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FGFR2 Genetic Variant C.1019A > G p.(Tyr340Cys) in a Fetus with Pfeiffer Type II Syndrome Diagnosed by a Combination of 3D Ultrasound Phenotyping and DNA Sequencing

AbstractA 38-year-old woman was referred at 20 weeks' gestation for multiple fetal anomalies detected on routine ultrasound screening. Initial findings included dolichocephaly, ventriculomegaly, craniofacial abnormalities, and limb anomalies, which led to the suspicion of a skeletal dysplasia. While microarray analysis was normal, rapid fetal exome sequencing identified a de novo pathogenic variant in the FGFR2 gene (c.1019A > G p.(Tyr340Cys)). Initially classified as a variant of uncertain significance due to initial ultrasound suspicion, targeted three and four dimensional ultrasound phenotyping revealed characteristic features of Pfeiffer syndrome type 2, including cloverleaf skull, proptosis, hypertelorism, broad thumbs and big toes, and radial-humeral synostosis. This case demonstrates the crucial interplay between advanced genetic testing and detailed ultrasound assessment in prenatal diagnosis. Accurate interpretation of genetic variants requires meticulous ultrasound phenotyping in a multidisciplinary setting, particularly for complex and rare conditions such as Pfeiffer syndrome type 2.

Cerebroplacental ratio in low-risk pregnancies: the RATIO37 trial.

Soluble fms-like tyrosine kinase 1-to-placental growth factor ratio predicts time to delivery and mode of birth.

Considerations for gestational age, delivery indication, and therapies in preeclampsia prediction.

A cluster randomised trial of a complex intervention to reduce anaemia and cardiometabolic risk during pregnancy and in the first year following birth in women living in rural India

Perinatal mental health in India in the states of Haryana and Telangana: A district level situational analysis

Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Comparison of Associations with Different Macular Inner Retinal Thickness Parameters in a Large Cohort: The UK Biobank.

PURPOSE: To describe and compare associations with macular retinal nerve fiber layer (mRNFL), ganglion cell complex (GCC), and ganglion cell-inner plexiform layer (GCIPL) thicknesses in a large cohort. DESIGN: Cross-sectional study. PARTICIPANTS: We included 42 044 participants in the UK Biobank. The mean age was 56 years. METHODS: Spectral-domain OCT macular images were segmented and analyzed. Corneal-compensated intraocular pressure (IOPcc) was measured with the Ocular Response Analyzer (Reichert, Corp., Buffalo, NY). Multivariable linear regression was used to examine associations with mean mRNFL, GCC, and GCIPL thicknesses. Factors examined were age, sex, ethnicity, height, body mass index (BMI), smoking status, alcohol intake, Townsend deprivation index, education level, diabetes status, spherical equivalent, and IOPcc. MAIN OUTCOME MEASURES: Thicknesses of mRNFL, GCC, and GCIPL. RESULTS: We identified several novel independent associations with thinner inner retinal thickness. Thinner inner retina was associated with alcohol intake (most significant for GCIPL: -0.46 μm for daily or almost daily intake compared with special occasion only or never [95% confidence interval (CI), 0.61-0.30]; P = 1.1×10-8), greater social deprivation (most significant for GCIPL: -0.28 μm for most deprived quartile compared with least deprived quartile [95% CI, -0.42 to -0.14]; P = 6.6×10-5), lower educational attainment (most significant for mRNFL: -0.36 μm for less than O level compared with degree level [95% CI, -0.45 to 0.26]; P = 2.3×10-14), and nonwhite ethnicity (most significant for mRNFL comparing blacks with whites: -1.65 μm [95% CI, -1.86 to -1.43]; P = 2.4×10-50). Corneal-compensated intraocular pressure was associated most significantly with GCIPL (-0.04 μm/mmHg [95% CI, -0.05 to -0.03]; P = 4.0×10-10) and was not associated significantly with mRNFL (0.00 μm/mmHg [95% CI, -0.01 to 0.01]; P = 0.77). The variables examined explained a greater proportion of the variance of GCIPL (11%) than GCC (6%) or mRNFL (7%). CONCLUSIONS: The novel associations we identified may be important to consider when using inner retinal parameters as a diagnostic tool. Associations generally were strongest with GCIPL, particularly for IOP. This suggests that GCIPL may be the superior inner retinal biomarker for macular pathophysiologic processes and especially for glaucoma.

