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073 NOVEL ASSOCIATIONS BETWEEN VARIANTS OF THE ALPHA-1-ANTITRYPSIN GENE AND INFLAMMATORY BOWEL DISEASE A Elkadri, S Lal, J Stempak, A Griffiths, MS Silverberg, AH Steinhart BACKGROUND: Aberrant protease patterns have been demonstrated in the intestinal mucosa and stool of patients with IBD, implicating dysfunction in proteolytic enzymes in disease pathogenesis (See Folwaczny et al, Scand J Gastroenterol 1998). A1AT is one of the major serine protease inhibitors (SERPINs) in human plasma.
Mount Sinai Hospital IBD Centre and The Hospital for Sick Children, University of Toronto, Toronto, Ontario
AIM: To investigate possible associations between 9 single nucleotide polymorphisms (SNPs) of the A1AT gene and phenotypic subgroups of patients with Crohn's disease (CD) and ulcerative colitis (UC).
METHODS: 465 CD patients, 98 UC patients, and 96 healthy, unrelated controls were genotyped for 9 SNPs of A1AT (Chappel et al, Hum Mut 2006). Genotyping was performed using the Sequenom Mass-Array 7K system. Phenotypic classification was performed using the Montreal Classification (Silverberg M et al, Can J Gastro 2005). Chi-squared analysis was performed using SAS.
RESULTS: SNP9 (11377A/G) was found to be associated with both colonic CD (n=59) and UC (n=98); OR 1.909 (P=0.007, 95% CI 1.187-3.072) and 1.546 (P=0.034, 95% CI 1.032-2.316) respectively. SNPs 1 (-1973T/C) and 2 (-1716C/T) were found to be associated with pouchitis in UC (n=12); OR 3.268 (P=0.009, 95% CI 1.295-8.25) and 3.215 (P=0.02, 95% CI 1.153-8.964) respectively. SNP3 (65C/T) was found to be associated with ileal CD (n=150); OR 1.654 (P=0.036, 95% CI 1.031-2.651). All remaining SNPs were found to have no association with CD or UC at any location or phenotypic subgroup including perianal CD.
CONCLUSION: We describe novel associations between polymorphisms of the A1AT gene and IBD. In particular, the 11377A/G variant (SNP9), in our population, influences development of colonic inflammation in IBD with association to both UC and isolated Crohn's colitis. In addition SNPs 1 and 2 were associated with pouchitis in UC and SNP3 was associated with isolated ileal CD. Haplotypes of SNPs 1 and 2 have previously been found to demonstrate increased A1AT functional activity when compared to the wild type haplotype (Chappel et al, Hum Mut 2004). Functional outcomes have yet to be described for SNPs 3 and 9.