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Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer Disease: a Mendelian Randomization Analysis

Proitsi, Petroula, Lupton, Michelle K., Velayudhan, Latha, Newhouse, Stephen, Fogh, Isabella, Tsolaki, Magda, Daniilidou, Makrina, Pritchard, Megan, Kloszewska, Iwona, Soininen, Hilkka, Mecocci, Patrizia, Vellas, Bruno, Williams, Julie, Stewart, Robert, Sham, Pak, Lovestone, Simon and Powell, John F. 2014. Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer Disease: a Mendelian Randomization Analysis. Public Library of Science Medicine 11 (9) , e1001713. 10.1371/journal.pmed.1001713

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Abstract

Background Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD. Methods and Findings We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n = 10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p<5×10−8 and trait specific scores using SNPs associated exclusively with each trait at p<5×10−8 were developed. We used logistic regression to investigate whether the GRSs were associated with LOAD in each study and results were combined together by meta-analysis. We found no association between any of the full GRSs and LOAD (meta-analysis results: odds ratio [OR] = 1.005, 95% CI 0.82–1.24, p = 0.962 per 1 unit increase in HDL-c; OR = 0.901, 95% CI 0.65–1.25, p = 0.530 per 1 unit increase in LDL-c; OR = 1.104, 95% CI 0.89–1.37, p = 0.362 per 1 unit increase in triglycerides; and OR = 0.954, 95% CI 0.76–1.21, p = 0.688 per 1 unit increase in total cholesterol). Results for the trait specific scores were similar; however, the trait specific scores explained much smaller phenotypic variance. Conclusions Genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords: © 2014 Proitsi et al. 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 credited.
ISSN: 1549-1676
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 23 July 2014
Last Modified: 25 Apr 2019 16:26
URI: http://orca.cf.ac.uk/id/eprint/77335

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