Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms

<b>Background</b>: Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. <b>Methods and Results</b>: We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI –0.28 to 0.60 mm Hg) and diastolic blood pressure (–0.04 mm Hg, 95% CI –0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. <b>Conclusions</b>: Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans

Molecular phylogenetic and biogeographical analysis of Nitraria based on nuclear and chloroplast DNA sequences

Based upon DNA sequences from six plastid regions (rbcL, psbB-psbH, trnL-trnF, rpS16, psbA-trnH, rpS16-trnK) and the internal transcribed spacer (ITS) region of nuclear ribosomal DNA, the phylogenetic relationships in the genus Nitraria and family Nitrariaceae are investigated by using methods of maximum parsimony, maximum likelihood, and Bayesian inference. Our study strongly supports the monophyly of Nitraria. Nitraria can be divided into four parts, namely, the N. sphaerocarpa group, N. retusa group, the N. roborowskii and N. tangutorum group, and a group consisting of N. schoberi, N. komarovii, N. sibirica, and N. billardieri. Ancestral area reconstruction using S-Diva shows that eastern Central Asia is most likely the place of origin, and then dispersals occurred to western Central Asia, Africa, and Australia