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Genetic dissection of HLA-DRB1*15:01 and XL9 region variants in Japanese patients with systemic lupus erythematosus: primary role for HLA-DRB1*15:01

OBJECTIVE: Major histocompatibility complex strongly contributes to susceptibility to systemic lupus erythematosus (SLE). In the European populations, HLA-DRB1*03:01 and DRB1*15:01 are susceptibility alleles, but C4 locus was reported to account for the association of DRB1*03:01. With respect to DRB...

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Autores principales: Kawasaki, Aya, Kusumawati, Premita Ari, Kawamura, Yuka, Kondo, Yuya, Kusaoi, Makio, Amano, Hirofumi, Kusanagi, Yasuyoshi, Itoh, Kenji, Fujimoto, Takashi, Tamura, Naoto, Hashimoto, Hiroshi, Matsumoto, Isao, Sumida, Takayuki, Tsuchiya, Naoyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10255040/
https://www.ncbi.nlm.nih.gov/pubmed/37258043
http://dx.doi.org/10.1136/rmdopen-2023-003214
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author Kawasaki, Aya
Kusumawati, Premita Ari
Kawamura, Yuka
Kondo, Yuya
Kusaoi, Makio
Amano, Hirofumi
Kusanagi, Yasuyoshi
Itoh, Kenji
Fujimoto, Takashi
Tamura, Naoto
Hashimoto, Hiroshi
Matsumoto, Isao
Sumida, Takayuki
Tsuchiya, Naoyuki
author_facet Kawasaki, Aya
Kusumawati, Premita Ari
Kawamura, Yuka
Kondo, Yuya
Kusaoi, Makio
Amano, Hirofumi
Kusanagi, Yasuyoshi
Itoh, Kenji
Fujimoto, Takashi
Tamura, Naoto
Hashimoto, Hiroshi
Matsumoto, Isao
Sumida, Takayuki
Tsuchiya, Naoyuki
author_sort Kawasaki, Aya
collection PubMed
description OBJECTIVE: Major histocompatibility complex strongly contributes to susceptibility to systemic lupus erythematosus (SLE). In the European populations, HLA-DRB1*03:01 and DRB1*15:01 are susceptibility alleles, but C4 locus was reported to account for the association of DRB1*03:01. With respect to DRB1*15:01, strong linkage disequilibrium with a variant rs2105898T in the XL9 region, located between DRB1 and DQA1 and regulates HLA-class II expression levels, was reported; however, the causative allele remains to be determined. Leveraging the genetic background of the Japanese population, where DRB1*15:01 and DRB1*15:02 are commonly present and only DRB1*15:01 is associated with SLE, this study aimed to distinguish the genetic contribution of DRB1*15:01 and XL9 variants. METHODS: Among the XL9 variants, two (rs2105898 and rs9271593) previously associated variants in the European populations and two (rs9271375 and rs9271378) which showed a trend towards association in a Japanese Genome-Wide Association Study were selected. Associations of the XL9 variants and HLA-DRB1 were examined in 442 Japanese SLE patients and 779 controls. Genotyping of the XL9 variants was performed by TaqMan SNP Genotyping Assay and direct sequencing. HLA-DRB1 alleles were determined by PCR-reverse sequence-specific oligonucleotide probes. RESULTS: Among the XL9 variants, associations of rs2105898T and rs9271593C were replicated in the Japanese population. However, these associations became no longer significant when conditioned on DRB1*15:01. In contrast, the association of DRB1*15:01 remained significant after conditioning on the XL9 variants. CONCLUSION: In the Japanese population, HLA-DRB1*15:01 was found to be primarily associated with SLE, and to account for the apparent association of XL9 region.
