Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

BACKGROUND:Evidence on the direction and strength of association between maternal age and the prevalence of congenital heart defects (CHD) in different age group categories is conflicting. Some studies have illustrated different trends with an increase in prevalence in younger and older age groups while other studies have reported a linear relationship. Given the increase in maternal age over recent years, it is important to study the CHD prevalence by maternal age. OBJECTIVES:To examine the association between maternal age and the prevalence of CHD in Europe between 1995 and 2015 using population-based data from 24 registries belonging to the European Surveillance of Congenital Anomalies (EUROCAT) network. METHODS:Associations over time of all nonsyndromic CHD according to maternal age category and for three CHD severity groupings (severity group I: very severe; severity group II: severe; severity group III: less severe) were examined using Bayesian multilevel Poisson regression modeling. Further subgroup analyses were undertaken within four maternal age-bands: ≤24, 25-29, 30-34 and 35-44 years. Descriptive summaries are also presented. RESULTS:There were 51,608 nonsyndromic CHD cases in Europe over the 20-year study period. Total prevalence for all CHD combined was increased for younger mothers (≤24 years) and for mothers 35-44 years of age when compared with mothers aged 25-29 years (reference group) (IRR: 1.05, 95% CI: 1.02, 1.07). The total prevalence was increased for severity group I (very severe) only for younger mothers compared to those aged 25-29 years (IRR: 1.14, 95% CI: 1.04, 1.23). We found an increased prevalence of the following CHD subtypes: double outlet right ventricle (IRR:1.33, 95% CI: 1.09, 1.60), hypoplastic left heart syndrome (IRR: 1.18, 95% CI: 1.05, 1.32), hypoplastic right heart syndrome (IRR: 1.41, 95% CI: 1.05, 1.84), atrioventricular septal defect (IRR: 1.15, 95% CI: 1.01, 1.32), coarctation of aorta (IRR: 1.15, 95% CI: 1.03, 1.28) and atrial septal defect (IRR: 1.08, 95% CI: 1.02, 1.13). For older mothers (35-44 years) compared to the reference category, we observed an increased risk in the prevalence for severity group II (IRR: 1.09, 95% CI: 1.03, 1.14), severity group III (IRR: 1.05, 95% CI: 1.01, 1.08) and an increased prevalence of the CHD subtypes: Pulmonary valve stenosis (IRR: 1.22, 95% CI: 1.09, 1.34), ASD (IRR: 1.07, 95% CI: 1.02, 1.13), CoA (IRR: 1.18, 95% CI: 1.06, 1.32) and Tetralogy of Fallot (IRR: 1.14, 95% CI: 1.01, 1.28). Finally, for all age categories compared to the reference category, different associations of ASD and an increased prevalence of CoA was also observed. CONCLUSIONS:Based on data for cases of CHD from 24 European population-based registries, evidence of a positive association between maternal age and the total prevalence of CHD for younger (≤24 years old) and older (35-44 years old) mothers was observed. The results suggest that young maternal age (≤24 years old) is a factor associated with severe CHD phenotypes while a positive association between advanced maternal age (35-44 years old) and mild CHD phenotypes was observed.