FFPred 3: feature-based function prediction for all Gene Ontology domains.

Predicting protein function has been a major goal of bioinformatics for several decades, and it has gained fresh momentum thanks to recent community-wide blind tests aimed at benchmarking available tools on a genomic scale. Sequence-based predictors, especially those performing homology-based transfers, remain the most popular but increasing understanding of their limitations has stimulated the development of complementary approaches, which mostly exploit machine learning. Here we present FFPred 3, which is intended for assigning Gene Ontology terms to human protein chains, when homology with characterized proteins can provide little aid. Predictions are made by scanning the input sequences against an array of Support Vector Machines (SVMs), each examining the relationship between protein function and biophysical attributes describing secondary structure, transmembrane helices, intrinsically disordered regions, signal peptides and other motifs. This update features a larger SVM library that extends its coverage to the cellular component sub-ontology for the first time, prompted by the establishment of a dedicated evaluation category within the Critical Assessment of Functional Annotation. The effectiveness of this approach is demonstrated through benchmarking experiments, and its usefulness is illustrated by analysing the potential functional consequences of alternative splicing in human and their relationship to patterns of biological features.

Genome-wide analysis identifies 66 variants underlying anatomical variation in human neuroendocrine structures and reveals links to testosterone

The changing spectrum of cardiovascular diseases.

Global, regional, and national prevalence of child and adolescent overweight and obesity, 1990-2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021.

BACKGROUND: Despite the well documented consequences of obesity during childhood and adolescence and future risks of excess body mass on non-communicable diseases in adulthood, coordinated global action on excess body mass in early life is still insufficient. Inconsistent measurement and reporting are a barrier to specific targets, resource allocation, and interventions. In this Article we report current estimates of overweight and obesity across childhood and adolescence, progress over time, and forecasts to inform specific actions. METHODS: Using established methodology from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021, we modelled overweight and obesity across childhood and adolescence from 1990 to 2021, and then forecasted to 2050. Primary data for our models included 1321 unique measured and self-reported anthropometric data sources from 180 countries and territories from survey microdata, reports, and published literature. These data were used to estimate age-standardised global, regional, and national overweight prevalence and obesity prevalence (separately) for children and young adolescents (aged 5-14 years, typically in school and cared for by child health services) and older adolescents (aged 15-24 years, increasingly out of school and cared for by adult services) by sex for 204 countries and territories from 1990 to 2021. Prevalence estimates from 1990 to 2021 were generated using spatiotemporal Gaussian process regression models, which leveraged temporal and spatial correlation in epidemiological trends to ensure comparability of results across time and geography. Prevalence forecasts from 2022 to 2050 were generated using a generalised ensemble modelling approach assuming continuation of current trends. For every age-sex-location population across time (1990-2050), we estimated obesity (vs overweight) predominance using the log ratio of obesity percentage to overweight percentage. FINDINGS: Between 1990 and 2021, the combined prevalence of overweight and obesity in children and adolescents doubled, and that of obesity alone tripled. By 2021, 93·1 million (95% uncertainty interval 89·6-96·6) individuals aged 5-14 years and 80·6 million (78·2-83·3) aged 15-24 years had obesity. At the super-region level in 2021, the prevalence of overweight and of obesity was highest in north Africa and the Middle East (eg, United Arab Emirates and Kuwait), and the greatest increase from 1990 to 2021 was seen in southeast Asia, east Asia, and Oceania (eg, Taiwan [province of China], Maldives, and China). By 2021, for females in both age groups, many countries in Australasia (eg, Australia) and in high-income North America (eg, Canada) had already transitioned to obesity predominance, as had males and females in a number of countries in north Africa and the Middle East (eg, United Arab Emirates and Qatar) and Oceania (eg, Cook Islands and American Samoa). From 2022 to 2050, global increases in overweight (not obesity) prevalence are forecasted to stabilise, yet the increase in the absolute proportion of the global population with obesity is forecasted to be greater than between 1990 and 2021, with substantial increases forecast between 2022 and 2030, which continue between 2031 and 2050. By 2050, super-region obesity prevalence is forecasted to remain highest in north Africa and the Middle East (eg, United Arab Emirates and Kuwait), and forecasted increases in obesity are still expected to be largest across southeast Asia, east Asia, and Oceania (eg, Timor-Leste and North Korea), but also in south Asia (eg, Nepal and Bangladesh). Compared with those aged 15-24 years, in most super-regions (except Latin America and the Caribbean and the high-income super-region) a greater proportion of those aged 5-14 years are forecasted to have obesity than overweight by 2050. Globally, 15·6% (12·7-17·2) of those aged 5-14 years are forecasted to have obesity by 2050 (186 million [141-221]), compared with 14·2% (11·4-15·7) of those aged 15-24 years (175 million [136-203]). We forecasted that by 2050, there will be more young males (aged 5-14 years) living with obesity (16·5% [13·3-18·3]) than overweight (12·9% [12·2-13·6]); while for females (aged 5-24 years) and older males (aged 15-24 years), overweight will remain more prevalent than obesity. At a regional level, the following populations are forecast to have transitioned to obesity (vs overweight) predominance before 2041-50: children and adolescents (males and females aged 5-24 years) in north Africa and the Middle East and Tropical Latin America; males aged 5-14 years in east Asia, central and southern sub-Saharan Africa, and central Latin America; females aged 5-14 years in Australasia; females aged 15-24 years in Australasia, high-income North America, and southern sub-Saharan Africa; and males aged 15-24 years in high-income North America. INTERPRETATION: Both overweight and obesity increased substantially in every world region between 1990 and 2021, suggesting that current approaches to curbing increases in overweight and obesity have failed a generation of children and adolescents. Beyond 2021, overweight during childhood and adolescence is forecast to stabilise due to further increases in the population who have obesity. Increases in obesity are expected to continue for all populations in all world regions. Because substantial change is forecasted to occur between 2022 and 2030, immediate actions are needed to address this public health crisis. FUNDING: Bill & Melinda Gates Foundation and Australian National Health and Medical Research Council.

