Felodipine-metoprolol combination tablet: A valuable option to initiate antihypertensive therapy?

The aim of the present study was to assess the efficacy and tolerability of a calcium antagonist/β-blocker fixed combination tablet used as first-line antihypertesnive therapy in comparison with an angiotensin converting enzyme inhibitor and placebo. Patients with uncomplicated essential hypertension (diastolic blood pressure between 95 and 110 mm Hg at the end of a 4-week run-in period) were randomly allocated to a double-blind, 12-week treatment with either a combination tablet of felodipine and metoprolol (Logimax), 5/50 mg daily (n = 321), enalapril, 10 mg daily (n = 321), or placebo (n = 304), with the possibility of doubling the dose after 4 or 8 weeks of treatment if needed (diastolic blood pressure remaining >90 mm Hg). The combined felodipine-metoprolol treatment controlled blood pressure (diastolic ≤90 mm Hg 24 h after dose) in 72% of patients after 12 weeks, as compared with 49% for enalapril and 30% for placebo. A dose adjustment was required in 38% of patients receiving the combination, in 63% of patients allocated to placebo, and 61% of enalapril-treated patients. The overall incidence of adverse events was 54.5% during felodipine-metoprolol treatment; the corresponding values for enalapril and placebo were 51.7% and 47.4%, respectively. Withdrawal of treatment due to adverse events occurred in 18 patients treated with the combination, in 10 patients on enalapril, and 12 patients on placebo. No significant change in patients' well-being was observed in either of the three study groups. These results show that a fixed combination tablet of felodipine and metoprolol allows to normalize blood pressure in a substantially larger fraction of patients than enalapril given alone. This improved efficacy is obtained without impairing the tolerability. The fixed-dose combination of felodipine and metoprolol, therefore, may become a valuable option to initiate antihypertensive treatment. Am J Hypertens 1999;12:915-920 © 1999 American Journal of Hypertension, Lt

Anthropogenic natal environmental effects on life histories in a wild bird population

Recent work suggests that the environment experienced in early life can alter life histories in wild populations [1, 2, 3, 4 and 5], but our understanding of the processes involved remains limited [6 and 7]. Since anthropogenic environmental change is currently having a major impact on wild populations [8], this raises the possibility that life histories may be influenced by human activities that alter environmental conditions in early life. Whether this is the case and the processes involved remain unexplored in wild populations. Using 23 years of longitudinal data on the Mauritius kestrel (Falco punctatus), a tropical forest specialist, we found that females born in territories affected by anthropogenic habitat change shifted investment in reproduction to earlier in life at the expense of late life performance. They also had lower survival rates as young adults. This shift in life history strategy appears to be adaptive, because fitness was comparable to that of other females experiencing less anthropogenic modification in their natal environment. Our results suggest that human activities can leave a legacy on wild birds through natal environmental effects. Whether these legacies have a detrimental effect on populations will depend on life history responses and the extent to which these reduce individual fitness

Predictors of children's secondhand smoke exposure at home: a systematic review and narrative synthesis of the evidence

BACKGROUND: Children's exposure to secondhand smoke (SHS) has been causally linked to a number of childhood morbidities and mortalities. Over 50% of UK children whose parents are smokers are regularly exposed to SHS at home. No previous review has identified the factors associated with children's SHS exposure in the home. AIM: To identify by systematic review, the factors which are associated with children's SHS exposure in the home, determined by parent or child reports and/or biochemically validated measures including cotinine, carbon monoxide or home air particulate matter. METHODS: Electronic searches of MEDLINE, EMBASE, PsychINFO, CINAHL and Web of Knowledge to July 2014, and hand searches of reference lists from publications included in the review were conducted. FINDINGS: Forty one studies were included in the review. Parental smoking, low socioeconomic status and being less educated were all frequently and consistently found to be independently associated with children's SHS exposure in the home. Children whose parents held more negative attitudes towards SHS were less likely to be exposed. Associations were strongest for parental cigarette smoking status; compared to children of non-smokers, those whose mothers or both parents smoked were between two and 13 times more likely to be exposed to SHS. CONCLUSION: Multiple factors are associated with child SHS exposure in the home; the best way to reduce child SHS exposure in the home is for smoking parents to quit. If parents are unable or unwilling to stop smoking, they should instigate smoke-free homes. Interventions targeted towards the socially disadvantaged parents aiming to change attitudes to smoking in the presence of children and providing practical support to help parents smoke outside the home may be beneficial

Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies

Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low–BMI cases are larger than those estimated from high–BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-control-covariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled false-positive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1×10−9). The improvement varied across diseases with a 16% median increase in χ2 test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci

2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy

Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204-A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10 â ̂'9). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities

2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy.

Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10(-9)). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.NovartisEli Lilly and CompanyAstraZenecaAbbViePfizer UKCelgeneEisaiGenentechMerck Sharp and DohmeRocheCancer Research UKGovernment of CanadaArray BioPharmaGenome CanadaNational Institutes of HealthEuropean CommissionMinistère de l'Économie, de l’Innovation et des Exportations du QuébecSeventh Framework ProgrammeCanadian Institutes of Health Researc

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.352

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.Peer reviewe

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways