Pharmacogenetics of ACE Inhibitor-Induced Angioedema and Cough: a Systematic Review and Meta-Analysis

Abstract

Aim: Angioedema and cough are the two most important adverse effects of ACE inhibitors (ACEIs). Evidence exists that ACEI-related angioedema/cough is partly genetically determined and several genes have been identified to play a role in the development of ACEI-related adverse effects. Materials & methods: This study was performed in order to evaluate the evidence of these genetic associations and ACEIs‘ adverse effects. After removing duplicates and critical appraisal, 19 studies were considered to be eligible to review; 14 articles about cough and five articles about angioedema. A separate meta-analysis was performed for the most studied ACE insertion/deletion polymorphism (rs4646994) and its association with cough. Results & conclusion: One gene region (XPNPEP2) was associated with ACEI-induced angioedema in three studies. In our meta-analysis we did not find a significant association between the ACE insertion/deletion polymorphism and ACEI cough.

Original submitted 27 September 2012; Revision submitted 6 December 2012

KEYWORDS::

• ACE I/D
• ACEI
• angioedema
• cough
• meta-analysis

Financial & competing interests disclosure

The Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, has received unrestricted research funding from The Netherlands Organisation for Health Research and Development, the Dutch Health Care Insurance Board, the Royal Dutch Pharmacists Association, the private–public funded Top Institute Pharma (www.tipharma.nl, includes cofunding from universities, government and industry), the EU Innovative Medicines Initiative, EU 7th Framework Program, the Dutch Medicines Evaluation Board, the Dutch Ministry of Health and Industry (including GlaxoSmithKline, Pfizer and others). FW Asselbergs is supported by a clinical fellowship from The Netherlands Organization for Health Research and Development (ZonMw grant 90700342). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

The Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, has received unrestricted research funding from The Netherlands Organisation for Health Research and Development, the Dutch Health Care Insurance Board, the Royal Dutch Pharmacists Association, the private�public funded Top Institute Pharma (www.tipharma.nl, includes cofunding from universities, government and industry), the EU Innovative Medicines Initiative, EU 7th Framework Program, the Dutch Medicines Evaluation Board, the Dutch Ministry of Health and Industry (including GlaxoSmithKline, Pfizer and others). FW Asselbergs is supported by a clinical fellowship from The Netherlands Organization for Health Research and Development (ZonMw grant 90700342). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.