Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.

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.

• Authors: Guido J Falcone, Elayna Kirsch, Julian N Acosta, Rommell B Noche, Audrey Leasure, Sandro Marini, Jaeyoon Chung, Magdy Selim, James F Meschia, Devin L Brown, Bradford B Worrall, David L Tirschwell, Jeremiasz M Jagiella, Helena Schmidt, Jordi Jimenez-Conde, Israel Fernandez-Cadenas, Arne Lindgren, Agnieszka Slowik, Dipender Gill, Michael Holmes, Chia-Ling Phuah, Nils H Petersen, Charles N Matouk Md, Murat Gunel, Lauren Sansing, Derrick Bennett, Zhengming Chen, Luan L Sun, Robert Clarke, Robin G Walters, Thomas M Gill, Alessandro Biffi, Sekar Kathiresan, Carl D Langefeld, Daniel Woo, Jonathan Rosand, Kevin N Sheth, Christopher D Anderson, International Stroke Genetics Consortium
• Journal: Annals of neurology (Ann Neurol) Vol. 88 Issue 1 Pg. 56-66 (07 2020) ISSN: 1531-8249 [Electronic] United States
• PMID: 32277781 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 American Neurological Association.

Chemical References

• Cholesterol, HDL
• Cholesterol, LDL
• Triglycerides

Topics

• Aged
• Aged, 80 and over
• Cerebral Hemorrhage (blood, genetics)
• Cholesterol, HDL (blood, genetics)
• Cholesterol, LDL (blood, genetics)
• Female
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Triglycerides (blood, genetics)