Role of APRIL (TNFSF13) polymorphisms in the susceptibility to systemic lupus erythematosus in Japanese

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.