IMPLICAZIONI CLINICHE DEI POLIMORFISMI GENETICI NELLE ULCERE VENOSE DEGLI ARTI INFERIORI:UN MODELLO DI DANNO E RIPARAZIONE TISSUTALE

Introduction. Tissue injury and reparative processes are multi-factorial and complex mechanisms, where genetics has a role and gene-gene and gene-environment interactions play pivotal functions. Several gene variants (SNPs, single nucleotide polymorphism) have a definite role in etiopathogenesis, diagnosis and prognosis of venous leg ulcers (VLU), thus, the SNPs’s identification in patients is basic for the diagnosis and prognosis of this disease. We had already demonstrated that some gene polymorphisms aid to ulcer onset and other polymorphisms influence the ulcer extension and healing after superficial venous surgery. With the present study, we would like to verify if some gene polymorphisms interfer in ulcer healing with the same medical treatment. Materials and Methods. From February 2007 to October 2008 we enrolled in our study 45 consecutive patients with VLU, 18 male e 27 female, with a median age of 72.9 years (range 20-95 years). The median initial ulcer size was 8.8 cm2 (range 0.3-62.3 cm2with a wide spectrum of disease duration, from 30 days to 20 years. We draw blood to any patient to determine the gene polymorphisms of our interest (HFE, FXIII, MMP12) and we did weekly dressing changes with the same therapeutic strategy (advanced dressing, plus multilayer elastic bandaging) made up by the same physician, to riduce the “human variability” and so catch the real role of gene and molecular variants. The study lasted 12 weeks. The study endpoints were: 1) to establish the healing rate after 12 weeks of treatment; 2) to determine tha risponders in function of Margolis Index (reduction of ulcer size of at least 50% after 4 weeks of treatment); 3) to verify if exist a correlation between gene variants, healing, responders. Results. For FXIII gene polymorphisms (VV,VL, LL) we did not find statistically significant differences neither for healing rate at week 12th, nor for Margolis Index (P=ns). Same conclusions for HFE gene polymorphisms (HD e HH). For matrix metalloprotease 12 (MMP12) gene polymorphisms (AA, AG, GG), we found that the homozygous AA genotype increases 2.27 times the healing probability (OR= 2.27, CI 0.5-10.25), instead the –G carriers are 3.28 times more responders (OR=3.28, CI 0.58-18.36). Discussione. What we noted in this study, seems to be contradictory with what we demonstrated before for the MMP12 gene variants, that means the association with –G allele and smaller ulcer size. Really, also for patient population –G carrier has a smaller ulcer and moreover a greater probability to reduce ulcer size of at least 50% after 4 weeks of treatment. So, the only discrepancy, seems to be the greater probability to heal for the homozygous aa carriers, but, we can explain that, examinig the tissue injury and reparative process. This is extremely complex, dynamic, multi-fasic and multi-factorial, thus it is possible that enzymes traditionally considered of tissue injury like MMPs, could play a role in different phases of tissue remodelling in reparative process, maybe with different functions in reparative phases according to the specific MMMP family, or, in the same family, according to the different gene polymorphisms.