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

Prospects for the CERN Axion Solar Telescope Sensitivity to 14.4 keV Axions

The CERN Axion Solar Telescope (CAST) is searching for solar axions using the 9.0 T strong and 9.26 m long transverse magnetic field of a twin aperture LHC test magnet, where axions could be converted into X-rays via reverse Primakoff process. Here we explore the potential of CAST to search for 14.4 keV axions that could be emitted from the Sun in M1 nuclear transition between the first, thermally excited state, and the ground state of 57Fe nuclide. Calculations of the expected signals, with respect to the axion-photon coupling, axion-nucleon coupling and axion mass, are presented in comparison with the experimental sensitivity.Comment: 4 pages, 1 figure. Submitted to Nucl. Instr. and Meth.

Search for solar axion emission from 7Li and D(p,gamma)3He nuclear decays with the CAST gamma-ray calorimeter

We present the results of a search for a high-energy axion emission signal from 7Li (0.478 MeV) and D(p,gamma)3He (5.5 MeV) nuclear transitions using a low-background gamma-ray calorimeter during Phase I of the CAST experiment. These so-called "hadronic axions" could provide a solution to the long-standing strong-CP problem and can be emitted from the solar core from nuclear M1 transitions. This is the first such search for high-energy pseudoscalar bosons with couplings to nucleons conducted using a helioscope approach. No excess signal above background was found.Comment: 20 pages, 8 figures, final version to be published in JCA

Long-term aircraft noise exposure and risk of hypertension in postmenopausal women

Background: Studies of the association between aircraft noise and hypertension are complicated by inadequate control for potential confounders and a lack of longitudinal assessments, and existing evidence is inconclusive. Objectives: We evaluated the association between long-term aircraft noise exposure and risk of hypertension among post-menopausal women in the Women's Health Initiative Clinical Trials, an ongoing prospective U.S. cohort. Methods: Day-night average (DNL) and night equivalent sound levels (Lnight) were modeled for 90 U.S. airports from 1995 to 2010 in 5-year intervals using the Aviation Environmental Design Tool and linked to participant geocoded addresses from 1993 to 2010. Participants with modeled exposures ≥45 A-weighted decibels (dB [A]) were considered exposed, and those outside of 45 dB(A) who also did not live in close proximity to unmodeled airports were considered unexposed. Hypertension was defined as systolic/diastolic blood pressure ≥140/90 mmHg or inventoried/self-reported antihypertensive medication use. Using time-varying Cox proportional hazards models, we estimated hazard ratios (HRs) for incident hypertension when exposed to DNL or Lnight ≥45 versus <45 dB(A), controlling for sociodemographic, behavioral, and environmental/contextual factors. Results/discussion: There were 18,783 participants with non-missing DNL exposure and 14,443 with non-missing Lnight exposure at risk of hypertension. In adjusted models, DNL and Lnight ≥45 db(A) were associated with HRs of 1.00 (95% confidence interval [CI]: 0.93, 1.08) and 1.06 (95%CI: 0.91, 1.24), respectively. There was no evidence supporting a positive exposure-response relationship, and findings were robust in sensitivity analyses. Indications of elevated risk were seen among certain subgroups, such as those living in areas with lower population density (HRinteraction: 0.84; 95%CI: 0.72, 0.98) or nitrogen dioxide concentrations (HRinteraction: 0.82; 95%CI: 0.71, 0.95), which may indicate lower ambient/road traffic noise. Our findings do not suggest a relationship between aircraft noise and incident hypertension among older women in the U.S., though associations in lower ambient noise settings merit further investigation

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK

Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10−8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy

The search for solar axions in the CAST experiment

The CAST (CERN Axion Solar Telescope) experiment at CERN searches for solar axions with energies in the keV range. It is possible that axions are produced in the core of the sun by the interaction of thermal photons with virtual photons of strong electromagnetic fields. In this experiment, the solar axions can be reconverted to photons in the transversal field of a 9 Tesla superconducting magnet. At both ends of the 10m-long dipole magnet three different X-ray detectors were installed, which are sensitive in the interesting photon energy range. Preliminary results from the analysis of the 2004 data are presented: g$_{a\gamma}<0.9\times10^{-10}$ GeV$^{-1}$ at 95% C.L. for axion masses m$_{a} <$ 0.02 eV. At the end of 2005, data started to be taken with a buffer gas in the magnet pipes in order to extend the sensitivity to axion masses up to 0.8 eV.The CAST (CERN Axion Solar Telescope) experiment at CERN searches for solar axions with energies in the keV range. It is possible that axions are produced in the core of the sun by the interaction of thermal photons with virtual photons of strong electromagnetic fields. In this experiment, the solar axions can be reconverted to photons in the transversal field of a 9 Tesla superconducting magnet. At both ends of the 10m-long dipole magnet three different X-ray detectors were installed, which are sensitive in the interesting photon energy range. Preliminary results from the analysis of the 2004 data are presented: g$_{a\gamma}<0.9\times10^{-10}$ GeV$^{-1}$ at 95% C.L. for axion masses m$_{a} <$ 0.02 eV. At the end of 2005, data started to be taken with a buffer gas in the magnet pipes in order to extend the sensitivity to axion masses up to 0.8 eV