scholarly journals Blood Pressure and Risk of Atrial Fibrillation: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Matthew Craig Hyman ◽  
Michael Craig Levin ◽  
Dipender Gill ◽  
Venexia Walker ◽  
Marios K Georgakis ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Blood Pressure ◽  
Calcium Channel ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Summary Statistics ◽  
Uk Biobank ◽  
International Consortium ◽  
The Impact ◽  
The Relationship

Abstract Importance: Observational studies have shown an association between hypertension and atrial fibrillation (AF). Aggressive blood pressure management in patients with known AF reduces overall arrhythmia burden, but it remains unclear whether hypertension is causative for AF. Objective: The primary objective of this study was to investigate the relationship between blood pressure and risk of AF using genetic proxies for blood pressure within a Mendelian randomization (MR) framework. We secondarily explored the relationship between genetically proxied use of anti-hypertensive drugs and risk of AF. Design: Two-sample MR was performed using an inverse-variance weighted meta-analysis with weighted median MR and Egger intercept tests performed as sensitivity analyses. Genetic proxies for the anti-hypertensive drug classes were used to investigate the impact of these therapies on the risk of AF. Setting: International Consortium of Blood Pressure, UK Biobank and Atrial Fibrillation Genetics Consortium. Participants: Summary statistics for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis (>750,000 individuals of European ancestry). Summary statistics for AF were obtained from the 2018 Atrial Fibrillation Genetics Consortium multi-ethnic GWAS (>65,000 AF cases and >522,000 referents). Exposure: Genetically predicted SBP, DBP and PP as quantified by risk scores. Main Outcome: Odds ratio for AF per 10 mmHg increase in genetically proxied blood pressure. Results: Ten mmHg increases in genetically proxied SBP, DBP or PP were associated with increased odds of AF (SBP: OR 1.17, 95% CI 1.11-1.22, p=1x10-11; DBP: OR 1.25, 95% CI 1.16-1.35, p=3x10-8; PP: OR 1.1, 95% CI 1.0-1.2, p=0.05). Ten mmHg decreases in SBP estimated by genetic proxies of anti-hypertensive medications showed calcium channel blockers (OR 0.66, 95% CI 0.57-0.76, p=8x10-9) and beta-blockers (OR 0.61, 95% CI 0.46-0.81, p=6x10-4) decreased the risk of AF. Conclusions and Relevance: Blood pressure-increasing genetic variants were associated with increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction through pharmacologic intervention, and specifically calcium channel blockade or beta blockade could reduce the risk of AF.

scholarly journals Genetically Predicted Blood Pressure and Risk of Atrial Fibrillation

Hypertension ◽  
2021 ◽  
Author(s):  
Matthew C. Hyman ◽  
Michael G. Levin ◽  
Dipender Gill ◽  
Venexia M. Walker ◽  
Marios K. Georgakis ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Calcium Channel ◽  
Diastolic Blood Pressure ◽  
Pulse Pressure ◽  
Mendelian Randomization ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
The Relationship

Observational studies have shown an association between hypertension and atrial fibrillation (AF). Aggressive blood pressure management in patients with known AF reduces overall arrhythmia burden, but it remains unclear whether hypertension is causative for AF. To address this question, this study explored the relationship between genetic predictors of blood pressure and risk of AF. We secondarily explored the relationship between genetically proxied use of antihypertensive drugs and risk of AF. Two-sample Mendelian randomization was performed using an inverse-variance weighted meta-analysis with weighted median Mendelian randomization and Egger intercept tests performed as sensitivity analyses. Summary statistics for systolic blood pressure, diastolic blood pressure, and pulse pressure were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis and AF from the 2018 Atrial Fibrillation Genetics Consortium multiethnic genome-wide association studies. Increases in genetically proxied systolic blood pressure, diastolic blood pressure, or pulse pressure by 10 mm Hg were associated with increased odds of AF (systolic blood pressure: odds ratio [OR], 1.17 [95% CI, 1.11–1.22]; P =1×10 −11 ; diastolic blood pressure: OR, 1.25 [95% CI, 1.16–1.35]; P =3×10 −8 ; pulse pressure: OR, 1.1 [95% CI, 1.0–1.2]; P =0.05). Decreases in systolic blood pressure by 10 mm Hg estimated by genetic proxies of antihypertensive medications showed calcium channel blockers (OR, 0.66 [95% CI, 0.57–0.76]; P =8×10 −9 ) and β-blockers (OR, 0.61 [95% CI, 0.46–0.81]; P =6×10 −4 ) decreased the risk of AF. Blood pressure–increasing genetic variants were associated with increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction with calcium channel blockade or β-blockade could reduce the risk of AF.

