Aims: Statins are first-line therapy for cardiovascular prevention, yet the effects of statins on lipoprotein subclasses and circulating fatty acids remain unclear. Statin usage may further influence other pathways beyond lipid lowering. We aim to assess the detailed metabolic effects of starting statin therapy by quantitative NMR metabolomics profiling in 4 longitudinal cohort studies with 2 20 years of follow-up (including ALSPAC mothers).

Hypotheses: Starting statin usage is associated of all LDL lipids to a similar extend, but deviating patterns may be observed for detailed VLDL subclasses and their cholesterol and triglyceride levels. We hypothesize that statin lower all fatty acid concentrations, but more so for omega-6 fatty acids than for omega-3 and mono-unsaturated fatty acids. Finally, we will assess the effects of statins on numerous small molecules (including amino acids, glycolysis precursors and ketone bodies) to examine potential non-lipid effects of statins. Longitudinal analyses will be corroborated by genetic analysis, using established genetic instruments to proxy the effect of the statin target: HMGCoA reductase inhibition. Analyses: Associations with starting statin usage with NMR-based metabolite data will be meta-analysed in 4 cohorts including ALSPAC mothers. Genetic associations of 2 SNPs in HMGCR will be tested in 9 population-based cohorts including ALSPAC children & mothers.

Confounding variables: Longitudinal analyses will be adjusted for age and sex. Genetic analyses will be adjusted for age, gender, and population structure if available.