A novel polymorphism of the human APRIL gene is associated with systemic lupus erythematosus

T. Koyama, H. Tsukamoto, K. Masumoto, D. Himeji, K. Hayashi1, M. Harada and T. Horiuchi

Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582 and
1 Institute of Genetic Information, Kyushu University, Fukuoka 812-8582, Japan


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. We investigated the association of gene polymorphisms in APRIL, a new member of the TNF family, with systemic lupus erythematosus.

Methods. 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.

Results. 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. 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).

Conclusion. The 67G allele of APRIL may be a contributing factor in the pathogenesis of SLE.

KEY WORDS: APRIL, Systemic lupus erythematosus, Polymorphism, Exon-specific PCR-SSCP.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease characterized by the production of autoantibodies against a spectrum of nuclear antigens [1]. 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 [1].

A strong genetic basis of SLE was supported by familial aggregation [2] and increased concordance rates among monozygotic twins compared with dizygotic twins and other full siblings [3]. Genome scans have detected linkage with several loci, including 1p36, 1q41-44, 2q37, 4q28-31 and 20p12-13 [49]. Association studies have shown a genetic association with major histocompatibility complex (MHC) alleles [1012] and non-MHC genes, such as genes encoding immunoglobulin receptors, cytokines and molecules involved in apoptosis [1318].

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 [19]. 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 [20]. Originally, APRIL was reported to have a regulatory role in tumour growth [19]. 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 [21]. 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 [22, 23]. Serum levels of BAFF have been reported to be elevated in patients with SLE [24]. 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) [2527]. 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 [28, 29]. 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 [30]. 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
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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). Genomic DNA and total RNA were prepared from PBMC as described previously [31].

Analysis of the genomic structure of human APRIL
Genomic DNA prepared from PBMC from the unaffected controls was used in this analysis. A pair of APRIL-specific primers, 5'-ATGCCAGCCTCATCTCCTTTC-3' and 5'-TCACAGTTTCACAAACCCCAGG-3', was used to amplify the segment including the entire coding region of APRIL. The PCR reaction was performed for 5 min at 94°C followed by 40 cycles of 30 s at 94°C, 1 min at 66°C and 2 min at 72°C using a DNA thermal cycler (Perkin-Elmer, Norwalk, CT, USA). The PCR product was sequenced completely by using a BigDye terminator cycle sequencing kit (Perkin-Elmer) and an ABI Prism 310 genetic analyser (Perkin-Elmer). Full-length APRIL cDNA was amplified by reverse transcriptase PCR (RT-PCR) using the primers 5'-CGAGGCTTCCTAGAGGGACT-3' and 5'-AAGCAGGGCTTGATCAGAAA-3' as described previously [32]. The RNA used for cDNA synthesis was derived from healthy human PBMC.

PCR-SSCP analysis
The primers used for PCR are shown in Table 1Go. These primers were designed to amplify the entire length of each exon according to the genomic DNA sequence of APRIL. All of the SLE patients and unaffected individuals were studied by PCR-SSCP analysis. PCR was carried out using [{alpha}-32P]dCTP, GeneAmp reagents and AmpliTaq DNA polymerase (Perkin-Elmer). PCR reactions were conducted for 5 min at 96°C followed by 30 cycles of 30 s at 94°C, 30 s at 60°C and 1 min at 72°C. The PCR products were diluted with formamide dyes [95% formamide, 20 mM disodium EDTA (ethylenediamine tetraacetate), 0.05% bromophenol blue and 0.05% xylene cyanol] and denatured at 80°C for 5 min. They were then subjected to electrophoresis on 5% polyacrylamide gel (acrylamide:bisacrylamide ratio 49:1) at 25°C with 5% glycerol, or at 4°C without glycerol, under a constant current of 40 mA/gel, using 45 mM Tris borate and 1 mM EDTA buffer at pH 8.3. DNA fragments were visualized by exposing the gels on Kodak film (Eastman Kodak, Rochester, NY, USA).


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TABLE 1. Primer sequences for analysis of the APRIL gene

 

DNA sequence analysis
The nucleotide sequences of the samples that showed different SSCP patterns were determined by direct sequencing. The PCR products were amplified, and both sense and anti-sense strands were sequenced directly with an ABI Prism 310 genetic analyser (Perkin-Elmer) using the same primers as those for the SSCP analysis.

Statistical analysis
The {chi}2 test was used to compare genotype and allele frequencies in unaffected controls and SLE patients and to investigate the association of the polymorphisms with clinical manifestations of SLE. P values less than 0.05 were considered significant. An analysis of linkage disequilibrium was performed using the software package EH [33] (ftp://linkage.rockfeller.edu/software/eh).


