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

Genes & Immunity volume 10, pages 457–469 (2009)Cite this article

A Corrigendum to this article was published on 02 September 2009

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.

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Acknowledgements

We thank Dr Raul Torres (National Jewish Health and University of Colorado Denver School of Medicine) for providing the pL53In vector, Dr Yong Choi (Ochsner Clinic Foundation) for providing the HK FDC line, and Carissa Homme and Lauren Kuhlman (University of Colorado Denver School of Medicine, Aurora, CO, USA) for technical assistance. We also thank Dr Peter Gregersen (Feinstein Institute for Medical Research, Manhassat, NY, USA) for contributing DNA samples from control subjects to LLAS, and the Wake Forest University Health Sciences Center for Public Health Genomics for assistance with the principal component analysis of the genotyping data from LLAS1. The pL53In constructs were sequenced by the University of Colorado Cancer Center DNA Sequencing and Analysis Core (http://loki.uchsc.edu), which is supported by the NIH/NCI Cancer Core Support Grant (P30 CA046934). The quality of the RNA samples prepared from healthy human subjects was evaluated in the University of Colorado Cancer Center Microarray Core. Quantitative RT-PCR was carried out in the DERC Molecular Biology Core Facility, which is supported by National Institutes of Health (NIH) grant P30 DK57516. Other support for this work included grants from the American College of Rheumatology Research and Education Foundation, the Alliance for Lupus Research, the US Department of Veterans Affairs, Kirkland Scholar/Hospital for Special Surgery and Rheuminations, and NIH (NIAID-DAIT-BAA-05-11, N01 AR12253, N01 AR62277, P01 AR049084, P20 RR015577, P20 RR020143, P30 AR053483, P50 AR48940, R01 DE015223, R01 AI31584, R01 AI070983R01 AR42460, and R37 AI24717).

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Author notes

  1. K B Douglas, D C Windels and J Zhao: These authors contributed equally to this work.

Authors and Affiliations

  1. University of Colorado Denver School of Medicine, Aurora, CO, USA

    K B Douglas, D C Windels, A V Gadeliya & S A Boackle

  2. University of California, Los Angeles, Los Angeles, CA, USA,

    J Zhao, H Wu & B P Tsao

  3. Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    K M Kaufman, J B Harley, J Merrill, P M Gaffney, J A James, K L Moser & M E Alarcón-Riquelme

  4. University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    K M Kaufman, J B Harley, J Merrill & J A James

  5. US Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA

    K M Kaufman & J B Harley

  6. University of Alabama at Birmingham, Birmingham, AL, USA

    R P Kimberly, G S Alarcón, E E Brown & J C Edberg

  7. Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    R Ramsey-Goldman

  8. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    M Petri

  9. University of Texas-Houston Health Science Center, Houston, TX, USA

    J D Reveille

  10. University of Puerto Rico, San Juan, Puerto Rico,

    L M Vilá

  11. Uppsala University, Uppsala, Sweden

    M E Alarcón-Riquelme

  12. Imperial College, Hammersmith Hospital, London, UK

    T J Vyse

  13. Medical University of South Carolina, Charleston, SC, USA

    G S Gilkeson

  14. University of Southern California, Los Angeles, CA, USA

    C O Jacob

  15. Section on Statistical Genetics and Bioinformatics, Wake Forest University Health Sciences, Winston-Salem, NC, USA

    J T Ziegler & C D Langefeld

  16. School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, Western Australia, Australia

    D Ulgiati

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  1. K B Douglas
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Correspondence to S A Boackle.

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Douglas, K., Windels, D., Zhao, J. et al. Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing. Genes Immun 10, 457–469 (2009). https://doi.org/10.1038/gene.2009.27

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