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Alfredo Jose Mansur - One of the best experts on this subject based on the ideXlab platform.
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gender related associations of genetic polymorphisms of α adrenergic Receptors endothelial nitric oxide synthase and Bradykinin B2 Receptor with treadmill exercise test responses
Open Heart, 2014Co-Authors: Rafael Amorim Belo Nunes, Alexandre C Pereira, Jose Eduardo Krieger, Lucia Pereira Barroso, Alfredo Jose MansurAbstract:Background Treadmill exercise test responses have been associated with cardiovascular prognosis in individuals without overt heart disease. Neurohumoral and nitric oxide responses may influence cardiovascular performance during exercise testing. Therefore, we evaluated associations between functional genetic polymorphisms of α-adrenergic Receptors, endothelial nitric oxide synthase, Bradykinin Receptor B2 and treadmill exercise test responses in men and women without overt heart disease. Methods We enrolled 766 (417 women; 349 men) individuals without established heart disease from a check-up programme at the Heart Institute, University of Sao Paulo Medical School. Exercise capacity, chronotropic reserve, maximum heart-rate achieved, heart-rate recovery, exercise systolic blood pressure (SBP), exercise diastolic blood pressure (DBP) and SBP recovery were assessed during exercise testing. Genotypes for the α-adrenergic Receptors ADRA1A Arg347Cys (rs1048101), ADRA2A 1780 C>T (rs553668), ADRA2B Del 301–303 (rs28365031), endothelial nitric synthase (eNOS) 786 T>C (rs2070744), eNOS Glu298Asp (rs1799983) and BK2R (rs5810761) polymorphisms were assessed by PCR and high-resolution melting analysis. Results Maximum SBP was associated with ADRA1A rs1048101 (p=0.008) and BK2R rs5810761 (p=0.008) polymorphisms in men and ADRA2A rs553668 (p=0.008) and ADRA2B rs28365031 (p=0.022) in women. Maximum DBP pressure was associated with ADRA2A rs553668 (p=0.002) and eNOS rs1799983 (p=0.015) polymorphisms in women. Exercise capacity was associated with eNOS rs2070744 polymorphisms in women (p=0.01) and with eNOS rs1799983 in men and women (p=0.038 and p=0.024). Conclusions The findings suggest that genetic variants of α-adrenergic Receptors and Bradykinin B2 Receptor may be involved with blood pressure responses during exercise tests. Genetic variants of endothelial nitric oxide synthase may be involved with exercise capacity and blood pressure responses during exercise tests. These responses may be gender-related.
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exercise induced muscle vasodilatation and genetic polymorphisms of alpha adrenergic Receptors endothelial nitric oxide synthase and Bradykinin Receptor B2 in individuals without overt heart disease
European Heart Journal, 2013Co-Authors: R Belo A Nunes, Alexandre C Pereira, Lucia Pereira Barroso, Maria Urbana P B Rondon, Carlos Eduardo Negrao, Alfredo Jose MansurAbstract:Purpose: Impaired peripheral vasodilatation has been associated with atherosclerosis and cardiovascular disease. The aim of this study was evaluate associations between common genetic polymorphisms of alpha-adrenergic Receptors (ADRA1A, ADRA2A and ADRA2B), endothelial nitric oxide synthase (eNOS) and bradykin Receptor B2 (BK2R) and exercise-induced muscle vasodilatation in men and women without established cardiovascular disease. Methods: We enrolled 766 (417 women and 349 men) individuals without established heart disease that had attended a check-up program at an University Hospital. The muscle vasodilation was studied with venous occlusion plethysmography and determined by the increase of forearm vascular conductance (forearm blood flow/ mean arterial blood pressure) during 3-minute isometric handgrip exercise. Genotypes for the ADRA1A Arg347Cys (rs1048101), ADRA2A C1780T (rs553668), ADRA2B Del 301-303 (rs28365031), eNOS 786T/C (rs2070744), eNOS Glu298Asp (rs1799983) and BK2R (rs5810761) polymorphisms were assessed by polymerase chain reaction (PCR) followed by high resolution melting (HRM) analysis with the Rotor-Gene 6000(®) instrument. Laboratory and demographic data were collected for all participants. Statistical analysis was performed with linear mixed models for women and men. Results: The genotype frequencies were under Hardy-Weinberg equilibrium, except for the ADRA2B Del301-303 polymorphism. The ADRA2A C1780T polymorphism was significantly associated with forearm vascular conductance increase in men. Men with TT genotype have higher muscle vasodilatation than carriers of CT and CC genotypes (P = 0.035). The eNOS 786 T/C polymorphism was significantly associated with forearm vascular conductance increase in women. Women with CC genotype have higher muscle vasodilatation than carriers of TC and TT genotypes (P = 0.029). Conclusions: The polymorphisms ADRA2A C1780T and eNOS 786T/C influenced the exercise-induced muscle vasodilatation in this study. These findings suggest that genetic variants of alpha-adrenergic Receptors and endothelial nitric oxide synthase may be important to regulation of vascular function in apparently healthy individuals and these responses may be gender-related.
