Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 6, Issue 1, Pages 63-72Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.112.963140
Keywords
carotid intima-media thickness; lipids; mendelian randomization
Funding
- British Heart Foundation (BHF) [PG/07/133/24260, RG/08/008, SP/07/007/23671]
- BHF
- National Institutes of Health
- National Heart, Lung, and Blood Institute [HL36310]
- MRC Population Health Scientist Fellowship [G0802432]
- Medical Research Council
- Health and Safety Executive
- Department of Health
- National Institute on Aging [AG13196]
- Agency for Health Care Policy Research [HS06516]
- John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health
- European Commission [QLG1-CT-2002-00896]
- Swedish Heart-Lung Foundation
- Swedish Research Council [8691, 0593]
- Knut and Alice Wallenberg Foundation
- Torsten and Ragnar Soderberg Foundation
- Foundation for Strategic Research
- Stockholm County Council [562 183]
- Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet
- Stockholm County Council
- Academy of Finland [110413]
- BHF [RG2008/014]
- Italian Ministry of Health
- Magnus Bergwall Foundation
- MRC
- BHF Program
- Medical Research Foundation
- MRC [G0802432]
- National Heart, Lung, and Blood Institute
- [FS/2005/125]
- British Heart Foundation [PG/09/022/26739, RG/08/008/25291, SP/07/007/23671] Funding Source: researchfish
- Economic and Social Research Council [ES/J023299/1] Funding Source: researchfish
- Medical Research Council [MC_UU_12015/1, G0802432] Funding Source: researchfish
- ESRC [ES/J023299/1] Funding Source: UKRI
- MRC [MC_UU_12015/1, G0802432] Funding Source: UKRI
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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 approximate to 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. (Circ Cardiovasc Genet. 2013;6:63-72.)
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