Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing
2009 (English)In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 10, no 5, 457-469 p.Article in journal (Refereed) Published
Genetic factors influence susceptibility to systemic lupus erythematosus (SLE). A recent family-based analysis in Caucasian and Chinese populations provided evidence for association of single-nucleotide polymorphisms (SNPs) in the complement receptor 2 (CR2/CD21) gene with SLE. Here we confirmed this result in a case-control analysis of an independent European-derived population including 2084 patients with SLE and 2853 healthy controls. A haplotype formed by the minor alleles of three CR2 SNPs (rs1048971, rs17615, rs4308977) showed significant association with decreased risk of SLE (30.4% in cases vs 32.6% in controls, P=0.016, OR=0.90 (0.82-0.98)). Two of these SNPs are in exon 10, directly 5' of an alternatively spliced exon preferentially expressed in follicular dendritic cells (FDC), and the third is in the alternatively spliced exon. Effects of these SNPs and a fourth SNP in exon 11 (rs17616) on alternative splicing were evaluated. We found that the minor alleles of these SNPs decreased splicing efficiency of exon 11 both in vitro and ex vivo. These findings further implicate CR2 in the pathogenesis of SLE and suggest that CR2 variants alter the maintenance of tolerance and autoantibody production in the secondary lymphoid tissues where B cells and FDCs interact.
Place, publisher, year, edition, pages
2009. Vol. 10, no 5, 457-469 p.
alternative splicing, systemic lupus erythematosus, complement receptors, single-nucleotide polymorphisms, B cells, follicular dendritic cells
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-122926DOI: 10.1038/gene.2009.27ISI: 000268168800010PubMedID: 19387458OAI: oai:DiVA.org:uu-122926DiVA: diva2:311403