ORPHA: 100057, 91385;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq26.1 | {Angioedema induced by ACE inhibitors, susceptibility to} | 300909 | 3 | XPNPEP2 | 300145 |
A number sign (#) is used with this entry because of evidence that susceptibility to angioedema induced by angiotensin-converting enzyme (ACE; 106280) inhibitors (AEACEI) is conferred by variation in the XPNPEP2 gene (300145) on chromosome Xq25.
Approximately 40 million people take ACE inhibitors (ACEi) to treat hypertension and cardiovascular disease. A small proportion of white patients who take ACEi (0.1-0.7%) develop angioedema (AEACEI) (Israili and Hall, 1992; Vleeming et al., 1998), a potentially life-threatening side effect characterized by swelling of the face, lips, tongue, and airway that can lead to suffocation and death if severe. ACEi-associated angioedema is 4 to 5 times more prevalent among African Americans (Brown et al., 1996; Coats, 2002). Other risk factors include female sex, smoking, immunosuppressant therapy, and seasonal allergies. The pathophysiology of ACEi-associated angioedema is thought to be related to increased circulating bradykinin, which is normally degraded by ACE. During pharmacologic ACE inhibition, bradykinin is primarily degraded by aminopeptidase P (summary by Duan et al., 2005 and Woodard-Grice et al., 2010). Aminopeptidase P is encoded by 3 genes: XPNPEP1 (602443) on chromosome 10q25, XPNPEP2 (300145) on chromosome Xq25, and XPNPEP3 (613553) on chromosome 22q13.
Blais et al. (1999) and Adam et al. (2002) reported significantly lower plasma aminopeptidase P (APP) activities in patients with a history of AEACEI. Adam et al. (2002) found significantly decreased plasma activity of aminopeptidase P among 39 hypertensive patients with a history of ACEi-induced angioedema compared to 39 hypertensive patients who did not have ACEi-associated side effects (p = 0.003), suggesting that decreased concentrations of aminopeptidase P may be a predisposing factor to developing the disorder. Among 20 unrelated individuals with ACEi-associated angioedema, Duan et al. (2005) found that the mean plasma activity of aminopeptidase P was decreased compared to controls, but a third of affected individuals had normal or high plasma activity, suggesting that additional risk factors are involved in determining risk for this type of angioedema.
By genomewide linkage analysis of 8 large pedigrees in which 1 individual had ACEi-associated angioedema, Duan et al. (2005) found significant linkage (lod of 3.75) to a locus on the X chromosome that included the XPNPEP2 candidate gene. Patient analysis identified a large coding deletion segregating in 1 pedigree and an upstream SNP, C-2399A (300145.0001) (rs3788853), that segregated in the remaining 7 pedigrees. Measured genotype analysis strongly suggested that the linkage signal for APP activity at this locus was accounted for predominantly by the SNP association. Four affected males carried the A allele, 1 affected male carried the C allele, 1 affected female had a C/C genotype, and 1 affected female had the C/A genotype. Duan et al. (2005) concluded that this represented a significant association of this SNP to ACEi-induced angioedema. Among 20 unrelated patients with ACEi-associated angioedema, there was an association between decreased plasma activity of aminopeptidase P and the A allele. Eight of 20 cases carried the A allele, either in the hemizygous, heterozygous, or homozygous state (frequency of 27.3%) compared to 11 of 60 controls (frequency of 11.1%; p = 0.0364). The findings indicated that variable plasma aminopeptidase activity is partially regulated by genetic factors, with about 34% of phenotypic variation resulting from genotypic differences, and Duan et al. (2005) suggested that variation in the XPNPEP2 gene may specifically contribute to the development of ACEi-associated angioedema.