Jonas Ghouse - One of the best experts on this subject based on the ideXlab platform.
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association of variants near the Bradykinin Receptor B2 gene with angioedema in patients taking ace inhibitors
Journal of the American College of Cardiology, 2021Co-Authors: Jonas Ghouse, Gustav Ahlberg, Laura Andreasen, Karina Banasik, Soren Brunak, Michael Schwinn, Ina Holst Larsen, Oscar Petersen, Erik SorensenAbstract:Abstract Background Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. Objectives The aim of this study was to identify genetic factors associated with ACE inhibitor–associated angioedema. Methods A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. Results The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor–treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor–treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P Conclusions In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the Bradykinin Receptor B2 gene were associated with increased risk for ACE inhibitor–related angioedema.
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common variants near the Bradykinin Receptor B2 gene are associated with angioedema induced by angiotensin converting enzyme inhibitor treatment a genome wide association study
medRxiv, 2020Co-Authors: Jonas Ghouse, Gustav Ahlberg, Laura Andreasen, Karina Banasik, Soren Brunak, Michael Schwinn, Ina Holst LarsenAbstract:ABSTRACT Objective Angioedema is a rare, but potentially life-threatening adverse reaction, associated with angiotensin-converting-enzyme inhibitors (ACEi). Identification of potential genetic factors related to this adverse event may help identify at-risk patients. Design, Setting and Participants A genome-wide association study (GWAS) involving patients of European descent, all taking ACEi was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as persons with an angioedema event and a filled prescription for an ACEi 180 days prior to the event. Controls were defined as persons with continuous treatment with ACEi without any history of angioedema. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were computed for angioedema risk by logistic mixed model regression analysis. Summary statistics from the discovery and the replication cohorts were analyzed with a fixed effects meta-analysis model. Exposure Single-nucleotide polymorphisms associated with ACEi-associated angioedema. Main outcome Hospital record of angioedema. Results The discovery cohort consisted of 462 cases and 53,391 ACEi-treated controls. The replication cohort consisted of 144 cases and 1,345 ACEi-treated controls. In the discovery cohort, we identified one locus, residing at chromosome 14q32.2, that was associated with angioedema at the genome-wide significance level of P Conclusion In this GWAS, involving individuals treated with ACEi, we found that common variants located in close proximity to the Bradykinin Receptor B2 gene were associated with ACEi-related angioedema. BDKRB2 genotype-directed therapy may aid in improving safety in evidence-based clinical decision-making.
