Abstract 360: Genetic Variants Associated With ACE Inhibitor-Associated Angioedema
We conducted a genomewide association study in 179 individuals with ACE inhibitor-associated angioedema and 489 ACE inhibitor-exposed controls from Nashville, TN and Marshfield, WI. We performed a replication study in 19 cases and 57 age-, sex-, and ancestry-matched controls from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). There were no genomewide significant associations (p<5x10-8) of any SNP with angioedema in either African or European Americans. Sixteen SNPs in African Americans and 41 SNPs in European Americans that were moderately associated with angioedema (p<10-4) were evaluated for replication in ONTARGET. The T allele of rs500766, a SNP in the gene encoding for protein kinase C θ, was associated with a reduced risk of angioedema in both the Nashville/Marshfield sample (OR 0.42, 95% CI 0.28-0.63, p=2.97x10-5 in the additive model and OR 0.42, 95% CI 0.26-0.67, p=3.04x10-4 in the dominant model) and in ONTARGET (OR 0.28, 95% CI 0.09-0.89, p=0.030 in the dominant model). The G allele of rs2724635, a SNP in ETS variant gene 6, was associated with increased risk of ACE inhibitor-associated angioedema in both the Nashville/Marshfield sample (OR 2.78, 95%CI 1.67-4.00, p=2.73x10-5 in the additive model; OR 3.23, 95%CI 1.75-6.25, p=2.11x10-4 dominant model; OR 5.56, 95%CI 1.85-16.6, p=2.01x10-3 recessive mode) and in the ONTARGET sample (OR 3.27, 95%CI 1.03-10.35, p=0.044 in the recessive model). We also conducted a candidate-gene study, using the smaller ONTARGET sample for discovery, and the Nashville/Marshfield study for replication. In the candidate gene study, rs989692 in the gene encoding for neprilysin (MME), was significantly associated with angioedema in ONTARGET and in African Americans in the Nashville/Marshfield sample. Variants in genes involved in immune regulation and in neprilysin, an enzyme that degrades bradykinin and substance P, were associated with ACE inhibitor-associated angioedema.
- © 2012 by American Heart Association, Inc.