Causal Relevance of Blood Lipid Fractions in the Development of Carotid Atherosclerosis: Mendelian Randomization Analysis.

BACKGROUND: -Carotid intima-media thickness (CIMT), a subclinical measure of atherosclerosis, is associated with risk of coronary heart disease (CHD) events. Statins reduce progression of CIMT and CHD risk in proportion to the reduction in low-density lipoprotein cholesterol (LDL-C). However, interventions targeting triglycerides or high density lipoprotein cholesterol (HDL-C) have produced inconsistent effects on CIMT and CHD risk, making it uncertain whether such agents are ineffective for CHD prevention or whether CIMT is an inadequate marker of HDL-C or triglyceride-mediated effects. We aimed to determine the causal association between the three major blood lipid fractions and common CIMT using Mendelian randomisation (MR) analysis. METHODS AND RESULTS: -Gene scores specific for LDL-C, HDL-C and triglycerides were derived based on single nucleotide polymorphisms (SNPs) from a gene-centric array in around 5000 individuals (Cardiochip scores) and from a genome-wide association meta-analysis in over 100,000 individuals (Global Lipids Genetic Consortium (GLGC) scores). These were used as instruments in an MR analysis in two prospective cohort studies. A genetically-predicted 1 mmol/L higher LDL-C concentration was associated with a higher common CIMT by 0.03 mm (95% CI=0.01-0.04) and 0.04 mm (95% CI=0.02-0.06) based on the Cardiochip and GLGC scores, respectively. HDL-C and triglycerides were not causally associated with CIMT. CONCLUSIONS: -Our findings confirm a causal relationship between LDL-C and CIMT but not with HDL-C and triglycerides. At present, the suitability of CIMT as a surrogate marker in trials of cardiovascular therapies targeting HDL-C and triglycerides is questionable and requires further study.