Endothelin axis polymorphisms in patients with scleroderma
Corresponding Author
Carmen Fonseca
Royal Free and University College Medical School, London, UK
Royal Free and University College Medical School, Center for Rheumatology and Connective Tissue Diseases, Department of Medicine, University College London Hampstead Campus, Rowland Hill Street, Hampstead, London NW3 2PF, UKSearch for more papers by this authorElizabeth Renzoni
Royal Brompton Hospital and Imperial College of Science, Technology and Medicine, London, UK
Search for more papers by this authorAnna Lagan
Royal Brompton Hospital and Imperial College of Science, Technology and Medicine, London, UK
Search for more papers by this authorChristopher Bunn
Royal Free and University College Medical School, London, UK
Search for more papers by this authorNeil McHugh
Royal National Hospital for Rheumatic Diseases, Bath, UK
Search for more papers by this authorKen I. Welsh
Royal Brompton Hospital and Imperial College of Science, Technology and Medicine, London, UK
Search for more papers by this authorRon M. Du Bois
Royal Brompton Hospital and Imperial College of Science, Technology and Medicine, London, UK
Search for more papers by this authorChristopher P. Denton
Royal Free and University College Medical School, London, UK
Dr. Denton has received consulting fees (less than $10,000 each) from Actelion Pharmaceuticals, Encysive Pharmaceuticals, and Genzyme.
Search for more papers by this authorCarol Black
Royal Free and University College Medical School, London, UK
Search for more papers by this authorD. Abraham
Royal Free and University College Medical School, London, UK
Search for more papers by this authorCorresponding Author
Carmen Fonseca
Royal Free and University College Medical School, London, UK
Royal Free and University College Medical School, Center for Rheumatology and Connective Tissue Diseases, Department of Medicine, University College London Hampstead Campus, Rowland Hill Street, Hampstead, London NW3 2PF, UKSearch for more papers by this authorElizabeth Renzoni
Royal Brompton Hospital and Imperial College of Science, Technology and Medicine, London, UK
Search for more papers by this authorAnna Lagan
Royal Brompton Hospital and Imperial College of Science, Technology and Medicine, London, UK
Search for more papers by this authorChristopher Bunn
Royal Free and University College Medical School, London, UK
Search for more papers by this authorNeil McHugh
Royal National Hospital for Rheumatic Diseases, Bath, UK
Search for more papers by this authorKen I. Welsh
Royal Brompton Hospital and Imperial College of Science, Technology and Medicine, London, UK
Search for more papers by this authorRon M. Du Bois
Royal Brompton Hospital and Imperial College of Science, Technology and Medicine, London, UK
Search for more papers by this authorChristopher P. Denton
Royal Free and University College Medical School, London, UK
Dr. Denton has received consulting fees (less than $10,000 each) from Actelion Pharmaceuticals, Encysive Pharmaceuticals, and Genzyme.
Search for more papers by this authorCarol Black
Royal Free and University College Medical School, London, UK
Search for more papers by this authorD. Abraham
Royal Free and University College Medical School, London, UK
Search for more papers by this authorAbstract
Objective
To evaluate the distribution of polymorphisms in the endothelin 1 (EDN1), endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB) genes in systemic sclerosis (SSc; scleroderma) and SSc subsets.
Methods
Two hundred five patients with SSc and 255 healthy controls were screened for polymorphisms in EDN1, EDNRA, and EDNRB, using sequence-specific primer–polymerase chain reaction. The polymorphisms studied were at the following positions: for EDN1, −1370 (T-1370G) of the promoter, +138 of exon 1 (+138 A/−), +85 of exon 3 (E106E), and +23 of exon 5 (K198N); for EDNRA, −231 of exon 1 (G-231A), and +69(H323H) and +105 (E335E) of exon 6; for EDNRB, +2841 of exon 2 (EDNRB-3), −2547 of exon 3 (EDNRB-2), and −2446 of exon 3 (EDNRB-1).
Results
No significant differences between the SSc group as a whole and control subjects were observed for any of the investigated polymorphisms in EDN1, EDNRA, and EDNRB. However, compared with patients with limited cutaneous SSc, patients with diffuse skin involvement had an increased frequency of allele carriage of EDNRB-1A (76.8% versus 54.4%; P = 0.002), EDNRB-2A (79.7% versus 60.2%; P = 0.006), and EDNRB-3G (79.7% versus 56.6%; P = 0.001). Significantly increased carriage frequencies for EDNRA alleles H323H/C and E335E/A were observed in SSc patients with anti–RNA polymerase (anti-RNAP) antibodies, compared with both anti-RNAP–negative SSc patients (P < 0.05) and control subjects (P < 0.005).
Conclusion
The finding of associations between endothelin receptors A and B and distinct clinical and immunologic SSc subsets supports the role of endothelin and its receptors in the pathogenesis of SSc. However, these findings and their functional significance need to be confirmed and investigated in future studies.
REFERENCES
- 1 Black CM. The aetiopathogenesis of systemic sclerosis: thick skin—thin hypotheses. The Parkes Weber lecture 1994. J R Coll Physicians Lond 1995; 29: 119–30.
- 2 Cepeda EJ, Reveille JD. Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance. Curr Opin Rheumatol 2004; 16: 723–32.
- 3 Gilchrist FC, Bunn C, Foley PJ, Lympany PA, Black CM, Welsh KI, et al. Class II HLA associations with autoantibodies in scleroderma: a highly significant role for HLA-DP. Genes Immun 2001; 2: 76–81.
- 4 Kuwana M, Kaburaki J, Arnett FC, Howard RF, Medsger TA Jr, Wright TM. Influence of ethnic background on clinical and serologic features in patients with systemic sclerosis and anti–DNA topoisomerase I antibody. Arthritis Rheum 1999; 42: 465–74.
- 5 Reveille JD, Fischbach M, McNearney T, Friedman AW, Aguilar MB, Lisse J, et al. Systemic sclerosis in 3 US ethnic groups: a comparison of clinical, sociodemographic, serologic, and immunogenetic determinants. Semin Arthritis Rheum 2001; 30: 332–46.
- 6 Englert H, Small-McMahon J, Chambers P, O'Connor H, Davis K, Manolios N, et al. Familial risk estimation in systemic sclerosis. Aust N Z J Med 1999; 29: 36–41.
- 7 Vyse TJ, Todd JA. Genetic analysis of autoimmune disease. Cell 1996; 85: 311–8.
- 8 Mayes MD, Lacey JV Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 2003; 48: 2246–55.
- 9 Maricq HR, Weinrich MC, Keil JE, Smith EA, Harper FE, Nussbaum AI, et al. Prevalence of scleroderma spectrum disorders in the general population of South Carolina. Arthritis Rheum 1989; 32: 998–1006.
- 10 Steen VD, Oddis CV, Conte CG, Janoski J, Casterline GZ, Medsger TA Jr. Incidence of systemic sclerosis in Allegheny County, Pennsylvania: a twenty-year study of hospital-diagnosed cases, 1963–1982. Arthritis Rheum 1997; 40: 441–5.
- 11 Arnett FC, Howard RF, Tan F, Moulds JM, Bias WB, Durban E, et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma: association with an Amerindian HLA haplotype. Arthritis Rheum 1996; 39: 1362–70.
- 12 Gladman DD, Kung TN, Siannis F, Pellett F, Farewell VT, Lee P. HLA markers for susceptibility and expression in scleroderma. J Rheumatol 2005; 32: 1481–7.
- 13 Miyawaki S, Asanuma H, Nishiyama S, Yoshinaga Y. Clinical and serological heterogeneity in patients with anticentromere antibodies. J Rheumatol 2005; 32: 1488–94.
- 14 Derk CT, Jimenez SA. Systemic sclerosis: current views of its pathogenesis. Autoimmun Rev 2003; 2: 181–91.
- 15 Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 1992; 166: 255–63.
- 16 Herrick AL. Vascular function in systemic sclerosis. Curr Opin Rheumatol 2000; 12: 527–33.
- 17 Muller DN, Mervaala EM, Schmidt F, Park JK, Dechend R, Genersch E, et al. Effect of bosentan on NF-κB, inflammation, and tissue factor in angiotensin II-induced end-organ damage. Hypertension 2000; 36: 282–90.
- 18 Nicoletti A, Michel JB. Cardiac fibrosis and inflammation: interaction with hemodynamic and hormonal factors. Cardiovasc Res 1999; 41: 532–43.
- 19 Shi-wen X, Denton CP, Dashwood MR, Abraham DJ, Black CM. Endothelin-1 regulation of intercellular adhesion molecule-1 expression in normal and sclerodermal fibroblasts. J Cardiovasc Pharmacol 1998; 31 Suppl 1: S545–7.
- 20 Shi-wen X, Denton CP, Dashwood MR, Holmes AM, Bou-Gharios G, Pearson JD, et al. Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. J Invest Dermatol 2001; 116: 417–25.
- 21 Danese C, Parlapiano C, Zavattaro E, Di Prima M, Campana E, Rota C, et al. ET-1 plasma levels during cold stress test in sclerodermic patients. Angiology 1997; 48: 965–8.
- 22 Cambrey AD, Harrison NK, Dawes KE, Southcott AM, Black CM, du Bois RM, et al. Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am J Respir Cell Mol Biol 1994; 11: 439–45.
- 23 Morelli S, Ferri C, Polettini E, Bellini C, Gualdi GF, Pittoni V, et al. Plasma endothelin-1 levels, pulmonary hypertension, and lung fibrosis in patients with systemic sclerosis. Am J Med 1995; 99: 255–60.
- 24 Yamane K, Miyauchi T, Suzuki N, Yuhara T, Akama T, Suzuki H, et al. Significance of plasma endothelin-1 levels in patients with systemic sclerosis. J Rheumatol 1992; 19: 1566–71.
- 25 Kadono T, Kikuchi K, Sato S, Soma Y, Tamaki K, Takehara K. Elevated plasma endothelin levels in systemic sclerosis. Arch Dermatol Res 1995; 287: 439–42.
