Endothelin axis polymorphisms in patients with scleroderma.
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).


CONCLUSIONS
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.
Fonseca
Carmen
C
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. c.fonseca@medsch.ucl.ac.uk
Renzoni
Elizabeth
E
Sestini
Piersante
P
Pantelidis
Panagiotis
P
Lagan
Anna
A
Bunn
Christopher
C
McHugh
Neil
N
Welsh
Ken I
KI
Du Bois
Ron M
RM
Denton
Christopher P
CP
Black
Carol
C
Abraham
D
D
D016232:Endothelins / Q000235:genetics*; D005091:Exons; D006801:Humans; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D044022:Receptor, Endothelin A / Q000235:genetics*; D044023:Receptor, Endothelin B / Q000235:genetics*; D012016:Reference Values; D012595:Scleroderma, Systemic / Q000235:genetics*; D012867:Skin / Q000473:pathology
D016232:Endothelins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B