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Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study

BACKGROUND: Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these...

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Autores principales: Østergaard, Søren D., Mukherjee, Shubhabrata, Sharp, Stephen J., Proitsi, Petroula, Lotta, Luca A., Day, Felix, Perry, John R. B., Boehme, Kevin L., Walter, Stefan, Kauwe, John S., Gibbons, Laura E., Larson, Eric B., Powell, John F., Langenberg, Claudia, Crane, Paul K., Wareham, Nicholas J., Scott, Robert A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469461/
https://www.ncbi.nlm.nih.gov/pubmed/26079503
http://dx.doi.org/10.1371/journal.pmed.1001841
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author Østergaard, Søren D.
Mukherjee, Shubhabrata
Sharp, Stephen J.
Proitsi, Petroula
Lotta, Luca A.
Day, Felix
Perry, John R. B.
Boehme, Kevin L.
Walter, Stefan
Kauwe, John S.
Gibbons, Laura E.
Larson, Eric B.
Powell, John F.
Langenberg, Claudia
Crane, Paul K.
Wareham, Nicholas J.
Scott, Robert A.
author_facet Østergaard, Søren D.
Mukherjee, Shubhabrata
Sharp, Stephen J.
Proitsi, Petroula
Lotta, Luca A.
Day, Felix
Perry, John R. B.
Boehme, Kevin L.
Walter, Stefan
Kauwe, John S.
Gibbons, Laura E.
Larson, Eric B.
Powell, John F.
Langenberg, Claudia
Crane, Paul K.
Wareham, Nicholas J.
Scott, Robert A.
author_sort Østergaard, Søren D.
collection PubMed
description BACKGROUND: Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). METHODS AND FINDINGS: We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, N (SNPs) = 49), fasting glucose (N (SNPs) = 36), insulin resistance (N (SNPs) = 10), body mass index (BMI, N (SNPs) = 32), total cholesterol (N (SNPs) = 73), HDL-cholesterol (N (SNPs) = 71), LDL-cholesterol (N (SNPs) = 57), triglycerides (N (SNPs) = 39), systolic blood pressure (SBP, N (SNPs) = 24), smoking initiation (N (SNPs) = 1), smoking quantity (N (SNPs) = 3), university completion (N (SNPs) = 2), and years of education (N (SNPs) = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP–AD associations from the International Genomics of Alzheimer’s Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62–0.91]; p = 3.4 × 10(−3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(−8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51–0.89]; p = 6.5 × 10(−3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses. CONCLUSIONS: Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure—or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications—may reduce AD risk.
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spelling pubmed-44694612015-06-22 Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study Østergaard, Søren D. Mukherjee, Shubhabrata Sharp, Stephen J. Proitsi, Petroula Lotta, Luca A. Day, Felix Perry, John R. B. Boehme, Kevin L. Walter, Stefan Kauwe, John S. Gibbons, Laura E. Larson, Eric B. Powell, John F. Langenberg, Claudia Crane, Paul K. Wareham, Nicholas J. Scott, Robert A. PLoS Med Research Article BACKGROUND: Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). METHODS AND FINDINGS: We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, N (SNPs) = 49), fasting glucose (N (SNPs) = 36), insulin resistance (N (SNPs) = 10), body mass index (BMI, N (SNPs) = 32), total cholesterol (N (SNPs) = 73), HDL-cholesterol (N (SNPs) = 71), LDL-cholesterol (N (SNPs) = 57), triglycerides (N (SNPs) = 39), systolic blood pressure (SBP, N (SNPs) = 24), smoking initiation (N (SNPs) = 1), smoking quantity (N (SNPs) = 3), university completion (N (SNPs) = 2), and years of education (N (SNPs) = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP–AD associations from the International Genomics of Alzheimer’s Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62–0.91]; p = 3.4 × 10(−3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(−8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51–0.89]; p = 6.5 × 10(−3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses. CONCLUSIONS: Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure—or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications—may reduce AD risk. Public Library of Science 2015-06-16 /pmc/articles/PMC4469461/ /pubmed/26079503 http://dx.doi.org/10.1371/journal.pmed.1001841 Text en © 2015 Østergaard et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Østergaard, Søren D.
Mukherjee, Shubhabrata
Sharp, Stephen J.
Proitsi, Petroula
Lotta, Luca A.
Day, Felix
Perry, John R. B.
Boehme, Kevin L.
Walter, Stefan
Kauwe, John S.
Gibbons, Laura E.
Larson, Eric B.
Powell, John F.
Langenberg, Claudia
Crane, Paul K.
Wareham, Nicholas J.
Scott, Robert A.
Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study
title Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study
title_full Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study
title_fullStr Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study
title_full_unstemmed Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study
title_short Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study
title_sort associations between potentially modifiable risk factors and alzheimer disease: a mendelian randomization study
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4469461/
https://www.ncbi.nlm.nih.gov/pubmed/26079503
http://dx.doi.org/10.1371/journal.pmed.1001841
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