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P682. Identification of catalase and Mn-SOD gene polymorphisms and their implication in Crohn's disease pathology

M. Iborra1, M. Inés2, J. Panés3, J.P. Gisbert4, E. Cabré5, M. Esteve6, A. Cañas-Ventura7, E. García-Planella8, M. Peñalva9, E. Busó10, B. Beltrán1, 1Hospital La Fe, Gastroenterology. CIBEREHD, Valencia, Spain, 2Fundación Investigación Sanitaria Hospital La Fe. CIBEREHD, Valencia, Spain, 3Hospital Clínic i Provincial de Barcelona. CIBEREHD, Gastroenterology, Barcelona, Spain, 4Hospital de la Princesa, Aparato Digestivo, Madrid, Spain, 5Hospital Universitari Germans Trias i Pujol, Gastroenterology, Badalona-Barcelona, Spain, 6Hospital Universitari Mútua de Terrassa, Fundació per la Recerca Mútua de Terrassa. CIBEREHD, Gastroenterology, Terrasa-Barcelona, Spain, 7Hospital del Mar, Gastroenterology, Barcelona, Spain, 8Hospital de la Santa Creu i Sant Pau, Gastroenterology, Barcelona, Spain, 9Hospital Universitari de Bellvitge, Gastroenterology, Hospitalet de Llobregat-Barcelona, Spain, 10Universitat de Valencia, Unidad Central de Investigación. Facultad de Medicina, Valencia, Spain

Background

We have previously demonstrated that oxidative stress in Crohn's disease (CD) depends on an increased production of H2O2. Catalase (CAT) which should detoxify this radical showed in CD patients a permanent inhibition of activity, protein concentration and gene expression. In contrast, all this showed to be increased in Mn-SOD enzyme but during active disease. Therefore, genetic variations within these antioxidant genes (CAT and Mn-SOD) could be implicated in the pathogenesis of CD. Aims: To determinate whether single nucleotide polymorphisms (SNPs) from CAT and Mn-SOD genes are associated with the risk of CD and their influence of the clinical characteristics.

Methods

Retrospective cohort study based on data obtained from ENEIDA registry. We evaluated a Caucasian Spanish cohort of 414 CD and 576 age-matched healthy controls. Genomic DNA was analyzed for 16 SNPs of the CAT gene (rs1001179, rs1141718, rs12273124, rs17886155, rs2268064, rs2284365, rs3758730, rs475043, rs494024, rs4987023, rs525938, rs564250, rs5746129, rs704724, rs769217 and rs7943316) and for 2 SNPs of Mn-SOD gene (rs2758346 and rs5746096). Genotyping analysis was performed by the Sequenom MassArray® platform. Three genetic models (recessive, log-additive, and co-dominant) were used to statistically quantify the genetic association of the studied SNPs to the frequency of CD adjusting for covariates (age, smoking, sex, disease location, and disease behaviour).

Results

In genotype-association SNP analysis the CAT SNPs rs1001179, rs475043 and rs525938 and the SOD-Mn SNP rs2758346 showed a significant association with CD (p < 0.001). Multivariate analysis using a backwards logistic regression model showed that smoking CD patients with the CAT SNP rs475043 A/G genotype had significantly more often penetrating disease (p = 0.009). Smoking CD patients, who were homozygous T/T carriers of the SOD-Mn SNP rs2758346, had significantly more often non-stricturing, non-penetrating disease (p = 0.023), while that C/T heterozygous CD patients with this SNP had significantly more often stricturing disease (p = 0.014). None of the analyzed SNPs was correlated with disease location, age and sex.

Conclusion

The CAT SNPs rs475043 and rs525938 and the SOD-Mn SNP rs2758346 modulate the susceptibility and the phenotype of CD. Our study proposes a combined genetic, phenotypic, and environmental (smoking) approach in an attempt to better understand the pathogenia of CD.