Angiotensinogen and transforming growth factor β1:: novel genes in the pathogenesis of Crohn's disease

Background: Angiotensin peptides may act locally as cytokines in several organ systems with elevated mucosal levels present in Crohn's disease. A variant in the angiotensinogen gene promoter results in increased peptide production, while transforming growth factor b1 (TGFb1) codon 25 variants demonstrate variable peptide production, predisposing to fibrosis in several organs. Aims: Conduct an Australian-based analysis of the angiotensinogen-6 variant in two independent inflammatory bowel disease (IBD) cohorts, and examine the role of angiotensinogen-6 and TGFb1 codon 25 variants in shaping Crohn's disease phenotype. Methods: IBD Patients (Crohn's disease = 347, ulcerative colitis = 147) and CD families (n = 148) from two cohorts, together with 185 healthy controls were genotyped for angiotensinogen-6. Genotype-phenotype analyses were performed for both angiotensinogen-6 and TGFb1 codon 25. Results: Angiotensinogen-6 AA genotype was significantly associated with Crohn's disease (p = 0.007, OR = 2.38, CI = 1.32-4.32) in cohort 1, but not in the smaller cohort 2 (p = 0.19). The association remained significant when the two cohorts were combined (p = 0.008), and in a TDT family analysis (p = 0.03). TGF 1 codon 25 was associated with stricturing Crohn's disease (p = 0.01, OR = 2.63, CI = 1.16 5.88) and a shorter time to intestinal resection (p = 0.06). Conclusions: The association of the angiotensinogen-6 variant with Crohn's disease supports a potential role for angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in disease treatment.