Correspondence
Polymorphism of the Cholesteryl Ester Transfer Protein Gene
N Engl J Med 1998; 338:1624-1626May 28, 1998
- Article
To the Editor:
The study of polymorphism of the gene for cholesteryl ester transfer protein (CETP), reported by Kuivenhoven et al. (Jan. 8 issue),1 has negative implications in the era of managed care and cost containment. The authors demonstrated that in a population of middle-aged men, only those with a certain CETP genotype had a benefit from pravastatin therapy in the form of a delay in the angiographic progression of coronary atherosclerosis. This group of patients represented about one third of those studied. The implication is that someday only patients with a certain genotype will be given a reductase inhibitor to prevent the progression of atherosclerosis. This is wrong.
The benefits of reductase inhibitors go far beyond what we routinely measure.2 Reductase inhibitors have effects on cell proliferation, immune function, and macrophage metabolism that are independent of cholesterol lowering. They can improve endothelial function and decrease thrombogenesis. The purpose of the treatment of atherosclerosis is to decrease end points such as myocardial infarction, coronary-artery bypass surgery, percutaneous coronary angioplasty, and death. The polymorphism of the CETP gene predicted only the slowing of the angiographic progression of coronary disease.
There have been several well-designed randomized trials in which reductase inhibitors did favorably affect the outcome.3-5 Clinical decisions should be based on these studies. Analysis of genetic polymorphisms is still a research tool, and basing treatment on it can potentially deny persons lifesaving treatment. It does not belong in the clinical arena.
5 ReferencesMark R. Goldstein, M.D.
Healthplex, Springfield, PA 190641
Kuivenhoven JA ,Jukema JW ,Zwinderman AH , et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. N Engl J Med 1998;338:86-93
Full Text | Web of Science | Medline2
Vaughan CJ ,Murphy MB ,Buckley BM . Statins do more than just lower cholesterol. Lancet 1996;348:1079-1082[Erratum, Lancet 1997;349:214.]
CrossRef | Web of Science | Medline3
Scandinavian Simvastatin Survival Study Group
Web of Science | Medline4
Shepherd J ,Cobbe SM ,Ford I , et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-1307
Full Text | Web of Science | Medline5
Sacks FM ,Pfeffer MA ,Moye LA , et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-1009
Full Text | Web of Science | Medline
To the Editor:
Kuivenhoven et al. do not mention that the effect of the B1B2 CETP genotype on lipoprotein levels is likely to be influenced by environmental factors. In a case–control study, Fumeron et al. showed that high-density lipoprotein (HDL) cholesterol was increased in subjects with the B2B2 genotype only when they ingested at least 25 g of alcohol per day.1 In that study, the cardioprotective effect of the B2B2 CETP genotype was restricted to the subjects who consumed the highest amounts of alcohol. In a study of patients with insulin-dependent diabetes, we recently demonstrated that the ratio of very-low-density lipoprotein cholesterol plus low-density lipoprotein (LDL) cholesterol to HDL cholesterol fell in response to a linoleic acid–enriched, low-cholesterol diet in B1B1 homozygotes but not in B1B2 heterozygotes.2 Thus, it would be interesting to include alcohol intake and dietary composition in the analysis of the effect of this polymorphism of the CETP gene on the progression of coronary atherosclerosis.
In addition, Kuivenhoven et al. state that there was no difference in the plasma lipoprotein response to pravastatin in the B1B1, B1B2, and B2B2 genotype groups. This may not be true. Assuming that there were no differences in base-line LDL and HDL cholesterol levels between the pravastatin and placebo groups, it can be calculated that the ratio of LDL to HDL cholesterol fell from 4.9 to 2.9 (i.e., by 2.0) in the group with the B1B1 genotype. This ratio decreased from 4.6 to 2.9 (i.e., by 1.7) in the group with the B1B2 genotype and from 4.3 to 2.7 (i.e., by 1.6) in the group with the B2B2 genotype. These results suggest that the decrease in the ratio of LDL to HDL cholesterol may have been about 20 percent greater in the group with the B1B1 genotype than in the other groups. If this difference is significant, it may explain, at least in part, the more favorable outcome in the pravastatin-treated B1B1 homozygotes.
2 ReferencesRobin P.F. Dullaart, M.D., Ph.D.
University Hospital Groningen, 9700 RB Groningen, the NetherlandsArie van Tol, Ph.D.
