Alexander E. Merkler, MD

Rutten-Jacobs LCA, Traylor M, Adib-Samii P, Thijs V, Sudlow C, Rothwell PM, et al. Association of MTHFR C677T Genotype With Ischemic Stroke Is Confined to Cerebral Small Vessel Disease Subtype. Stroke. 2016

Discovering modifiable risk factors of ischemic stroke is the future of stroke prevention. Hyperhomocysteinemia is associated with an increased risk of stroke and the most common MHTFR mutation, the MHTFR C677T mutation, leads to increased levels of homocysteine. However, previous studies evaluating the effect of lowering homocysteine levels with B vitamins have been negative in terms of reducing overall stroke risk. 

In the current manuscript, Dr. Rutten-Jacobs et al evaluate the association between the MHTFR C677T variant and small vessel disease. The authors evaluated the association between the MHTFR C677T mutation and both stroke subtype and white matter hyperintensity volume under the hypothesis that hyperhomocysteinemia only increases the risk of small vessel disease. In addition, as previous literature has shown an association between hypertension and homocysteine, the authors stratified patients by the presence of hypertension.

The authors identified 1359 cases of lacunar strokes, almost 4000 cases of large vessel and cardioembolic strokes and over 14 000 controls. The MHTFR C677T mutation was significantly associated with lacunar stroke and white matter hyperintensity volume, but not with other stroke subtypes. Furthermore, stratifying the lacunar strokes by hypertension status, confirmed the association the MHTFR C677T mutation with lacunar strokes in hypertensive, but not in normotensive patients.

The MHTFR C677T variant is associated with an elevated risk of specifically lacunar stroke and in patients who are hypertensive. The study adds further support that hyperhomocysteinemia is a risk factor for small vessel disease but not other subtypes of ischemic stroke. The manuscript should serve as a prime example of the importance of correctly choosing an outcome – perhaps B vitamins may successfully reduce stroke in patients with hyperhomocysteinemia when specifically lacunar stroke is chosen as the outcome of interest.