Genetic Screening of C2399A SNP associated with the XPNPEP2 gene in South African hypertensive, ACE inhibitor induced angioedema in patients and controls

Joalice Stark2, Raymond Moholisa1, Ed Sturrock1, Brian Rayner1, Elizabeth Owen1. 1University of Cape Town, Cape Town, South Africa, 2Brighton & Sussex Medical School, Royal Sussex County Hospital, Brighton, United Kingdom.

Angiotensin converting enzyme inhibitors (ACEi) are an important class of drugs widely used by more than 40 million patients worldwide. They are used as standard treatments for hypertension, congestive cardiac failure and diabetes. Angioedema is an adverse effect associated the use of ACEi which is significantly more common in Black and Coloured South Africans than in the Caucasian population. This serious adverse effect is frequently life-threatening and fatal. The use of ACEi such as enalapril precipitates severe anaphylactic reactions which are induced by activation of bradykinin, a vasodilatory and pro-inflammatory nonapeptide. Angioedema may only be associated with the use of enalapril and not other classes of ACEi such as perindopril or ramipril. The incidence of ACEi associated angioedema (AEi) as a life-threatening adverse effect has been associated with a Single Nucleotide Polymorphism (SNP) C2399A in the XPNPEP2 gene which encodes membrane bound Aminopeptidase (APP) enzyme1.

The gene is located on the X chromosome. We performed a preliminary investigation to ascertain whether there is any association between AEi and the C2399A SNP genotype in the local Black and Coloured African population in Cape Town, South Africa.

Patients were randomly recruited from the hypertension clinic at Groote Schuur Hospital, Cape Town. EDTA blood samples were collected from patients with a known history of AEi caused by enalapril (n=24) and controls with hypertension on enalapril with no incidence of AEi for at least 2 years (n=85). Allele-specific primers were used for the detection of the C or A allele associated with XPNPEP2. Female patients are also being investigated for X-inactivation patterns to detect subtle skewing of the ratio.

To date a total of 24 patients with AEi have been tested, 18 were female (75%), 13 coloured (54%) and 11 (46%) Black African. When compared to controls 29% of Black African and 8% of Coloured patients attending the hypertensive clinic had a history of AEi. There were no gender differences between AEi patients and controls.

All male patients exhibited either A or C allele genotypes. All female patients exhibited CC, AA or CA genotypes. In AEi patients the A allele frequency was 16% in males and 26% in females. In controls the A allele frequency was 33% in males and 28% in females. Lyonisation of the X allele in females is still being investigated.

In conclusion, more female than male and more Black African than Coloured patients presented with enalapril induced angioedema at the hypertensive clinic in Cape Town South Africa. Preliminary results indicate no association with C2399A in the XPNPEP2 gene to angioedema in these patients.

Qing LD, et al., A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors. Am J Hum Genet, 2005. 77: p. 617-626.