MTHFR and Stroke: Because such studies have properties similar to those of intention-to-treat analyses in randomized controlled trials,12 the problems of observational studies, eg, reverse causality and bias due to confounding factors, are avoided.13 In addition, genetic variants have larger effects on intermediate features than on the disease itself.14 The MTHFR C677T polymorphism is already established as an instrument: a study using Mendelian randomization reported that homocysteine level, as determined by MTHFR C677T gene variant, was associated with an increased risk for stroke.15