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Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage

Falcone, Guido J. ; Kirsch, Elayna ; Acosta, Julian N. ; Noche, Rommell B. ; Leasure, Audrey ; Marini, Sandro ; Chung, Jaeyoon ; Selim, Magdy ; Meschia, James F. and Brown, Devin L. , et al. (2020) In Annals of Neurology 88(1). p.56-66
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... (More)

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.

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type
Contribution to journal
publication status
published
subject
in
Annals of Neurology
volume
88
issue
1
pages
11 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85085108436
  • pmid:32277781
ISSN
0364-5134
DOI
10.1002/ana.25740
language
English
LU publication?
yes
id
2f318fd5-e74e-4926-84f4-bad8c082b46c
date added to LUP
2020-06-22 14:30:25
date last changed
2024-06-13 18:31:13
@article{2f318fd5-e74e-4926-84f4-bad8c082b46c,
  abstract     = {{<p>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 &lt; 1.00 × 10<sup>-100</sup>). 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 &gt; 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.</p>}},
  author       = {{Falcone, Guido J. and Kirsch, Elayna and Acosta, Julian N. and Noche, Rommell B. and Leasure, Audrey and Marini, Sandro and Chung, Jaeyoon and Selim, Magdy and Meschia, James F. and Brown, Devin L. and Worrall, Bradford B. and Tirschwell, David L. and Jagiella, Jeremiasz M. and Schmidt, Helena and Jimenez-Conde, Jordi and Fernandez-Cadenas, Israel and Lindgren, Arne and Slowik, Agnieszka and Gill, Dipender and Holmes, Michael and Phuah, Chia Ling and Petersen, Nils H. and Matouk, MD, Charles N. and Gunel, Murat and Sansing, Lauren and Bennett, Derrick and Chen, Zhengming and Sun, Luan L. and Clarke, Robert and Walters, Robin G. and Gill, Thomas M. and Biffi, Alessandro and Kathiresan, Sekar and Langefeld, Carl D. and Woo, Daniel and Rosand, Jonathan and Sheth, Kevin N. and Anderson, Christopher D.}},
  issn         = {{0364-5134}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{56--66}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Annals of Neurology}},
  title        = {{Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage}},
  url          = {{http://dx.doi.org/10.1002/ana.25740}},
  doi          = {{10.1002/ana.25740}},
  volume       = {{88}},
  year         = {{2020}},
}