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spelling pubmed-102550402023-06-10 Genetic dissection of HLA-DRB1*15:01 and XL9 region variants in Japanese patients with systemic lupus erythematosus: primary role for HLA-DRB1*15:01 Kawasaki, Aya Kusumawati, Premita Ari Kawamura, Yuka Kondo, Yuya Kusaoi, Makio Amano, Hirofumi Kusanagi, Yasuyoshi Itoh, Kenji Fujimoto, Takashi Tamura, Naoto Hashimoto, Hiroshi Matsumoto, Isao Sumida, Takayuki Tsuchiya, Naoyuki RMD Open Lupus OBJECTIVE: Major histocompatibility complex strongly contributes to susceptibility to systemic lupus erythematosus (SLE). In the European populations, HLA-DRB1*03:01 and DRB1*15:01 are susceptibility alleles, but C4 locus was reported to account for the association of DRB1*03:01. With respect to DRB1*15:01, strong linkage disequilibrium with a variant rs2105898T in the XL9 region, located between DRB1 and DQA1 and regulates HLA-class II expression levels, was reported; however, the causative allele remains to be determined. Leveraging the genetic background of the Japanese population, where DRB1*15:01 and DRB1*15:02 are commonly present and only DRB1*15:01 is associated with SLE, this study aimed to distinguish the genetic contribution of DRB1*15:01 and XL9 variants. METHODS: Among the XL9 variants, two (rs2105898 and rs9271593) previously associated variants in the European populations and two (rs9271375 and rs9271378) which showed a trend towards association in a Japanese Genome-Wide Association Study were selected. Associations of the XL9 variants and HLA-DRB1 were examined in 442 Japanese SLE patients and 779 controls. Genotyping of the XL9 variants was performed by TaqMan SNP Genotyping Assay and direct sequencing. HLA-DRB1 alleles were determined by PCR-reverse sequence-specific oligonucleotide probes. RESULTS: Among the XL9 variants, associations of rs2105898T and rs9271593C were replicated in the Japanese population. However, these associations became no longer significant when conditioned on DRB1*15:01. In contrast, the association of DRB1*15:01 remained significant after conditioning on the XL9 variants. CONCLUSION: In the Japanese population, HLA-DRB1*15:01 was found to be primarily associated with SLE, and to account for the apparent association of XL9 region. BMJ Publishing Group 2023-05-31 /pmc/articles/PMC10255040/ /pubmed/37258043 http://dx.doi.org/10.1136/rmdopen-2023-003214 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Lupus
Kawasaki, Aya
Kusumawati, Premita Ari
Kawamura, Yuka
Kondo, Yuya
Kusaoi, Makio
Amano, Hirofumi
Kusanagi, Yasuyoshi
Itoh, Kenji
Fujimoto, Takashi
Tamura, Naoto
Hashimoto, Hiroshi
Matsumoto, Isao
Sumida, Takayuki
Tsuchiya, Naoyuki
Genetic dissection of HLA-DRB1*15:01 and XL9 region variants in Japanese patients with systemic lupus erythematosus: primary role for HLA-DRB1*15:01
title Genetic dissection of HLA-DRB1*15:01 and XL9 region variants in Japanese patients with systemic lupus erythematosus: primary role for HLA-DRB1*15:01
title_full Genetic dissection of HLA-DRB1*15:01 and XL9 region variants in Japanese patients with systemic lupus erythematosus: primary role for HLA-DRB1*15:01
title_fullStr Genetic dissection of HLA-DRB1*15:01 and XL9 region variants in Japanese patients with systemic lupus erythematosus: primary role for HLA-DRB1*15:01
title_full_unstemmed Genetic dissection of HLA-DRB1*15:01 and XL9 region variants in Japanese patients with systemic lupus erythematosus: primary role for HLA-DRB1*15:01
title_short Genetic dissection of HLA-DRB1*15:01 and XL9 region variants in Japanese patients with systemic lupus erythematosus: primary role for HLA-DRB1*15:01
title_sort genetic dissection of hla-drb1*15:01 and xl9 region variants in japanese patients with systemic lupus erythematosus: primary role for hla-drb1*15:01
topic Lupus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10255040/
https://www.ncbi.nlm.nih.gov/pubmed/37258043
http://dx.doi.org/10.1136/rmdopen-2023-003214
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