Genetic dissection ofHLA-DRB1*15:01and XL9 region variants in Japanese patients with systemic lupus erythematosus: Primary role forHLA-DRB1*15:01

Abstract

ABSTRACTObjectiveMajor 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 (LD) 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 were performed by TaqMan SNP Genotyping Assay and direct sequencing.HLA-DRB1alleles were determined by polymerase chain reaction-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.WHAT IS ALREADY KNOWN ON THIS TOPICThe association ofHLA-DRB1*03:01with susceptibility to systemic lupus erythematosus (SLE) was reported to be secondarily caused by linkage disequilibrium (LD) with copy number reduction ofC4, which has the primary role.A possibility has been hypothesized that the association ofHLA-DRB1*15:01with SLE may possibly be caused by LD with XL9 region variants, associated with expression levels of HLA-class II; however, due to strong LD betweenDRB1*15:01and XL9 variants, this hypothesis could not be addressed in the European populations.WHAT THIS STUDY ADDSIn the Japanese population, two commonDRB1*15alleles,DRB1*15:01andDRB1*15:02, are present, both in LD with XL9 variants. However, onlyDRB1*15:01is associated with SLE.Leveraging the population difference in the genetic background, we demonstrated thatDRB1*15:01, rather than XL9 region variants, is primarily associated with SLE in the Japanese population.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYThis study provides us with critical information in understanding the respective roles ofHLAgenes 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.