Woodard-Grice et al. (2010) found that no difference in serum APP activity between 169 cases with a history of ACE inhibitor-associated angioedema and 397 ACE inhibitor-exposed controls. There was a significant association between the -2399A allele and decreased serum APP activity in both men and women, but the APP activity was lower in men regardless of genotype. There was no association between -2399C-A genotype and case-control status in women. However, there was an association between the A allele and ACEi-associated angioedema among men, which was attributed mainly to African American race. The frequency of the A allele in African American men with a history of angioedema was 31.3%, whereas it was 13.3% in ACEi-exposed African American men who did not develop the disorder. Multivariant analysis confirmed this race effect among men. Woodard-Grice et al. (2010) concluded that it is unlikely that variation in the XPNPEP2 gene accounts for the majority of ACEi-associated angioedema.
In a case-control study of 34 individuals with ACEi-induced angioedema and 127 control samples, Cilia La Corte et al. (2011) found that an ATG haplotype in the 5-prime region of the XPNPEP2 gene (c.-2399C-A; 300145.0001; c.-1612G-T; and c.-393G-A) was significantly associated with the disorder (odds ratio of 4.87, p = 0.002). This haplotype was associated with decreased plasma APP activity and decreased luciferase gene expression compared to other haplotypes of these SNPs. Cilia La Corte et al. (2011) concluded that the ATG haplotype of XPNPEP2 is functional and contributes to the development of ACEi-angioedema through a reduction in APP activity.
Adam, A., Cugno, M., Molinaro, G., Perez, M., Lepage, Y., Agostini, A. Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors. Lancet 359: 2088-2089, 2002. [PubMed: 12086766] [Full Text: https://doi.org/10.1016/S0140-6736(02)08914-6]
Blais, C., Jr., Marc-Aurele, J., Simmons, W. H., Loute, G., Thibault, P., Skidgel, R. A., Adam, A. Des-Arg9-bradykinin metabolism in patients who presented hypersensitivity reactions during hemodialysis: role of serum ACE and aminopeptidase P. Peptides 20: 421-430, 1999. [PubMed: 10458510] [Full Text: https://doi.org/10.1016/s0196-9781(99)00020-0]
Brown, N. J., Ray, W. A., Snowden, M., Griffin, M. R. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin. Pharm. Ther. 60: 8-13, 1996. [PubMed: 8689816] [Full Text: https://doi.org/10.1016/S0009-9236(96)90161-7]
Cilia La Corte, A. L., Carter, A. M., Rice, G. I., Duan, Q. L., Rouleau, G. A., Adam, A., Grant, P. J., Hooper, N. M. A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor-induced angioedema. Hum. Mutat. 32: 1326-1331, 2011. [PubMed: 21898657] [Full Text: https://doi.org/10.1002/humu.21579]
Coats, A. J. S. Omapatrilat--the story of overture and octave. Int. J. Cardiol. 86: 1-4, 2002. [PubMed: 12243845] [Full Text: https://doi.org/10.1016/s0167-5273(02)00389-3]
Duan, Q. L., Nikpoor, B., Dube, M.-P., Molinaro, G., Meijer, I. A., Dion, P., Rochefort, D., Saint-Onge, J., Flury, L., Brown, N. J., Gainer, J. V., Rouleau, J. L., and 12 others. A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors. Am. J. Hum. Genet. 77: 617-626, 2005. [PubMed: 16175507] [Full Text: https://doi.org/10.1086/496899]
Israili, Z. H., Hall, W. D. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology. Ann. Intern. Med. 117: 234-242, 1992. [PubMed: 1616218] [Full Text: https://doi.org/10.7326/0003-4819-117-3-234]
Vleeming, W., van Amsterdam, J. G. C., Stricker, B. H. C., de Wildt, D. J. ACE inhibitor-induced angioedema: incidence, prevention and management. Drug. Saf. 18: 171-188, 1998. [PubMed: 9530537] [Full Text: https://doi.org/10.2165/00002018-199818030-00003]
Woodard-Grice, A. V., Lucisano, A. C., Byrd, J. B., Stone, E. R., Simmons, W. H., Brown, N. J. Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema. Pharmacogenet. Genomics 20: 532-536, 2010. [PubMed: 20625347] [Full Text: https://doi.org/10.1097/FPC.0b013e32833d3acb]