Fonseca Carmen, Renzoni Elizabeth, Sestini Piersante, Pantelidis Panagiotis, Lagan Anna, Bunn Christopher, McHugh Neil, Welsh Ken I, Du Bois Ron M, Denton Christopher P, Black Carol, Abraham D
Royal Free and University College Medical School, Center for Rheumatology and Connective Tissue Diseases, Department of Medicine, University College London Hampstead Campus, Hampstead, London NW3 2PF, UK.
Arthritis Rheum. 2006 Sep;54(9):3034-42. doi: 10.1002/art.22036.
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.
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).
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).
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.
评估内皮素1（EDN1）、内皮素受体A（EDNRA）和内皮素受体B（EDNRB）基因多态性在系统性硬化症（SSc；硬皮病）及其亚组中的分布情况。
采用序列特异性引物聚合酶链反应，对205例SSc患者和255名健康对照者进行EDN1、EDNRA和EDNRB基因多态性筛查。研究的多态性位点如下：EDN1基因，启动子的-1370（T-1370G）、外显子1的+138（+138 A/-）、外显子3的+85（E106E）和外显子5的+23（K198N）；EDNRA基因，外显子1的-231（G-231A）、外显子6的+69（H323H）和+105（E335E）；EDNRB基因，外显子2的+2841（EDNRB-3）、外显子3的-2547（EDNRB-2）和外显子3的-2446（EDNRB-1）。
在EDN1、EDNRA和EDNRB基因中，所研究的任何多态性在SSc组整体与对照受试者之间均未观察到显著差异。然而，与局限性皮肤型SSc患者相比，弥漫性皮肤受累患者中EDNRB-1A等位基因携带频率增加（76.8%对54.4%；P = 0.002），EDNRB-2A等位基因携带频率增加（79.7%对60.2%；P = 0.006），EDNRB-3G等位基因携带频率增加（79.7%对56.6%；P = 0.001）。与抗RNA聚合酶（抗RNAP）抗体阴性的SSc患者（P < 0.05）和对照受试者（P < 0.005）相比，抗RNAP抗体阳性的SSc患者中EDNRA等位基因H323H/C和E335E/A的携带频率显著增加。
内皮素受体A和B与不同的临床和免疫性SSc亚组之间存在关联，这一发现支持了内皮素及其受体在SSc发病机制中的作用。然而，这些发现及其功能意义需要在未来的研究中得到证实和进一步研究。