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Structure of the human APRIL gene
To detect polymorphisms of the human APRIL gene by exon-specific PCR-SSCP, we first determined the human APRIL gene structure. A fragment spanning 1.8 kilobases (kb) of the human APRIL gene was obtained by PCR amplification of genomic DNA derived from an unaffected individual (Fig. 1Go). The entire sequence of the fragment was determined. The exon–intron junctions were identified by comparing the genomic sequence with that of the human APRIL cDNA (Table 2Go). Kelly et al. [34] reported two other isoforms of APRIL, TRDL-1ß and TRDL-1{gamma}, both of which have a shorter 5' untranslated region (UTR) and a longer 3' UTR than APRIL cDNA. We were able to amplify the cDNA fragment by RT-PCR using a pair of primers based on the beginning of the 5' UTR of the APRIL cDNA and the end of the 3' UTR of the TRDL-1ß cDNA. The fragment contained the 5' UTR and the entire coding region of APRIL cDNA and the 3' UTR of TRDL-1ß, which was longer than that of APRIL cDNA, suggesting that the full-length 3' UTR of APRIL was 485 base pairs (bp) longer than that of the APRIL cDNA reported. The human APRIL gene comprised at least six exons with five introns and spanned approximately 2.8 kb of genomic DNA (Fig. 1Go). The nucleotide sequences corresponding to the coding region of the APRIL gene were in agreement with the cDNA sequence published by Hahne et al. [19]. The exons ranged in size from 48 to 877 bp and the introns from 143 to 326 bp. The 5' and 3' splice donor and splice acceptor sequences followed the usual AG/GT pattern (Table 2Go).



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FIG. 1. (a) Genomic structure of the human APRIL gene. Exons are represented as closed boxes and coding regions as solid boxes. Introns are represented as the lines connecting the boxes in the gene structure. The arrows indicate the location of primers for exon-specific PCR/SSCP. (b) Splice variants of APRIL. Coding regions are indicated by dotted boxes. Two other isoforms of APRIL, TRDL-1ß and TRDL-1{gamma}, have a shorter 5' UTR than APRIL cDNA. TRDL-1ß was generated by alternative splicing of the exon 3. TRDL-1{gamma} has a deletion of a part of exon 6 (181 bp). The arrow shows the end of the 3' UTR of the APRIL cDNA reported by Hahne et al. [19].

 

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TABLE 2. Intron–exon structure

 

Identification of polymorphisms in the human APRIL gene
First, we designed exon-specific oligonucleotide primers according to the genomic DNA sequence of APRIL (Table 1Go). All six exons were analysed by exon-specific PCR-SSCP in 148 unaffected individuals and 146 SLE patients. The PCR products for exons 1 and 2 displayed aberrantly migrating bands both in unaffected individuals and in SLE patients (Fig. 2aGo). Nucleotide sequencing revealed two polymorphisms at codon 67 in exon 1 and codon 96 in exon 2. Both polymorphisms were caused by a single nucleotide substitution. At amino acid residue 67, the first nucleotide G of the codon GGG for Gly was replaced by A, which resulted in an amino acid change from Gly to Arg (G67R). At codon 96, the second nucleotide A was replaced by G, which resulted in an amino acid change from Asn (AAT) to Ser (AGT) (N96S). Both polymorphisms were novel and located in the extracellular domain of APRIL (Fig. 2bGo). The nucleotide sequences for 50 DNA samples derived from unaffected controls were completely identical to the band patterns displayed by PCR-SSCP. There were no other polymorphisms in the coding region of the human APRIL gene.



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FIG. 2. (a) PCR-SSCP analysis of APRIL genomic DNA. Lane 1, homozygote for the 67G allele; Lane 2, 67G/R heterozygote; Lane 3, 67R homozygote; Lane 4, 96N homozygote; Lane 5, 96S homozygote; Lane 6, 96N/S heterozygote. (b) Locations of polymorphisms in the APRIL protein. CP, cytoplasmic; TM, transmembrane; EC, extracellular.

 

Association of APRIL allele 67G with SLE
We analysed the frequencies of APRIL polymorphisms in patients with SLE and unaffected controls by exon-specific PCR-SSCP. The distribution of APRIL alleles and genotypes at codons 67 and 96 is shown in Table 2Go. The allele frequency of Gly at codon 67 (67G) was significantly increased in SLE patients (0.662) compared with controls (0.575) [odds ratio (OR) 1.45, 95% confidence interval (CI) 1.12–1.78, P=0.0302] (Table 3AGo). The frequency of individuals who possessed at least one 67G allele among SLE patients (136 of 148, 91.9%) was significantly higher than that in normal controls (117 of 146, 80.1%) (OR 2.8, 95% CI 1.37–5.75, P=0.0036). G67R and N96S were in linkage disequilibrium (D'=0.480, P=0.009). However, there were no significant differences between SLE patients and healthy controls in the genotype and allele frequencies of polymorphisms at codon 96 (N96S) (Table 3BGo). Although we investigated the association of allele 67G with the clinical manifestations of SLE (age at onset, nephritis, CNS lupus, antinuclear antibodies, hypocomplementaemia, anti-double-stranded DNA antibodies, anti-ribonucleoprotein antibodies, anti-Sm antibodies), the clinical features were not significantly different between SLE patients with and without the 67G allele (data not shown). These results indicate that the 67G allele of APRIL is associated with SLE susceptibility but not with a particular phenotype of SLE.


