Abstract MP13: Polygenic Susceptibility to Atrial Fibrillation is Associated With Silent Cerebrovascular Disease in Stroke-Free Persons Without Atrial Fibrillation

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Cameron Both ◽  
Julian Acosta ◽  
Natalia Szejko ◽  
Kevin N Vanent ◽  
Audrey C Leasure ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
White Matter ◽  
Cerebrovascular Disease ◽  
Genetic Risk ◽  
Community Dwelling ◽  
Uk Biobank ◽  
High Genetic Risk ◽  
History Of ◽  
The Uk ◽  
Study Participants

Introduction: Clinically silent cerebrovascular disease is present in 40% of persons over the age of 60. We hypothesize that polygenic susceptibility to atrial fibrillation is associated with the burden of white matter disease in persons without atrial fibrillation or history of ischemic stroke. Methods: We conducted a nested genetic and neuroimaging study within the UK Biobank, a large cohort study that enrolled community dwelling Britons aged 40 to 65 at recruitment. We used data on a subcohort of patients evaluated with brain MRIs. The volume of white matter hyperintensities (WMH) was estimated using the BIANCA lesion segmentation tool. Genomic data was ascertained via genotyping with the Affymetrix UK Biobank Axiom array followed by imputation with 1000 Genomes reference panels. To model the polygenic susceptibility to atrial fibrillation (AFIB), we constructed a polygenic risk score (PRS) using 957 independent genetic risk variants known to significantly associate with atrial fibrillation. We used logistic and linear regression to test for association between the PRS and WMH. Results: A total of 38,914 study participants underwent brain MRI imaging in the UK Biobank. Of these, we excluded 124 (0.3%) with a history of stroke and 926 (2.4%) with AFIB. 37,864 study participants were included in this study, of which 19,059 (50.3%) had WMH. High genetic risk of AFIB was not associated with no-versus-any WMH (p=0.51). When evaluating persons with WMH lesions, high genetic risk of AFIB was associated with higher WMH volume (per 1 SD increase of the PRS, beta 0.019, SE 0.006; p=0.01). Gender was an important effect modifier of this association (interaction p=0.03): while high genetic risk of AFIB was associated with a significant increase in WMH volume in females (per 1 SD increase of the PRS, beta 0.03, SE 0.008; p<0.001), no association was found for males (p=0.99). Conclusions: Polygenic susceptibility to atrial fibrillation is associated with more severe silent cerebrovascular disease in persons without atrial fibrillation. Further research should evaluate whether this genetic information can be used to identify persons for tailored diagnostic or therapeutic interventions.

Abstract 16105: Depression Modulates Polygenic Risk of Cardiovascular and Cardiometabolic Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Michael C Honigberg ◽  
Amy Sarma ◽  
Nandita Scott ◽  
Malissa J Wood ◽  
Pradeep Natarajan
Keyword(s):  
Atrial Fibrillation ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Health Behaviors ◽  
Genetic Risk ◽  
Cardiometabolic Disease ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Artery Disease ◽  
The Uk

Introduction: Depression is associated with an increased risk of coronary artery disease (CAD). Whether depression modifies genetic risk of cardiovascular and cardiometabolic disease is unknown. Methods: We included genotyped, unrelated European ancestry individuals in the UK Biobank. Using genome-wide significant single nucleotide polymorphisms (SNPs) from studies external to the UK Biobank, we generated polygenic risk scores (PRS) for coronary artery disease (CAD, 74 SNPs), hypertension (75 SNPs), type 2 diabetes (T2D, 64 SNPs), atrial fibrillation (25 SNPs), and ischemic stroke (11 SNPs). Participants were stratified by PRS for each condition as low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk. Cox models tested the association of depression frequency with each incident condition among individuals with high PRS, with adjustment for age, sex, the first 20 principal components, genotyping array, and Townsend deprivation index. Additional models further adjusted for health behaviors (exercise, tobacco and alcohol use, vegetable and fresh fruit intake) and tested associations across the PRS spectrum. Results: Among 348,083 individuals, 78,664 (22.6%) reported depression in the past 2 weeks, including 14,776 (4.2%) with depression more than half of days. Depression burden modified the risk of incident CAD across the spectrum of CAD polygenic risk (Figure 1A). Among individuals with high PRS, lack of depression was associated with lower risk of incident CAD (HR 0.70, 95% 0.58-0.86), hypertension (HR 0.58, 95% CI 0.50-0.67), T2D (HR 0.48, 95% CI 0.41-0.55), and atrial fibrillation (HR 0.74, 95% CI 0.62-0.89) compared to those with a high burden of depression. These risk reductions were minimally attenuated after further adjustment for health behaviors (Figure 1B). Conclusions: Lower burden of depression was associated was decreased risks of cardiovascular disease among individuals at high genetic cardiovascular risk.

scholarly journals Obesity impairs cognitive function via metabolic syndrome and cerebrovascular disease: an SEM analysis in 15,000 adults from the UK Biobank

