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Relative effects of LDL-C on ischemic stroke and coronary disease A Mendelian randomization study

Journal article
Authors E. Valdes-Marquez
S. Parish
R. Clarke
T. Stari
B. B. Worrall
J. C. Hopewell
A. Slowik
A. Hofman
A. Algra
A. P. Reiner
A. S. F. Doney
A. Gschwendtner
A. Ilinca
A. K. Giese
A. Lindgren
A. M. Vicente
B. Norrving
B. G. Nordestgaard
B. D. Mitchell
B. M. Psaty
C. L. Carty
C. L. M. Sudlow
C. Anderson
C. R. Levi
C. L. Satizabal
C. N. A. Palmer
D. M. Gamble
D. Woo
D. Saleheen
E. B. Ringelstein
E. M. Valdimarsson
E. G. Holliday
G. Davies
G. Chauhan
G. Pasterkamp
G. B. Boncoraglio
G. Kuhlenbaumer
G. Thorleifsson
G. J. Falcone
G. Pare
H. Schmidt
H. Delavaran
H. S. Markus
H. J. Aparicio
I. Deary
I. Cotlarciuc
I. Fernandez-Cadenas
J. F. Meschia
J. M. Liu
J. Montaner
J. Pera
J. Cole
J. R. Attia
J. Rosand
J. M. Ferro
J. C. Bis
K. Furie
K. Stefansson
K. Berger
K. Kostulas
K. Rannikmae
M. A. Ikram
M. Benn
M. Dichgans
M. Pandolfo
M. Traylor
M. Walters
M. Sale
M. A. Nalls
M. Fornage
N. R. van Zuydam
P. Sharma
P. Abrantes
P. I. W. de Bakker
P. Higgins
P. Lichtner
P. M. Rothwell
P. Amouyel
Q. Yang
R. Malik
R. Schmidt
R. Lemmens
S. W. van der Laan
S. L. Pulit
S. Abboud
S. A. Oliveira
S. Gretarsdottir
S. Debette
S. R. Williams
S. Bevan
S. J. Kittner
S. Seshadri
T. Mosley
T. W. K. Battey
Turgut Tatlisumak
U. Thorsteinsdottir
V. N. S. Thijs
W. T. Longstreth
W. Zhao
W. M. Chen
Y. C. Cheng
Isgc, Isgc,
Published in Neurology
Volume 92
Issue 11
Pages E1176-E1187
ISSN 0028-3878
Publication year 2019
Published at Institute of Neuroscience and Physiology
Pages E1176-E1187
Language en
Links dx.doi.org/10.1212/wnl.000000000000...
Keywords density-lipoprotein-cholesterol, risk-factors, heart-disease, genetic-variants, statin therapy, metaanalysis, subtypes, pcsk9, reduction, bmi, Neurosciences & Neurology
Subject categories Neuroscience

Abstract

Objective To examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach. We undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity. A 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68, p = 1.1 x 10(-8)). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 x 10(-3)) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 x 10(-3)) when compared with that for CHD. In contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.

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