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.
authors.affiliation: University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Douglas
authors.forename: D C
authors.initials: DC
authors.lastname: Windels
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: A V
authors.initials: AV
authors.lastname: Gadeliya
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.forename: K M
authors.initials: KM
authors.lastname: Kaufman
authors.forename: J B
authors.initials: JB
authors.lastname: Harley
authors.forename: J
authors.initials: J
authors.lastname: Merrill
authors.forename: R P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: G S
authors.initials: GS
authors.lastname: Alarcón
authors.forename: E E
authors.initials: EE
authors.lastname: Brown
authors.forename: J C
authors.initials: JC
authors.lastname: Edberg
authors.forename: R
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.forename: M
authors.initials: M
authors.lastname: Petri
authors.forename: J D
authors.initials: JD
authors.lastname: Reveille
authors.forename: L M
authors.initials: LM
authors.lastname: Vilá
authors.forename: P M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: J A
authors.initials: JA
authors.lastname: James
authors.forename: K L
authors.initials: KL
authors.lastname: Moser
authors.forename: M E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.forename: T J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: G S
authors.initials: GS
authors.lastname: Gilkeson
authors.forename: C O
authors.initials: CO
authors.lastname: Jacob
authors.forename: J T
authors.initials: JT
authors.lastname: Ziegler
authors.forename: C D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: D
authors.initials: D
authors.lastname: Ulgiati
authors.forename: B P
authors.initials: BP
authors.lastname: Tsao
authors.forename: S A
authors.initials: SA
authors.lastname: Boackle
mesh_terms: D017398:Alternative Splicing; D001483:Base Sequence; D016022:Case-Control Studies; D005091:Exons; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008969:Molecular Sequence Data; D017464:Receptors, Complement 3d / Q000235:genetics*
chemical_list: D017464:Receptors, Complement 3d