A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis

Mirko Manetti, Yannick Allanore, Lucile Revillod, Cinzia Fatini, Serena Guiducci, Giovanna Cuomo, Claudia Bonino, Valeria Riccieri, Laura Bazzichi, Vasiliki Liakouli, Paola Cipriani, Roberto Giacomelli, Rosanna Abbate, Stefano Bombardieri, Guido Valesini, Carlomaurizio Montecucco, Gabriele Valentini, Lidia Ibba-Manneschi, Marco Matucci-Cerinic

Research output: Contribution to journalArticlepeer-review

Abstract

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). Conclusion The UPAR rs344781 gene variant is associated with the SSc vascular phenotype.

Original languageEnglish
Pages (from-to)247-256
Number of pages10
JournalArthritis and Rheumatism
Volume63
Issue number1
DOIs
Publication statusPublished - Jan 2011

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

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