Cholesteryl Ester Transfer Protein (CETP) Genotype and Reduced CETP Levels Associated With Decreased Prevalence of Hypertension

OBJECTIVES: To clarify whether reduced cholesteryl ester transfer protein (CETP) activity carries inherent blood pressure risks and to infer whether the increased blood pressure and elevated mortality associated with torcetrapib are idiosyncratic or characteristic of this class of drugs.PATIENTS AND METHODS: We examined the associations among CETP genotype, phenotype, and blood pressure in a cohort of 521 older adults (who have complete data for the variables required in our primary analysis) enrolled between November 1, 1998, and June 30, 2003, in our ongoing studies of genes associated with longevity, including a cohort with a high prevalence of a genotype coding for a reduced activity variant of CETP and low levels of CETP.RESULTS: The prevalence of hypertension was actually lower among homozygotes for the variant CETP (48% vs 60% among those with wild-type and 65% among heterozygotes; P=.03). Low levels of CETP were associated with reduced prevalence of hypertension (65% in highest tertile, 59% in middle tertile, and 55% in lowest tertile; P=.04) and lower systolic blood pressure (140.8, 138.1, 136.2 mm Hg, respectively; P=.03).CONCLUSION: Reduced levels of CETP are associated with lower, not higher, blood pressure. The adverse results with torcetrapib, if mediated through blood pressure, are likely to represent effects of this specific drug, rather than a result of lower CETP levels.CETP = cholesteryl ester transfer protein; CI = confidence interval; HDL = high-density lipoprotein; LDL = low-density lipoprotein; SNP = single nucleotide polymorphismA decrease in cholesteryl ester transfer protein (CETP) leads to increased high-density lipoprotein (HDL) cholesterol levels and lipoprotein particle size, which may provide significant cardiovascular protection.¹ Earlier work by our group has shown that homozygosity for a single nucleotide polymorphism (SNP), resulting in substitution of valine (V) for isoleucine (I) at codon 405 in the CETP gene, is overrepresented in centenarians.² Therefore, this finding, validated in an independent study,³ suggests that this mutation may contribute to healthy aging by protection from several age-related diseases.⁴ Individuals homozygous for this SNP have decreased CETP levels, increased HDL cholesterol levels, and increased lipoprotein particle sizes. Homozygosity for this SNP is seen significantly more often in the offspring of parents with exceptional longevity than in the offspring of parents with shorter life spans.² Furthermore, a recent review found a consistent association between lower CETP levels, caused by several different genotypes, and decreased risk of coronary artery disease.⁵ These observations suggest that interventions that reduce CETP levels might promote cardiovascular health and contribute to longevity.Despite the potential cardiovascular benefits of lower CETP levels, a phase 3 trial of torcetrapib, a CETP inhibitor, was terminated early because of increased risk of death due to cardiovascular disease in the active treatment group.⁶ Torcetrapib has been associated with increased blood pressure,⁷ which is suspected of contributing to the observed increase in mortality. Other investigators have called for investigation of the connection between low CETP levels and blood pressure.⁸To examine whether naturally occurring CETP polymorphism, decreased CETP levels, increased HDL cholesterol levels, and increased lipoprotein particle sizes are associated with increased blood pressure, we analyzed data from our cohorts of older adults. We reasoned that if blood pressure is independent of spontaneous CETP levels, the problems found in the torcetrapib trial may be specific collateral effects of that drug and not generalizable to its pharmacological class. However, if reduction in CETP levels, due to genetic or other causes, is associated with increased blood pressure, beneficial effects of low CETP levels may apply only to those who have lived to old age or it may be that resulting higher blood pressure levels are tolerated because of other beneficial effects.