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TABLE 3. Comparison of APRIL polymorphisms between healthy controls and patients with SLE

 


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this study, we determined for the first time the genetic structure of the APRIL gene, enabling us to perform systemic analysis for the association of APRIL gene polymorphism with SLE. Two novel polymorphisms, 67G and 96N, were identified. The former was associated with SLE when studied either by allele or by genotype frequency in a Japanese population.

The TNF family is known to have an important role in immune regulation and inflammation. Involvement of the TNF family in autoimmunity has been suggested by the autoimmune phenotypes observed in mice with TNF family transgenes or gene knockouts [22, 35, 36]. APRIL has a regulatory role in B-cell proliferation [19, 28]. Recently, it has been reported that APRIL affects the T-cell response [37], and that dendritic cells induce CD40-independent immunoglobulin class switching through APRIL [38]. Furthermore, the soluble decoy receptors for APRIL prolong the survival of lupus-prone NZBWF1 mice [29, 30]. These lines of evidence suggest that APRIL may be involved in the pathogenesis of SLE.

TNF family ligands are known to be synthesized as membrane-bound proteins, several of which have been shown to be cleaved proteolytically into a soluble form [39]. TNF-{alpha} and Fas ligand are processed by metalloproteinase [40], whereas BAFF and tumor necrosis factor-like weak inducer of apoptosis (TWEAK) are reported to be cleaved at a multibasic motif, R-X-K/R-R, by furin convertase [21, 41]. In the case of APRIL, it has been shown to be cleaved by a furin convertase at the RKRR motif of amino acids 101–104 [20]. We identified two novel polymorphisms of APRIL, G67R and R96S, both of which were single-nucleotide polymorphisms with amino acid substitution. Both polymorphisms were located in the stalk region of the extracellular domain and remained on the membrane side after cleavage. Of these, only the 67G allele was associated with SLE. The amino acid substitution from Gly to Arg may change the structure of the whole molecule because it is a substitution from a non-polar to a charged polar (basic) amino acid. Several functional changes may be caused by G67R polymorphism. First, the furin protease cleaves not only the motif R-X-K/R-R but also the motif R-X-X-R [20]. The amino acid substitution at codon 67 from G to R induces the R-X-X-R motif at amino acids 64–67, which can serve as a new furin cleavage site, resulting in more effective cleavage of APRIL. Because, in general, there are functional differences between the membrane forms and soluble forms of TNF family ligands [42], the different cleavage rate of APRIL may cause functional differences. Secondly, the TNF ligand family molecules assemble as a homotrimer; the interactions among subunits involve the extracellular carboxy terminal domains [40]. The G67R polymorphism may have some influence on the formation of the homotrimer, resulting in altered binding affinity to the receptors. Thirdly, it has been reported recently that the outside-to-inside (reverse) signal is transmitted through the membrane form of TNF family ligands, such as TNF-{alpha}, Fas-L and TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) [4345]. The G67R polymorphism may modify this reverse signal. Functional studies to address these issues are being attempted.

APRIL is located on chromosome 17p13.1, which was not included in the loci detected by the linkage analysis [29]. As it is difficult to detect genetic factors with low relative risks by this approach, a candidate gene may exist at a locus but not be detected by linkage analysis. As the linkage disequilibrium between G67R and N96S was incomplete, only 67G was associated with the disease. We cannot exclude an alternative explanation for the association of the G67R polymorphism with SLE—that G67R may be in linkage disequilibrium with another candidate gene on the same chromosome encoding the other protein.

The genomic structure of the APRIL gene presented in this report provides further understanding of the molecular basis of APRIL isoforms. Kelly et al. [34] reported two isoforms of APRIL, called TRDL-1ß and TRDL-1{gamma}. TRDL-1ß was generated by alternative splicing of exon 3. In TRDL-1{gamma}, a part of exon 6 (181 bp) was deleted. These isoforms had a longer 3' UTR with a poly(A) tail than that of the APRIL cDNA reported by Hahne et al. [19]. We cloned the cDNA spanning approximately 1.8 kb, which contains the entire exon 3 and exon 6 with a full-length 3' UTR. This indicates that the full-length APRIL transcript and its two isoforms contain a 3' UTR 485 bp longer than that reported by Hahne et al.

In summary, we have identified the genomic structure of the APRIL gene and two novel polymorphisms, one of which, 67G, was significantly associated with SLE in a Japanese population. This study provides the basis for a replication study of this APRIL polymorphism in other ethnic groups. Further studies on the association of APRIL polymorphisms with other autoimmune diseases and cancer are warranted.


    Acknowledgments
 
This work was supported in part by grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (to HT).


    Notes
 
Correspondence to: H. Tsukamoto, Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: tsukamot{at}intmed1.med.kyushu-u.ac.jp Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 2 September 2002; Accepted 8 January 2003





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