Abstract
Recent studies indicated a substantial role of BLyS (BAFF, TNFSF13B) in the pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in humans and in animal models. This study was conducted to screen for polymorphisms of human BLYS, and to examine whether they are involved in the genetic susceptibility to human SLE and RA. A systematic polymorphism screening was performed in the coding region, 5′ and 3′ untranslated regions, and promoter region of human BLYS. Association of the detected polymorphisms with SLE and RA was analyzed in 221 Japanese patients with RA, 156 with SLE, and 227 healthy individuals, using the case–control approach. Four single nucleotide polymorphisms (SNPs) in the promoter, one SNP in intron 1, and one rare nonsynonymous substitution (Ala105Thr) in the coding region were detected. The BLYS SNPs were found to form three common haplotypes. Significant association with the susceptibility to SLE or RA was not observed. However, a tendency for the increase of −871T/T genotype was observed in SLE patients with anti-Sm antibody (P=0.082). BLYS mRNA level was significantly elevated in the monocytes from individuals carrying −871T (P=0.010). In addition, although statistically not significant, 105Thr allele was slightly increased in patients with RA compared with controls (P=0.058). Characterizing the functional and clinical significance of these new SNPs requires further study.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 digital issues and online access to articles
$119.00 per year
only $19.83 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Moore PA, Belvedere O, Orr A et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator Science 1999 285: 260–263
Schneider P, MacKay F, Steiner V et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth J Exp Med 1999 189: 1747–1756
Shu HB, Hu WH, Johnson H . TALL-l is a novel member of the TNF family that is down-regulated by mitogens J Leukoc Biol 1999 65: 680–683
Gross JA, Johnston J, Mudri S et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease Nature 2000 404: 995–999
Nardelli B, Belvedere O, Roschke V et al. Synthesis and release of B-lymphocyte stimulator from myeloid cells Blood 2001 97: 198–204
Mackay F, Woodcock SA, Lawton P et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations J Exp Med 1999 190: 1697–1710
Khare SD, Sarosi I, Xia XZ et al. Severe B cell hyperplasia and autoimmune disease in TALL-l transgenic mice Proc Natl Acad Sci USA 2000 97: 3370–3375
Thompson JS, Schneider P, Kalled SL et al. BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population J Exp Med 2000 192: 129–135
Do RK, Hatada E, Lee H, Tourigny MR, Hilbert D, Chen-Kiang S . Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response J Exp Med 2000 192: 953–964
Batten M, Groom J, Cachero TG et al. BAFF mediates survival of peripheral immature B lymphocytes J Exp Med 2000 192: 1453–1466
Gross JA, Dillon SR, Mudri S et al. TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. Impaired B cell maturation in mice lacking BLyS Immunity 2001 15: 289–302
Rennert P, Schneider P, Cachero TG et al. A soluble form of B cell maturation antigen, a receptor for the tumor necrosis factor family member APRIL, inhibits tumor cell growth J Exp Med 2000 192: 1677–1684
Marsters SA, Yan M, Pitti RM, Haas PE, Dixit VM, Ashkenazi A . Interaction of the TNF homologues BLyS and APRIL with the TNF receptor homologues BCMA and TACI Curr Biol 2000 10: 785–788
Laabi Y, Gras MP, Carbonnel F et al. A new gene, BCM, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;pl3) translocation in a malignant T cell lymphoma EMBO J 1992 11: 3897–3904
Laabi Y, Gras MP, Brouet JC, Berger R, Larsen CJ, Tsapis A . The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed Nucleic Acids Res 1994 22: 1147–1154
Madry C, Laabi Y, Callebaut I et al. The characterization of murine BCMA gene defines it as a new member of the tumor necrosis factor receptor superfamily Int lmmunol 1998 10: 1693–1702
von Bulow GU, Bram RJ . NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor receptor superfamily Science 1997 278: 138–141
