TY - JOUR
T1 - Association of MTHFR C677T Genotype with Ischemic Stroke Is Confined to Cerebral Small Vessel Disease Subtype
AU - Rutten-Jacobs, Loes C.A.
AU - Traylor, Matthew
AU - Adib-Samii, Poneh
AU - Thijs, Vincent
AU - Sudlow, Cathie
AU - Rothwell, Peter M.
AU - Boncoraglio, Giorgio
AU - Dichgans, Martin
AU - Meschia, James
AU - Maguire, Jane
AU - Levi, Christopher
AU - Rost, Natalia S.
AU - Rosand, Jonathan
AU - Hassan, Ahamad
AU - Bevan, Steve
AU - Markus, Hugh S.
N1 - Funding Information:
We thank all study staff and participants for their important contributions. Study-specifc collaborators are reported in the online-only Data Supplement. Collection of the UK Young Lacunar Stroke DNA Study (DNA Lacunar) was primarily supported by the Wellcome Trust (WT072952) with additional support from the Stroke Association (TSA 2010/01). Genotyping of the DNA Lacunar samples and Dr Traylor were supported by a Stroke Association Grant (TSA 2013/01). Genotyping of WTCCC2 ischemic stroke study was funded by the Wellcome Trust. The Oxford Vascular Study has been funded by Wellcome Trust, Wolfson Foundation, UK Stroke Association, British Heart Foundation, Dunhill Medical Trust, National Institute of Health Research (NIHR), Medical Research Council, and the NIHR Oxford Biomedical Research Centre. Funding for the genotyping at Massachusetts General Hospital was provided by the Massachusetts General Hospital-Deane Institute for the Integrative Study of Atrial Fibrillation and Stroke and the National Institute of Neurological Disorders and Stroke (U01 NS069208). Dr Rutten-Jacobs was supported by a Stroke Association/British Heart Foundation programme grant (TSA BHF 2010/01). Dr Adib-Samii was supported by a Medical Research Council (United Kingdom) training fellowship. Drs Markus and Bevan are supported by the National Institute for Health Research Cambridge University Hospitals Comprehensive Biomedical Research Centre. Dr Markus is supported by a National Institute for Health Research Senior Investigator award. Dr Thijs is supported by a Clinical Investigator Grant from the scientifc research fund, Fonds Wetenschappelijk Onderzoek Flanders. Dr Levi is supported by a National Health and Medical Research Council (NHMRC Australia) Practitioner Fellowship and the Australian Stroke Genetics Collaboration has received Project Grant support from the NHMRC (App 1010287). Dr Rost was supported by a National Institute of Neurological Disorders and Stroke grant (R01 NS082285-01). Professor Rothwell is in receipt of an NIHR Senior Investigator Award and a Wellcome Trust Senior Investigator Award. We also acknowledge the use of the facilities of the Acute Vascular Imaging Centre, Oxford, and the Cardiovascular Clinical Research Facility, Oxford. The sponsors of the study had no role in the study design, data collection, data analysis, interpretation, writing of the article, or the decision to submit the article for publication.
Publisher Copyright:
© 2016 American Heart Association, Inc.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - Elevated plasma homocysteine levels are associated with stroke. However, this might be a reflection of bias or confounding because trials have failed to demonstrate an effect from homocysteine lowering in stroke patients, although a possible benefit has been suggested in lacunar stroke. Genetic studies could potentially overcome these issues because genetic variants are inherited randomly and are fixed at conception. Therefore, we tested the homocysteine levels-associated genetic variant MTHFR C677T for association with magnetic resonance imaging-confirmed lacunar stroke and compared this with associations with large artery and cardioembolic stroke subtypes. Methods-We included 1359 magnetic resonance imaging-confirmed lacunar stroke cases, 1824 large artery stroke cases, 1970 cardioembolic stroke cases, and 14 448 controls, all of European ancestry. Furthermore, we studied 3670 ischemic stroke patients in whom white matter hyperintensities volume was measured. We tested MTHFR C677T for association with stroke subtypes and white matter hyperintensities volume. Because of the established association of homocysteine with hypertension, we additionally stratified for hypertension status. Results-MTHFR C677T was associated with lacunar stroke (P=0.0003) and white matter hyperintensity volume (P=0.04), but not with the other stroke subtypes. Stratifying the lacunar stroke cases for hypertension status confirmed this association in hypertensive individuals (P=0.0002), but not in normotensive individuals (P=0.30). Conclusions-MTHFR C677T was associated with magnetic resonance imaging-confirmed lacunar stroke, but not large artery or cardioembolic stroke. The association may act through increased susceptibility to, or interaction with, high blood pressure. This heterogeneity of association might explain the lack of effect of lowering homocysteine in secondary prevention trials which included all strokes.
AB - Elevated plasma homocysteine levels are associated with stroke. However, this might be a reflection of bias or confounding because trials have failed to demonstrate an effect from homocysteine lowering in stroke patients, although a possible benefit has been suggested in lacunar stroke. Genetic studies could potentially overcome these issues because genetic variants are inherited randomly and are fixed at conception. Therefore, we tested the homocysteine levels-associated genetic variant MTHFR C677T for association with magnetic resonance imaging-confirmed lacunar stroke and compared this with associations with large artery and cardioembolic stroke subtypes. Methods-We included 1359 magnetic resonance imaging-confirmed lacunar stroke cases, 1824 large artery stroke cases, 1970 cardioembolic stroke cases, and 14 448 controls, all of European ancestry. Furthermore, we studied 3670 ischemic stroke patients in whom white matter hyperintensities volume was measured. We tested MTHFR C677T for association with stroke subtypes and white matter hyperintensities volume. Because of the established association of homocysteine with hypertension, we additionally stratified for hypertension status. Results-MTHFR C677T was associated with lacunar stroke (P=0.0003) and white matter hyperintensity volume (P=0.04), but not with the other stroke subtypes. Stratifying the lacunar stroke cases for hypertension status confirmed this association in hypertensive individuals (P=0.0002), but not in normotensive individuals (P=0.30). Conclusions-MTHFR C677T was associated with magnetic resonance imaging-confirmed lacunar stroke, but not large artery or cardioembolic stroke. The association may act through increased susceptibility to, or interaction with, high blood pressure. This heterogeneity of association might explain the lack of effect of lowering homocysteine in secondary prevention trials which included all strokes.
KW - Cerebral small vessel disease
KW - MTHFR
KW - genetic association
KW - homocysteine
KW - hypertension
KW - lacunar stroke
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U2 - 10.1161/STROKEAHA.115.011545
DO - 10.1161/STROKEAHA.115.011545
M3 - Article
C2 - 26839351
AN - SCOPUS:84959303728
VL - 47
SP - 646
EP - 651
JO - Stroke
JF - Stroke
SN - 0039-2499
IS - 3
ER -