scholarly journals Estimating the Population Benefits of Blood Pressure Lowering: A Wide-Angled Mendelian Randomization Study in UK Biobank

2021 ◽  
Author(s):  
Hannah Higgins ◽  
Amy M. Mason ◽  
Susanna C. Larsson ◽  
Dipender Gill ◽  
Claudia Langenberg ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Diseases ◽  
Mendelian Randomization ◽  
Population Based ◽  
European Ancestry ◽  
Uk Biobank ◽  
Blood Pressure Lowering ◽  
Pressure Lowering ◽  
Long Term Impact

AbstractBackgroundThe causal relevance of elevated blood pressure for several cardiovascular diseases is uncertain, as is the population impact of blood pressure lowering on risk of cardiovascular diseases more broadly. This study systematically assesses evidence of causality for various cardiovascular diseases in a two-sample Mendelian randomization framework, and estimates the potential reduction in the prevalence of these diseases attributable to long-term population shifts in the distribution of systolic blood pressure (SBP).Methods and ResultsWe investigated associations of genetically-predicted SBP as predicted by 256 genetic variants with 21 cardiovascular diseases in UK Biobank, a population-based cohort of UK residents. The sample consisted of 376,703 participants of European ancestry aged 40-69 years at baseline. Genetically-predicted SBP was positively associated with 14 of the outcomes (p<0.002), including dilated cardiomyopathy, endocarditis, peripheral vascular disease, and rheumatic heart disease. Using genetic variation to estimate the long-term impact of blood pressure lowering on disease, population reductions in SBP were predicted to result in an overall 16.9% (95% confidence interval (CI): 12.2-21.3%) decrease in morbidity for a 5 mmHg decrease from a population mean of 137.7 mmHg, 30.8% (95% CI: 22.8-38.0%) for a 10 mmHg decrease, and 56.2% (95% CI: 43.7-65.9%) decrease for a 22.7 mmHg decrease in SBP (22.7 mmHg represents a shift from the current mean SBP to 115 mmHg).ConclusionsRisk of many cardiovascular diseases is influenced by long-term differences in SBP. The burden of a broad range of CVDs could be substantially reduced by long-term population-wide reductions in the distribution of blood pressure.

scholarly journals Estimating the Population Benefits of Blood Pressure Lowering: A Wide‐Angled Mendelian Randomization Study in UK Biobank

2021 ◽  
Author(s):  
Hannah Higgins ◽  
Amy M. Mason ◽  
Susanna C. Larsson ◽  
Dipender Gill ◽  
Claudia Langenberg ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mendelian Randomization ◽  
Population Based ◽  
European Ancestry ◽  
Uk Biobank ◽  
Blood Pressure Lowering ◽  
Pressure Lowering ◽  
Long Term Impact ◽  
Early Late

