Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: a pharmacogenomics study from the CHARGE consortium

Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD

Leveraging population admixture to characterize the heritability of complex traits.

Despite recent progress on estimating the heritability explained by genotyped SNPs (h(2)g), a large gap between h(2)g and estimates of total narrow-sense heritability (h(2)) remains. Explanations for this gap include rare variants or upward bias in family-based estimates of h(2) due to shared environment or epistasis. We estimate h(2) from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (h(2)γ). We show that h(2)γ = 2FSTCθ(1 - θ)h(2), where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We applied this approach to the analysis of 13 phenotypes in 21,497 African-American individuals from 3 cohorts. For height and body mass index (BMI), we obtained h(2) estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of h(2)g in these and other data but smaller than family-based estimates of h(2)

Determinants of child labor in Malawi and Tanzania

Using the Malawi Integrated Household Survey of 2009 and the Tanzania National Panel Survey of 2010, this study seeks to understand the factors that increase a child`s likelihood of labor participation. A greater percentage of children in the Tanzania sample than those from the Malawi sample participate in child labor. Logistic regression analyses showed that, as hypothesized, the greatest influence on child labor observed at the individual level is the child`s school enrollment status. Enrollment reduces the likelihood of engaging in child labor in both countries. When tested in the combined model older children in Tanzania remain at higher risk of child labor participation, school enrolled children in both countries are less likely to be child laborers and the rural based children in Tanzania have higher odds of being child laborers. At the household level, a father with at least a primary education in Malawi is associated with a lesser likelihood of participation. At the community level, living in a rural area drastically increases the odds for child labor participation in Tanzania. In view of these results, country specific solutions to prevent child labor maybe necessary, given the different predictors of child labor participation in each country

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis

Error and bias geocoding school and student's home addresses

Zandbergen and Green (2007) recently described the effect of positional error on the distance between geocoded addresses and major roads, an often-used proxy for traffic-related exposures. They found a 200–500 m range of mean positional errors in their study of 126 Orange County, Florida, public school addresses, a somewhat higher range than that associated with geocodes assigned by four commercial vendors to a larger variety and number of street addresses in the 48 contiguous U.S. states (Whitsel et al. 2006). In both studies, however, the ranges exceeded commonly used thresholds for identifying those at greatest potential risk of traffic-related exposures, raising due cause for concern

Stimulating somatosensory psychophysics: a double-blind, sham-controlled study of the neurobiological mechanisms of tDCS

In this study, the influence of tDCS on vibrotactile adaptation is investigated. Double-blind tDCS (Anodal/Sham) of 1 mA was delivered for 600 s to electrodes positioned in a somatosensory/contralateral orbit montage. Stimulation was applied between blocks of the implemented amplitude discrimination tasks. Amplitude discrimination thresholds were significantly degraded during adaptation trials, compared to those achieved at baseline but tDCS failed to modify task performance. Using Bayesian statistics, this finding was revealed to constitute substantial evidence for the null hypothesis. The failure of DC stimulation to alter performance is discussed in the context of several factors that may have confounded the induction of changes in cortical plasticity

Racial differences in blood pressure response to calcium channel blocker monotherapy: A meta-analysis

Background A systematic literature review was conducted to determine whether US blacks and whites have differential blood pressure (BP) response to calcium channel blocker (CCB) monotherapy.MethodsSix published studies made up the final cohort of eligible articles. Multiple treatment groups within some studies led to a total of eight sets of estimates for BP reduction with a total of 6,851 white or nonblack participants and 3,371 black participants.ResultsThe pooled difference in systolic blood pressure (SBP) change between blacks and whites was 2.7 mm Hg (95% confidence interval (CI): 4.0, 1.3) with blacks having greater response. The difference in diastolic blood pressure (DBP) between blacks and whites was 0.4 mm Hg (95% CI: 1.0, 0.3) with blacks having greater response. Using a dichotomous outcome measure, whites were found to be just as likely as blacks to attain the DBP goal of 90 mm Hg or a 10 mm Hg or greater change (relative risk: 1.00 95% CI: 0.91, 1.11). In addition, examination of the continuous distribution of BP responses of whites and blacks showed over 90% overlap in treatment response.ConclusionAssessment of differential response to CCB monotherapy by race in published data depends on choice of outcome metric. Nonetheless, the results of this systematic review indicate that BP response is qualitatively similar in US blacks and whites, suggesting that patient race is not likely to offer any clinical utility for decisions about the likely effect of this antihypertensive therapy. © 2009 American Journal of Hypertension, Ltd

The environmental epidemiology of atrial Arrhythmogenesis

Atrial fibrillation (AF) is the most common cardiac arrhythmia seen in clinical practice, and makes an important contribution to cardiovascular disease (CVD) and all-cause mortality. The focus of AF research has recently shifted, from concentrating on treatments and complications, to the evaluation of putative risk factors including ambient air pollution. Although the present study pertains specifically to AF, much of its content is drawn from, and therefore is applicable to, the study of other arrhythmias, the conduct of which is confronted by many of the same challenges. Meeting these challenges involves recognising the collective importance of 1. large, ethnically and geographically diverse, clinically well-characterised populations; 2. methods for reducing uncertainty in outcome ascertainment, distinguishing effects of pervasive environmental exposures and improving their estimation; 3. approaches to evaluation of susceptibility; and 4. strategies for informing regulatory policies designed to help control population-level risks for CVD

Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: A pharmacogenomics study from the CHARGE consortium

Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk ofmajor cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regressionmodels to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genom