Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker-Induced Angioedema.

Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI-induced angioedema (ACEI-AE) or ARB-induced angioedema (ARB-AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI-AE, ARB-AE, and 658 controls) was performed using exome-enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI-AE and ARB-AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89-4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI-AE or ARB-AE, P = 2.09 × 10-3 . A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49-3.27, P = 6.30 × 10-9 ) times the odds of having ACEI-AE or ARB-AE. The increased risk due to the common Leiden allele was confirmed in a genome-wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect-causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI-AE or ARB-AE.

Angioedema Spotlight: A Closer Examination of Sacubitril/Valsartan Safety Results.

Incorporation of neprilysin inhibition into heart failure pharmacotherapy regimens has recently been recommended by U.S. guidelines, based on results from the PARADIGM-HF trial comparing sacubitril/valsartan to enalapril. While most of the discussion has focused on efficacy, a closer examination of the safety results, particularly the incidence of angioedema during the run-in and double-blind periods, is also warranted. Although no major safety concerns were identified, an angioedema risk comparable to enalapril was found, primarily in the black population. Therefore, despite combination with an angiotensin receptor blocker, which historically has a lower incidence of angioedema, the addition of neprilysin inhibition yields an angioedema risk profile comparable to angiotensin converting enzyme (ACE) inhibitors. Clinicians should recognize this safety risk when prescribing sacubitril/valsartan and remain vigilant in counseling patients regarding the signs and symptoms of angioedema. As recommended by the guidelines, avoiding sacubitril/valsartan use concurrently or within 36 hours of the last dose of an ACE inhibitor or in patients with a history of angioedema is also crucial to minimize angioedema risk and prevent patient harm.

Angioedema deaths in the United States, 1979-2010.

BACKGROUND: Hospital admission data indicate that the angioedema incidence has increased during the past several decades. Little is known about mortality trends. OBJECTIVES: To count the number of deaths associated with angioedema in the United States, investigate correlations with age, sex, race, and other contributory causes, and analyze trends from 1979 to 2010. METHODS: All US death certificates in which angioedema was listed as an underlying or contributing cause of death during 1979 to 2010 were analyzed. Age-adjusted mortality rates were analyzed by age, sex, and race. Other conditions designated as the underlying cause of death were investigated. RESULTS: From 1979 to 2010, there were 5,758 deaths in which angioedema was listed as a contributing cause. The age-adjusted death rate for hereditary angioedema decreased from 0.28 (95% confidence interval [CI] 0.25-0.32) to 0.06 (95% CI 0.05-0.08) per million persons per year. Conversely, mortality for angioedema increased from 0.24 (95% CI 0.21-0.27) to 0.34 (95% CI 0.31-0.37) per million. Blacks constituted 55% of angioedema deaths that were associated with use of angiotensin-converting enzyme inhibitors. On death certificates that listed hereditary angioedema as the underlying cause of death, cancer (frequently lymphoma or leukemia) was the second most commonly listed cause. CONCLUSION: Angioedema-associated deaths were very rare from 1979 to 2010. Hereditary angioedema deaths became even more so, whereas nonhereditary angioedema deaths increased. Risks associated with angiotensin-converting enzyme inhibitors were higher in blacks. Lack of specific coding for acquired angioedema most likely explains the observed association between cancer and hereditary angioedema. In the future, more granular coding systems may help distinguish hereditary from acquired angioedema.

Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema.

OBJECTIVE: The objective of this study was to identify genetic variants associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. PARTICIPANTS AND METHODS: We carried out a genome-wide association study in 175 individuals with ACE inhibitor-associated angioedema and 489 ACE inhibitor-exposed controls from Nashville (Tennessee) and Marshfield (Wisconsin). We tested for replication in 19 cases and 57 controls who participated in Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). RESULTS: There were no genome-wide significant associations of any single-nucleotide polymorphism (SNP) with angioedema. Sixteen SNPs in African Americans and 41 SNPs in European Americans were associated moderately with angioedema (P<10) and evaluated for association in ONTARGET. The T allele of rs500766 in PRKCQ was associated with a reduced risk, whereas the G allele of rs2724635 in ETV6 was associated with an increased risk of ACE inhibitor-associated angioedema in the Nashville/Marshfield sample and ONTARGET. In a candidate gene analysis, rs989692 in the gene encoding neprilysin (MME), an enzyme that degrades bradykinin and substance P, was significantly associated with angioedema in ONTARGET and Nashville/Marshfield African Americans. CONCLUSION: Unlike other serious adverse drug effects, ACE inhibitor-associated angioedema is not associated with a variant with a large effect size. Variants in MME and genes involved in immune regulation may be associated with ACE inhibitor-associated angioedema.

Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema.

