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Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.
Ann Neurol. 2020 07; 88(1):56-66.AN

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+Show Affiliations

Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.Center for Genomic Medicine, Massachusetts General Hospital (MGH), Boston, MA, USA.Center for Genomic Medicine, Massachusetts General Hospital (MGH), Boston, MA, USA.Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.Stroke Program, Department of Neurology, University of Michigan Health System, Ann Arbor, MI, USA.Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA, USA.Stroke Center, Harborview Medical Center, University of Washington, Seattle, WA, USA.Department of Neurology, Jagiellonian University Medical College, Kraków, Poland.Institute of Molecular Biology and Medical Biochemistry, Medical University Graz, Graz, Austria.Neurovascular Research Unit, Department of Neurology, Institut Municipal d'Investigacio' Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain. Program in Inflammation and Cardiovascular Disorders, Institut Municipal d'Investigacio' Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona, Spain.Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain.Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden. Department of Neurology, Skåne University Hospital, Lund, Sweden.Department of Neurology, Jagiellonian University Medical College, Kraków, Poland.Department of Epidemiology and Biostatistics and Department of Stroke Medicine, Imperial College London, London, UK.Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK. 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.Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.Division of Vascular Neurology and Stroke, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.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.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.Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK. 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.Department of Internal Medicine, Geriatric Medicine, Yale School of Medicine, New Haven, CT, USA.Center for Genomic Medicine, Massachusetts General Hospital (MGH), Boston, MA, USA. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA. Division of Behavioral Neurology, Department of Neurology, MGH, Boston, MA, USA. Division of Psychiatry, Department of Psychiatry, MGH, Boston, MA, USA.Center for Genomic Medicine, Massachusetts General Hospital (MGH), Boston, MA, USA. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA. Cardiovascular Disease Prevention Center, MGH, Boston, MA, USA.Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.Center for Genomic Medicine, Massachusetts General Hospital (MGH), Boston, MA, USA. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA. Department of Neurology, MGH, Boston, MA, USA. Henry and Allison McCance Center for Brain Health, MGH, Boston, MA, USA.Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.Center for Genomic Medicine, Massachusetts General Hospital (MGH), Boston, MA, USA. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA. Department of Neurology, MGH, Boston, MA, USA. Henry and Allison McCance Center for Brain Health, MGH, Boston, MA, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32277781

Citation

Falcone, Guido J., et al. "Genetically Elevated LDL Associates With Lower Risk of Intracerebral Hemorrhage." Annals of Neurology, vol. 88, no. 1, 2020, pp. 56-66.
Falcone GJ, Kirsch E, Acosta JN, et al. Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage. Ann Neurol. 2020;88(1):56-66.
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., ... Anderson, C. D. (2020). Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage. Annals of Neurology, 88(1), 56-66. https://doi.org/10.1002/ana.25740
Falcone GJ, et al. Genetically Elevated LDL Associates With Lower Risk of Intracerebral Hemorrhage. Ann Neurol. 2020;88(1):56-66. PubMed PMID: 32277781.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage. AU - Falcone,Guido J, AU - Kirsch,Elayna, AU - Acosta,Julian N, AU - Noche,Rommell B, AU - Leasure,Audrey, AU - Marini,Sandro, AU - Chung,Jaeyoon, AU - Selim,Magdy, AU - Meschia,James F, AU - Brown,Devin L, AU - Worrall,Bradford B, AU - Tirschwell,David L, AU - Jagiella,Jeremiasz M, AU - Schmidt,Helena, AU - Jimenez-Conde,Jordi, AU - Fernandez-Cadenas,Israel, AU - Lindgren,Arne, AU - Slowik,Agnieszka, AU - Gill,Dipender, AU - Holmes,Michael, AU - Phuah,Chia-Ling, AU - Petersen,Nils H, AU - Matouk Md,Charles N, AU - Gunel,Murat, AU - Sansing,Lauren, AU - Bennett,Derrick, AU - Chen,Zhengming, AU - Sun,Luan L, AU - Clarke,Robert, AU - Walters,Robin G, AU - Gill,Thomas M, AU - Biffi,Alessandro, AU - Kathiresan,Sekar, AU - Langefeld,Carl D, AU - Woo,Daniel, AU - Rosand,Jonathan, AU - Sheth,Kevin N, AU - Anderson,Christopher D, AU - ,, Y1 - 2020/05/07/ PY - 2019/09/27/received PY - 2020/04/01/revised PY - 2020/04/03/accepted PY - 2021/07/01/pmc-release PY - 2020/4/12/pubmed PY - 2020/10/21/medline PY - 2020/4/12/entrez SP - 56 EP - 66 JF - Annals of neurology JO - Ann Neurol VL - 88 IS - 1 N2 - 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. SN - 1531-8249 UR - https://www.unboundmedicine.com/medline/citation/32277781/Genetically_Elevated_LDL_Associates_with_Lower_Risk_of_Intracerebral_Hemorrhage_ L2 - https://doi.org/10.1002/ana.25740 DB - PRIME DP - Unbound Medicine ER -