- 26 Vancheeswaran R, Magoulas T, Efrat G, Wheeler-Jones C, Olsen I, Penny R, et al. Circulating endothelin-1 levels in systemic sclerosis subsets: a marker of fibrosis or vascular dysfunction? J Rheumatol 1994; 21: 1838–44.
- 27 Kawaguchi Y, Suzuki K, Hara M, Hidaka T, Ishizuka T, Kawagoe M, et al. Increased endothelin-1 production in fibroblasts derived from patients with systemic sclerosis. Ann Rheum Dis 1994; 53: 506–10.
- 28 Abraham DJ, Vancheeswaran R, Dashwood MR, Rajkumar VS, Pantelides P, Xu SW, et al. Increased levels of endothelin-1 and differential endothelin type A and B receptor expression in scleroderma-associated fibrotic lung disease. Am J Pathol 1997; 151: 831–41.
- 29 Levin ER. Endothelins. N Engl J Med 1995; 333: 356–63.
- 30 Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol 2001; 41: 851–76.
- 31 Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980; 23: 581–90.
- 32 Leroy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988; 15: 202–5.
- 33 Denton CP, Cailes JB, Phillips GD, Wells AU, Black CM, Bois RM. Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol 1997; 36: 239–43.
- 34 DeMarco PJ, Weisman MH, Seibold JR, Furst DE, Wong WK, Hurwitz EL, et al. Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum 2002; 46: 2983–9.
- 35 Bunn CC, Denton CP, Shi-wen X, Knight C, Black CM. Anti-RNA polymerases and other autoantibody specificities in systemic sclerosis. Br J Rheumatol 1998; 37: 15–20.
- 36 Bunce M, Fanning GC, Welsh KI. Comprehensive, serologically equivalent DNA typing for HLA-B by PCR using sequence-specific primers (PCR-SSP). Tissue Antigens 1995; 45: 81–90.
- 37
Wallenstein S,
Hodge SE,
Weston A.
Logistic regression model for analyzing extended haplotype data.
Genet Epidemiol
1998;
15:
173–81.
10.1002/(SICI)1098-2272(1998)15:2<173::AID-GEPI5>3.0.CO;2-7 CAS PubMed Web of Science® Google Scholar
- 38 Pagani F, Baralle FE. Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 2004; 5: 389–96.
- 39 Vancheeswaran R, Azam A, Black C, Dashwood MR. Localization of endothelin-1 and its binding sites in scleroderma skin. J Rheumatol 1994; 21: 1268–76.
- 40 Korn JH, Mayes M, Matucci CM, Rainisio M, Pope J, Hachulla E, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004; 50: 3985–93.
- 41 Snyder MJ, Jacobs MR, Grau RG, Wilkes DS, Knox KS. Resolution of severe digital ulceration during a course of Bosentan therapy. Ann Intern Med 2005; 142: 802–3.
- 42 Fanning GC, Welsh KI, Bunn C, Du Bois R, Black CM. HLA associations in three mutually exclusive autoantibody subgroups in UK systemic sclerosis patients. Br J Rheumatol 1998; 37: 201–7.
- 43 Reveille JD. Molecular genetics of systemic sclerosis. Curr Opin Rheumatol 1995; 7: 522–8.
- 44 Kuwana M, Inoko H, Kameda H, Nojima T, Sato S, Nakamura K, et al. Association of human leukocyte antigen class II genes with autoantibody profiles, but not with disease susceptibility in Japanese patients with systemic sclerosis. Intern Med 1999; 38: 336–44.
- 45 Genth E, Mierau R, Genetzky P, von Muhlen CA, Kaufmann S, von Wilmowsky H, et al. Immunogenetic associations of scleroderma-related antinuclear antibodies. Arthritis Rheum 1990; 33: 657–65.
- 46 Baur X, Rihs HP, Altmeyer P, Degens P, Conrad K, Mehlhorn J, et al. Systemic sclerosis in German uranium miners under special consideration of autoantibody subsets and HLA class II alleles. Respiration 1996; 63: 368–75.
- 47 Sato H, Lagan AL, Alexopoulou C, Vassilakis DA, Ahmad T, Pantelidis P, et al. The TNF-863A allele strongly associates with anticentromere antibody positivity in scleroderma. Arthritis Rheum 2004; 50: 558–64.
- 48 Hudson LL, Rocca KM, Kuwana M, Pandey JP. Interleukin-10 genotypes are associated with systemic sclerosis and influence disease-associated autoimmune responses. Genes Immun 2005; 6: 274–8.
- 49 Harvey GR, Butts S, Rands AL, Patel Y, McHugh NJ. Clinical and serological associations with anti-RNA polymerase antibodies in systemic sclerosis. Clin Exp Immunol 1999; 117: 395–402.
- 50 Steen VD, Medsger TA Jr, Osial TA Jr, Ziegler GL, Shapiro AP, Rodnan GP. Factors predicting development of renal involvement in progressive systemic sclerosis. Am J Med 1984; 76: 779–86.