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common variants near the Bradykinin Receptor B2 gene are associated with angioedema induced by angiotensin converting enzyme inhibitor treatment a genome wide association study
medRxiv, 2020Co-Authors: Jonas Ghouse, Gustav Ahlberg, Laura Andreasen, Karina Banasik, Soren Brunak, Michael Schwinn, I H LaursenAbstract:ObjectiveAngioedema is a rare, but potentially life-threatening adverse reaction, associated with angiotensin-converting-enzyme inhibitors (ACEi). Identification of potential genetic factors related to this adverse event may help identify at-risk patients. Design, Setting and ParticipantsA genome-wide association study (GWAS) involving patients of European descent, all taking ACEi was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as persons with an angioedema event and a filled prescription for an ACEi 180 days prior to the event. Controls were defined as persons with continuous treatment with ACEi without any history of angioedema. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were computed for angioedema risk by logistic mixed model regression analysis. Summary statistics from the discovery and the replication cohorts were analyzed with a fixed effects meta-analysis model. ExposureSingle-nucleotide polymorphisms associated with ACEi-associated angioedema. Main outcomeHospital record of angioedema. ResultsThe discovery cohort consisted of 462 cases and 53,391 ACEi-treated controls. The replication cohort consisted of 144 cases and 1,345 ACEi-treated controls. In the discovery cohort, we identified one locus, residing at chromosome 14q32.2, that was associated with angioedema at the genome-wide significance level of P <5 x 10-8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR 1.62; 95 % CI 1.38 to 1.90; P = 4.3 x 10-9). This variant was validated in our replication cohort with similar direction and effect size (OR 1.60; 95 % CI 1.13 to 2.25; P = 7.2 x 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mmHg per T allele; 95 % CI -0.83 to -0.10; P = 0.013) and diastolic blood pressure (-0.26 mmHg per T allele; 95 % CI -0.46 to -0.05; P = 0.013). ConclusionIn this GWAS, involving individuals treated with ACEi, we found that common variants located in close proximity to the Bradykinin Receptor B2 gene were associated with ACEi-related angioedema. BDKRB2 genotype-directed therapy may aid in improving safety in evidence-based clinical decision-making.
Alexandre C Pereira - One of the best experts on this subject based on the ideXlab platform.
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gender related associations of genetic polymorphisms of α adrenergic Receptors endothelial nitric oxide synthase and Bradykinin B2 Receptor with treadmill exercise test responses
Open Heart, 2014Co-Authors: Rafael Amorim Belo Nunes, Alexandre C Pereira, Jose Eduardo Krieger, Lucia Pereira Barroso, Alfredo Jose MansurAbstract:Background Treadmill exercise test responses have been associated with cardiovascular prognosis in individuals without overt heart disease. Neurohumoral and nitric oxide responses may influence cardiovascular performance during exercise testing. Therefore, we evaluated associations between functional genetic polymorphisms of α-adrenergic Receptors, endothelial nitric oxide synthase, Bradykinin Receptor B2 and treadmill exercise test responses in men and women without overt heart disease. Methods We enrolled 766 (417 women; 349 men) individuals without established heart disease from a check-up programme at the Heart Institute, University of Sao Paulo Medical School. Exercise capacity, chronotropic reserve, maximum heart-rate achieved, heart-rate recovery, exercise systolic blood pressure (SBP), exercise diastolic blood pressure (DBP) and SBP recovery were assessed during exercise testing. Genotypes for the α-adrenergic Receptors ADRA1A Arg347Cys (rs1048101), ADRA2A 1780 C>T (rs553668), ADRA2B Del 301–303 (rs28365031), endothelial nitric synthase (eNOS) 786 T>C (rs2070744), eNOS Glu298Asp (rs1799983) and BK2R (rs5810761) polymorphisms were assessed by PCR and high-resolution melting analysis. Results Maximum SBP was associated with ADRA1A rs1048101 (p=0.008) and BK2R rs5810761 (p=0.008) polymorphisms in men and ADRA2A rs553668 (p=0.008) and ADRA2B rs28365031 (p=0.022) in women. Maximum DBP pressure was associated with ADRA2A rs553668 (p=0.002) and eNOS rs1799983 (p=0.015) polymorphisms in women. Exercise capacity was associated with eNOS rs2070744 polymorphisms in women (p=0.01) and with eNOS rs1799983 in men and women (p=0.038 and p=0.024). Conclusions The findings suggest that genetic variants of α-adrenergic Receptors and Bradykinin B2 Receptor may be involved with blood pressure responses during exercise tests. Genetic variants of endothelial nitric oxide synthase may be involved with exercise capacity and blood pressure responses during exercise tests. These responses may be gender-related.
