IgE-Mediated Systemic Anaphylaxis And Its Association With Gene Polymorphisms Of ACE, Angiotensinogen And Chymase

Abstract

Background

The renin-angiotensin system (RAS) protects the circulation against sudden falls in systemic blood pressure via generation of angiotensin II (AII). Previously, we demonstrated that patients with anaphylaxis involving airway angioedema and cardiovascular collapse (AACVS) had significantly increased “I” gene polymorphisms of the angiotensin-converting-enzymes (ACE). This is associated with lower serum ACE and AII levels and was not seen in anaphylaxis without collapse nor atopics and healthy controls.

Objectives

To examine the angiotensinogen (AGT-M235T) and chymase gene (CMA-1 A1903G) polymorphisms in these original subjects.

Method

122 patients with IgE-mediated anaphylaxis, 119 healthy controls and 52 atopics had polymorphisms of the AGT gene and chymase gene examined by polymerase chain reactions and gel electrophoresis. Their previous ACE genotypes were included for the analysis.

Results

AGT-MM genes (associated with low AGT levels) were significantly increased in anaphylaxis (Terr’s classification). When combined with ACE, anaphylaxis showed increased MM/II gene pairing (p<0.0013) consistent with lower RAS activity. For chymase, there was increased pairing of MM/AG (p<0.005) and AG/II and AG/ID (p<0.0073) for anaphylaxis consistent with lower RAS activity. A tri-allelic ensemble of the 6 commonest gene combinations for the healthy controls and anaphylaxis confirmed this difference (p=0.0001); for anaphylaxis, genes were predominately MM/AG/II or ID, while healthy controls were DD/MT/AG or GG patterns.

Conclusion

Our gene polymorphisms show lower RAS activity for anaphylaxis especially AACVS. Animal models of anaphylaxis are focused on endothelial nitric oxide (eNO) which is shown to be the mediator of fatal shock and prevented by eNO-blockade. The interaction of AII and eNO controls the microcirculation in man. High serum AII levels reduce eNO activity, so higher RAS-activity could protect against shock. Our data shows low RAS activity in anaphylaxis especially AACVS, suggesting the influence of these genes on shock are via AII levels and its effects on eNO.

Keywords:

• IgE-mediated anaphylaxis
• angiotensinogen M235T
• chymase CMA1-1903
• angioedema
• ACE genotype
• endothelial nitric oxide

Acknowledgments

The authors thank Irina Chisster for statistical analysis and advice. This study received funding from the R&D department at St Helier Hospital. A Warner is currently affiliated with Allergy UK Charity and N Sumar is currently affiliated with Centre for Clinical Education, Institute of Medical & Biomedical Education, St Georges University of London.

Abbreviations

ACE, angiotensin-converting enzyme; HC, healthy controls; AACVS, airway angioedema & cardiovascular collapse; CRA, cutaneous & mild respiratory anaphylaxis; BK, bradykinin; AI, angiotensin-1; AII, angiotensin-2; RAS, renin-angiotensin system; AGT, angiotensinogen; CMA-1 1903, Chymase gene polymorphisms; alpha-2M, alpha-2-macroglobulin; IgE, immunoglobulin E; BP, blood pressure; BMI, body mass index; DNA, deoxyribonucleic acid; ATR₁- receptor, angiotensin-II receptor-1; ACEI, angiotensin-converting enzyme inhibitor; eNO, endothelial nitric oxide.

Disclosure

The authors report no conflicts of interest in this work.