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

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ABSTRACT 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 (LD) 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 were performed by TaqMan SNP Genotyping Assay and direct sequencing. HLA-DRB1 alleles were determined by polymerase chain reaction-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. WHAT IS ALREADY KNOWN ON THIS TOPIC The association of HLA-DRB1*03:01 with susceptibility to systemic lupus erythematosus (SLE) was reported to be secondarily caused by linkage disequilibrium (LD) with copy number reduction of C4 , which has the primary role. A possibility has been hypothesized that the association of HLA-DRB1*15:01 with SLE may possibly be caused by LD with XL9 region variants, associated with expression levels of HLA-class II; however, due to strong LD between DRB1*15:01 and XL9 variants, this hypothesis could not be addressed in the European populations. WHAT THIS STUDY ADDS In the Japanese population, two common DRB1*15 alleles, DRB1*15:01 and DRB1*15:02 , are present, both in LD with XL9 variants. However, only DRB1*15:01 is associated with SLE. Leveraging the population difference in the genetic background, we demonstrated that DRB1*15:01 , rather than XL9 region variants, is primarily associated with SLE in the Japanese population. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY This study provides us with critical information in understanding the respective roles of HLA genes and their regulatory regions in the development of SLE. This study also shows the usefulness of association studies in multiple populations with different genetic backgrounds in the identification of causative variants.

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