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Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study.
Stroke. 2018 04; 49(4):820-827.S

Abstract

BACKGROUND AND PURPOSE

Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR).

METHODS

Summary data on 185 genome-wide lipids-associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance-weighted MR was used to obtain the causal estimates. Inverse-variance-weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias.

RESULTS

A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04-1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10-1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67-0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes.

CONCLUSIONS

LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes.

Authors+Show Affiliations

From the Department of Clinical Sciences, Lund University, Malmö, Sweden (G.H., G.E., O.M., M.O.-M.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (G.H.); Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (S.C.L.); and Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, United Kingdom (M.T., H.S.M.). George.Hindy@med.lu.se.From the Department of Clinical Sciences, Lund University, Malmö, Sweden (G.H., G.E., O.M., M.O.-M.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (G.H.); Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (S.C.L.); and Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, United Kingdom (M.T., H.S.M.).From the Department of Clinical Sciences, Lund University, Malmö, Sweden (G.H., G.E., O.M., M.O.-M.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (G.H.); Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (S.C.L.); and Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, United Kingdom (M.T., H.S.M.).From the Department of Clinical Sciences, Lund University, Malmö, Sweden (G.H., G.E., O.M., M.O.-M.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (G.H.); Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (S.C.L.); and Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, United Kingdom (M.T., H.S.M.).From the Department of Clinical Sciences, Lund University, Malmö, Sweden (G.H., G.E., O.M., M.O.-M.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (G.H.); Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (S.C.L.); and Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, United Kingdom (M.T., H.S.M.).From the Department of Clinical Sciences, Lund University, Malmö, Sweden (G.H., G.E., O.M., M.O.-M.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (G.H.); Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (S.C.L.); and Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, United Kingdom (M.T., H.S.M.).From the Department of Clinical Sciences, Lund University, Malmö, Sweden (G.H., G.E., O.M., M.O.-M.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (G.H.); Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (S.C.L.); and Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, United Kingdom (M.T., H.S.M.).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

29535274

Citation

Hindy, George, et al. "Role of Blood Lipids in the Development of Ischemic Stroke and Its Subtypes: a Mendelian Randomization Study." Stroke, vol. 49, no. 4, 2018, pp. 820-827.
Hindy G, Engström G, Larsson SC, et al. Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study. Stroke. 2018;49(4):820-827.
Hindy, G., Engström, G., Larsson, S. C., Traylor, M., Markus, H. S., Melander, O., & Orho-Melander, M. (2018). Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study. Stroke, 49(4), 820-827. https://doi.org/10.1161/STROKEAHA.117.019653
Hindy G, et al. Role of Blood Lipids in the Development of Ischemic Stroke and Its Subtypes: a Mendelian Randomization Study. Stroke. 2018;49(4):820-827. PubMed PMID: 29535274.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study. AU - Hindy,George, AU - Engström,Gunnar, AU - Larsson,Susanna C, AU - Traylor,Matthew, AU - Markus,Hugh S, AU - Melander,Olle, AU - Orho-Melander,Marju, AU - ,, Y1 - 2018/03/13/ PY - 2017/10/13/received PY - 2018/01/19/revised PY - 2018/02/15/accepted PY - 2018/3/15/pubmed PY - 2019/4/10/medline PY - 2018/3/15/entrez KW - cholesterol, HDL KW - cholesterol, LDL KW - polymorphism, single nucleotide KW - stroke KW - triglycerides SP - 820 EP - 827 JF - Stroke JO - Stroke VL - 49 IS - 4 N2 - BACKGROUND AND PURPOSE: Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR). METHODS: Summary data on 185 genome-wide lipids-associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance-weighted MR was used to obtain the causal estimates. Inverse-variance-weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias. RESULTS: A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04-1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10-1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67-0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes. CONCLUSIONS: LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes. SN - 1524-4628 UR - https://www.unboundmedicine.com/medline/citation/29535274/Role_of_Blood_Lipids_in_the_Development_of_Ischemic_Stroke_and_its_Subtypes:_A_Mendelian_Randomization_Study_ L2 - https://www.ahajournals.org/doi/10.1161/STROKEAHA.117.019653?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -