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Cardiovascular Risk Factors and MRI Markers of Cerebral Small Vessel Disease: A Mendelian Randomization Study
Victoria Taylor-Bateman1, Dipender Gill2, Marios K Georgakis2
1From Clinical Pharmacology (V.T.-B., P.M., M.T.), William Harvey Research Institute, Queen Mary University of London; Department of Epidemiology and Biostatistics (D.P.), School of Public Health, and Department of Medicine (D.G.), Centre for Pharmacology and Therapeutics, Imperial College London; Novo Nordisk Research Centre (D.G., M.T.), Oxford; Clinical Pharmacology and Therapeutics Section (D.G.), Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St. George's, University of London; Clinical Pharmacology Group (D.G.), Pharmacy and Medicines Directorate, St. George's University Hospitals NHS Foundation Trust, London, UK; Institute for Stroke and Dementia Research (M.G., R.M.), University Hospital of Ludwig-Maximilians-University, Munich, Germany; National Institute for Health Research Barts Cardiovascular Biomedical Research Centre (P.M.), Queen Mary University of London; The Barts Heart Centre and NIHR Barts Biomedical Research Centre-Barts Health NHS Trust (M.T.), William Harvey Research Institute, Queen Mary University London, UK; Center for Genomic Medicine (M.K.G.), Massachusetts General Hospital, Boston; and Program in Medical and Population Genetics (M.K.G.), Broad Institute of Harvard and the Massachusetts Institute of Technology, Boston. v.j.taylor-bateman@qmul.ac.uk.
Insights
Higher blood pressure and body mass index (BMI) causally increase the risk of cerebral small vessel disease (CSVD). Managing these cardiovascular risk factors may help reduce CSVD burden.
Area of Science:
- Neurology
- Genetics
- Cardiovascular Medicine
Background:
- Cerebral small vessel disease (CSVD) is linked to cardiovascular risk factors, but causal relationships are uncertain.
- Observational studies face challenges like reverse causation and confounding, necessitating robust methods to establish causality.
Purpose of the Study:
- To employ Mendelian randomization (MR) to investigate the causal role of cardiovascular risk factors in the etiology of CSVD.
- To identify specific cardiovascular risk factors causally associated with neuroimaging markers of CSVD.
Main Methods:
- Utilized large-scale genome-wide association studies (GWAS) data from European ancestry.
- Applied Mendelian randomization (MR) to assess associations between genetic proxies of risk factors (blood pressure, BMI, lipids, diabetes, smoking, alcohol) and CSVD neuroimaging features (WMH, FA, MD) in UK Biobank participants (N=31,855).
- Employed inverse-weighted median, weighted median, MR-Egger, and pleiotropy-minimizing approaches for primary and validation analyses; multivariable MR was used for joint effects.
Main Results:
- Consistent evidence showed higher genetically proxied systolic and diastolic blood pressures were associated with increased white matter hyperintensities (WMH), and altered fractional anisotropy (FA) and mean diffusivity (MD).
- Higher genetically proxied body mass index (BMI) was associated with increased WMH.
- Associations for other factors like lipids, diabetes, and smoking were less consistent and not reproducible across all validation methods.
Conclusions:
- Genetic predisposition to elevated blood pressure, particularly diastolic blood pressure, and higher BMI causally contributes to a greater burden of cerebral small vessel disease.
- Targeted management of hypertension and obesity may be crucial for reducing the incidence and progression of CSVD.
Background And Objectives:
Cardiovascular risk factors have been implicated in the etiology of cerebral small vessel disease (CSVD); however, whether the associations are causal remains unclear in part due to the susceptibility of observational studies to reverse causation and confounding. Here, we use mendelian randomization (MR) to determine which cardiovascular risk factors are likely to be involved in the etiology of CSVD.
Methods:
We used data from large-scale genome-wide association studies of European ancestry to identify genetic proxies for blood pressure, blood lipids, body mass index (BMI), type 2 diabetes, smoking initiation, cigarettes per day, and alcohol consumption. MR was performed to assess their association with 3 neuroimaging features that are altered in CSVD (white matter hyperintensities [WMH], fractional anisotropy [FA], and mean diffusivity [MD]) using genetic summary data from the UK Biobank (N = 31,855). Our primary analysis used inverse-weighted median MR, with validation using weighted median, MR-Egger, and a pleiotropy-minimizing approach. Finally, multivariable MR was performed to study the effects of multiple risk factors jointly.
Results:
MR analysis showed consistent associations across all methods for higher genetically proxied systolic and diastolic blood pressures with WMH, FA, and MD and for higher genetically proxied BMI with WMH. There was weaker evidence for associations between total cholesterol, low-density lipoprotein, smoking initiation, pulse pressure, and type 2 diabetes liability and at least 1 CSVD imaging feature, but these associations were not reproducible across all validation methods used. Multivariable MR analysis for blood pressure traits found that the effect was primarily through genetically proxied diastolic blood pressure across all CSVD traits.
Discussion:
Genetic predisposition to higher blood pressure, primarily diastolic blood pressure, and to higher BMI is associated with a higher burden of CSVD, suggesting a causal role. Improved management and treatment of these risk factors could reduce the burden of CSVD.
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