MTHFR C677T genotype and small vessel disease

BACKGROUND AND PURPOSE: 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.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 ischaemic 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. Dr Markus and Dr 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 scientific 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 manuscript, or the decision to submit the manuscript for publication.This is the final version of the article. It first appeared from the American Heart Association via http://dx.doi.org/10.1161/STROKEAHA.115.01154

Increased Risk of Pregnancy Complications After Stroke : The FUTURE Study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation)

Background and Purpose-The study goal was to investigate the prevalence of pregnancy complications and pregnancy loss in women before, during, and after young ischemic stroke/transient ischemic attack. Methods-In the FUTURE study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation), a prospective young stroke study, we assessed the occurrence of pregnancy, miscarriages, and pregnancy complications in 223 women aged 18 to 50 years with a first-ever ischemic stroke/transient ischemic attack. Pregnancy complications (gestational hypertension, diabetes mellitus, preeclampsia, and hemolysis, elevated liver enzymes, low platelet count syndrome) were assessed before, during, and after stroke using standardized questionnaires. Primary outcome was occurrence of pregnancy complications and the rate of pregnancy loss compared with the Dutch population. Secondary outcome was the risk of recurrent vascular events after stroke, stratified by a history of hypertensive disorder in pregnancy. Results-Data were available for 213 patients. Mean age at event was 39.6 years (SD=7.8) and mean follow-up 9.5 years (SD=8.5). Miscarriages occurred in 35.2% and fetal death in 6.2% versus 13.5% and 0.9% in the Dutch population, respectively (P<0.05). In nulliparous women after stroke (n=22), in comparison with Dutch population, there was a high prevalence of hypertensive disorders in pregnancy (33.3 versus 12.2%; P<0.05), hemolysis, elevated liver enzymes, low platelet count syndrome (9.5 versus 0.5%; P<0.05), and early preterm delivery <32 weeks (9.0 versus 1.4%; P<0.05). In primi/multiparous women (n=141) after stroke, 29 events occurred (20-year cumulative risk 35.2%; 95% confidence interval, 21.3-49.0), none during subsequent pregnancies, and a history of a hypertensive disorder in pregnancy did not modify this risk (log-rank P=0.62). Conclusions-When compared with the general population, women with young stroke show higher rates of pregnancy loss throughout their lives. Also, after stroke, nulliparous women more frequently experienced serious pregnancy complications