Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Maroteau C

PROVIDER: S-EPMC10306231 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Maroteau Cyrielle C Siddiqui Moneeza Kalhan MK Veluchamy Abirami A Carr Fiona F White Myra M Cassidy Andrew J AJ Baranova Ekaterina V EV Rasmussen Eva R ER Eriksson Niclas N Bloch Katarzyna M KM Brown Nancy J NJ Bygum Anette A Hallberg Par P Karawajczyk Malgorzata M Magnusson Patrik K E PKE Yue Qun-Ying QY Syvänen Ann-Christine AC von Buchwald Christian C Alfirevic Ana A Maitland-van der Zee Anke H AH Wadelius Mia M Palmer Colin N A CNA

Clinical pharmacology and therapeutics 20200718 6

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 ce ...[more]

PMID: 32496628

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Project description:Angioedema is a relatively rare but potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). As with hereditary forms of angioedema (HAE), this adverse reaction is mediated by bradykinin. Research suggests that ACEi/ARB-induced angioedema has a multifactorial etiology. In addition, recent case reports suggest that some ACEi/ARB-induced angioedema patients may carry pathogenic HAE variants. The aim of the present study was to investigate the possible association between ACEi/ARB-induced angioedema and HAE genes via systematic molecular genetic screening in a large cohort of ACEi/ARB-induced angioedema cases. Targeted re-sequencing of five HAE-associated genes (SERPING1, F12, PLG, ANGPT1, and KNG1) was performed in 212 ACEi/ARB-induced angioedema patients recruited in Germany/Austria, Sweden, and Denmark, and in 352 controls from a German cohort. Among patients, none of the identified variants represented a known pathogenic variant for HAE. Moreover, no significant association with ACEi/ARB-induced angioedema was found for any of the identified common [minor allele frequency (MAF) >5%] or rare (MAF < 5%) variants. However, several non-significant trends suggestive of possible protective effects were observed. The lowest p-value for an individual variant was found in PLG (rs4252129, p.R523W, p = 0.057, p.adjust > 0.999, Fisher's exact test). Variant p.R523W was found exclusively in controls and has previously been associated with decreased levels of plasminogen, a precursor of plasmin which is part of a pathway directly involved in bradykinin production. In addition, rare, potentially functional variants (MAF < 5%, Phred-scaled combined annotation dependent depletion score >10) showed a nominally significant enrichment in controls both: 1) across all five genes; and 2) in the F12 gene alone. However, these results did not withstand correction for multiple testing. In conclusion, our results suggest that HAE-associated mutations are, at best, a rare cause of ACEi/ARB-induced angioedema. Furthermore, we were unable to identify a significant association between ACEi/ARB-induced angioedema and other variants in the investigated genes. Further studies with larger sample sizes are warranted to draw more definite conclusions concerning variants with limited effect sizes, including protective variants.

Project description:Rationale & objectiveThe use of renin-angiotensin system (RAS) inhibitors is standard of care in people with early to moderate chronic kidney disease (CKD). Less is known regarding the efficacy of RAS inhibitors in very advanced CKD. In this study, we describe patterns of use of RAS inhibitors and associations of these patterns of use with risk for CKD progression and mortality in patients with advanced CKD.Study designPropensity-matched cohort study.Settings & participantsWe identified 678 participants who were enrolled in the multicenter Chronic Renal Insufficiency Cohort (CRIC) Study with estimated glomerular filtration rates (eGFRs) < 30 mL/min/1.73 m2 at the baseline visit.ExposureUse of RAS inhibitors within the first year after the baseline visit, characterized by 4 patterns of use: never users, always users, dynamic users, and new users.OutcomesProgression to end-stage renal disease (ESRD) and all-cause mortality.Analytical approachWe generated propensity scores and matched participants in the always users group with a 1:1 ratio with a participant from the other 3 groups, matching by age, sex, race, diabetes, hypertension, systolic blood pressure, eGFR, urinary protein-creatinine ratio, and serum potassium level. Cox models were used to test the association of patterns of RAS inhibitor use with risk for kidney failure and death.ResultsOf the 678 participants with eGFRs < 30 mL/min/1.73 m2, 57% were identified as always users of RAS inhibitors during the 1 year, 23% as never users, 13% as dynamic users, and 7% as new users. We found no differences in risk for ESRD across patterns of RAS inhibitor use (never users [HR, 1.09; 95% CI, 0.71-1.67], dynamic users [HR, 1.46; 95% CI, 0.83-2.55], new users [HR, 0.78; 95% CI, 0.33-1.84] vs the always users reference group). Similarly, there was no association of patterns of RAS inhibitor use with death (never users [HR, 1.02; CI, 0.74-1.40], dynamic users [HR, 1.23; 95% CI, 0.80-1.90], new users [HR, 1.10; 95% CI, 0.63-1.92] vs always users).LimitationsObservational study.ConclusionsUse of RAS inhibitors in patients with eGFRs < 30 mL/min/1.73 m2 is heterogeneous..We found no difference in risk for progression to ESRD or mortality across patterns of RAS inhibitor use. Further research is required to identify optimal prescribing strategies of RAS inhibitors during advanced stages of CKD.

Project description:Background:Angiotensin-converting enzyme inhibitors/angiotensin receptor blocker (ACE-I/ARB) improve outcomes in patients with heart failure and reduced left-ventricular (LV) systolic function. However, these medications can cause a rise in serum creatinine and their benefits in patients with HF accompanied by kidney disease are less certain. Objective:To characterize associations between estimated glomerular filtration rate (eGFR), patterns of ACE-Is and ARBs use, and 1-year survival following hospitalization for heart failure (HF). Design:We formed a retrospective cohort study of patients admitted with HF and followed HF medication prescriptions using the pharmaceutical information network, stratified by discharge eGFR. Setting:Cardiology services in 3 centers in Southern Alberta, Canada. Patients:The study cohort included patients admitted to hospital with a clinical diagnosis of HF. Measurements:eGFR was determined from inpatient laboratory data prior to discharge. Outpatient prescription data prior to and following the index hospitalization was obtained using the Pharmaceutical Information Network of Alberta and survival was determined from provincial vital statistics. Methods:Characteristics of the HF cohort were obtained from the Admissions Module of the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) database. Multivariable Cox proportional hazards models were used to evaluate the association between time-varying ACE-I/ARB use, and mortality, and to test whether eGFR modified this association. Results:Totally, 1404 patients were included. Within the first 3 months following discharge, ACE-I/ARBs were used in 71%, 67%, 62%, and 52% for those with eGFR > 90, 45-89, 30-44, and < 30 mL/min/1.73 m2, respectively, with differences in use persisting after 1 year of follow-up. Patients with eGFR < 45 mL/min/1.73 m2 had significantly lower rates of ACE-I/ARB use following hospitalization. In adjusted models, ACE-I/ARB use following discharge was associated with 25% lower risk of mortality (Hazard Ratio [HR]: 0.75, 95% confidence interval [CI]: 0.61-0.92; P < 0.01), without evidence that this association differed by eGFR (P = 0.75). Limitations:LV function measurements were not available for the cohort. Due to the observation design of the study, treatment-selection bias may be present. Conclusion:Patients with HF and reduced eGFR at time of hospital discharge were less likely to receive ACE-I/ARB despite these medications being associated with lower mortality independent of eGFR. These findings demonstrate the need for further research on strategies for safe use of ACE-I and ARB in patients with HF and kidney disease.

Dataset Information

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

Publications

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

Similar Datasets

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