Association of MTHFR C677T genotype with ischemic stroke is confined to cerebral small vessel disease subtype

Rutten-Jacobs, Loes C. A. and Traylor, Matthew and Adib-Samii, Poneh and Thijs, Vincent and Sudlow, Cathie and Rothwell, Peter M. and Boncoraglio, Giorgio and Dichgans, Martin and Meschia, James and Maguire, Jane and Levi, Christopher and Rost, Natalia S. and Rosand, Jonathan and Hassan, Ahamad and Bevan, Steve and Markus, Hugh S. (2016) Association of MTHFR C677T genotype with ischemic stroke is confined to cerebral small vessel disease subtype. Stroke: a Journal of Cerebral Circulation, 47 (3). pp. 646-651. ISSN 0039-2499

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Item Type:Article
Item Status:Live Archive

Abstract

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.

Keywords:Stroke, NotOAChecked
Subjects:C Biological Sciences > C400 Genetics
Divisions:College of Science > School of Life Sciences
ID Code:23604
Deposited On:01 Aug 2016 20:48

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