...
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doaj-3b3192b3a152432c80f148b2c691dde02020-11-25T02:06:28ZengBMCArthritis Research & Therapy1478-63622020-04-012211810.1186/s13075-020-02148-5MHC associations of ankylosing spondylitis in East Asians are complex and involve non-HLA-B27 HLA contributionsGeng Wang0Tae-Hwan Kim1Zhixiu Li2Adrian Cortes3Kwangwoo Kim4So-Young Bang5Paul Leo6Matthew A. Brown7Huji Xu8Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical UniversityDepartment of Biology, Kyung Hee UniversityTranslational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research InstituteWellcome Trust Centre for Human Genetics, University of OxfordDepartment of Biology, Kyung Hee UniversityDepartment of Rheumatology, Hanyang University Hospital for Rheumatic DiseasesTranslational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research InstituteGuy’s & St Thomas’ NHS Foundation Trust and King’s College London NIHR Biomedical Research CentreDepartment of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical UniversityAbstract Background The association of HLA-B*27 with AS is amongst the strongest of any known association of a common variant with any human disease. Nonetheless, there is strong evidence indicating that other HLA-B alleles are involved in the disease. European ethnicity studies have demonstrated risk associations with HLA-B*40 and multiple other HLA-B, HLA-A, and HLA class II alleles, and demonstrated that in that ethnic group, the amino acid sequence at position 97 in HLA-B is the key determinant of HLA associations with AS. A recent study in Korean AS cases and controls additionally identified association at HLA-C*15:02. In the current study, we examined the MHC associations of AS in an expanded East Asian cohort. Methods A total of 1637 Chinese, Taiwanese, and Korean AS cases meeting the modified New York Criteria for AS, and 1589 ethnically matched controls, were genotyped with the Illumina Immunochip, including a dense coverage of the MHC region. HLA genotypes and amino acid composition were imputed using the SNP2HLA programme using the Han-MHC reference panel based on the data of Han Chinese subjects (n = 9689), and association tested using logistic regression controlling for population stratification effects. Results A strong association was seen with HLA-B*27 (odds ratio (OR) = 205.3, P = 5.76 × 10−244). Controlling for this association, the strongest risk association is seen with HLA-C*15 at genome-wide significant level (OR = 7.62, P = 9.30 × 10−19), and confirmed association is also seen with HLA-B*40 at suggestive level (OR = 1.65, P = 2.54 × 10−4). At amino acid level, the strongest association seen in uncontrolled analysis was with histidine at position 114 in HLA-B (P = 7.24 × 10−241), but conditional analyses suggest that the primary amino acid associations are with lysine at position 70 and asparagine at position 97. Restriction of the ERAP1 association with HLA-B27-positive AS, previously reported in European subjects, was confirmed in East Asians. Conclusions This study confirms in East Asians that the HLA associations of AS are multiple, including previously reported associations at HLA-B*27, HLA-B*40, and HLA-C*15, as well as novel association with HLA-DQB1*04. The HLA-B associations are driven by the amino acids at positions 70 and 97, in the B pocket of HLA-B.http://link.springer.com/article/10.1186/s13075-020-02148-5Ankylosing spondylitisHLAAssociation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Geng Wang Tae-Hwan Kim Zhixiu Li Adrian Cortes Kwangwoo Kim So-Young Bang Paul Leo Matthew A. Brown Huji Xu |
spellingShingle |
Geng Wang Tae-Hwan Kim Zhixiu Li Adrian Cortes Kwangwoo Kim So-Young Bang Paul Leo Matthew A. Brown Huji Xu MHC associations of ankylosing spondylitis in East Asians are complex and involve non-HLA-B27 HLA contributions Arthritis Research & Therapy Ankylosing spondylitis HLA Association |
author_facet |
Geng Wang Tae-Hwan Kim Zhixiu Li Adrian Cortes Kwangwoo Kim So-Young Bang Paul Leo Matthew A. Brown Huji Xu |
author_sort |
Geng Wang |
title |
MHC associations of ankylosing spondylitis in East Asians are complex and involve non-HLA-B27 HLA contributions |
title_short |
MHC associations of ankylosing spondylitis in East Asians are complex and involve non-HLA-B27 HLA contributions |
title_full |
MHC associations of ankylosing spondylitis in East Asians are complex and involve non-HLA-B27 HLA contributions |
title_fullStr |
MHC associations of ankylosing spondylitis in East Asians are complex and involve non-HLA-B27 HLA contributions |
title_full_unstemmed |
MHC associations of ankylosing spondylitis in East Asians are complex and involve non-HLA-B27 HLA contributions |
title_sort |
mhc associations of ankylosing spondylitis in east asians are complex and involve non-hla-b27 hla contributions |
publisher |
BMC |
series |
Arthritis Research & Therapy |
issn |
1478-6362 |
publishDate |
2020-04-01 |
description |
Abstract Background The association of HLA-B*27 with AS is amongst the strongest of any known association of a common variant with any human disease. Nonetheless, there is strong evidence indicating that other HLA-B alleles are involved in the disease. European ethnicity studies have demonstrated risk associations with HLA-B*40 and multiple other HLA-B, HLA-A, and HLA class II alleles, and demonstrated that in that ethnic group, the amino acid sequence at position 97 in HLA-B is the key determinant of HLA associations with AS. A recent study in Korean AS cases and controls additionally identified association at HLA-C*15:02. In the current study, we examined the MHC associations of AS in an expanded East Asian cohort. Methods A total of 1637 Chinese, Taiwanese, and Korean AS cases meeting the modified New York Criteria for AS, and 1589 ethnically matched controls, were genotyped with the Illumina Immunochip, including a dense coverage of the MHC region. HLA genotypes and amino acid composition were imputed using the SNP2HLA programme using the Han-MHC reference panel based on the data of Han Chinese subjects (n = 9689), and association tested using logistic regression controlling for population stratification effects. Results A strong association was seen with HLA-B*27 (odds ratio (OR) = 205.3, P = 5.76 × 10−244). Controlling for this association, the strongest risk association is seen with HLA-C*15 at genome-wide significant level (OR = 7.62, P = 9.30 × 10−19), and confirmed association is also seen with HLA-B*40 at suggestive level (OR = 1.65, P = 2.54 × 10−4). At amino acid level, the strongest association seen in uncontrolled analysis was with histidine at position 114 in HLA-B (P = 7.24 × 10−241), but conditional analyses suggest that the primary amino acid associations are with lysine at position 70 and asparagine at position 97. Restriction of the ERAP1 association with HLA-B27-positive AS, previously reported in European subjects, was confirmed in East Asians. Conclusions This study confirms in East Asians that the HLA associations of AS are multiple, including previously reported associations at HLA-B*27, HLA-B*40, and HLA-C*15, as well as novel association with HLA-DQB1*04. The HLA-B associations are driven by the amino acids at positions 70 and 97, in the B pocket of HLA-B. |
topic |
Ankylosing spondylitis HLA Association |
url |
http://link.springer.com/article/10.1186/s13075-020-02148-5 |
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