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exercise induced muscle vasodilatation and genetic polymorphisms of alpha adrenergic Receptors endothelial nitric oxide synthase and Bradykinin Receptor B2 in individuals without overt heart disease
European Heart Journal, 2013Co-Authors: R Belo A Nunes, Alexandre C Pereira, Lucia Pereira Barroso, Maria Urbana P B Rondon, Carlos Eduardo Negrao, Alfredo Jose MansurAbstract:Purpose: Impaired peripheral vasodilatation has been associated with atherosclerosis and cardiovascular disease. The aim of this study was evaluate associations between common genetic polymorphisms of alpha-adrenergic Receptors (ADRA1A, ADRA2A and ADRA2B), endothelial nitric oxide synthase (eNOS) and bradykin Receptor B2 (BK2R) and exercise-induced muscle vasodilatation in men and women without established cardiovascular disease. Methods: We enrolled 766 (417 women and 349 men) individuals without established heart disease that had attended a check-up program at an University Hospital. The muscle vasodilation was studied with venous occlusion plethysmography and determined by the increase of forearm vascular conductance (forearm blood flow/ mean arterial blood pressure) during 3-minute isometric handgrip exercise. Genotypes for the ADRA1A Arg347Cys (rs1048101), ADRA2A C1780T (rs553668), ADRA2B Del 301-303 (rs28365031), eNOS 786T/C (rs2070744), eNOS Glu298Asp (rs1799983) and BK2R (rs5810761) polymorphisms were assessed by polymerase chain reaction (PCR) followed by high resolution melting (HRM) analysis with the Rotor-Gene 6000(®) instrument. Laboratory and demographic data were collected for all participants. Statistical analysis was performed with linear mixed models for women and men. Results: The genotype frequencies were under Hardy-Weinberg equilibrium, except for the ADRA2B Del301-303 polymorphism. The ADRA2A C1780T polymorphism was significantly associated with forearm vascular conductance increase in men. Men with TT genotype have higher muscle vasodilatation than carriers of CT and CC genotypes (P = 0.035). The eNOS 786 T/C polymorphism was significantly associated with forearm vascular conductance increase in women. Women with CC genotype have higher muscle vasodilatation than carriers of TC and TT genotypes (P = 0.029). Conclusions: The polymorphisms ADRA2A C1780T and eNOS 786T/C influenced the exercise-induced muscle vasodilatation in this study. These findings suggest that genetic variants of alpha-adrenergic Receptors and endothelial nitric oxide synthase may be important to regulation of vascular function in apparently healthy individuals and these responses may be gender-related.
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vascular reactivity and ace activity response to exercise training are modulated by the 9 9 Bradykinin B2 Receptor gene functional polymorphism
Physiological Genomics, 2013Co-Authors: Cleber Rene Alves, Guilherme Barreto Alves, Alexandre C Pereira, Ivani C Trombetta, Rodrigo Goncalves Dias, Gloria F Mota, Tiago Fernandes, Jose Eduardo Krieger, C E Negrao, Edilamar Menezes De OliveiraAbstract:The Bradykinin Receptor B2 (BDKRB2) gene +9/−9 polymorphism has been associated with higher gene transcriptional activity, and characteristics of cardiovascular phenotypes and physical performance....
Lucia Pereira Barroso - One of the best experts on this subject based on the ideXlab platform.
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gender related associations of genetic polymorphisms of α adrenergic Receptors endothelial nitric oxide synthase and Bradykinin B2 Receptor with treadmill exercise test responses
Open Heart, 2014Co-Authors: Rafael Amorim Belo Nunes, Alexandre C Pereira, Jose Eduardo Krieger, Lucia Pereira Barroso, Alfredo Jose MansurAbstract:Background Treadmill exercise test responses have been associated with cardiovascular prognosis in individuals without overt heart disease. Neurohumoral and nitric oxide responses may influence cardiovascular performance during exercise testing. Therefore, we evaluated associations between functional genetic polymorphisms of α-adrenergic Receptors, endothelial nitric oxide synthase, Bradykinin Receptor B2 and treadmill exercise test responses in men and women without overt heart disease. Methods We enrolled 766 (417 women; 349 men) individuals without established heart disease from a check-up programme at the Heart Institute, University of Sao Paulo Medical School. Exercise capacity, chronotropic reserve, maximum heart-rate achieved, heart-rate recovery, exercise systolic blood pressure (SBP), exercise diastolic blood pressure (DBP) and SBP recovery were assessed during exercise testing. Genotypes for the α-adrenergic Receptors ADRA1A Arg347Cys (rs1048101), ADRA2A 1780 C>T (rs553668), ADRA2B Del 301–303 (rs28365031), endothelial nitric synthase (eNOS) 786 T>C (rs2070744), eNOS Glu298Asp (rs1799983) and BK2R (rs5810761) polymorphisms were assessed by PCR and high-resolution melting analysis. Results Maximum SBP was associated with ADRA1A rs1048101 (p=0.008) and BK2R rs5810761 (p=0.008) polymorphisms in men and ADRA2A rs553668 (p=0.008) and ADRA2B rs28365031 (p=0.022) in women. Maximum DBP pressure was associated with ADRA2A rs553668 (p=0.002) and eNOS rs1799983 (p=0.015) polymorphisms in women. Exercise capacity was associated with eNOS rs2070744 polymorphisms in women (p=0.01) and with eNOS rs1799983 in men and women (p=0.038 and p=0.024). Conclusions The findings suggest that genetic variants of α-adrenergic Receptors and Bradykinin B2 Receptor may be involved with blood pressure responses during exercise tests. Genetic variants of endothelial nitric oxide synthase may be involved with exercise capacity and blood pressure responses during exercise tests. These responses may be gender-related.