BACKGROUND Research on cognitive and school functioning domains of health-related quality of life (HRQOL) for children and adolescents with congenital heart disease (CHD) presents inconsistencies. OBJECTIVES To summarize and synthesize data on school and cognitive function domains of HRQOL for children and young people (CYP) with CHD. METHODS Five electronic databases MEDLINE, Scopus, PsycINFO, EMBASE, ERI, and citations were systematically searched. We included original-research articles reporting the cognitive and school function domains of HRQOL for children and young people with CHD (child and parent reports included). Both fixed and random-effects meta-analyses were performed to estimate pooled mean test scores for cognitive and school function. A total of 34 studies met our inclusion criteria and were synthesized narratively, 17 studies were included in formal meta-analyses. RESULTS Self-reported cognitive function was lower for children and young people with CHD than healthy controls (SMD -0.28 (-0.42, -0.15)). Parental reports demonstrated similar results to self-reports (SMD -0.54 (-0.91, -0.18)). School function was lower in children and young people with CHD compared with healthy controls in self-reported (SMD -0.30 (-0.48, -0.13)) and parent reported HRQOL (SMD -0.49 (0.64, -0.36)). Self-reported school function domain scores were lower for young (<8 years) (SMD -0.65 (-1.32, 0.03)) and older children (8-18 years) (SMD -0.25 (-0.47, -0.03)) with CHD than their peers. Similarly, parents reported lower school function domain scores for young (<8 years) (SMD -0.68 (-1.29, -0.07)) and older (8-18 years) (SMD -0.46 (-068, -0.25)) children with CHD than typically developing peers. CONCLUSION Children born with CHD may experience lower cognitive and school function HRQOL scores than healthy controls (self and proxy-report). This is consistent with a subgroup meta-analysis of young (<8 years) and older (8 years old or more) children with CHD reporting lower school function scores compared to controls.

BACKGROUND:The total prevalence of congenital heart defects (CHDs) varies by populations and over time. Studies that examine trends in the prevalence of CHD in different regions may shed light on our understanding of the occurrence of CHD and the impact of different risk factors.OBJECTIVES:To examine trends in total and live birth prevalence of nonsyndromic CHD in Europe between the years 2008 and 2015 and to investigate if the decreasing trend reported by previous studies is continuing.METHODS:Cases of CHD delivered between January 1, 2008 and December 31, 2015 notified to 25 population-based EUROCAT (European Surveillance of Congenital Anomalies) registries in 14 countries, formed the population-based case-series. Prevalence (total/live) rates and 95% confidence intervals were calculated as the number of cases per 10,000 births (live and stillbirths). Time trends in prevalence of all nonsyndromic CHDs and for three CHD severity groups (very severe, severe, and less severe) were plotted using a Poisson regression multilevel approach.RESULTS:The total prevalence of nonsyndromic CHD was 57.1 per 10,000 births (live births and stillbirths) for the 8-year period and remained stable across the three CHD severity groups while the live birth prevalence was 60.2 per 10,000 births. There was considerable variation in the reported total CHD prevalence and the direction of trends by registry. A decreasing prevalence of CHD was observed for the Norway and England/Wales registries, whereas the CHD prevalence increased for registries in Italy and Croatia.CONCLUSIONS:The total prevalence of CHD in Europe between the years 2008 and 2015 remained stable for all CHD and across the three CHD severity groups. The decreasing trend reported by previous studies has not continued. However, we found significant differences in the total and live birth prevalence by registry.

In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150,134 European ancestry individuals and sought significant evidence for independent replication in a further 228,245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9 and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12,607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in BP regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.

Respiratory diseases account for one in five deaths in the UK.(1) Lung transplantation is the only realistic therapeutic option for selected patients with end-stage chronic lung disease and provides dramatic improvements in both survival and quality of life. In younger patients with life-threatening cystic fibrosis (CF) lung disease, median survival after lung transplant now exceeds 10 years. However, 20-30% of patients waiting for lung transplantation will die before a donor organ becomes available. Although a shortage of multiorgan donors contributes, the main problem is that in multiorgan donors lungs are very susceptible to dysfunction, and about 80% of potential donor lungs in the UK are deemed unusable for clinical lung transplantation. It has previously been suggested that, in addition to promoting more organ donation, better use of existing organ donors is an important way to increase the numbers of lung transplants performed, 2 and many centres worldwide have increased donor lung use by accepting more 'marginal' or 'extended criteria' donors. This, however, is not without risks to early post-transplantation outcomes. 3 The major early cause of death after lung transplantation is primary graft dysfunction (PGD), a severe lung injury akin to acute respiratory distress syndrome. Evidence that PGD has a major impact on survival comes from experience in several centres worldwide, 4 and from the International Society for Heart and Lung Transplantation (ISHLT); the reported incidences of PGD are up to 25%, and PGD is associated with 30-day mortality of 50%, compared with < 10% among those without PGD.(5) There is, therefore, an urgent clinical need to safely increase the utilisation of donor lungs from the existing donor pool without negatively impacting on early survival after lung transplant.

