Mendelian randomization analysis of cholesteryl ester transfer protein and subclinical atherosclerosis: A population-based study.
BACKGROUND
Several trials to prevent cardiovascular disease by inhibiting cholesteryl ester transfer protein (CETP) have failed, except Randomized EValuation of the Effects of Anacetrapib through Lipid-modification. Thus far, it is unclear to what extent CETP is causally related to measures of atherosclerosis.


OBJECTIVE
The aim of the article was to study the causal relationship between genetically determined CETP concentration and carotid intima-media thickness (cIMT) in a population-based cohort study.


METHODS
In the Netherlands Epidemiology of Obesity study, participants were genotyped, and cIMT was measured by ultrasonography. We examined the relation between a weighted genetic risk score for CETP concentration, based on 3 single-nucleotide polymorphisms that have previously been shown to largely determine CETP concentration and cIMT using Mendelian randomization in the total population and in strata by sex, Framingham 10-year risk, (pre)diabetes, high-density lipoprotein cholesterol, triglycerides, and statin use.


RESULTS
We analyzed 5655 participants (56% women) with a mean age of 56 (range 44-66) years, body mass index of 26 (range 17-61) kg/m2, and serum CETP of 2.47 (range 0.68-5.33) μg/mL. There was no evidence for a causal relation between genetically determined CETP and cIMT in the total population, but associations were differently directed in men (16 μm per μg/mL increase in genetically determined CETP; 95% confidence interval: -8, 39) and women (-8 μm; -25, 9). Genetically determined CETP appeared to be associated with cIMT in normoglycemic men (26 μm; -1, 52) and in (pre)diabetic women (48 μm; -2, 98).


CONCLUSION
In this population-based study, there was no causal relation between genetically determined CETP concentration and cIMT in the total population although we observed directionally differing effects in men and women. Stratified results suggested associations in individuals with different cardiometabolic risk factor profiles, which require replication.
['Christen|Tim|T|', 'Trompet|Stella|S|', 'Noordam|Raymond|R|', 'Blauw|Lisanne L|LL|', 'Gast|Karin B|KB|', 'Rensen|Patrick C N|PCN|', 'Willems van Dijk|Ko|K|', 'Rosendaal|Frits R|FR|', 'de Mutsert|Renée|R|', 'Jukema|J Wouter|JW|', '|||']
D000328:Adult D000368:Aged D000483:Alleles D050197:Atherosclerosis D015992:Body Mass Index D059168:Carotid Intima-Media Thickness D002784:Cholesterol D053480:Cholesterol Ester Transfer Proteins D015331:Cohort Studies D005260:Female D005838:Genotype D006801:Humans D008297:Male D057182:Mendelian Randomization Analysis D008875:Middle Aged D020641:Polymorphism, Single Nucleotide D012307:Risk Factors D014280:Triglycerides D014463:Ultrasonography
Mendelian randomization Atherosclerosis Cohort Epidemiology Reverse cholesterol transport