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exercise induced muscle vasodilatation and genetic polymorphisms of alpha adrenergic Receptors endothelial nitric oxide synthase and Bradykinin Receptor B2 in individuals without overt heart disease
European Heart Journal, 2013Co-Authors: R Belo A Nunes, Alexandre C Pereira, Lucia Pereira Barroso, Maria Urbana P B Rondon, Carlos Eduardo Negrao, Alfredo Jose MansurAbstract:Purpose: Impaired peripheral vasodilatation has been associated with atherosclerosis and cardiovascular disease. The aim of this study was evaluate associations between common genetic polymorphisms of alpha-adrenergic Receptors (ADRA1A, ADRA2A and ADRA2B), endothelial nitric oxide synthase (eNOS) and bradykin Receptor B2 (BK2R) and exercise-induced muscle vasodilatation in men and women without established cardiovascular disease. Methods: We enrolled 766 (417 women and 349 men) individuals without established heart disease that had attended a check-up program at an University Hospital. The muscle vasodilation was studied with venous occlusion plethysmography and determined by the increase of forearm vascular conductance (forearm blood flow/ mean arterial blood pressure) during 3-minute isometric handgrip exercise. Genotypes for the ADRA1A Arg347Cys (rs1048101), ADRA2A C1780T (rs553668), ADRA2B Del 301-303 (rs28365031), eNOS 786T/C (rs2070744), eNOS Glu298Asp (rs1799983) and BK2R (rs5810761) polymorphisms were assessed by polymerase chain reaction (PCR) followed by high resolution melting (HRM) analysis with the Rotor-Gene 6000(®) instrument. Laboratory and demographic data were collected for all participants. Statistical analysis was performed with linear mixed models for women and men. Results: The genotype frequencies were under Hardy-Weinberg equilibrium, except for the ADRA2B Del301-303 polymorphism. The ADRA2A C1780T polymorphism was significantly associated with forearm vascular conductance increase in men. Men with TT genotype have higher muscle vasodilatation than carriers of CT and CC genotypes (P = 0.035). The eNOS 786 T/C polymorphism was significantly associated with forearm vascular conductance increase in women. Women with CC genotype have higher muscle vasodilatation than carriers of TC and TT genotypes (P = 0.029). Conclusions: The polymorphisms ADRA2A C1780T and eNOS 786T/C influenced the exercise-induced muscle vasodilatation in this study. These findings suggest that genetic variants of alpha-adrenergic Receptors and endothelial nitric oxide synthase may be important to regulation of vascular function in apparently healthy individuals and these responses may be gender-related.
Laura Andreasen - One of the best experts on this subject based on the ideXlab platform.
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association of variants near the Bradykinin Receptor B2 gene with angioedema in patients taking ace inhibitors
Journal of the American College of Cardiology, 2021Co-Authors: Jonas Ghouse, Gustav Ahlberg, Laura Andreasen, Karina Banasik, Soren Brunak, Michael Schwinn, Ina Holst Larsen, Oscar Petersen, Erik SorensenAbstract:Abstract Background Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. Objectives The aim of this study was to identify genetic factors associated with ACE inhibitor–associated angioedema. Methods A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. Results The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor–treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor–treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P Conclusions In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the Bradykinin Receptor B2 gene were associated with increased risk for ACE inhibitor–related angioedema.
