Rheumatology Advance Access originally published online on February 16, 2007
Rheumatology 2007 46(5):776-782; doi:10.1093/rheumatology/kem019
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Role of APRIL (TNFSF13) polymorphisms in the susceptibility to systemic lupus erythematosus in Japanese
1Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, 2Doctoral Program in Social and Environmental Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 3Tumor Suppression and Functional Genomics Project, National Cancer Center Research Institute, Tokyo, 4Department of Rheumatology and Internal Medicine, Juntendo University, Tokyo, 5Matsuta Clinic, Tokyo and 6Department of Rheumatology and Internal Medicine, Juntendo Koshigaya Hospital, Koshigaya, Japan
Correspondence to: N. Tsuchiya, Doctoral Program in Social and Environmental Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. E-mail: tsuchiya-tky{at}umin.net
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Abstract |
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Objectives. A polymorphism of APRIL, c.199G > A (Gly67Arg), has been reported to be associated with systemic lupus erythematosus (SLE) in Japanese. To identify the causative polymorphism, we screened for polymorphisms of APRIL as well as TWEAK (TNFSF12), a closely located gene that generates a fusion protein TWE-PRIL by intergenic splicing. Association of APRIL and TWEAK with rheumatoid arthritis (RA) was examined in parallel.
Methods. Polymorphisms were screened by direct sequencing. Association was analysed by case-control analysis using 266 SLE, 298 RA and 208 healthy individuals. Allele-specific difference in the mRNA level was examined using RNA difference plot analysis. Serum APRIL level was measured by ELISA.
Results. The protective effect of APRIL c.199A/A homozygotes in SLE was replicated (odds ratio 0.50, 95% confidence interval 0.30–0.83, P = 0.0073; pooled P = 0.0001, Pcorr = 0.007). In addition, association of c.287A > G (Asn96Ser, P = 0.0064, allele frequency) and c.*263C > T (3’ untranslated region, P = 0.025, allele frequency) was detected. c.199G-c.287A (67Gly-96Asn) haplotype was found to confer risk for SLE, while c.199A-c.287G (67Arg-96Ser) was protective. Association of TWEAK was observed neither for SLE nor RA. APRIL mRNA was increased in SLE-associated c.*263T allele. In addition, serum APRIL was undetectable in all six healthy controls homozygous for the protective c.199A-c.287G haplotype (P = 0.015).
Conclusions. In addition to replicating the protective role of APRIL c.199A/A, two additional SNPs in APRIL were found to be associated with SLE. Presence of a protective haplotype and a risk haplotype was demonstrated. The mechanism of association was suggested to be altered expression at the protein and mRNA levels.
KEY WORDS: Systemic lupus erythematosus, APRIL (TNFSF13), Polymorphism, Susceptibility, Genetics
Submitted 5 November 2006;
revised version accepted 9 January 2007.
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