Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.

Genetic and Biological Models of Epistasis to Predict Digital Ulcer Occurrence in Italian Systemic Sclerosis Patients

Beretta1,  Lorenzo, Santaniello1,  Alessandro, Mayo2,  Michael, Cappiello1,  Francesca, Marchini1,  Maurizio, Scorza1,  Raffaella

Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena and University of Milan. Italy, Milan, Italy,
University of Waikato, Hamilton, New Zealand, Hamilton, New Zealand


Digital ulcers (DUs) are a frequent complication of systemic sclerosis (SSc) that may occur in up to 50% of patients during their disease history and that constitute a significant cause of discomfort and morbidity. DUs are thought to be the consequence of endothelial injury and small-vessel vasculopathy, which may be sustained by immune system activation and cytokine release.


Twenty-two functional cytokine single nucleotide polymorphisms (SNPs) and 3 HLA-class I and II antigens, -including HLA-B*3501 which may contribute to regulate the endothelin-1 (ET-1) production (1), HLA-DR*11 and HLA-DR*07, previously associated with SSc in Italian subjects (2), were typed at the genomic level by polymerase chain-reaction in 200 Italian SSc patients. Associations with DUs were sought by parametric models and with the Multifactor Dimensionality Reduction (MDR) algorithm to depict the presence of gene-gene or gene-environment interactions. Biological models consistent with MDR results were built by means of Petri nets to better describe the metabolic significance of our findings.


On the exploratory analysis, the dcSSc subset was the only factor associated with DUs (p=0.045, ns after Bonferroni correction). Gene-gene and gene-environmental analysis showed that a 3-factor model comprising the IL-6 C-174G, the IL-2 G-330T SNPs and the HLA-B*3501 allele was associated with DUs (testing accuracy=66.9%, p<0.005 after permutation testing). Petri nets allowed us to build a biological model to explain the non-linear interactions among the abovementioned variables. The main findings that emerge from this model are the following: 1) IL-6 and HLA-B*3501 synergize to eventually determine DUs occurrence; 2) IL-6 may sustain/amplify HLAs responses; 3) IL-6 production is amplified by an autocrine loop where IL-2 acts as a co-enhancing factor.


We provide evidence for a complex genetic susceptibility to DUs in Italian SSc patients. In the model we found, IL-6 appears to be a key-factor in determining DUs occurrence. This model is biologically plausible and may constitute the basis for further translational research.

1.Santaniello, A. et al HLA-B35 upregulates the production of endothelin-1 in HLA-transfected cells: a possible pathogenetic role in pulmonary hypertension. Tissue Antigens. 2006;68:239–44.

2.Scorza, R et al: HLA-DR antigens, clinical manifestations and autoantibodies in Systemic Sclerosis (Scleroderma). EOS. 1992; 12: 157–162

To cite this abstract, please use the following information:
Beretta, Lorenzo, Santaniello, Alessandro, Mayo, Michael, Cappiello, Francesca, Marchini, Maurizio, Scorza, Raffaella; Genetic and Biological Models of Epistasis to Predict Digital Ulcer Occurrence in Italian Systemic Sclerosis Patients [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1740
DOI: 10.1002/art.26814

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