Genetically determined blood pressure, antihypertensive medications, and risk of Alzheimer’s disease: a Mendelian randomization study
Background: Observational studies suggest that the use of antihypertensive medications (AHMs) is associated with a reduced risk of Alzheimer’s disease (AD); however, these findings may be biased by confounding and reverse causality. We aimed to explore the effects of blood pressure (BP) and lowering systolic BP (SBP) via the protein targets of different AHMs on AD through a two-sample Mendelian randomization (MR) approach.
Methods: Genetic proxies from genome-wide association studies of BP traits and BP-lowering variants in genes encoding AHM targets were extracted. Estimates were calculated by inverse-variance weighted method as the main model. MR Egger regression and leave-one-out analysis were performed to identify potential violations.
Results: There was limited evidence that genetically predicted SBP/diastolic BP level affected AD risk based on 400/398 single nucleotide polymorphisms (SNPs), respectively (all P>0.05). Suitable genetic variants for β-blockers (1 SNP), angiotensin receptor blockers (1 SNP), calcium channel blockers (CCBs, 45 SNPs) and thiazide diuretics (5 SNPs) were identified. Genetic proxies for CCB [odds ratio (OR)=0.959, 95% confidence interval (CI)=0.941-0.977, P=3.92×10-6], and overall use of AHMs (OR=0.961, 95% CI=0.944-0.978, P=5.74×10-6, SNPs=52) were associated with a lower risk of AD. No notable heterogeneity and directional pleiotropy were identified (all P>0.05). Additional analyses partly support these results. No single SNP was driving the observed effects.
Conclusions: This MR analysis found evidence that genetically determined lowering BP was associated with a lower risk of AD and CCB was identified as a promising strategy for AD prevention.
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Genetically determined blood pressure, antihypertensive medications, and risk of Alzheimer’s disease: a Mendelian randomization study
Posted 01 Feb, 2021
On 09 Feb, 2021
On 31 Jan, 2021
On 30 Jan, 2021
Invitations sent on 30 Jan, 2021
On 30 Jan, 2021
Received 30 Jan, 2021
Received 30 Jan, 2021
On 24 Jan, 2021
On 24 Jan, 2021
On 24 Jan, 2021
Posted 16 Jan, 2021
Received 16 Jan, 2021
On 16 Jan, 2021
Received 10 Jan, 2021
On 09 Jan, 2021
Invitations sent on 09 Jan, 2021
On 09 Jan, 2021
On 06 Jan, 2021
On 06 Jan, 2021
On 06 Jan, 2021
On 26 Dec, 2020
Received 26 Dec, 2020
Received 07 Dec, 2020
On 06 Dec, 2020
Invitations sent on 05 Dec, 2020
On 05 Dec, 2020
On 30 Nov, 2020
On 30 Nov, 2020
On 30 Nov, 2020
On 28 Nov, 2020
Background: Observational studies suggest that the use of antihypertensive medications (AHMs) is associated with a reduced risk of Alzheimer’s disease (AD); however, these findings may be biased by confounding and reverse causality. We aimed to explore the effects of blood pressure (BP) and lowering systolic BP (SBP) via the protein targets of different AHMs on AD through a two-sample Mendelian randomization (MR) approach.
Methods: Genetic proxies from genome-wide association studies of BP traits and BP-lowering variants in genes encoding AHM targets were extracted. Estimates were calculated by inverse-variance weighted method as the main model. MR Egger regression and leave-one-out analysis were performed to identify potential violations.
Results: There was limited evidence that genetically predicted SBP/diastolic BP level affected AD risk based on 400/398 single nucleotide polymorphisms (SNPs), respectively (all P>0.05). Suitable genetic variants for β-blockers (1 SNP), angiotensin receptor blockers (1 SNP), calcium channel blockers (CCBs, 45 SNPs) and thiazide diuretics (5 SNPs) were identified. Genetic proxies for CCB [odds ratio (OR)=0.959, 95% confidence interval (CI)=0.941-0.977, P=3.92×10-6], and overall use of AHMs (OR=0.961, 95% CI=0.944-0.978, P=5.74×10-6, SNPs=52) were associated with a lower risk of AD. No notable heterogeneity and directional pleiotropy were identified (all P>0.05). Additional analyses partly support these results. No single SNP was driving the observed effects.
Conclusions: This MR analysis found evidence that genetically determined lowering BP was associated with a lower risk of AD and CCB was identified as a promising strategy for AD prevention.
Figure 1
Figure 2
Figure 3
Figure 4