Background The causal relevance of elevated blood pressure for several cardiovascular diseases (CVDs) is uncertain, as is the population impact of blood pressure lowering. This study systematically assesses evidence of causality for various CVDs in a 2‐sample Mendelian randomization framework, and estimates the potential reduction in the prevalence of these diseases attributable to long‐term population shifts in the distribution of systolic blood pressure (SBP). Methods and Results We investigated associations of genetically predicted SBP as predicted by 256 genetic variants with 21 CVDs in UK Biobank, a population‐based cohort of UK residents. The sample consisted of 376 703 participants of European ancestry, aged 40 to 69 years at recruitment. Genetically predicted SBP was positively associated with 14 of the outcomes ( P <0.002), including dilated cardiomyopathy, endocarditis, peripheral vascular disease, and rheumatic heart disease. Using genetic variation to estimate the long‐term impact of blood pressure lowering on disease in a middle‐aged to early late‐aged UK‐based population, population reductions in SBP were predicted to result in an overall 16.9% (95% CI, 12.2%–21.3%) decrease in morbidity for a 5–mm Hg decrease from a population mean of 137.7 mm Hg, 30.8% (95% CI, 22.8%–38.0%) decrease for a 10–mm Hg decrease, and 56.2% (95% CI, 43.7%–65.9%) decrease for a 22.7–mm Hg decrease in SBP (22.7 mm Hg represents a shift from the current mean SBP to 115 mm Hg). Conclusions Risk of many CVDs is influenced by long‐term differences in SBP. The burden of a broad range of CVDs could be substantially reduced by long‐term population‐wide reductions in the distribution of blood pressure.

scholarly journals Genetic susceptibility, elevated blood pressure, and risk of atrial fibrillation: a Mendelian randomization study

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Milad Nazarzadeh ◽  
Ana-Catarina Pinho-Gomes ◽  
Zeinab Bidel ◽  
Dexter Canoy ◽  
Abbas Dehghan ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Blood Pressure ◽  
Coronary Heart Disease ◽  
Genetic Susceptibility ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Elevated Blood ◽  
Uk Biobank ◽  
Drug Classes ◽  
The Uk

Abstract Background Whether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual’s genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are expected to reduce this risk. Methods First, causality of association was assessed through two-sample Mendelian randomization, using data from two independent genome-wide association studies that included a population of one million Europeans in total. Second, the UK Biobank data of 329,237 participants at baseline was used to study the effect of BP on AF according to genetic susceptibility of developing AF. Third, a possible treatment effect with major BP-lowering drug classes on AF risk was predicted through genetic variants in genes encode the therapeutic targets of each drug class. Estimated drug effects were compared with effects on incident coronary heart disease, for which direct trial evidence exists. Results The two-sample Mendelian randomization analysis indicated that, on average, exposure to a higher systolic BP increased the risk of AF by 19% (odds ratio per each 10-mmHg [OR] 1.19 [1.12 to 1.27]). This association was replicated in the UK biobank using individual participant data. However, in a further genetic risk-stratified analysis, there was evidence for a linear gradient in the relative effects of systolic BP on AF; while there was no conclusive evidence of an effect in those with low genetic risk, a strong effect was observed among those with high genetic susceptibility for AF. The comparison of predicted treatment effects using genetic proxies for three main drug classes (angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers) suggested similar average effects for the prevention of atrial fibrillation and coronary heart disease. Conclusions The effect of elevated BP on the risk of AF is likely to be causal, suggesting that BP-lowering treatment may be effective in AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility risk for AF.

Contrasting Broad- and Clinically- defined Polygenic Indicators of Depression and Depression-related Phenotypes in Adults and Children

2020 ◽  
Author(s):  
John E. McGeary ◽  
Chelsie Benca-Bachman ◽  
Victoria Risner ◽  
Christopher G Beevers ◽  
Brandon Gibb ◽  
...  
Keyword(s):  
Suicidal Ideation ◽  
Cognitive Reappraisal ◽  
Twin Studies ◽  
European Ancestry ◽  
Summary Statistics ◽  
Depression Severity ◽  
Uk Biobank ◽  
Polygenic Scores ◽  
Adults And Children ◽  
The Uk

