@article{92b9859d5fa54f2ca2c0c3019c160b50,
title = "Complement receptor 2 polymorphisms associated with systemic lupus erythematosus modulate alternative splicing",
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.",
author = "Douglas, {K. B.} and Windels, {D. C.} and J. Zhao and Gadeliya, {A. V.} and H. Wu and Kaufman, {K. M.} and Harley, {J. B.} and J. Merrill and Kimberly, {R. P.} and Alarc{\'o}n, {G. S.} and Brown, {E. E.} and Edberg, {J. C.} and R. Ramsey-Goldman and M. Petri and Reveille, {J. D.} and Vil{\'a}, {L. M.} and Gaffney, {P. M.} and James, {J. A.} and Moser, {K. L.} and Alarc{\'o}n-Riquelme, {M. E.} and Vyse, {T. J.} and Gilkeson, {G. S.} and Jacob, {C. O.} and Ziegler, {J. T.} and Langefeld, {C. D.} and D. Ulgiati and Tsao, {B. P.} and Boackle, {S. A.}",
note = "Funding Information: 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 Greger-sen (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-B AA-05-11, N01 AR12253, N01 AR62277, P01 AR049084, P20",
year = "2009",
doi = "10.1038/gene.2009.27",
language = "English (US)",
volume = "10",
pages = "457--469",
journal = "Genes and Immunity",
issn = "1466-4879",
publisher = "Springer Nature",
number = "5",
}