Erasmus University, 3000 DR Rotterdam, the Netherlands1
Fumeron F ,Betoulle D ,Luc G , et al. Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction. J Clin Invest 1995;96:1664-1671
CrossRef | Web of Science | Medline2
Dullaart RP ,Hoogenberg K ,Riemens SC , et al. Cholesteryl ester transfer protein gene polymorphism is a determinant of HDL cholesterol and of the lipoprotein response to a lipid-lowering diet in type 1 diabetes. Diabetes 1997;46:2082-2087
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We demonstrated a relation between a common variant of the CETP locus and the progression of atherosclerosis in the Regression Growth Evaluation Statin Study (REGRESS). Specifically, our article describes the association between this gene locus and the angiographic response to pravastatin in a large cohort of men with angiographically documented atherosclerosis.
Drs. Dullaart and van Tol ask whether environmental factors such as the use of alcohol and dietary composition had any effect on the relation described. They also suggest that pravastatin may have differentially influenced LDL:HDL ratios among the patients with different TaqIB genotypes and that this may explain the differences in the angiographic outcome.
In our cohort, alcohol consumption did not affect the association between the TaqIB genotype and the angiographic outcome in the control group or the group treated with pravastatin. We were unable to test for the effects of dietary composition, but all our patients were adhering to the strict National Cholesterol Education Program Step 1 diet, so differential effects of diet on any variable are highly unlikely. Published studies of associations among the locus of the CETP gene, CETP plasma activities, lipoprotein levels, and environmental factors have yielded various results,1-4 perhaps because of differences in inclusion criteria or the ethnic background of subjects.
With regard to the effect of the LDL:HDL ratio on the clinical benefit in the three subgroups, the results are in keeping with our statement that the plasma lipoprotein response to pravastatin did not differ among the three groups. Testing for the LDL:HDL ratio as a possible confounder of the pharmacogenetic interaction described did not yield statistically significant results.
Unfortunately, Dr. Goldstein misinterpreted our data in stating that we demonstrated that pravastatin benefited only one third of the study population. We demonstrated that carriers of the B2B2 genotype, representing only 16 percent of our cohort, had less reduction in the progression of coronary atherosclerosis with pravastatin treatment than patients with the B1B2 or B1B1 genotype. Moreover, we stated that our results were valid only for the progression of coronary disease, not for clinical events. We share Dr. Goldstein's enthusiasm with regard to the pleiotropic effect of 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors and fully agree that stratification according to genetic polymorphisms does not (yet) belong in the clinical arena.
4 ReferencesJan Albert Kuivenhoven, Ph.D.
Massachusetts Institute of Technology, Cambridge, MA 02139John J.P. Kastelein, M.D.
Academic Medical Center, 1105 AZ Amsterdam, the Netherlands1
Kondo I ,Berg K ,Drayna D ,Lawn R . DNA polymorphism at the locus for human cholesteryl ester transfer protein (CETP) is associated with high density lipoprotein cholesterol and apolipoprotein levels. Clin Genet 1989;35:49-56
CrossRef | Web of Science | Medline2
Fumeron F ,Betoulle D ,Luc G , et al. Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction. J Clin Invest 1995;96:1664-1671
CrossRef | Web of Science | Medline3
Hannuksela ML ,Liinamaa MJ ,Kesaniemi YA ,Savolainen MJ . Relation of polymorphisms in the cholesteryl ester transfer protein gene to transfer protein activity and plasma lipoprotein levels in alcohol drinkers. Atherosclerosis 1994;110:35-44
CrossRef | Web of Science | Medline4
Freeman DJ ,Griffin BA ,Holmes AP , et al. Regulation of plasma HDL cholesterol and subfraction distribution by genetic and environmental factors: associations between the TaqIB RFLP in the CETP gene and smoking and obesity. Arterioscler Thromb 1994;14:336-344
CrossRef | Medline
- Citing Articles (2)
Citing Articles
1
Michael M Hoffmann, Bernhard R Winkelmann, Heinrich Wieland, Winfried März. (2001) The significance of genetic polymorphisms in modulating the response to lipid-lowering drugs. Pharmacogenomics 2:2, 107-121
CrossRef2
Jose M. Ordovas, Ernst J. Schaefer. (1999) Treatment of dyslipidemia: Genetic interactions with diet and drug therapy. Current Atherosclerosis Reports 1:1, 16-23
CrossRef