Global, regional, and national prevalence of adult overweight and obesity, 1990-2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021.

BACKGROUND: Overweight and obesity is a global epidemic. Forecasting future trajectories of the epidemic is crucial for providing an evidence base for policy change. In this study, we examine the historical trends of the global, regional, and national prevalence of adult overweight and obesity from 1990 to 2021 and forecast the future trajectories to 2050. METHODS: Leveraging established methodology from the Global Burden of Diseases, Injuries, and Risk Factors Study, we estimated the prevalence of overweight and obesity among individuals aged 25 years and older by age and sex for 204 countries and territories from 1990 to 2050. Retrospective and current prevalence trends were derived based on both self-reported and measured anthropometric data extracted from 1350 unique sources, which include survey microdata and reports, as well as published literature. Specific adjustment was applied to correct for self-report bias. Spatiotemporal Gaussian process regression models were used to synthesise data, leveraging both spatial and temporal correlation in epidemiological trends, to optimise the comparability of results across time and geographies. To generate forecast estimates, we used forecasts of the Socio-demographic Index and temporal correlation patterns presented as annualised rate of change to inform future trajectories. We considered a reference scenario assuming the continuation of historical trends. FINDINGS: Rates of overweight and obesity increased at the global and regional levels, and in all nations, between 1990 and 2021. In 2021, an estimated 1·00 billion (95% uncertainty interval [UI] 0·989-1·01) adult males and 1·11 billion (1·10-1·12) adult females had overweight and obesity. China had the largest population of adults with overweight and obesity (402 million [397-407] individuals), followed by India (180 million [167-194]) and the USA (172 million [169-174]). The highest age-standardised prevalence of overweight and obesity was observed in countries in Oceania and north Africa and the Middle East, with many of these countries reporting prevalence of more than 80% in adults. Compared with 1990, the global prevalence of obesity had increased by 155·1% (149·8-160·3) in males and 104·9% (95% UI 100·9-108·8) in females. The most rapid rise in obesity prevalence was observed in the north Africa and the Middle East super-region, where age-standardised prevalence rates in males more than tripled and in females more than doubled. Assuming the continuation of historical trends, by 2050, we forecast that the total number of adults living with overweight and obesity will reach 3·80 billion (95% UI 3·39-4·04), over half of the likely global adult population at that time. While China, India, and the USA will continue to constitute a large proportion of the global population with overweight and obesity, the number in the sub-Saharan Africa super-region is forecasted to increase by 254·8% (234·4-269·5). In Nigeria specifically, the number of adults with overweight and obesity is forecasted to rise to 141 million (121-162) by 2050, making it the country with the fourth-largest population with overweight and obesity. INTERPRETATION: No country to date has successfully curbed the rising rates of adult overweight and obesity. Without immediate and effective intervention, overweight and obesity will continue to increase globally. Particularly in Asia and Africa, driven by growing populations, the number of individuals with overweight and obesity is forecast to rise substantially. These regions will face a considerable increase in obesity-related disease burden. Merely acknowledging obesity as a global health issue would be negligent on the part of global health and public health practitioners; more aggressive and targeted measures are required to address this crisis, as obesity is one of the foremost avertible risks to health now and in the future and poses an unparalleled threat of premature disease and death at local, national, and global levels. FUNDING: Bill & Melinda Gates Foundation.

