CETP Genes, Metabolic Effects, and Coronary Disease Risk
Authors: Peter W. F. Wilson
Journal: JAMA (2008)

THE BURDEN OF ATHEROSCLEROTIC CORONARY HEART disease (CHD) is tremendous—both genes and environment contribute to this problem. From a clinical perspective, physicians are well aware of the importance of genetic lipid abnormalities in the causation of CHD. The best studied genetic lipid abnormality is familial hypercholesterolemia (FH), which can cause clinical findings such as xanthomas, early atherosclerosis, and premature CHD. Approximately 1 out of 500 of the population are FH heterozygotes and 1 out of 1 000 000 are homozgotes. It has been estimated that FH accounts for approximately 6% of CHD on a population basis. The availability of widespread gene testing in population studies has turned the tables, and now it is possible to investigate the role of gene variants that initially do not manifest with clinical signs and symptoms. For example, apolipoprotein E4 variants are common and affect more than 20% of the population, and also are associated with higher low-density lipoprotein cholesterol (LDL-C) levels and increased CHD risk. It has been estimated that apolipoprotein E4 is responsible for approximately 11% of CHD in the population. In this issue of JAMA, Thompson and colleagues summarize information related to cholesteryl ester transfer protein (CETP) genotypes, CETP metabolic action, lipoprotein cholesterol levels, and CHD risk. Cholesteryl ester transfer protein is involved in intermediary cholesterol trafficking as an important regulator of reverse cholesterol transport. High-density lipoprotein (HDL) particles absorb cholesterol from the arterial wall, transfer this lipid to other plasma lipid particles via CETP, and the transferred cholesterol is subsequently delivered to the liver. There is great interest in developing pharmacological agents to favorably affect these mechanisms, up-regulate reverse cholesterol transport, and potentially reduce atherosclerosis via this pathway. The amount of information reviewed by Thompson et al is massive—their review includes data from more than 113 000 individuals across 92 studies. The authors provide summary analyses related to CETP genotype effects on biochemical phenotypes related to CETP metabolism, HDLcholesterol (HDL-C) level (a traditional risk factor for which the blood level is partly determined by CETP activity), and CHD risk estimates. The CETP genotype relationship to CHD risk reported by Thompson et al is similar to that reported in a metaanalysis that focused on the CETP TaqIB variants. The study by Thompson et al answers the call for a comprehensive analysis of the gene effects related to CETP, its metabolites, and CHD risk, and differs from previous analyses by including much more data, especially concerning the intermediate biomarkers related to CETP metabolism, and by providing information on CETP gene variants other than TaqIB. The authors also report that CETP variants are common and the alleles they investigate affect at least half of the population. As shown in Figure 2 in the article by Thompson et al, CETP gene variants were associated with a CETP mass that was typically reduced by approximately 6% to 10%, CETP activity was 6% to 9% lower, HDL-C levels ranged from 3% to 5% higher, apolipoprotein A-I levels were 1% to 2% lower, and triglycerides were typically 2% lower. The CETP gene variant associations were also associated with modestly favorable effects on LDL-C (0 to −2%) and apolipoprotein B (typically approximately −2%). The associations with LDL-C and apolipoprotein B might not have been anticipated because CETP is largely considered a facilitator of reverse cholesterol transport and gene variants of CETP would probably not be expected to be associated with favorable effects on other metabolic pathways. The authors demonstrate that genetic variants of CETP are relatively common—minor allele frequencies are −631C A (8%), −629C A (48%-52%), TaqIB (42%), I405V (35%-42%), and D442G ( 1%-3%). The associations between CETP mass and function are consistently in expected directions and would be anticipated to favorably affect HDL-C levels. Does this study change what clinicians should think about genes and CHD risk? This investigation broadens the field and shows that a genotype intimately related to HDL me-