2020 ◽  
Author(s):  
Filip Morys ◽  
Mahsa Dadar ◽  
Alain Dagher
Keyword(s):  
Metabolic Syndrome ◽  
Cognitive Impairment ◽  
White Matter ◽  
Cerebrovascular Disease ◽  
Cortical Thickness ◽  
White Matter Hyperintensities ◽  
Uk Biobank ◽  
Central Nervous System Damage ◽  
The Uk ◽  
The Relationship

AbstractChronic obesity is associated with several complications, including cognitive impairment and dementia. However, we have piecemeal knowledge of the mechanisms linking obesity to central nervous system damage. Adiposity leads to the metabolic syndrome, consisting of inflammation, hypertension, dyslipidemia and insulin resistance. In turn, these metabolic abnormalities cause cerebrovascular dysfunction, which may cause white and grey matter tissue loss and consequent cognitive impairment. While there have been several neuroimaging studies linking adiposity to changes in brain morphometry, a comprehensive investigation of the relationship has so far not been done. Here we use structural equation modelling applied to over 15,000 individuals from the UK Biobank to identify the causal chain that links adiposity to cognitive dysfunction. We found that body mass index and waist-to-hip ratio were positively related to higher plasma C-reactive protein, dyslipidemia, occurrence of hypertension and diabetes, all of which were in turn related to cerebrovascular disease as measured by volume of white matter hyperintensities on magnetic resonance imaging. White mater hyperintensities were associated with lower cortical thickness and volume and higher subcortical volumes, which were associated with cognitive deficits on tests of visuospatial memory, fluid intelligence, and working memory among others. In follow-up analyses we found that inflammation, hypertension and diabetes mediated 20% of the relationship between obesity and cerebrovascular disease and that cerebrovascular disease mediated a significant proportion of the relationship between obesity and cortical thickness and volume. We also showed that volume of white matter hyperintensities was related to decreased fractional anisotropy and increased mean diffusivity in the majority of white matter tracts, pointing to white matter dysconnectivity as a major cause of impaired cognition. Our results have clinical implications, supporting a role for the management of adiposity in the prevention of late-life dementia and cognitive decline.

Abstract 71: Sex and Genetic Predisposition Synergistically Influence Risk of Stroke and Myocardial Infarction in Middle-Aged Persons Without Risk Factors

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Guido J Falcone ◽  
Julian Acosta ◽  
Audrey C Leasure ◽  
Kevin N Vanent ◽  
Rommell B Noche ◽  
...  
Keyword(s):  
Risk Factors ◽  
Myocardial Infarction ◽  
Genetic Predisposition ◽  
Genetic Risk ◽  
Vascular Risk Factors ◽  
Vascular Risk ◽  
Uk Biobank ◽  
Middle Aged ◽  
High Genetic Risk ◽  
The Uk

Background and Hypothesis: Driven by aging-related physiological changes, the incidence of stroke and myocardial infarction rises rapidly in persons aged >40 years. A significant proportion of these acute vascular events (AVE) take place in persons without vascular risk factors. We tested the hypothesis that sex and genetic predisposition synergistically increase the risk of AVE in middle-aged persons without vascular risk factors. Methods: We analyzed data from the UK Biobank, a prospective longitudinal study that enrolled persons aged 40 to 69 years. Our analysis was restricted to middle-aged participants, defined as those aged 40 to 60 years. Prevalent and incident cases of stroke (ischemic and hemorrhagic) and myocardial infarction were included. To quantify the genetic predisposition to sustain an AVE, we constructed a polygenic risk score using 68 independent (R 2 <0.1) genetic variants known to associate (p<5x10 -8 ) with AVE. Participants were classified as having low, intermediate or high genetic risk according to tertiles of the score. We used Cox models for association and interaction testing. Results: Of the 502,536 study participants enrolled in the UK Biobank, 303,295 (60%) did not have any vascular risk factors. During the follow-up period, there were 5,746 AVEs, including 1,954 strokes and 3,792 myocardial infarctions. The cumulative risk of AVE was 0.12% (n=352), 0.46% (n = 1,386) and 1.32% (n = 4,008) at ages 40, 50 and 60 years (test-for-trend p<0.001). The risk of AVE was 3 times greater in men than women (HR 3.30, 95%CI 3.08 - 3.53). Compared to persons with low genetic risk, those with intermediate and high genetic risk had a 22% (HR 1.22, 95%CI 1.13 - 1.32) and 52% (HR 1.52, 95%CI 1.41 - 1.65) increase in risk of AVE, respectively. There was significant synergy (interaction) between sex and genetic predisposition: compared to females with low genetic risk, males with high genetic risk had 4 times (HR 3.91, 95%CI 3.58 - 4.26) the risk of AVE (interaction analysis p<0.001). Conclusion: Genetic information constitutes a promising tool to risk stratify middle-aged persons without vascular risk factors. The synergistic effect of sex and genetic predisposition points to specific subgroups that could benefit from aggressive preventive interventions.

