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Angiotensinogen and transforming growth factor β1: novel genes in the pathogenesis of Crohn’s disease
  1. G E Hume1,
  2. E V Fowler1,
  3. D Lincoln2,
  4. R Eri1,
  5. D Templeton3,
  6. T H Florin4,
  7. J A Cavanaugh5,
  8. G L Radford-Smith3
  1. 1Crohn’s and Colitis Laboratory, Clinical Research Centre, Royal Brisbane & Women’s Hospital Research Foundation, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
  2. 2Cancer & Population Studies, Queensland Institute of Medical Research, Brisbane
  3. 3Department of Gastroenterology, Royal Brisbane & Women’s Hospital, Brisbane
  4. 4Department of Gastroenterology, Mater Adult Hospital, South Brisbane, Australia
  5. 5Medical Genetics Research Unit, ANU Medical School, Canberra Hospital, Woden, Australia
  1. Correspondence to:
 G E Hume
 Department of Gastroenterology, Royal Brisbane & Women’s Hospital, Brisbane, Queensland 4029, Australia;georgiaH{at}qimr.edu.au

Abstract

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 β1 (TGFβ1) 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 TGFβ1 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 TGFβ1 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.

  • ACE, angiotensin-converting enzyme
  • AII, angiotensin II
  • IBD, inflammatory bowel disease
  • PCR, polymerase chain reaction
  • RBWH, Royal Brisbane and Women’s Hospital
  • TNBS, trinitrobenzene sulphonic acid
  • TDT, transmission disequilibrium test
  • TGFβ1, transforming growth factor β1
  • TNFα, tumour necrosis factor α

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Footnotes

  • Funding: GEH is supported by an NH&MRC postgraduate medical scholarship; EVF is supported by the Reginald Ferguson Fellowship, University of Queensland; DT is supported by a research grant from Pfizer Australia; and GLR-S is supported by a Practioner Fellowship from the Queensland Institute of Medical Research and the Royal Brisbane and Womens Hospital Research Foundation.

  • Competing interests: None.

  • Ethical approval: The necessary ethics committee approval was obtained for the study.

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