Journal
GENES AND IMMUNITY
Volume 10, Issue 5, Pages 457-469Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2009.27
Keywords
alternative splicing; systemic lupus erythematosus; complement receptors; single-nucleotide polymorphisms; B cells; follicular dendritic cells
Categories
Funding
- NIH/NCI Cancer Core [P30 CA046934]
- National Institutes of Health (NIH) [P30 DK57516]
- American College of Rheumatology Research and Education Foundation
- Alliance for Lupus Research
- US Department of Veterans Affairs
- Kirkland Scholar/Hospital for Special Surgery and Rheuminations
- NIH [NIAID-DAIT-B AA-05-11, N01 AR12253, N01 AR62277, P01 AR049084, P20 RR015577, P20 RR020143, P30 AR053483, P50 AR48940, R01 DE015223, R01 AI31584, R01 AI070983R01 AR42460, R37 AI24717]
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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 50 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. Genes and Immunity (2009) 10, 457-469; doi: 10.1038/gene.2009.27; published online 23 April 2009
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