Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites.

Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts.

Open Targets Genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics.

Open Targets Genetics (https://genetics.opentargets.org) is an open-access integrative resource that aggregates human GWAS and functional genomics data including gene expression, protein abundance, chromatin interaction and conformation data from a wide range of cell types and tissues to make robust connections between GWAS-associated loci, variants and likely causal genes. This enables systematic identification and prioritisation of likely causal variants and genes across all published trait-associated loci. In this paper, we describe the public resources we aggregate, the technology and analyses we use, and the functionality that the portal offers. Open Targets Genetics can be searched by variant, gene or study/phenotype. It offers tools that enable users to prioritise causal variants and genes at disease-associated loci and access systematic cross-disease and disease-molecular trait colocalization analysis across 92 cell types and tissues including the eQTL Catalogue. Data visualizations such as Manhattan-like plots, regional plots, credible sets overlap between studies and PheWAS plots enable users to explore GWAS signals in depth. The integrated data is made available through the web portal, for bulk download and via a GraphQL API, and the software is open source. Applications of this integrated data include identification of novel targets for drug discovery and drug repurposing.

A community-based cluster randomised controlled trial in rural Bangladesh to evaluate the impact of the use of iron-folic acid supplements early in pregnancy on the risk of neonatal mortality: the Shonjibon trial.

BACKGROUND: Iron-deficiency is the most common nutritional deficiency globally. Due to the high iron requirements for pregnancy, it is highly prevalent and severe in pregnant women. There is strong evidence that maternal iron deficiency anaemia increases the risk of adverse perinatal outcomes. However, most of the evidence is from observational epidemiological studies except for a very few randomised controlled trials. IFA supplements have also been found to reduce the preterm delivery rate and neonatal mortality attributable to prematurity and birth asphyxia. These results combined indicate that IFA supplements in populations of iron-deficient pregnant women could lead to a decrease in the number of neonatal deaths mediated by reduced rates of preterm delivery. In this paper, we describe the protocol of a community-based cluster randomised controlled trial that aims to evaluate the impact of maternal antenatal IFA supplements on perinatal outcomes. METHODS/DESIGN: The effect of the early use of iron-folic acid supplements on neonatal mortality will be examined using a community based, cluster randomised controlled trial in five districts with 30,000 live births. In intervention clusters trained BRAC village volunteers will identify pregnant women & provide iron-folic acid supplements. Groundwater iron levels will be measured in all study households using a validated test kit. The analysis will follow the intention to treat principle. We will compare neonatal mortality rates & their 95% confidence intervals adjusted for clustering between treatment groups in each groundwater iron-level group. Cox proportional hazards mixed models will be used for mortality outcomes & will include groundwater iron level as an interaction term in the mortality model. DISCUSSION: This paper aims to describe the study protocol of a community based randomised controlled trial evaluating the impact of the use of iron-folic acid supplements early in pregnancy on the risk of neonatal mortality. This study is critical because it will determine if antenatal IFA supplements commenced in the first trimester of pregnancy, rather than later, will significantly reduce neonatal deaths in the first month of life, and if this approach is cost-effective. TRIAL REGISTRATION: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) on 31 May 2012. The registration ID is ACTRN12612000588897 .

A community-based cluster randomised controlled trial to evaluate the effectiveness of different bundles of nutrition-specific interventions in improving mean length-for-age z score among children at 24 months of age in rural Bangladesh: study protocol.

BACKGROUND: Prevalence of stunting among under-five children in Bangladesh is 36%, varying with geographic and socio-economic characteristics. Previously, research groups statistically modelled the effect of 10 individual nutrition-specific interventions targeting the critical first 1000 days of life from conception, on lives saved and costs incurred in countries with the highest burden of stunted children. However, primary research on the combined effects of these interventions is limited. Our study directly addresses this gap by examining the effect of combinations of 5 preventive interventions on length-for-age z-scores (LAZ) among 2-years old children. METHODS: This community-based cluster randomised trial (c-RCT) compares 4 intervention combinations against one comparison arm. Intervention combinations are: 1) Behaviour change communication (BCC) on maternal nutrition during pregnancy, exclusive breastfeeding, and complementary feeding, along with prenatal nutritional supplement (PNS) and complementary food supplement (CFS); 2) BCC with PNS; 3) BCC with CFS; and 4) BCC alone. The comparison arm receives only routine health and nutrition services. From a rural district, 125 clusters were selected and randomly assigned to any one of the five study arms by block randomisation. A bespoke automated tab-based system was developed linking data collection, intervention delivery and project supervision. Total sample size is 1500 pregnant women, with minimum 1050 resultant children expected to be retained, powered to detect a difference of at least 0.4 in the mean LAZ score of children at 24 months, the main outcome variable, between the comparison arm and each intervention arm. Length and other anthropometric measurements, nutritional intake and other relevant data on mother and children are being collected during enrolment, twice during pregnancy, postpartum monthly till 6 months, and every third month thereafter till 24 months. DISCUSSION: This c-RCT explores the effectiveness of bundles of preventive nutrition intervention approaches addressing the critical window of opportunity to mitigate childhood stunting. The results will provide robust evidence as to which bundle(s) can have significant effect on linear growth of children. Our study also will have policy-level implications for prioritising intervention(s) tackling stunting. TRIAL REGISTRATION: The study was retrospectively registered on May 2, 2016 and is available online at ClinicalTrials.gov (ID: NCT02768181 ).

Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity.

BACKGROUND: Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries. METHODS: In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions. FINDINGS: MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10-4; OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10-4; OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications. INTERPRETATION: Our study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets. FUNDING: No.

An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci.

Genome-wide association studies (GWASs) have identified many variants associated with complex traits, but identifying the causal gene(s) is a major challenge. In the present study, we present an open resource that provides systematic fine mapping and gene prioritization across 133,441 published human GWAS loci. We integrate genetics (GWAS Catalog and UK Biobank) with transcriptomic, proteomic and epigenomic data, including systematic disease-disease and disease-molecular trait colocalization results across 92 cell types and tissues. We identify 729 loci fine mapped to a single-coding causal variant and colocalized with a single gene. We trained a machine-learning model using the fine-mapped genetics and functional genomics data and 445 gold-standard curated GWAS loci to distinguish causal genes from neighboring genes, outperforming a naive distance-based model. Our prioritized genes were enriched for known approved drug targets (odds ratio = 8.1, 95% confidence interval = 5.7, 11.5). These results are publicly available through a web portal ( http://genetics.opentargets.org ), enabling users to easily prioritize genes at disease-associated loci and assess their potential as drug targets.

Bangladesh: a success case in combating childhood diarrhoea.

BACKGROUND: Bangladesh had a large reduction in childhood deaths due to diarrhoeal disease in recent decades. This paper explores the preventive, promotive, curative and contextual drivers that helped Bangladesh achieve this exemplary success. METHODS: Primary and secondary data collection approaches were used to document trends in reduction of Diarrhoea Specific Mortality Rate (DSMR) between 1980 and 2015, understand what policies and programmes played key roles, and estimate the contribution of specific interventions that were implemented during the period. Data acquisition involved relevant document reviews and in-depth interviews with key stake-holders. A systematic search of literature was undertaken to explore socio-economic, aetiological, behavioural, and nutritional drivers of diarrhoeal disease reduction in Bangladesh. Finally, we used LiST (Lives Saved Tool) to model the contributions of the relevant interventions during three time periods (1980-2015, 1980-2000 and 2000-2015), and to project the number of lives saved in 2030 (compared to 2015) if these interventions were implemented at near universal coverage (90%). RESULTS: The factors which likely had the most impact on DSMR were the coordinated efforts of the Government of Bangladesh (GoB) with non-government organizations (NGOs) and the private sector that enabled swift implementation, at scale, of interventions like oral rehydration solution (ORS) and zinc, promotion of breastfeeding, handwashing and sanitary latrines (WASH), as well as improvements in female education and nutrition. Compared to 1980, we found ORS and reduction in stunting prevalence had the greatest impact on DSMR, saving roughly 70 000 lives combined in 2015. Until 2000, ORS had a higher contribution to DSMR reduction than reduction in stunting prevalence. This proportionate contribution was reversed during 2000-2015. At near universal coverage (90%) of combined direct diarrhoeal disease, nutrition and WASH interventions, we project that an additional 5356 deaths due to diarrhoea could be averted in 2030. CONCLUSION: Bangladesh's achievement in reduction of DSMR highlights the important role of an enabling policy environment that fostered coordinated efforts of the public and private sectors and NGOs for maximal impact. To maintain this momentum, evidence-based interventions should be scaled up at universal coverage.

Plasma triglycerides as a risk factor for chronic kidney disease in type 2 diabetes mellitus: Evidence from northeastern Thailand.

AIMS: To investigate the observational association between plasma triglyceride and CKD in patients with T2DM. METHODS: A hospital-based retrospective registry was used to obtain data of 3,748 T2DM patients from May 2016 to October 2016. Anthropometric measurements and biochemical reports of T2DM patients with CKD were obtained by data extraction of medical records. CKD was defined according to the estimated glomerular filtration rate (eGFR< 60 mL/min/1.73 m2). Multiple logistic regression was used to determine the association between plasma triglyceride and CKD. RESULTS: The mean age of the participants was 61.4 ±â€¯11.0 years, and a majority of them was female (64%) with poor glycemic control (83%), increased plasma triglyceride (51%) and 27% of T2DM patients had CKD. There was a significant trend towards deteriorating renal function (lower eGFR) with categorically raised triglyceride levels. After controlling for age, sex and other confounders, 'borderline high' (adjusted odds ratio (OR): 1.24, 95% confidence interval (CI): 1.01-1.54), 'high' (adjusted OR: 1.52, 95% CI: 1.24-1.85) and 'very high' (adjusted OR: 3.40, 95% CI: 1.94-5.94) triglyceride level groups had higher likelihood to have CKD compared to normal triglyceride level. CONCLUSION: CKD was associated with a higher level of plasma triglyceride among patients with T2DM. These results support the rationale to screen and manage increased triglyceride in routine clinical practices among persons with diabetes to prevent CKD.