Twin studies indicate that 30-40% of the disease liability for depression can be attributed to genetic differences. Here, we assess the explanatory ability of polygenic scores (PGS) based on broad- (PGSBD) and clinical- (PGSMDD) depression summary statistics from the UK Biobank using independent cohorts of adults (N=210; 100% European Ancestry) and children (N=728; 70% European Ancestry) who have been extensively phenotyped for depression and related neurocognitive phenotypes. PGS associations with depression severity and diagnosis were generally modest, and larger in adults than children. Polygenic prediction of depression-related phenotypes was mixed and varied by PGS. Higher PGSBD, in adults, was associated with a higher likelihood of having suicidal ideation, increased brooding and anhedonia, and lower levels of cognitive reappraisal; PGSMDD was positively associated with brooding and negatively related to cognitive reappraisal. Overall, PGS based on both broad and clinical depression phenotypes have modest utility in adult and child samples of depression.

scholarly journals Variation in VKORC1 Is Associated with Vascular Dementia

2021 ◽  
Vol 80 (3) ◽  
pp. 1329-1337
Author(s):  
Jure Mur ◽  
Daniel L. McCartney ◽  
Daniel I. Chasman ◽  
Peter M. Visscher ◽  
Graciela Muniz-Terrera ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Vascular Dementia ◽  
Genetic Variant ◽  
Warfarin Dose ◽  
Uk Biobank ◽  
Parental History ◽  
Genome Wide ◽  
History Of ◽  
First Time ◽  
The Relationship

Background: The genetic variant rs9923231 (VKORC1) is associated with differences in the coagulation of blood and consequentially with sensitivity to the drug warfarin. Variation in VKORC1 has been linked in a gene-based test to dementia/Alzheimer’s disease in the parents of participants, with suggestive evidence for an association for rs9923231 (p = 1.8×10–7), which was included in the genome-wide significant KAT8 locus. Objective: Our study aimed to investigate whether the relationship between rs9923231 and dementia persists only for certain dementia sub-types, and if those taking warfarin are at greater risk. Methods: We used logistic regression and data from 238,195 participants from UK Biobank to examine the relationship between VKORC1, risk of dementia, and the interplay with warfarin use. Results: Parental history of dementia, APOE variant, atrial fibrillation, diabetes, hypertension, and hypercholesterolemia all had strong associations with vascular dementia (p < 4.6×10–6). The T-allele in rs9923231 was linked to a lower warfarin dose (βperT - allele = –0.29, p < 2×10–16) and risk of vascular dementia (OR = 1.17, p = 0.010), but not other dementia sub-types. However, the risk of vascular dementia was not affected by warfarin use in carriers of the T-allele. Conclusion: Our study reports for the first time an association between rs9923231 and vascular dementia, but further research is warranted to explore potential mechanisms and specify the relationship between rs9923231 and features of vascular dementia.

scholarly journals Genetic susceptibility, elevated blood pressure and risk of atrial fibrillation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Nazarzadeh ◽  
A Pinho-Gomes ◽  
Z Bidel ◽  
D Canoy ◽  
A Dehghan ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Blood Pressure ◽  
Genetic Susceptibility ◽  
Genetic Risk ◽  
Funding Source ◽  
Individual Participant Data ◽  
Elevated Blood ◽  
Uk Biobank ◽  
Drug Classes ◽  
Individual Participant

