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Abstract Objective. We investigated the association of gene polymorphisms in APRIL, a new member of the TNF family, with systemic lupus erythematosus.

To detect polymorphisms of the human APRIL gene by exon‐specific polymerase chain reaction–single‐strand conformation polymorphism (PCR‐SSCP) analysis, we first determined the structure of the human APRIL gene. We designed exon‐specific oligonucleotide primers according to the genomic DNA sequence of APRIL. All of the coding regions in exons of the APRIL gene were analysed by exon‐specific PCR‐SSCP in 148 SLE patients and 146 unaffected controls, then the nucleotide sequences of exons that displayed aberrant bands were determined. The human APRIL gene comprised at least six exons with five introns, spanning approximately 2.8 kilobases of the genomic DNA. By exon‐specific PCR‐SSCP, we identified two novel polymorphisms at codons 67 and 96. Both had amino acid substitutions: G67R and N96S respectively.

Lupus Erythematosus Overview. 4/11= 95% Specificity; 85% Sensitivity. Current and novel therapeutics in the treatment of systemic lupus.

Only the 67G allele was associated with SLE in 148 Japanese SLE patients, with allele frequency 0.662 compared with 0.575 for 146 unaffected controls ( P=0.0302). The frequency of the individuals who possessed at least one 67G allele in SLE patients (91.9%) was significantly higher than that in the unaffected controls (80.1%) ( P=0.0036). The 67G allele of APRIL may be a contributing factor in the pathogenesis of SLE. , Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease characterized by the production of autoantibodies against a spectrum of nuclear antigens []. Multiple autoantibodies induce tissue damage by either binding directly to self antigens or inducing inflammation following the tissue deposition of immune complexes.

These autoantibodies are produced by autoreactive B lymphocytes in the presence or absence of autoreactive T lymphocytes []. A strong genetic basis of SLE was supported by familial aggregation [] and increased concordance rates among monozygotic twins compared with dizygotic twins and other full siblings [].

Genome scans have detected linkage with several loci, including 1p36, 1q41‐44, 2q37, 4q28‐31 and 20p12‐13 [–]. Association studies have shown a genetic association with major histocompatibility complex (MHC) alleles [–] and non‐MHC genes, such as genes encoding immunoglobulin receptors, cytokines and molecules involved in apoptosis [–]. A new member of the tumour necrosis factor (TNF) family, a proliferation‐inducing ligand (APRIL, also called TRDL, TNFSF13 and TALL‐2), has been described recently []. APRIL is a type II membrane protein of 250 amino acids and its extracellular domain is cleaved at the RKRR motif of amino acid 101–104 by a furin convertase and then secreted []. Originally, APRIL was reported to have a regulatory role in tumour growth []. APRIL is a close sequence homologue of the recently reported B‐cell activation factor (BAFF, also known as BlyS/zTNF4/TALL‐1), also a member of the TNF family [].

BAFF allows survival and differentiation of a subset of immature B lymphocytes, and BAFF‐transgenic mice develop a lupus‐like phenotype characterized by high titres of anti‐DNA antibodies, hypergammaglobulinaemia and glomerulonephritis [, ]. Serum levels of BAFF have been reported to be elevated in patients with SLE []. These results suggest that BAFF may play a crucial role in the survival of the autoreactive B cells in SLE. BAFF binds to three receptors in the TNF receptor family: BAFF‐receptor (BAFF‐R), B‐cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI) [–]. APRIL has also been shown to play a regulatory role in B‐cell proliferation by binding to BCMA and TACI on B lymphocytes, and is expected to bind to an unknown APRIL‐specific receptor on tumour cells [, ]. The treatment of lupus‐prone NZBWF1 mice with soluble TACI–immunoglobulin fusion protein (soluble decoy receptor for BAFF and APRIL) inhibits the development of proteinuria and prolongs survival of the animal []. These findings indicate that APRIL as well as BAFF may be involved in the development of SLE.

In the present study, we investigated mutation(s) or polymorphism(s) of the APRIL gene which may lead to altered APRIL signalling and the development of SLE. We first determined the genetic structure of the human APRIL gene. Then, we performed a systematic search for polymorphisms or mutations in all six exons of the APRIL gene by polymerase chain reaction–single‐strand conformation polymorphism (PCR‐SSCP) analysis using intron‐based exon‐specific primers. We identified two novel polymorphisms at codons 67 and 96, and demonstrated that the 67G allele was significantly increased in patients with SLE.

Materials and methods Patients We studied 148 patients (138 females, 10 males) diagnosed as having SLE according to the 1982 revised criteria of the American College of Rheumatology, and 146 unaffected controls. All of the patients and controls were Japanese, and the patients were followed at our out‐patient rheumatology facility at Kyushu University Hospital. The median age of the patients was 43.0 yr (range 13–69 yr). Informed consent was obtained from each patient and control. Peripheral blood mononuclear cells (PBMC) were prepared from the heparinized blood of the SLE patients and the controls using Lymphocyte Separation Medium (ICN Biochemicals, Aurora, OH, USA).