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; 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.
Biochemistry and Molecular Biology, School of Chemistry and Biochemistry, The University of Western Australia, Perth, Western Australia, Australia.
Mark N
MN
Cruickshank
Mahdad
M
Karimi
Rhonda L
RL
Mason
Emily
E
Fenwick
Tim
T
Mercer
Betty P
BP
Tsao
Susan A
SA
Boackle
Daniela
D
Ulgiati
D020121:5' Untranslated Regions; D001402:B-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017464:Receptors, Complement 3d / Q000235:genetics* / Q000276:immunology; D014158:Transcription, Genetic
D020121:5' Untranslated Regions; D017464:Receptors, Complement 3d