Contemporary epidemiology of hospitalised heart failure with reduced versus preserved ejection fraction in England: a retrospective, cohort study of whole-population electronic health records.

BACKGROUND: Heart failure is common, complex, and often associated with coexisting chronic medical conditions and a high mortality. We aimed to assess the epidemiology of people admitted to hospital with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), including the period covering the COVID-19 pandemic, which was previously not well characterised. METHODS: In this retrospective, cohort study, we used whole-population electronic health records with 57 million individuals in England to identify patients hospitalised with heart failure as the primary diagnosis in any consultant episode of an in-patient admission to a National Health Service (NHS) hospital. We excluded individuals with less than 1 year of medical history records in primary or secondary care; admissions to NHS hospitals for which less than 10% of heart failure cases were linkable to the National Heart Failure Audit (NHFA); individuals younger than 18 years at the time of the heart failure hospitalisation; and patients who died in hospital during the index heart failure admission. For patients with new onset heart failure, we assessed incidence rates of 30-day and 1-year all-cause and cause-specific (cardiovascular, non-cardiovascular, and heart failure-related) emergency rehospitalisation and mortality after discharge, and dispensed guideline-recommended medical therapy (GRMT). Follow-up occurred from the index admission to the earliest occurrence of the event of interest, death, or end of data coverage. We estimated adjusted hazard ratios (HRs) to compare HFrEF with HFpEF. We computed population-attributable fractions to quantify the percentage of outcomes attributable to coexisting chronic medical conditions. FINDINGS: Among 233 320 patients identified who survived the index heart failure admission across 335 NHS hospitals between Jan 1, 2019, and Dec 31, 2022, 101 320 (43·4%) had HFrEF, 71 910 (30·8%) had HFpEF, and 60 090 (25·8%) had an unknown classification. In patients with new onset heart failure, there were reductions in all-cause 30-day (-5·2% [95% CI -7·7 to -2·6] in 2019-22) and 1-year rehospitalisation rates (-3·9% [-6·6 to -1·2]). Declining 30-day rehospitalisation rates affected patients with HFpEF (-4·8% [-9·2 to -0·2]) and HFrEF (-6·2% [-10·5 to -1·6]), although 1-year rates were not statistically significant for patients with HFpEF (-2·2% [-6·6 to 2·3] vs -5·7% [-10·6 to -0·5] for HFrEF). There were no temporal trends in incidence rates of 30-day or 1-year mortality after discharge. The rates of all-cause (HR 1·20 [1·18-1·22]) and cause-specific rehospitalisation were uniformly higher in those with HFpEF than those with HFrEF. Patients with HFpEF also had higher rates of 1-year all-cause mortality after discharge (HR 1·07 [1·05-1·09]), driven by excess risk of non-cardiovascular death (HR 1·25 [1·21-1·29]). Rates of rehospitalisation and mortality were highest in patients with coexisting chronic kidney disease, chronic obstructive pulmonary disease, dementia, and liver disease. Chronic kidney disease contributed to 6·5% (5·6-7·4) of rehospitalisations within 1 year for HFrEF and 5·0% (4·1-5·9) of rehospitalisations for HFpEF, double that of any other coexisting condition. There was swift implementation of newer GRMT, but markedly lower dispensing of these medications in patients with coexisting chronic kidney disease. INTERPRETATION: Rates of rehospitalisation in patients with heart failure in England have decreased during 2019-22. Further population health improvements could be reached through enhanced implementation of GRMT, particularly in patients with coexisting chronic kidney disease, who, despite being at high risk, remain undertreated. FUNDING: Wellcome Trust, Health Data Research UK, British Heart Foundation Data Science Centre.

