A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis.
OBJECTIVE
The UPAR gene encodes a pleiotropic receptor (urokinase-type plasminogen activator receptor [uPAR]) involved in fibrosis, immunity, angiogenesis, and vascular remodeling. Previous studies have implicated uPAR in systemic sclerosis (SSc) vasculopathy and impaired angiogenesis. We undertook this study to investigate whether UPAR gene promoter polymorphisms might be associated with SSc phenotypes in the European Caucasian population.


METHODS
We studied a total population of 1,339 individuals. The Italian discovery cohort comprised 388 SSc patients and 391 healthy controls. The French replication cohort consisted of 344 SSc patients and 216 healthy controls. The UPAR rs344781 and rs4251805 single-nucleotide polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism assay.


RESULTS
In the Italian cohort, the rs344781 G allele was associated with SSc-related digital ulceration (odds ratio [OR] 1.39), pulmonary arterial hypertension (PAH) (OR 1.81), anticentromere antibody (ACA) positivity (OR 1.45), and limited cutaneous SSc (lcSSc) (OR 1.37). The rs344781 GG genotype was associated with SSc-related (OR 3.79), ACA-positive SSc (OR 2.17), and lcSSc (OR 1.96). Allelic and genotypic associations with SSc-related digital ulceration and ACA-positive SSc were replicated in the French sample. Combined analyses showed an association of the rs344781 G allele and GG genotype with SSc-related digital ulceration (allele OR 1.41, genotype OR 2.15), SSc-related PAH (allele OR 1.65, genotype OR 3.16), ACA-positive SSc (allele OR 1.47, genotype OR 2.40), and lcSSc (allele OR 1.34, genotype OR 1.77). In a multivariate logistic regression analysis model including the above associated phenotypes of SSc patients, the rs344781 GG genotype remained an independent risk factor for SSc-related digital ulceration (OR 1.96) and SSc-related PAH (OR 2.68).


CONCLUSIONS
The UPAR rs344781 gene variant is associated with the SSc vascular phenotype.
Manetti
Mirko
M
University of Florence and Excellence Centre for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies, Florence, Italy. mirkomanetti@yahoo.it
Allanore
Yannick
Y
Revillod
Lucile
L
Fatini
Cinzia
C
Guiducci
Serena
S
Cuomo
Giovanna
G
Bonino
Claudia
C
Riccieri
Valeria
V
Bazzichi
Laura
L
Liakouli
Vasiliki
V
Cipriani
Paola
P
Giacomelli
Roberto
R
Abbate
Rosanna
R
Bombardieri
Stefano
S
Valesini
Guido
G
Montecucco
Carlomaurizio
C
Valentini
Gabriele
G
Ibba-Manneschi
Lidia
L
Matucci-Cerinic
Marco
M
D000328:Adult; D000368:Aged; D000483:Alleles; D016009:Chi-Square Distribution; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics*; D012595:Scleroderma, Systemic / Q000150:complications / Q000235:genetics*; D014652:Vascular Diseases / Q000150:complications / Q000235:genetics*
C524898:PLAUR protein, human; D055293:Receptors, Urokinase Plasminogen Activator