BACKGROUND: Angioedema is a rare adverse effect of angiotensin-converting enzyme (ACE) inhibitors, which occurs more commonly in women and black Americans. Angioedema is thought to result from decreased degradation of vasoactive peptides. During ACE inhibition, bradykinin is primarily inactivated by aminopeptidase P (APP). Earlier studies have provided conflicting data with regard to serum APP activity in patients with a history of ACE inhibitor-associated angioedema. A single nucleotide polymorphism, -2399C>A (rs3788853, C-2399A), in XPNPEP2, the X-linked gene that encodes membranous APP, has been reported to associate with APP activity. OBJECTIVE: To test the hypothesis that the relationship between XPNPEP2 C-2399A genotype and APP activity or ACE inhibitor-associated angioedema is sex-dependent and race-dependent. METHODS: We compared C-2399A genotype frequencies in 169 cases with a history of ACE inhibitor-associated angioedema and 397 ACE inhibitor-exposed controls. Controls were prespecified to be 50% white, 50% black, and 50% women. Cases and controls were group matched for age and smoking. RESULTS: XPNPEP2 C-2399A genotype associated with serum APP activity in both men and women. Serum APP activity was lower in men than in women, independent of genotype. XPNPEP2 -2399 A/ genotype was associated with an increased risk of angioedema in men [odds ratio 2.17 (1.09-4.32), P=0.03] in multivariate analysis. The A/ genotype was associated with angioedema in black men (P=0.03) but not in white men. CONCLUSION: APP activity is lower in men and the XPNPEP2 C-2399A polymorphism associates with ACE inhibitor-associated angioedema in men but not women.

Angioedema due to ACE inhibitors: increased risk in patients of African origin.

AIMS: To determine patterns in presentation, risk factors, management and outcome of patients with ACE inhibitor associated angioedema in one British teaching hospital. METHODS: Cases of ACE inhibitor associated angioedema in patients presenting to the City Hospital, Birmingham between 1993 and 1999 were collected and entered prospectively onto a computerised register. RESULTS: A total of 20 cases (mean age 60 years, range 42-82 years) of ACE inhibitor associated angioedema were reported (11 female and 9 male) with 65% (n=13) of patients being black/Afro-Caribbean. In 70% of cases (n=14), angioedema occurred within 4 weeks of starting therapy, although three patients presented following long-term treatment (24-48 months). ACE inhibitors were continued in 50% (n=10) patients, despite at least one documented episode of angioedema. Admission to hospital was necessary in 40% (n=8) patients, with three of these admitted to the intensive care unit, and one of these died as a result of severe laryngeal obstruction. CONCLUSIONS: ACE inhibitor related angioedema is a serious and potentially fatal complication which is relatively rare in the general population, but is more common amongst black/Afro-Caribbean patients. ACE inhibitors are frequently continued following an episode of angioedema and it is important that these episodes are minimised by prompt cessation of the drug, careful patient counselling and heightened awareness in all clinicians who prescribe this common group of drugs.

Hereditary angioedema: an unusual case in an African-American woman.

Hereditary angioedema is a rare disorder characterized by a localized subepithelial edema and swelling of the gastrointestinal and upper respiratory tract. The disorder is estimated to occur in 1 in 50,000 to 150,000 individuals. However, the prevalence of the disorder among the African-American population is uncertain. This is a case report of hereditary angioedema occurring in an African-American woman whose symptoms persisted for more than a decade prior to diagnosis.

Increased sensitivity to bradykinin among African Americans.

BACKGROUND: Angioedema is a potentially life-threatening side effect of angiotensin-converting enzyme (ACE) inhibitors. Although the mechanism of angioedema is not certain, bradykinin has been implicated in its pathogenesis. Compared with Caucasians, African Americans are at an increased risk of ACE inhibitor-associated angioedema, independent of ACE inhibitor dose or concurrent medications. Because urinary kallikrein levels are decreased in African Americans with hypertension, we hypothesized that endogenous bradykinin levels may be decreased in African Americans and that they therefore may be more sensitive to ACE inhibitor-induced increases in bradykinin or to exogenous bradykinin. OBJECTIVE: To test this hypothesis, we measured the wheal response to intradermal injection of bradykinin in salt-replete hypertensive and normotensive African Americans and Caucasians. METHODS: Two doses of bradykinin, 1 microgram and 10 micrograms, were administered on separate days in a randomized, double-blind fashion. RESULTS: Higher bradykinin dose (analysis of variance: F = 38.33, p < 0.001), African American race (analysis of variance: F = 17.90, p < 0.001), and hypertension (analysis of variance: F = 4.37, p = 0.05) were all associated with an increased wheal response to bradykinin. CONCLUSION: These data provide additional support for racial differences in the kallikrein-kinin system and also implicate abnormalities of the tissue kallikrein-kinin system in essential hypertension.