Transcriptional effects of a lupus-associated polymorphism in the 5′ untranslated region (UTR) of human complement receptor 2 (CR2/CD21)

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic component that determines risk. A common three single-nucleotide polymorphism (SNP) haplotype of the complement receptor 2 (CR2) gene has been associated with increased risk of SLE ( Wu et al., 2007 and Douglas et al., 2009), and a less common haplotype consisting of the major allele at SNP1 and minor alleles at SNP2 and 3 confers protection (Douglas et al., 2009). SNP1 (rs3813946), which is located in the 5′ untranslated region (UTR) of the CR2 gene, altered transcriptional activity of a CR2 promoter–luciferase reporter gene construct transiently transfected into a B cell line ( Wu et al., 2007) and had an independent effect in the protective haplotype (Douglas et al., 2009). In this study, we show that this SNP alters transcriptional activity in a transiently transfected non B-cell line as well as in stably transfected cell lines, supporting its relevance in vivo. Furthermore, the allele at this SNP affects chromatin accessibility of the surrounding sequence and transcription factor binding. These data confirm the effects of rs3813946 on CR2 transcription, identifying the 5′ UTR to be a novel regulatory element for the CR2 gene in which variation may alter gene function and modify the development of lupus.

► Common three SNP haplotype of the CR2 gene is associated with increased risk of SLE.
► The 5′ UTR SNP shows altered transcriptional activity of CR2 promoter reporter gene.
► This SNP also alters transcriptional activity in stably transfected cells.
► The 5′ UTR SNP affects chromatin accessibility of the surrounding sequence.
► rs3813946 affects transcription factor binding.
► Binding of previously unidentified transcription factors to rs3813946 shown in vivo.
► Identifies the 5′ UTR to be a novel regulatory element.