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

Shah S., Casas J.-P., Drenos F., Whittaker J., Deanfield J., Swerdlow D.I., Holmes M.V., Kivimaki M., Langenberg C., Wareham N., Gertow K., Sennblad B., Strawbridge R.J., Baldassarre D., Veglia F., Tremoli E., Gigante B., De Faire U., Kumari M., Talmud P.J., Hamsten A., Humphries S.E. and Hingorani A.D. (2013) Causal relevance of blood lipid fractions in the development of carotid atherosclerosis mendelian randomization analysis. Circulation: Cardiovascular Genetics, 6 1: 63-72. doi:10.1161/CIRCGENETICS.112.963140

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Author Shah S.
Casas J.-P.
Drenos F.
Whittaker J.
Deanfield J.
Swerdlow D.I.
Holmes M.V.
Kivimaki M.
Langenberg C.
Wareham N.
Gertow K.
Sennblad B.
Strawbridge R.J.
Baldassarre D.
Veglia F.
Tremoli E.
Gigante B.
De Faire U.
Kumari M.
Talmud P.J.
Hamsten A.
Humphries S.E.
Hingorani A.D.
Title Causal relevance of blood lipid fractions in the development of carotid atherosclerosis mendelian randomization analysis
Journal name Circulation: Cardiovascular Genetics   Check publisher's open access policy
ISSN 1942-325X
Publication date 2013-02-01
Year available 2012
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1161/CIRCGENETICS.112.963140
Open Access Status File (Author Post-print)
Volume 6
Issue 1
Start page 63
End page 72
Total pages 10
Place of publication New York, United States
Publisher Lippincott Williams & Wilkins
Language eng
Subject 2705 Cardiology and Cardiovascular Medicine
2716 Genetics (clinical)
1311 Genetics
Formatted 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.

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.
Keyword Carotid intima-media thickness
Mendelian randomization
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID PG/07/133/24260
562 183
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Non HERDC
Queensland Brain Institute Publications
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