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.1 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.2 It has been estimated that FH accounts for approximately 6% of CHD on a population basis.3

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.4 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.5-6 It has been estimated that apolipoprotein E4 is responsible for approximately 11% of CHD in the population.3

In this issue of JAMA, Thompson and colleagues7 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.8-9

The amount of information reviewed by Thompson et al7 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, HDL-cholesterol (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 meta-analysis that focused on the CETP TaqIB variants.10 The study by Thompson et al7 answers the call for a comprehensive analysis of the gene effects related to CETP, its metabolites, and CHD risk,11 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,7 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 metabolism affects risk for CHD on a population basis. The study includes data from a large number of participants and shows that CETP gene variants are associated with modest effects on intermediary metabolism related to CETP and HDL-C levels. Overall, gene variants related to CETP were associated with approximately 5% effects on CETP metabolites, similar percentage effects on HDL-C levels, and differences in expected directions related to CHD risk.

How can the current study be placed into a scientific perspective? An important strength is that the authors present gene data, information related to intermediary metabolism information, and CHD risk in the same article. Their scientific presentation allows a view through a lens that provides greater metabolic depth of field than usual, and lends insights into the pathophysiology of atherosclerosis that are not usually met with meta-analyses.

Do the study results affect what a clinician should think about the importance of reverse cholesterol transport? The answer is yes. Modestly greater HDL-C levels have been shown to be important determinants of reduced CHD risk in population studies,10 and CETP gene variants are one of the determinants of these HDL-C concentrations. A greater question is whether large-scale reviews related to gene variants and clinical outcomes affect current thinking about disease risk. In their article on mendelian randomization, Davey Smith and Ebrahim12 describe how genetic epidemiology can further the understanding of disease, such as with a common situation—a new genetic marker is associated with risk for a disease but it is uncertain where the science, clinical interpretation, and public health importance lead after that. Without effective interventions that can modify the related metabolic process, the result is scientific discovery and promise but no solutions.

Are the findings reported by Thompson et al7 confounded by other factors, and how should meta-analyses that use genetic information be interpreted? The current study effectively provides a triangulation of gene—metabolism—outcome effects. Similarly, Tracy13 has recently recommended "deep phenotyping" and detailed biochemical characterization of study participants to further the understanding of the role of genetic factors as risk factors for clinical disease. Such an approach can potentially involve many more metabolic markers, physiological measures, and assessments of subclinical disease processes than have been available in population research related to atherosclerosis in the past. The data reported by Thompson et al attempt to follow elements of this approach.

In the future, more summary analyses that include genetic information, metabolic information, and clinical outcomes should be expected. These studies help to understand the landscape of genes and disease, and also may help to discern how the environment interacts with genes to cause metabolic derangements and disease.14 In most cases, the overall effects of individual genes are not likely to be great, especially for a complex disease process like atherosclerosis for which many factors contribute to causality. Larger metabolic effects and disease relative risks may accompany less common alleles, such as with FH. On the other hand, small effects can generally be expected to accompany common alleles, such as with CETP variants. Population attributable risk estimates for the influence of low HDL-C on CHD risk range from 24% to 37%.3 The CETP variants help to explain some of this risk, but no doubt many more genes are involved and genetic interactions with other genes and specific environmental factors will also need to be investigated in greater depth to understand the contributions of HDL metabolism to risk of atherosclerotic disease.14

References

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