Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage

Guido J. Falcone, Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
Elayna Kirsch, Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
Julian N. Acosta, Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
Rommell B. Noche, Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
Audrey Leasure, Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
Sandro Marini, Center for Genomic Medicine, Massachusetts General Hospital (MGH), Boston, MA, USA.
Jaeyoon Chung, Center for Genomic Medicine, Massachusetts General Hospital (MGH), Boston, MA, USA.
Magdy Selim, Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.
James F. Meschia, Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Devin L. Brown, Stroke Program, Department of Neurology, University of Michigan Health System, Ann Arbor, MI, USA.
Bradford B. Worrall, Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA, USA.
David L. Tirschwell, Stroke Center, Harborview Medical Center, University of Washington, Seattle, WA, USA.
Jeremiasz M. Jagiella, Department of Neurology, Jagiellonian University Medical College, Kraków, Poland.
Helena Schmidt, Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Graz, Austria.
Jordi Jimenez-Conde, Neurovascular Research Unit, Department of Neurology, Institut Municipal d'Investigacio' Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain.
Israel Fernandez-Cadenas, Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain.
Arne Lindgren, Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden.
Agnieszka Slowik, Department of Neurology, Jagiellonian University Medical College, Kraków, Poland.
Dipender Gill, Department of Epidemiology and Biostatistics and Department of Stroke Medicine, Imperial College London, London, UK.
Michael Holmes, Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
Chia-Ling Phuah, Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Nils H. Petersen, Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
Charles N. Matouk Md, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Murat Gunel, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Lauren Sansing, Division of Vascular Neurology and Stroke, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
Derrick Bennett, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
Zhengming Chen, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
Luan L. Sun, Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Robert Clarke, Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
Robin G. Walters, Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
Thomas M. Gill, Department of Internal Medicine, Geriatric Medicine, Yale School of Medicine, New Haven, CT, USA.

Document Type

Article

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 ). 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.

Medical Subject Headings

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)

Publication Date

7-1-2020

Publication Title

Annals of neurology

E-ISSN

1531-8249

Volume

88

Issue

1

First Page

56

Last Page

66

PubMed ID

32277781

Digital Object Identifier (DOI)

10.1002/ana.25740

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