Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Families as Partners in Hospital Error and Adverse Event Surveillance

ImportanceMedical errors and adverse events (AEs) are common among hospitalized children. While clinician reports are the foundation of operational hospital safety surveillance and a key component of multifaceted research surveillance, patient and family reports are not routinely gathered. We hypothesized that a novel family-reporting mechanism would improve incident detection.ObjectiveTo compare error and AE rates (1) gathered systematically with vs without family reporting, (2) reported by families vs clinicians, and (3) reported by families vs hospital incident reports.Design, setting, and participantsWe conducted a prospective cohort study including the parents/caregivers of 989 hospitalized patients 17 years and younger (total 3902 patient-days) and their clinicians from December 2014 to July 2015 in 4 US pediatric centers. Clinician abstractors identified potential errors and AEs by reviewing medical records, hospital incident reports, and clinician reports as well as weekly and discharge Family Safety Interviews (FSIs). Two physicians reviewed and independently categorized all incidents, rating severity and preventability (agreement, 68%-90%; κ, 0.50-0.68). Discordant categorizations were reconciled. Rates were generated using Poisson regression estimated via generalized estimating equations to account for repeated measures on the same patient.Main outcomes and measuresError and AE rates.ResultsOverall, 746 parents/caregivers consented for the study. Of these, 717 completed FSIs. Their median (interquartile range) age was 32.5 (26-40) years; 380 (53.0%) were nonwhite, 566 (78.9%) were female, 603 (84.1%) were English speaking, and 380 (53.0%) had attended college. Of 717 parents/caregivers completing FSIs, 185 (25.8%) reported a total of 255 incidents, which were classified as 132 safety concerns (51.8%), 102 nonsafety-related quality concerns (40.0%), and 21 other concerns (8.2%). These included 22 preventable AEs (8.6%), 17 nonharmful medical errors (6.7%), and 11 nonpreventable AEs (4.3%) on the study unit. In total, 179 errors and 113 AEs were identified from all sources. Family reports included 8 otherwise unidentified AEs, including 7 preventable AEs. Error rates with family reporting (45.9 per 1000 patient-days) were 1.2-fold (95% CI, 1.1-1.2) higher than rates without family reporting (39.7 per 1000 patient-days). Adverse event rates with family reporting (28.7 per 1000 patient-days) were 1.1-fold (95% CI, 1.0-1.2; P = .006) higher than rates without (26.1 per 1000 patient-days). Families and clinicians reported similar rates of errors (10.0 vs 12.8 per 1000 patient-days; relative rate, 0.8; 95% CI, .5-1.2) and AEs (8.5 vs 6.2 per 1000 patient-days; relative rate, 1.4; 95% CI, 0.8-2.2). Family-reported error rates were 5.0-fold (95% CI, 1.9-13.0) higher and AE rates 2.9-fold (95% CI, 1.2-6.7) higher than hospital incident report rates.Conclusions and relevanceFamilies provide unique information about hospital safety and should be included in hospital safety surveillance in order to facilitate better design and assessment of interventions to improve safety

Families as Partners in Hospital Error and Adverse Event Surveillance

ImportanceMedical errors and adverse events (AEs) are common among hospitalized children. While clinician reports are the foundation of operational hospital safety surveillance and a key component of multifaceted research surveillance, patient and family reports are not routinely gathered. We hypothesized that a novel family-reporting mechanism would improve incident detection.ObjectiveTo compare error and AE rates (1) gathered systematically with vs without family reporting, (2) reported by families vs clinicians, and (3) reported by families vs hospital incident reports.Design, setting, and participantsWe conducted a prospective cohort study including the parents/caregivers of 989 hospitalized patients 17 years and younger (total 3902 patient-days) and their clinicians from December 2014 to July 2015 in 4 US pediatric centers. Clinician abstractors identified potential errors and AEs by reviewing medical records, hospital incident reports, and clinician reports as well as weekly and discharge Family Safety Interviews (FSIs). Two physicians reviewed and independently categorized all incidents, rating severity and preventability (agreement, 68%-90%; κ, 0.50-0.68). Discordant categorizations were reconciled. Rates were generated using Poisson regression estimated via generalized estimating equations to account for repeated measures on the same patient.Main outcomes and measuresError and AE rates.ResultsOverall, 746 parents/caregivers consented for the study. Of these, 717 completed FSIs. Their median (interquartile range) age was 32.5 (26-40) years; 380 (53.0%) were nonwhite, 566 (78.9%) were female, 603 (84.1%) were English speaking, and 380 (53.0%) had attended college. Of 717 parents/caregivers completing FSIs, 185 (25.8%) reported a total of 255 incidents, which were classified as 132 safety concerns (51.8%), 102 nonsafety-related quality concerns (40.0%), and 21 other concerns (8.2%). These included 22 preventable AEs (8.6%), 17 nonharmful medical errors (6.7%), and 11 nonpreventable AEs (4.3%) on the study unit. In total, 179 errors and 113 AEs were identified from all sources. Family reports included 8 otherwise unidentified AEs, including 7 preventable AEs. Error rates with family reporting (45.9 per 1000 patient-days) were 1.2-fold (95% CI, 1.1-1.2) higher than rates without family reporting (39.7 per 1000 patient-days). Adverse event rates with family reporting (28.7 per 1000 patient-days) were 1.1-fold (95% CI, 1.0-1.2; P = .006) higher than rates without (26.1 per 1000 patient-days). Families and clinicians reported similar rates of errors (10.0 vs 12.8 per 1000 patient-days; relative rate, 0.8; 95% CI, .5-1.2) and AEs (8.5 vs 6.2 per 1000 patient-days; relative rate, 1.4; 95% CI, 0.8-2.2). Family-reported error rates were 5.0-fold (95% CI, 1.9-13.0) higher and AE rates 2.9-fold (95% CI, 1.2-6.7) higher than hospital incident report rates.Conclusions and relevanceFamilies provide unique information about hospital safety and should be included in hospital safety surveillance in order to facilitate better design and assessment of interventions to improve safety

A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process