Approved research

Association between ketohexokinase mutations and adverse cardiovascular risk factors and outcomes

Lay summary

Essential fructosuria (EF) is an asymptomatic condition caused by those mutations in the ketohexokinase (KHK) gene that lead to loss of the ability to metabolize fructose. EF occurs with a frequency of 1 in 100,000 to 130,000 individuals who have mutations in both copies of the KHK gene, resulting in an abnormal KHK protein. Given the high concentration of fructose in the typical Western diet, blocking the function of KHK and the normal processing of fructose is an intriguing potential target for drug development. Our proposal is to use the genetic data from the UK Biobank to identify a cohort of individuals with (likely undiagnosed) EF and compare the cardiovascular and metabolic profile of these individuals to that of a matched cohort of individuals without these KHK mutations. Cohorts will be compared on the basis of both concurrently measured outcomes, such as body mass index and lipid levels, as well as long-term clinical outcomes, including the onset of diabetes and/or ischemic heart disease. Results suggesting that human KHK 'knock-outs' have a favorable cardio-metabolic profile could help validate KHK as a therapeutic target and spur development of novel medicinal agents.