Higher blood pressure is associated with increased cardiovascular and renal disease and premature mortality. Although some of the biological pathways and disease endpoints linked to blood pressure changes are well understood, a large number of them remain unexplained. Higher blood pressure is associated with other risk factors for cardiovascular and renal disease, including dyslipideamia, hyperglycaemia and insulin resistance (referred to collectively as metabolites) and higher levels of inflammatory markers, which might mediate any causal effect of higher blood pressure on later disease. But associations with these other risk factors and their joint role in causing later disease could reflect several different alternatives:

1.Blood pressure causes variation in these other risk factors and via these effects causes later CVD and other diseases.

2.These other risk factors cause variation in blood pressure and the primary causal agents are the metabolites/inflammatory markers with blood pressure being more downstream and proximal to disease endpoints.

3.There is a bidirectional causal relationship between BP and metabolites/inflammatory markers

4.There is no causal relationship between blood pressure and metabolites/inflammatory markers, but rather the association is confounded, for example by socioeconomic position, lifestyle characteristics and obesity. .

In preliminary analyses, we have already identified a number of metabolites from the NMR platform that are strongly correlated with BP. We want to extend this work by using Mendelian randomization (MR) to determine whether the relationships are causal and if so which direction they are in (i.e. to distinguish which of the 3 alternatives listed above is most likely).

With UCLEB we can increase the number of available individuals to more than 30 000, all with blood pressure measurements, GWAS or other array genotyping, and NMR metabolites and inflammatory markers.

We will use the known BP genetic instruments to assess whether BP is causally related to the metabolites and inflammatory markers (alternative 1 or 3 above vs 4) and metabolite instruments from recent GWAS to test whether metabolites are causally related to BP (alternative 2 or 3 vs 4).