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common variants near the Bradykinin Receptor B2 gene are associated with angioedema induced by angiotensin converting enzyme inhibitor treatment a genome wide association study
medRxiv, 2020Co-Authors: Jonas Ghouse, Gustav Ahlberg, Laura Andreasen, Karina Banasik, Soren Brunak, Michael Schwinn, Ina Holst LarsenAbstract:ABSTRACT Objective Angioedema is a rare, but potentially life-threatening adverse reaction, associated with angiotensin-converting-enzyme inhibitors (ACEi). Identification of potential genetic factors related to this adverse event may help identify at-risk patients. Design, Setting and Participants A genome-wide association study (GWAS) involving patients of European descent, all taking ACEi was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as persons with an angioedema event and a filled prescription for an ACEi 180 days prior to the event. Controls were defined as persons with continuous treatment with ACEi without any history of angioedema. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were computed for angioedema risk by logistic mixed model regression analysis. Summary statistics from the discovery and the replication cohorts were analyzed with a fixed effects meta-analysis model. Exposure Single-nucleotide polymorphisms associated with ACEi-associated angioedema. Main outcome Hospital record of angioedema. Results The discovery cohort consisted of 462 cases and 53,391 ACEi-treated controls. The replication cohort consisted of 144 cases and 1,345 ACEi-treated controls. In the discovery cohort, we identified one locus, residing at chromosome 14q32.2, that was associated with angioedema at the genome-wide significance level of P Conclusion In this GWAS, involving individuals treated with ACEi, we found that common variants located in close proximity to the Bradykinin Receptor B2 gene were associated with ACEi-related angioedema. BDKRB2 genotype-directed therapy may aid in improving safety in evidence-based clinical decision-making.
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common variants near the Bradykinin Receptor B2 gene are associated with angioedema induced by angiotensin converting enzyme inhibitor treatment a genome wide association study
medRxiv, 2020Co-Authors: Jonas Ghouse, Gustav Ahlberg, Laura Andreasen, Karina Banasik, Soren Brunak, Michael Schwinn, I H LaursenAbstract:ObjectiveAngioedema is a rare, but potentially life-threatening adverse reaction, associated with angiotensin-converting-enzyme inhibitors (ACEi). Identification of potential genetic factors related to this adverse event may help identify at-risk patients. Design, Setting and ParticipantsA genome-wide association study (GWAS) involving patients of European descent, all taking ACEi was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as persons with an angioedema event and a filled prescription for an ACEi 180 days prior to the event. Controls were defined as persons with continuous treatment with ACEi without any history of angioedema. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were computed for angioedema risk by logistic mixed model regression analysis. Summary statistics from the discovery and the replication cohorts were analyzed with a fixed effects meta-analysis model. ExposureSingle-nucleotide polymorphisms associated with ACEi-associated angioedema. Main outcomeHospital record of angioedema. ResultsThe discovery cohort consisted of 462 cases and 53,391 ACEi-treated controls. The replication cohort consisted of 144 cases and 1,345 ACEi-treated controls. In the discovery cohort, we identified one locus, residing at chromosome 14q32.2, that was associated with angioedema at the genome-wide significance level of P <5 x 10-8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR 1.62; 95 % CI 1.38 to 1.90; P = 4.3 x 10-9). This variant was validated in our replication cohort with similar direction and effect size (OR 1.60; 95 % CI 1.13 to 2.25; P = 7.2 x 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mmHg per T allele; 95 % CI -0.83 to -0.10; P = 0.013) and diastolic blood pressure (-0.26 mmHg per T allele; 95 % CI -0.46 to -0.05; P = 0.013). ConclusionIn this GWAS, involving individuals treated with ACEi, we found that common variants located in close proximity to the Bradykinin Receptor B2 gene were associated with ACEi-related angioedema. BDKRB2 genotype-directed therapy may aid in improving safety in evidence-based clinical decision-making.