First trimester maternal infections and offspring congenital heart defects: a systematic review and meta-analysis

GPerturb: Gaussian process modelling of single-cell perturbation data.

Single-cell RNA sequencing and CRISPR screening enable high-throughput analysis of genetic perturbations at single-cell resolution. Understanding combinatorial perturbation effects is essential but challenging due to data sparsity and complex biological mechanisms. We present GPerturb, a Gaussian process-based sparse perturbation regression model designed to estimate gene-level perturbation effects. GPerturb employs an additive structure to separate signal from noise and captures sparse, interpretable effects from both discrete and continuous responses. It also provides uncertainty estimates for the presence and strength of perturbation effects on individual genes. We demonstrate the use GPerturb on both simulated and real-world datasets, characterising its competitive performance with current state-of-the-art methods. Furthermore, the model reveals meaningful gene-perturbation interactions and identifies effects consistent with known biology. GPerturb offers a novel approach for uncovering complex dependencies between gene expression and perturbations and advancing our understanding of gene regulation at the single-cell level.

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P 

An App-Based WHO Mental Health Guide for Depression Detection: A Cluster Randomized Clinical Trial.

IMPORTANCE: Depression detection in primary care remains limited in low- and middle-income countries despite increasing use of the World Health Organization Mental Health Gap Action Programme-Intervention Guide (mhGAP-IG). OBJECTIVE: To test an app version of the mhGAP-IG (e-mhGAP-IG) in Nepal and Nigeria to improve depression detection. DESIGN, SETTING, AND PARTICIPANTS: In this feasibility cluster randomized clinical trial conducted from February 14, 2021, to March 25, 2022, primary care facilities (unit of clustering) in Nepal and Nigeria were randomized to the standard mhGAP-IG training arm (control) or to training using the e-mhGAP-IG app (intervention). Primary care workers (PCWs) received training based on the arm assignment of their health care facility. Statistical analysis was conducted from July 20, 2022, through September 27, 2024. INTERVENTION: Training using standard mhGAP-IG vs training using the e-mhGAP-IG. MAIN OUTCOMES AND MEASURES: Analysis was performed on an intention-to-treat basis. The main outcome was accuracy of depression detection rates by PCWs, evaluated prior to mhGAP training and 5 to 8 months after training, measured as the percentage of patients who received a depression diagnosis by their PCWs compared with the number of patients who scored 10 or more on the locally validated 9-item Patient Health Questionnaire. Costs per patient detected were calculated. RESULTS: In Nepal, 25 facilities (67 PCWs; mean [SD] age, 35.3 [9.2] years; 52 men [78%]) were randomized: 13 facilities to standard mhGAP-IG training (36 PCWs) and 12 facilities to e-mhGAP-IG (31 PCWs). In Nigeria, 10 facilities (47 PCWs; mean [SD] age, 46.9 [7.5] years; 44 women [94%]) were randomized: 5 facilities to standard mhGAP-IG (25 PCWs) and 5 facilities to e-mhGAP-IG (22 PCWs). In Nepal, depression detection by PCWs in the standard mhGAP-IG arm increased from 0 of 43 patients before training to 15 of 92 patients after training (adjusted mean change [AMC], 16% [95% CI, 5%-28%]), and depression detection in the e-mhGAP-IG arm increased from 0 of 49 before training to 22 of 91 after training (AMC, 24% [95% CI, 12%-36%]). In Nigeria, depression detection in the standard mhGAP-IG arm increased from 5 of 36 patients before training to 25 of 75 patients after training (AMC, 19% [95% CI, 2%-37%]), and depression detection in the e-mhGAP-IG arm increased from 6 of 35 patients before training to 67 of 76 patients after training (AMC, 71% [95% CI, 57%-85%]). In facilities in the e-mhGAP-IG arm, the app was used for 59 of 616 assessments (10% of patients) in Nepal and 883 of 1077 assessments (82% of patients) in Nigeria. Cost per patient with depression detected using the e-mhGAP-IG was Nepali Rupiya (NPR) 1980 (US $14.79) in Nepal and naira (₦) 1462 (US $0.91) in Nigeria. CONCLUSIONS AND RELEVANCE: This feasibility cluster randomized clinical trial demonstrated that the use, cost, and potential clinical benefit of the e-mhGAP-IG varied by setting, highlighting the importance of multisite feasibility studies when evaluating digital innovations intended for health care systems worldwide. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04522453.

blood pressure-lowering and risk of cancer: an individual participant-level data meta-analysis and mendelian randomisation studies

Abstract Background The current body of randomised evidence concerning the effect of blood pressure lowering on the risk of cancer remains limited. Purpose We leveraged the strengths of both randomised controlled trials (RCTs) and genomic information to examine this question. Methods Individual-level data from 314,016 participants from 42 RCTs were pooled to investigate the effect of blood pressure lowering on the risk of cancer through one-stage individual participant data (IPD) meta-analysis. The primary outcome was incident cancer, defined as the first occurrence of any cancer diagnosed after randomisation. Pre-specified subgroup analyses were conducted to assess heterogeneity in effect by follow-up time and baseline age groups, sex, body mass index categories, smoking status and previous use of antihypertensive drugs. Secondary outcomes were cause-specific cancer death and site-specific cancer risk comprising breast, colorectal, kidney, lung, prostate, and skin. Cox proportional hazard regression, stratified by trials, were used for statistical analyses. For site-specific cancers, analyses were complemented with Mendelian randomisation analyses using naturally randomised genetic variants associated with blood pressure lowering, retrieved from genome-wide association studies involving participants of European ancestry. Results Over a median of 4 years (interquartile range 2), 17,954 participants in RCTs were diagnosed with cancer of any type and 4,878 participants were reported to have died with cancer as the cause of death. In the IPD meta-analysis that compared the treatment arm with the comparator, no associations were identified between reductions in either systolic or diastolic blood pressure and the risk of incident cancer (hazard ratios [HRs] per 5 mmHg reduction in systolic and per 3 mmHg diastolic blood pressure were 1.03 (95% confidence interval [CI] 0.99-1.06) and 1.03 [0.98-1.07], respectively). We also found no pattern of increasing or decreasing relative risk for incident cancer during the follow-up period, nor was there evidence of heterogeneity in treatment effects across baseline subgroups. No effect on the risk of cause-specific cancer death was identified for either systolic or diastolic blood pressure lowering. Considering site-specific cancers, we also found no evidence of effect, except for a possible link with lung cancer risk, with HRs of 1.17 [99.5% CI 1.02-1.32] for systolic blood pressure and 1.17 [99.5% CI 0.98-1.36] for diastolic blood pressure lowering. In Mendelian randomisation studies, no association was observed for genetically determined systolic and diastolic blood pressure and all the considered site-specific cancers, including overall lung cancer and its subtypes. Conclusion We found no consistent randomised evidence to suggest that blood pressure-lowering has a substantial effect, whether increasing or decreasing, on incident cancer, cause-specific cancer death, or selected site-specific cancers.