Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage

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

doi:10.1002/ana.25740

Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage

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 HolmesChia 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

Neurology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	56-66
Number of pages	11
Journal	Annals of neurology
Volume	88
Issue number	1
DOIs	https://doi.org/10.1002/ana.25740
State	Published - Jul 1 2020

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1002/ana.25740

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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, 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, CL, 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 2020, 'Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage', Annals of neurology, vol. 88, no. 1, pp. 56-66. https://doi.org/10.1002/ana.25740

@article{cfb891ac2de94114b297648d2c2baa41,

title = "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.",

author = "Falcone, {Guido J.} and Elayna Kirsch and Acosta, {Julian N.} and Noche, {Rommell B.} and Audrey Leasure and Sandro Marini and Jaeyoon Chung and Magdy Selim and Meschia, {James F.} and Brown, {Devin L.} and Worrall, {Bradford B.} and Tirschwell, {David L.} and Jagiella, {Jeremiasz M.} and Helena Schmidt and Jordi Jimenez-Conde and Israel Fernandez-Cadenas and Arne Lindgren and Agnieszka Slowik and Dipender Gill and Michael Holmes and Phuah, {Chia Ling} and Petersen, {Nils H.} and {Matouk, MD}, {Charles N.} and Murat Gunel and Lauren Sansing and Derrick Bennett and Zhengming Chen and Sun, {Luan L.} and Robert Clarke and Walters, {Robin G.} and Gill, {Thomas M.} and Alessandro Biffi and Sekar Kathiresan and Langefeld, {Carl D.} and Daniel Woo and Jonathan Rosand and Sheth, {Kevin N.} and Anderson, {Christopher D.}",

note = "Funding Information: This research has been conducted using the UK Biobank Resource. Financial support: G.J.F. receives grant support from the National Institutes of Health (K76AG059992 and R03NS112859), the American Heart Association (18IDDG34280056), the Yale Pepper Scholar Award (P30AG021342), and the Neurocritical Care Society Research Fellowship. T.M.G. receives grant support from the National Institutes of Health (P30AG021342 and K07AG043587). J.F.M. receives grant support from the Earl & Nyda Swanson Neurosciences Research Fund and the Harley N. and Rebecca N. Hotchkiss Endowed Fund in Neuroscience Research honoring Ken and Marietta. C.L.P. receives grant support from the American Heart Association (19CDA34620004). M.S. receives grant support from the National Institutes of Health (U01NS074425 and U01NS102289). M.H. receives grant support by the British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre and works in a unit that receives grant support from the UK Medical Research Council. S.M. receives grant support from the American Heart Association/American Stroke Association fellowship (18POST34080063). M.V.H. is supported by the British Heart Foundation (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. D.W. receives grant support from the National Institutes of Health (U24NS107200 and R01NS100417). J.R. receives grant support from the National Institutes of Health (R24NS092983, R01NS093870, T32NS100663, and R01NS100417). K.N.S. receives grant support from the National Institutes of Health (R03NS112859, U24NS107136, U24NS107215, and R01NR018335) and American Heart Association (17CSA33550004). C.D.A. receives grant support from the National Institutes of Health (K23NS086873 and R01NS103924), the American Heart Association (18SFRN34250007), the MGH Center for Genomic Medicine, and research grants from Bayer AG, and had has consulted for ApoPharma, Inc. Publisher Copyright: {\textcopyright} 2020 American Neurological Association",

year = "2020",

month = jul,

day = "1",

doi = "10.1002/ana.25740",

language = "English (US)",

volume = "88",

pages = "56--66",

journal = "Annals of neurology",

issn = "0364-5134",

publisher = "John Wiley and Sons Inc.",

number = "1",

}

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.

N1 - Funding Information: This research has been conducted using the UK Biobank Resource. Financial support: G.J.F. receives grant support from the National Institutes of Health (K76AG059992 and R03NS112859), the American Heart Association (18IDDG34280056), the Yale Pepper Scholar Award (P30AG021342), and the Neurocritical Care Society Research Fellowship. T.M.G. receives grant support from the National Institutes of Health (P30AG021342 and K07AG043587). J.F.M. receives grant support from the Earl & Nyda Swanson Neurosciences Research Fund and the Harley N. and Rebecca N. Hotchkiss Endowed Fund in Neuroscience Research honoring Ken and Marietta. C.L.P. receives grant support from the American Heart Association (19CDA34620004). M.S. receives grant support from the National Institutes of Health (U01NS074425 and U01NS102289). M.H. receives grant support by the British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre and works in a unit that receives grant support from the UK Medical Research Council. S.M. receives grant support from the American Heart Association/American Stroke Association fellowship (18POST34080063). M.V.H. is supported by the British Heart Foundation (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. D.W. receives grant support from the National Institutes of Health (U24NS107200 and R01NS100417). J.R. receives grant support from the National Institutes of Health (R24NS092983, R01NS093870, T32NS100663, and R01NS100417). K.N.S. receives grant support from the National Institutes of Health (R03NS112859, U24NS107136, U24NS107215, and R01NR018335) and American Heart Association (17CSA33550004). C.D.A. receives grant support from the National Institutes of Health (K23NS086873 and R01NS103924), the American Heart Association (18SFRN34250007), the MGH Center for Genomic Medicine, and research grants from Bayer AG, and had has consulted for ApoPharma, Inc. Publisher Copyright: © 2020 American Neurological Association

PY - 2020/7/1

Y1 - 2020/7/1

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.

AB - 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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JO - Annals of neurology

JF - Annals of neurology

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Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage

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