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 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

Neurology

Yale University
Massachusetts General Hospital
Harvard University
Mayo Clinic Florida
University of Michigan, Ann Arbor
University of Virginia
University of Washington
Jagiellonian University Medical College
Medical University of Graz
Autonomous University of Barcelona
Lund University
Imperial College London
University of Oxford
Washington University St. Louis
University of Cambridge
The Broad Institute of MIT and Harvard
Wake Forest University

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

55 Scopus citations

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
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

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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

@article{f4082775ef1246c3b32ae0d5dada9c21,

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 {\texttimes} 10-100). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95\% confidence interval [CI] = 0.85{\textendash}0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95\% CI = 0.81{\textendash}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{\textendash}0.98; p = 0.03) and 41\% lower risks of ICH (OR = 0.59; 95\% CI = 0.42{\textendash}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{\textendash}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 = "Publisher Copyright: {\textcopyright} 2020 American Neurological Association",

year = "2020",

month = jul,

day = "1",

doi = "10.1002/ana.25740",

language = "English",

volume = "88",

pages = "56--66",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley \& Sons Inc.",

number = "1",

}

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

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.

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.

UR - https://www.scopus.com/pages/publications/85085108436

U2 - 10.1002/ana.25740

DO - 10.1002/ana.25740

M3 - Article

C2 - 32277781

AN - SCOPUS:85085108436

SN - 0364-5134

VL - 88

SP - 56

EP - 66

JO - Annals of Neurology

JF - Annals of Neurology

IS - 1

ER -

Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage

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