title: Causal relevance of blood lipid fractions in the development of carotid atherosclerosis: Mendelian randomization analysis.
abstract: 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.
  
  
  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.
authors.affiliation: University College London Genetics Institute, University College London, London, United Kingdom.
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.forename: Juan-Pablo
authors.initials: JP
authors.lastname: Casas
authors.forename: Fotios
authors.initials: F
authors.lastname: Drenos
authors.forename: John
authors.initials: J
authors.lastname: Whittaker
authors.forename: John
authors.initials: J
authors.lastname: Deanfield
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Swerdlow
authors.forename: Michael V
authors.initials: MV
authors.lastname: Holmes
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.forename: Nick
authors.initials: N
authors.lastname: Wareham
authors.forename: Karl
authors.initials: K
authors.lastname: Gertow
authors.forename: Bengt
authors.initials: B
authors.lastname: Sennblad
authors.forename: Rona J
authors.initials: RJ
authors.lastname: Strawbridge
authors.forename: Damiano
authors.initials: D
authors.lastname: Baldassarre
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Veglia
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
authors.forename: Bruna
authors.initials: B
authors.lastname: Gigante
authors.forename: Ulf
authors.initials: U
authors.lastname: de Faire
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
mesh_terms: D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics; D002340:Carotid Artery Diseases / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D059168:Carotid Intima-Media Thickness; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood*
chemical_list: D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D014280:Triglycerides