Hatzoglou A, Roussel J, Bourgeade MF et al. TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF)1, TRAF2, and TRAF3 and activates NF-kappa B, elk-l, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase J lmmunol 2000 165: 1322–1330
Xia XZ, Treanor J, Senaldi G et al. TACI is a TRAF-interacting receptor for TALL-l, a tumor necrosis factor family member involved in B cell regulation J Exp Med 2000 192: 137–143
Thompson JS, Bixler SA, Qian F et al. BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF Science 2001 293: 2108–2111
Yan M, Brady JR, Chan B et al. Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency Curr Biol 2001 11: 1547–1552
Wang H, Marsters SA, Baker T et al. TACI-ligand interactions are required for T cell activation and collagen-induced arthritis in mice Nat lmmunol 2001 2: 632–637
Zhang J, Roschke V, Baker KP et al. Cutting edge: A role for B lymphocyte stimulator in systemic lupus erythematosus J lmmunol 2001 166: 6–10
Cheema GS, Roschke V, Hilbert DM, Stohl W . Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases Arthritis Rheum 2001 44: 1313–1319
Groom J, Kalled SL, Cutler AH et al. Association of BAFF/BLyS overexpresion an altered B cell differentiation with Sjögren's syndrome J Clin Invest 2002 109: 59–68
Moser KL, Neas BR, Salmon JE et al. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome lq in African-American pedigrees Proc Natl Acad Sci USA 1998 95: 14869–14874
Kawasaki A, Tsuchiya N, Fukazawa T, Hashimoto H, Tokunaga K . Presence of four major haplotypes in human BCMA gene: lack of association with systemic lupus erythematosus and rheumatoid arthritis Genes lmmun 2001 2: 276–279
Dunnen JT, Antonarakis SE . Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion Hum Mutat 2000 15: 7–12
Schneider S, Roessli D, Excoffier L ARLEQUIN ver 2.000: a software for population genetics data analysis
Hromas R, Collins SJ, Hickstein D et al. A retinoic acid-responsive human zinc finger gene, MZF-1, preferen-tially expressed in myeloid cells J Biol Chem 1991 266: 14183–14187
Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis Arthritis Rheum 1988 31: 315–324
Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus Arthritis Rheum 1982 25: 1271–1277
Kato H, Tsuchiya N, Tokunaga K . Single nucleotide polymorphisms in the coding regions of human CXC-chemokine receptors CXCR1, CXCR2 and CXCR3 Genes lmmun 2000 1: 330–337
Acknowledgements
The authors are indebted to Dr Jun Ohashi (Department of Human Genetics, The University of Tokyo) for statistical analysis, Dr Kunio Matsuta (Matsuta Clinic) for the recruitment of the patients, Dr Manabu Fujimoto (Department of Regenerative Medicine, Research Institute, International Medical Center of Japan), Dr Takeshi Suzuki (Department of Allergy and Rheumatology, The University of Tokyo) and Daisuke Sakurai (Department of Human Genetics, The University of Tokyo) for valuable suggestions.
Author information
Authors and Affiliations
Corresponding author
Additional information
This study was supported by the Grant-in-Aid for Scientific Research on Priority Areas (C) ‘Medical Genome Science’, the Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Science, Sports and Culture of Japan, and grants from the Ministry of Health, Labour and Welfare of Japan.
Rights and permissions
About this article
Cite this article
Kawasaki, A., Tsuchiya, N., Fukazawa, T. et al. Analysis on the association of human BLYS (BAFF, TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis. Genes Immun 3, 424–429 (2002). https://doi.org/10.1038/sj.gene.6363923
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gene.6363923
Keywords
This article is cited by
-
Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus
Scientific Reports (2022)
-
Lymphoma in Sjögren’s Syndrome: Predictors and Therapeutic Options
Current Treatment Options in Rheumatology (2020)
-
Susceptibility of BAFF-var allele carriers to severe SLE with occurrence of lupus nephritis
BMC Nephrology (2019)
-
High BAFF expression associated with active disease in systemic lupus erythematosus and relationship with rs9514828C>T polymorphism in TNFSF13B gene
Clinical and Experimental Medicine (2019)
-
The BAFF/APRIL system in SLE pathogenesis
Nature Reviews Rheumatology (2014)