Effect of genetic variants associated with plasma homocysteine levels on stroke risk

Ioana Cotlarciuc; Rainer Malik; Elizabeth G Holliday; Kourosh R Ahmadi; Guillaume Paré; Bruce M Psaty; Myriam Fornage; Nazeeha Hasan; Paul E Rinne; M Arfan Ikram; Hugh S Markus; Jonathan Rosand; Braxton D Mitchell; Steven J Kittner; James F Meschia; Joyce B J van Meurs; Andre G Uitterlinden; Bradford B Worrall; Martin Dichgans; Pankaj Sharma; METASTROKE and the International Stroke Genetics Consortium

doi:10.1161/STROKEAHA.114.005208

Effect of genetic variants associated with plasma homocysteine levels on stroke risk

Stroke. 2014 Jul;45(7):1920-4. doi: 10.1161/STROKEAHA.114.005208. Epub 2014 May 20.

Authors

Ioana Cotlarciuc¹, Rainer Malik², Elizabeth G Holliday², Kourosh R Ahmadi², Guillaume Paré², Bruce M Psaty², Myriam Fornage², Nazeeha Hasan², Paul E Rinne², M Arfan Ikram², Hugh S Markus², Jonathan Rosand², Braxton D Mitchell², Steven J Kittner², James F Meschia², Joyce B J van Meurs², Andre G Uitterlinden², Bradford B Worrall², Martin Dichgans², Pankaj Sharma²; METASTROKE and the International Stroke Genetics Consortium

Affiliations

¹ From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.). i.cotlarciuc@imperial.ac.uk.
² From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).

Abstract

Background and purpose: Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes.

Methods: Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs.

Results: One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes.

Conclusions: This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.

Keywords: genetic association studies; genetic risk score; homocysteine; stroke.

Publication types

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

MeSH terms

Brain Ischemia / blood
Brain Ischemia / genetics*
Cohort Studies
Europe
Genetic Association Studies*
Genetic Loci / genetics
Genetic Predisposition to Disease*
Genetic Variation*
Genome / genetics
Homocysteine / blood
Homocysteine / genetics*
Humans
Polymorphism, Single Nucleotide / genetics
Risk
Stroke / blood
Stroke / genetics*

Substances

Homocysteine

Abstract

Publication types

MeSH terms

Substances

Grants and funding