Background: Many patients awaiting lung transplantation die before a donor organ becomes available. Ex vivo lung perfusion (EVLP) allows initially unusable donor lungs to be assessed and reconditioned for clinical use. Objective: The objective of the Donor Ex Vivo Lung Perfusion in UK lung transplantation study was to evaluate the clinical effectiveness and cost-effectiveness of EVLP in increasing UK lung transplant activity. Design: A multicentre, unblinded, non-randomised, non-inferiority observational study to compare transplant outcomes between EVLP-assessed and standard donor lungs. Setting: Multicentre study involving all five UK officially designated NHS adult lung transplant centres. Participants: Patients aged ≥ 18 years with advanced lung disease accepted onto the lung transplant waiting list. Intervention: The study intervention was EVLP assessment of donor lungs before determining suitability for transplantation. Main outcome measures: The primary outcome measure was survival during the first 12 months following lung transplantation. Secondary outcome measures were patient-centred outcomes that are influenced by the effectiveness of lung transplantation and that contribute to the health-care costs. Results: Lungs from 53 donors unsuitable for standard transplant were assessed with EVLP, of which 18 (34%) were subsequently transplanted. A total of 184 participants received standard donor lungs. Owing to the early closure of the study, a non-inferiority analysis was not conducted. The Kaplan–Meier estimate of survival at 12 months was 0.67 [95% confidence interval (CI) 0.40 to 0.83] for the EVLP arm and 0.80 (95% CI 0.74 to 0.85) for the standard arm. The hazard ratio for overall 12-month survival in the EVLP arm relative to the standard arm was 1.96 (95% CI 0.83 to 4.67). Patients in the EVLP arm required ventilation for a longer period and stayed longer in an intensive therapy unit (ITU) than patients in the standard arm, but duration of overall hospital stay was similar in both groups. There was a higher rate of very early grade 3 primary graft dysfunction (PGD) in the EVLP arm, but rates of PGD did not differ between groups after 72 hours. The requirement for extracorporeal membrane oxygenation (ECMO) support was higher in the EVLP arm (7/18, 38.8%) than in the standard arm (6/184, 3.2%). There were no major differences in rates of chest radiograph abnormalities, infection, lung function or rejection by 12 months. The cost of EVLP transplants is approximately £35,000 higher than the cost of standard transplants, as a result of the cost of the EVLP procedure, and the increased ECMO use and ITU stay. Predictors of cost were quality of life on joining the waiting list, type of transplant and number of lungs transplanted. An exploratory model comparing a NHS lung transplant service that includes EVLP and standard lung transplants with one including only standard lung transplants resulted in an incremental cost-effectiveness ratio of £73,000. Interviews showed that patients had a good understanding of the need for, and the processes of, EVLP. If EVLP can increase the number of usable donor lungs and reduce waiting, it is likely to be acceptable to those waiting for lung transplantation. Study limitations include small numbers in the EVLP arm, limiting analysis to descriptive statistics and the EVLP protocol change during the study. Conclusions: Overall, one-third of donor lungs subjected to EVLP were deemed suitable for transplant. Estimated survival over 12 months was lower than in the standard group, but the data were also consistent with no difference in survival between groups. Patients receiving these additional transplants experience a higher rate of early graft injury and need for unplanned ECMO support, at increased cost. The small number of participants in the EVLP arm because of early study termination limits the robustness of these conclusions. The reason for the increased PGD rates, high ECMO requirement and possible differences in lung injury between EVLP protocols needs evaluation. Trial registration: Current Controlled Trials ISRCTN44922411. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 85. See the NIHR Journals Library website for further project information.