Protein network and pathway analysis in a pharmacogenetic study of cyclosporine treatment response in Greek patients with psoriasis

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Αντωνάτος, Χαράλαμπος

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Psoriasis is a chronic, inflammatory skin disease that affects 2-3% of the world's population. Due to its multifactorial nature, with the interaction of genetic and environmental factors contributing to its pathogenesis, multiple therapeutic approaches have been developed. Cyclosporine is an immunosuppressive drug that creates a complex with cyclophilin, aiming at the inactivation of the Nuclear Factor of T cells. Despite its high specificity and importance in the immune cascade of Psoriasis, the clinical heterogeneity displayed by the treatment response of patients with Psoriasis, as well as the multiple adverse effects, raises the need for the investigation of pharmacogenetic biomarkers. The aim of this dissertation is the pharmacogenetic analysis of Greek patients with psoriasis treated with cyclosporine, based on the reconstruction of the protein interaction network of the molecules involved in its mechanism of action. The protein interaction network was reconstructed using the PICKLE metabase. Through this, 27 polymorphisms in 22 genes encoding key proteins implicated in the drug's mechanism of action were selected. Forward, reverse and extension primers were designed through the iPLEX®GOLD platform and utilized for the genotyping of 200 Greek patients through the MassARRAY® system (Agena Bioscences). In addition to individual polymorphism analysis, haplotype analysis was performed in the additive inheritance model, with a frequency threshold of 10%. The common alleles of 2 polymorphisms, namely CALM1 rs12885713 (P=0.0005) and MALT1 rs2874116 (P=2.3×10-5), were found to be statistically significantly associated with patients' positive response to cyclosporine. Haplotype analysis further enhanced the predictive significance rs12885713 as a pharmacogenetic biomarkers in psoriasis (P=0.01). These findings have the potential not only of improving the treatment with cyclosporine prognosis but also of establishing the framework for the investigation of complex phenotypes in the context of pharmacogenetics.



Pharmacogenetics, Cyclosporine, Psoriasis