Abstract Background Whether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. Purpose We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual's genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are expected to reduce this risk. Methods First, causality of association was assessed through two-sample Mendelian Randomization (MR), using data from two independent genome-wide association studies that included a total of one million European population. Second, UK Biobank individual participant data of 329,237 participants at baseline was used to study the effect of BP on AF according to genetic susceptibility of developing AF. Third, a possible treatment effect with BP-lowering drug classes on AF risk was predicted through genetic variants in druggable genes that code proteins related to the function of each drug class. Estimated drug effects were compared with effects on incident coronary heart disease, for which direct trial evidence exists. Results The two-sample MR analysis indicated that on average each 10-mm Hg increment in systolic BP increased the risk of AF (odds ratio [OR]: 1.23 [1.11 to 1.36]). This association was replicated in the UK biobank using individual participant data. However, in a further genetic risk-stratified analysis, there was evidence for a linear gradient in the relative effects of systolic BP on AF; while there was no conclusive evidence of an effect in those with low genetic risk, a strong effect was observed among those with high genetic susceptibility for AF (Figure). The indirect comparison of predicted treatment effects using genetic proxies for three main drug classes (angiotensin-converting enzyme inhibitors, beta-blockers and calcium channel blockers) suggested similar average effects for prevention of atrial fibrillation and coronary heart disease. Conclusions The association between elevated BP and higher risk of AF is likely to be causal, suggesting that BP-lowering treatment may be effective in AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation

scholarly journals The relationship between diastolic blood pressure and the risk of cardiovascular events in patients with atrial fibrillation: the Fushimi AF registry

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Ikeda ◽  
M Iguchi ◽  
H Ogawa ◽  
Y Aono ◽  
K Doi ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Blood Pressure ◽  
Diastolic Blood Pressure ◽  
Cardiovascular Events ◽  
Left Ventricular ◽  
Cox Proportional Hazards ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
The Impact

Abstract Background Hypertension is one of the major risk factors of cardiovascular events in patients with atrial fibrillation (AF). However, relationship between diastolic blood pressure (DBP) and cardiovascular events in AF patients remains unclear. Methods The Fushimi AF Registry is a community-based prospective survey of AF patients in Japan. Follow-up data were available in 4,466 patients, and 4,429 patients with available data of DBP were examined. We divided the patients into three groups; G1 (DBP&lt;70 mmHg, n=1,946), G2 (70≤DBP&lt;80, n=1,321) and G3 (80≤DBP, n=1,162), and compared the clinical background and outcomes between groups. Results The proportion of female was grater in G1 group, and the patients in G1 group were older and had higher prevalence of heart failure (HF), diabetes mellitus (DM), chronic kidney disease (CKD). Prescription of beta blockers was higher in G1 group, but that of renin-angiotensin system-inhibitors and calcium channel blocker was comparable. During the median follow-up of 1,589 days, in Kaplan-Meier analysis, the incidence rates of cardiovascular events (composite of cardiac death, ischemic stroke and systemic embolism, major bleeding and HF hospitalization during follow up) were higher in G1 group and G3 group than G2 group (Figure 1). When we divided the patients based on the systolic blood pressure (SBP) at baseline (≥130 mmHg or &lt;130 mmHg), the incidence of rates of cardiovascular events were comparable among groups. Multivariate Cox proportional hazards regression analysis including female gender, age (≥75 years), higher SBP (≥130 mmHg), DM, pre-existing HF, CKD, low left ventricular ejection fraction (&lt;40%) and DBP (G1, G2, G3) revealed that DBP was an independent determinant of cardiovascular events (G1 group vs. G2 group; hazard ratio (HR): 1.40, 95% confidence intervals (CI): 1.19–1.64, G3 group vs. G2 group; HR: 1.23, 95% CI: 1.01–1.49). When we examined the impact of DBP according to 10 mmHg increment, patients with very low DBP (&lt;60 mmHg) (HR: 1.50,95% CI:1.24–1.80) and very high DBP (≥90 mmHg) (HR: 1.51,95% CI:1.15–1.98) had higher incidence of cardiovascular events than patients with DBP of 70–79 mmHg (Figure 2). However, when we examined the impact of SBP according to 20 mmHg increment, SBP at baseline was not associated with the incidence of cardiovascular events (Figure 3). Conclusion In Japanese patients with AF, DBP exhibited J curve association with higher incidence of cardiovascular events. Funding Acknowledgement Type of funding source: None

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