Causal relevance of blood lipid fractions in the development of carotid atherosclerosis mendelian randomization analysis

Sonia Shah, Juan Pablo Casas, Fotios Drenos, John Whittaker, John Deanfield, Daniel I. Swerdlow, Michael V. Holmes, Mika Kivimaki, Claudia Langenberg, Nick Wareham, Karl Gertow, Bengt Sennblad, Rona J. Strawbridge, Damiano Baldassarre, Fabrizio Veglia, Elena Tremoli, Bruna Gigante, Ulf De Faire, Meena Kumari, Philippa J. TalmudAnders Hamsten, Steve E. Humphries, Aroon D. Hingorani

Research output: Contribution to journalArticlepeer-review


Background-Carotid intima-media thickness (CIMT), a subclinical measure of atherosclerosis, is associated with risk of coronary heart disease events. Statins reduce progression of CIMT and coronary heart disease risk in proportion to the reduction in low-density lipoprotein cholesterol. However, interventions targeting triglycerides (TGs) or high-density lipoprotein cholesterol (HDL-C) have produced inconsistent effects on CIMT and coronary heart disease risk, making it uncertain whether such agents are ineffective for coronary heart disease prevention or whether CIMT is an inadequate marker of HDL-C or TG-mediated effects. We aimed to determine the causal association among the 3 major blood lipid fractions and common CIMT using mendelian randomization analysis. Methods and Results-Genetic scores specific for low-density lipoprotein cholesterol, HDL-C, and TGs were derived based on single nucleotide polymorphisms from a gene-centric array in ≈5000 individuals (Cardiochip scores) and from a genome-wide association meta-analysis in >100 000 individuals (Global Lipids Genetic Consortium scores). These were used as instruments in a mendelian randomization analysis in 2 prospective cohort studies. A genetically predicted 1 mmol/L higher low-density lipoprotein cholesterol concentration was associated with a higher common CIMT by 0.03 mm (95% confidence interval, 0.01-0.04) and 0.04 mm (95% confidence interval, 0.02-0.06) based on the Cardiochip and Global Lipids Genetic Consortium scores, respectively. HDL-C and TGs were not causally associated with CIMT. Conclusions-Our findings confirm a causal relationship between low-density lipoprotein cholesterol and CIMT but not with HDL-C and TGs. At present, the suitability of CIMT as a surrogate marker in trials of cardiovascular therapies targeting HDL-C and TGs is questionable and requires further study.

Original languageEnglish
Pages (from-to)63-72
Number of pages10
JournalCirculation: Cardiovascular Genetics
Issue number1
Publication statusPublished - Feb 2013


  • Carotid intima-media thickness
  • Lipids
  • Mendelian randomization

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics


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