Pamela A. McCaskie

Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms

Background— 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. Methods and Results— 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. Conclusions— 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.

SimHap GUI: An intuitive graphical user interface for genetic association analysis

BackgroundResearchers wishing to conduct genetic association analysis involving single nucleotide polymorphisms (SNPs) or haplotypes are often confronted with the lack of user-friendly graphical analysis tools, requiring sophisticated statistical and informatics expertise to perform relatively straightforward tasks. Tools, such as the SimHap package for the R statistics language, provide the necessary statistical operations to conduct sophisticated genetic analysis, but lacks a graphical user interface that allows anyone but a professional statistician to effectively utilise the tool.ResultsWe have developed SimHap GUI, a cross-platform integrated graphical analysis tool for conducting epidemiological, single SNP and haplotype-based association analysis. SimHap GUI features a novel workflow interface that guides the user through each logical step of the analysis process, making it accessible to both novice and advanced users. This tool provides a seamless interface to the SimHap R package, while providing enhanced functionality such as sophisticated data checking, automated data conversion, and real-time estimations of haplotype simulation progress.ConclusionSimHap GUI provides a novel, easy-to-use, cross-platform solution for conducting a range of genetic and non-genetic association analyses. This provides a free alternative to commercial statistics packages that is specifically designed for genetic association analysis.

The C-480T hepatic lipase polymorphism is associated with HDL-C but not with risk of coronary heart disease

High‐density lipoprotein cholesterol (HDL‐C) is a known predictor of coronary heart disease (CHD). Studies have shown that the C‐480T polymorphism of the hepatic lipase (HL) gene is predictive of HDL‐C; however, its observed relationship with the risk of CHD has been inconsistent. We analysed four biallelic polymorphisms in the HL gene in participants from three independent Western Australian populations. Samples were collected from two cross‐sectional studies of 1111 and 4822 community‐based subjects assessed for cardiovascular risk factors, and a third sample of 556 subjects with physician‐diagnosed CHD. Genotypes were tested for association with plasma lipids and the risk of CHD. All polymorphisms were highly correlated (D′ > 0.97, r2 > 0.90); therefore, only C‐480T was analysed. The −480T allele was significantly associated with an increase in HDL‐C of between 0.08 and 0.16 mmol/l in all three populations (p < 0.001). No associations with other lipids were observed, nor was an association with CHD in a case–control study of males. The TT genotype was however associated with decreased risk of myocardial infarction among cases (odds ratio = 0.39, 95% confidence interval = 0.19–0.78, p = 0.008). These findings replicate those of previous studies in three independent populations and suggest that the genetic determinants of CHD are complex and cannot be entirely explained through intermediate phenotypes.

Association of PPARγ allelic variation, osteoprotegerin and abdominal aortic aneurysm

Objective  We have previously demonstrated high concentrations of the glycoprotein osteoprotegerin (OPG) in biopsies of abdominal aortic aneurysm (AAA), and demonstrated that ligation of the nuclear receptor peroxisome proliferator‐activated receptor gamma (PPARγ) downregulates OPG in vitro and within a mouse model. The aims of this study were to assess the associations between circulating concentrations of OPG, polymorphisms of the gene encoding PPARγ (PPARG), AAA presence and growth.

Associations between anxious-depressed symptoms and cardiovascular risk factors in a longitudinal childhood study

OBJECTIVE To examine the influence of anxious/depressed scores on cardiovascular risk factors throughout childhood. METHODS Data from the Western Australian Pregnancy Cohort (Raine) Study, a study of 2900 pregnancies recruited between 1989 and 1991, were used. Anxious-depressed scores (derived from the Childhood Behavior Checklist), body mass index (BMI) and blood pressure were measured at 5 (n=1681), 8 (n=1697), 10 (n=1575) and 14 (n=1386) years. At age 14 depressive symptom scores (Beck Depression Inventory for Youth), anxious-depressed scores (Youth Self-Report (YSR) and Teacher Report Form (TRF)) and fasting lipid, glucose and insulin were also available. Cross sectional and longitudinal analyses were conducted. RESULTS At age 14, girls with higher anxious-depressed scores had higher BMI (p≤ 0.005) and homeostasis model assessment-estimated insulin resistance (p≤ 0.0001). This equated to a difference of 0.6 kg/m(2) and 0.3 units in predicted BMI and HOMA-IR respectively (top 5% vs. score of zero). Boys with higher anxious-depressed scores had lower systolic blood pressure trajectories (p=0.024). CONCLUSION Depressive scores appear to have differing influences on BMI, homeostasis model assessment-estimated insulin resistance and systolic blood pressure in boys and girls. Paradoxically boys with higher anxious-depressed scores had lower blood pressure throughout childhood.

The effect of missing data on linkage disequilibrium mapping and haplotype association analysis in the GAW14 simulated datasets

We used our newly developed linkage disequilibrium (LD) plotting software, JLIN, to plot linkage disequilibrium between pairs of single-nucleotide polymorphisms (SNPs) for three chromosomes of the Genetic Analysis Workshop 14 Aipotu simulated population to assess the effect of missing data on LD calculations. Our haplotype analysis program, SIMHAP, was used to assess the effect of missing data on haplotype-phenotype association. Genotype data was removed at random, at levels of 1%, 5%, and 10%, and the LD calculations and haplotype association results for these levels of missingness were compared to those for the complete dataset. It was concluded that ignoring individuals with missing data substantially affects the number of regions of LD detected which, in turn, could affect tagging SNPs chosen to generate haplotypes.

Associations between aggressive behaviour scores and cardiovascular risk factors in childhood

To examine the influence of aggressive behaviour scores on cardiovascular disease (CVD) risk factors throughout childhood.

Monoamine oxidase a gene polymorphisms common to blood pressure and depression scores in caucasian children

Abstract Background: Depression and cardiovascular disease risk factors develop in childhood. The objective of this study was to investigate cross sectional and longitudinal associations between blood pressure, mood