Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing

K. B. Douglas, D. C. Windels, J. Zhao, A. V. Gadeliya, H. Wu, K. M. Kaufman, J. B. Harley, J. Merrill, R. P. Kimberly, G. S. Alarcón, E. E. Brown, J. C. Edberg, R. Ramsey-Goldman, M. Petri, J. D. Reveille, L. M. Vilá, P. M. Gaffney, J. A. James, K. L. Moser, M. E. Alarcón-RiquelmeT. J. Vyse, G. S. Gilkeson, C. O. Jacob, J. T. Ziegler, C. D. Langefeld, D. Ulgiati, B. P. Tsao, S. A. Boackle

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)457-469
Number of pages13
JournalGenes and immunity
Volume10
Issue number5
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Immunology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing'. Together they form a unique fingerprint.

  • Cite this

    Douglas, K. B., Windels, D. C., Zhao, J., Gadeliya, A. V., Wu, H., Kaufman, K. M., Harley, J. B., Merrill, J., Kimberly, R. P., Alarcón, G. S., Brown, E. E., Edberg, J. C., Ramsey-Goldman, R., Petri, M., Reveille, J. D., Vilá, L. M., Gaffney, P. M., James, J. A., Moser, K. L., ... Boackle, S. A. (2009). Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing. Genes and immunity, 10(5), 457-469. https://doi.org/10.1038/gene.2009.27