Figure 5 Mendelian randomization of biomarkers on the same pathway Figure 5 | Mendelian randomization of biomarkers on the same pathway. a | Individuals who are homozygous for the ALDH2*1 variant can consume normal amounts of alcohol without symptoms of flushing and nausea, which can lead to increased alcohol intake and subsequent high blood pressure. However, because acetaldehyde is efficiently cleared by aldehyde dehydrogenase (ALDH2), the risk of oesophageal cancer is low. b | Individuals who are heterozygous for ALDH2*2 are likely to consume lower amounts of alcohol than those who are homozygous for the ALDH2*1 variant, given their symptoms of moderate flushing. This lower alcohol consumption leads to lower blood pressure. Reduced functioning of ALDH2 leads to increased acetaldehyde levels, which in turn results in increased risk of oesophageal cancer. c | Individuals homozygous for ALDH2*2 consume almost no alcohol, given the severe symptoms and, therefore, blood pressure levels are expected to be lower than in those who are heterozygous for ALDH2*2 or homozygous for the ALDH2*1 variant. Similarly, acetaldehyde levels in individuals homozygous for ALDH2*2 are also expected to be lower than in individuals heterozygous for the ALDH2*2 variant, resulting in lower risk of oesophageal cancer (and similar to or lower than carriers of ALDH2*1*1, depending on alcohol consumption). These figures are schematic representations and should not be interpreted as formal directed acyclic graphs. Holmes, M. V. et al. (2017) Mendelian randomization in cardiometabolic disease: challenges in evaluating causality Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.78