Falcone, GJ;
Kirsch, E;
Acosta, JN;
Noche, RB;
Leasure, A;
Marini, S;
Chung, J;
Selim, M;
Meschia, JF;
Brown, DL;
et al.
Falcone, GJ; Kirsch, E; Acosta, JN; Noche, RB; Leasure, A; Marini, S; Chung, J; Selim, M; Meschia, JF; Brown, DL; Worrall, BB; Tirschwell, DL; Jagiella, JM; Schmidt, H; Jimenez-Conde, J; Fernandez-Cadenas, I; Lindgren, A; Slowik, A; Gill, D; Holmes, M; Phuah, C-L; Petersen, NH; Matouk Md, CN; Gunel, M; Sansing, L; Bennett, D; Chen, Z; Sun, LL; Clarke, R; Walters, RG; Gill, TM; Biffi, A; Kathiresan, S; Langefeld, CD; Woo, D; Rosand, J; Sheth, KN; Anderson, CD; International Stroke Genetics Consortium
(2020)
Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.
Ann Neurol, 88 (1).
pp. 56-66.
ISSN 1531-8249
https://doi.org/10.1002/ana.25740
SGUL Authors: Gill, Dipender Preet Singh
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Abstract
OBJECTIVE: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. METHODS: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. RESULTS: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively. INTERPRETATION: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.
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Additional Information: | This is the peer reviewed version of the following article: Falcone, G.J., Kirsch, E., Acosta, J.N., Noche, R.B., Leasure, A., Marini, S., Chung, J., Selim, M., Meschia, J.F., Brown, D.L., Worrall, B.B., Tirschwell, D.L., Jagiella, J.M., Schmidt, H., Jimenez-Conde, J., Fernandez-Cadenas, I., Lindgren, A., Slowik, A., Gill, D., Holmes, M., Phuah, C.-L., Petersen, N.H., Matouk, MD, C.N., Gunel, M., Sansing, L., Bennett, D., Chen, Z., Sun, L.L., Clarke, R., Walters, R.G., Gill, T.M., Biffi, A., Kathiresan, S., Langefeld, C.D., Woo, D., Rosand, J., Sheth, K.N., Anderson, C.D. and (2020), Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage. Ann Neurol, 88: 56-66, which has been published in final form at https://doi.org/10.1002/ana.25740. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Keywords: | Aged, Aged, 80 and over, Cerebral Hemorrhage, Cholesterol, HDL, Cholesterol, LDL, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Triglycerides, International Stroke Genetics Consortium, Humans, Cerebral Hemorrhage, Genetic Predisposition to Disease, Triglycerides, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Female, Male, Cholesterol, LDL, Cholesterol, HDL, Genome-Wide Association Study, Aged, Aged, 80 and over, Cerebral Hemorrhage, Cholesterol, HDL, Cholesterol, LDL, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Triglycerides, Neurology & Neurosurgery, 1103 Clinical Sciences, 1109 Neurosciences | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Infection and Immunity Research Institute (INII) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Journal or Publication Title: | Ann Neurol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ISSN: | 1531-8249 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Language: | eng | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Publisher License: | Publisher's own licence | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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PubMed ID: | 32277781 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/113833 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Publisher's version: | https://doi.org/10.1002/ana.25740 |
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