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
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
复制标题
日本系统性红斑狼疮患者 HLA-DRB1*15:01 和 XL9 区域变异的基因剖析：HLA-DRB1*15:01 的主要作用
DOI：
10.1101/2023.04.05.23288103
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Naoyuki Tsuchiya
中科院分区：
文献类型：
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作者：
Aya Kawasaki;Premita Ari Kusumawati;Yuka Kawamura;Yuya Kondo;Makio Kusaoi;Hirofumi Amano;Yasuyoshi Kusanagi;Kenji Itoh;Takashi Fujimoto;Naoto Tamura;Hiroshi Hashimoto;Isao Matsumoto;Takayuki Sumida;Naoyuki Tsuchiya
目的：主要组织相容性复合体与系统性红斑狼疮（SLE）易感性密切相关。在欧洲人群中，HLA-DRB1*03:01和drb1 *15:01是易感等位基因，但据报道c4位点与drb1 *03:01相关。关于drb1 *15:01，报道了与位于drb1和dqa1之间的XL9区域的变体rs2105898T的强连锁不平衡，该区域调节hla - II类表达水平；然而，致病等位基因仍有待确定。利用日本人群的遗传背景，其中drb1 *15:01和drb1 *15:02普遍存在，并且只有drb1 *15:01与SLE相关，本研究旨在区分drb1 *15:01和XL9变体的遗传贡献。方法在XL9变异中，选择2个在欧洲人群中有关联的变异（rs2105898和rs9271593）和2个在日本全基因组关联研究中有关联趋势的变异（rs9271375和rs9271378）。在442名日本SLE患者和779名对照中检测了XL9变异和hla - drb1的相关性。采用TaqMan SNP基因分型法和直接测序对XL9变异进行基因分型。采用pcr -反序列特异性寡核苷酸探针检测hla - drb1等位基因。结果在XL9变异中，rs2105898T和rs9271593C的关联在日本人群中被复制。然而，这些关联在drb1 *15:01条件下不再显著。相比之下，drb1 *15:01的关联在XL9变异后仍然显著。结论在日本人群中，HLA-DRB1*15:01被发现主要与SLE相关，并解释了XL9区域的明显关联。
ObjectiveMajor histocompatibility complex strongly contributes to susceptibility to systemic lupus erythematosus (SLE). In the European populations,HLA-DRB1*03:01andDRB1*15:01are susceptibility alleles, butC4locus was reported to account for the association ofDRB1*03:01. With respect toDRB1*15:01, strong linkage disequilibrium with a variant rs2105898T in the XL9 region, located betweenDRB1andDQA1and regulates HLA-class II expression levels, was reported; however, the causative allele remains to be determined. Leveraging the genetic background of the Japanese population, whereDRB1*15:01andDRB1*15:02are commonly present and onlyDRB1*15:01is associated with SLE, this study aimed to distinguish the genetic contribution ofDRB1*15:01and XL9 variants.MethodsAmong 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 andHLA-DRB1were 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-DRB1alleles were determined by PCR-reverse sequence-specific oligonucleotide probes.ResultsAmong the XL9 variants, associations of rs2105898T and rs9271593C were replicated in the Japanese population. However, these associations became no longer significant when conditioned onDRB1*15:01. In contrast, the association ofDRB1*15:01remained significant after conditioning on the XL9 variants.ConclusionIn the Japanese population,HLA-DRB1*15:01was found to be primarily associated with SLE, and to account for the apparent association of XL9 region.