Abstract TMP58: Major Risk Factors and the Risk of All, Ischemic, and Hemorrhagic Stroke in Half a Million Women and Men in the UK Biobank

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Sanne Peters ◽  
Cheryl Carcel ◽  
Elizabeth Millet (deceased) ◽  
Mark Woodward
Keyword(s):  
Risk Factors ◽  
Atrial Fibrillation ◽  
Ischaemic Stroke ◽  
Low Socioeconomic Status ◽  
Cox Regression ◽  
Haemorrhagic Stroke ◽  
Uk Biobank ◽  
History Of ◽  
Specific Association ◽  
The Uk

Background: Major differences between women and men exist in the clinical presentation, medical care, and prognosis and outcomes of stroke. We assessed the sex-specific association of major risk factors and the risk of incident stroke, including its major subtypes, among women and men. Methods: Between 2006-10, the UK Biobank recruited over 500,000 participants aged 40-69 years across the UK. During 9 years of follow-up, 4,662 (44% women) cases of stroke were recorded among 471,971 (56% women) individuals without a history of cardiovascular disease at baseline. Cox regression models yielded adjusted hazard ratios (HRs), and women-to-men ratios of HRs (RHR), for stroke associated with seven risk factors. Results: The incidence rate per 10,000 person years was 8.66 (8.29; 9.04) in women and 13.96 (13.44; 14.50) in men for any stroke; 6.06 (5.75; 6.38) in women and 11.35 (10.88; 11.84) in men for ischaemic stroke, and 1.56 (1.41; 1.73) in women and 2.23 (2.02; 2.45) in men for haemorrhagic stroke. The magnitude of the relationship between increases in indices of blood pressure, body anthropometry, and lipid levels, diabetes mellitus, and atrial fibrillation and the risk of any stroke was similar between men and women. Hypertension (stage 2), current smoking, and a low socioeconomic status, respectively, were associated with a greater HR of any stroke in women than men; the RHRs were 1.36 (1.26; 1.47), 1.18 (1.02; 1.36), and 1.17 (1.03; 1.33). Diabetes was associated with a higher HR of ischaemic stroke in women than men (RHR: 1.25 [1.00; 1.56]). Atrial fibrillation was associated with a higher HR of haemorrhagic stroke in women than men (RHR: 2.80 [1.07; 7.36]). The incidence of stroke was higher among men than women for all risk factors, except type 1 diabetes and atrial fibrillation (haemorrhagic stroke only). Conclusion: Several risk factors are more strongly associated with the risk of any stroke or stroke subtypes in women compared with men. Despite this, the incidence of stroke in the presence of risk factors generally remains higher among men than women.

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.

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

Abstract 44: Associations of Atrial Fibrillation, Neuroimaging Measures of Cerebrovascular Disease and Alzheimer’S Disease-related Pathology, and Cognitive Impairment

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Jonathan Graff-Radford ◽  
Rosebud Roberts ◽  
Malini Madhavan ◽  
Alejandro Rabinstein ◽  
Ruth Cha ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
White Matter ◽  
Cerebrovascular Disease ◽  
Regression Models ◽  
Grey Matter ◽  
White Matter Hyperintensity ◽  
Carrier Status

The objective of this study was to investigate the cross-sectional associations of atrial fibrillation with neuroimaging measures of cerebrovascular disease and Alzheimer’s disease-related pathology, and their interaction with cognitive impairment. MRI scans of non-demented individuals (n=1044) from the population-based Mayo Clinic Study of Aging were analyzed for infarctions, total grey matter, hippocampal and white matter hyperintensity volumes. A subset of 496 individuals underwent FDG and C-11 Pittsburgh compound B (PiB) PET scans. We assessed the associations of atrial fibrillation with i) categorical MRI measures (cortical and subcortical infarctions) using multivariable logistic regression models, and with ii) continuous MRI measures ( hippocampal, total grey matter, and white matter hyperintensity volumes) and FDG-PET and PiB-PET measures using multivariable linear regression models, and adjusting for confounders. Among participants who underwent MRI (median age, 77.8, 51.6% male), 13.5% had atrial fibrillation. Presence of atrial fibrillation was associated with subcortical infarctions (odds ratio [OR], 1.83; p=0.002), cortical infarctions (OR, 1.91; p=0.03), total grey matter volume (Beta [β], -.025, p<.0001) after controlling for age, education, gender, APOE e4 carrier status, coronary artery disease, diabetes, history of clinical stroke, and hypertension. However, atrial fibrillation was not associated with white matter hyperintensity volume, hippocampal volume, Alzheimer’s pattern of FDG hypometabolism or PiB uptake. There was a significant interaction of cortical infarction (p for interaction=0.004) and subcortical infarction (p for interaction =0.015) with atrial fibrillation with regards to odds of mild cognitive impairment (MCI). Using subjects with no atrial fibrillation and no infarction as the reference, the OR (95% confidence intervals [CI]) for MCI was 2.98 (1.66, 5.35;p = 0.0002) among participants with atrial fibrillation and any infarction, 0.69 (0.36, 1.33;p= 0.27) for atrial fibrillation and no infarction, and 1.50 (0.96, 2.32;p = 0.07) for no atrial fibrillation and any infarction. These data highlight that atrial fibrillation is associated with MCI in the presence of infarctions.

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