Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

Background So far, more than 170 loci have been associated with circulating lipid levels through genomewide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. Methods We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ~60 000 individuals in the discovery stage and ~90 000 samples in the replication stage. Results Our study resu

Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein.

Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP) is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic background of inflammation and cardiometabolic phenotypes using published genome-wide association studies (GWAS). We also evaluated whether the pleiotropic effects of such loci were biological or mediated in nature. First, we examined whether 283 common variants identified for 10 cardiometabolic phenotypes in GWAS are associated with CRP level. Second, we tested whether 18 variants identified for serum CRP are associated with 10 cardiometabolic phenotypes. We used a Bonferroni corrected p-value of 1.1×10-04 (0.05/463) as a threshold of significance. We evaluated the independent pleiotropic effect on both phenotypes using individual level data from the Women Genome Health Study. Evaluating the genetic overlap between inflammation and cardiometabolic phenotypes, we found 13 pleiotropic regions. Additional analyses showed that 6 regions (APOC1, HNF1A, IL6R, PPP1R3B, HNF4A and IL1F10) appeared to have a pleiotropic effect on CRP independent of the effects on the cardiometabolic phenotypes. These included loci where individuals carrying the risk allele for CRP encounter higher lipid levels and risk of type 2 diabetes. In addition, 5 regions (GCKR, PABPC4, BCL7B, FTO and TMEM18) had an effect on CRP largely mediated through the cardiometabolic phenotypes. In conclusion, our results show genetic pleiotropy among inflammation and cardiometabolic phenotypes. In addition to reverse causation, our data suggests that pleiotropic genetic variants partially underlie the association between CRP and cardiometabolic phenotypes

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

The Observer XT: A tool for the integration and synchronization of multimodal signals

The Observer was originally developed as a manual event recorder for the collection, management, analysis, and presentation of observational data in animals. Because of the flexibility of later versions, it became clear that The Observer was suitable for almost any study involving collection of observational data in both animals and humans. Furthermore, the most recent version of The Observer (The Observer XT) allows the integration and synchronization of multimodal signals from various sources, such as observational, video, tracking, and physiological data. This article describes how The Observer XT was used to integrate and synchronize video, observational, tracking, and physiological data from an experiment carried out in 2001 at the Wageningen Institute of Animal Sciences of Wageningen University and Research Centre. The integration and synchronization of these multimodal signals in The Observer XT allows the user to draw a more complete picture of the phenomena under stud

Smoking Cessation Treatment for Parents Who Dual Use E-Cigarettes and Traditional Cigarettes

INTRODUCTION: An increasing number of parents use both e-cigarettes and cigarettes (dual users). Previous studies have shown that dual users may have higher rates of contemplating smoking cessation than parents who only smoke cigarettes. This study was aimed to assess the delivery of tobacco cessation treatment (prescription for nicotine replacement therapy and referral to the quitline) among parents who report being dual users vs. cigarette-only smokers. METHODS: A secondary analysis of parent survey data collected between April and October 2017 at 10 pediatric primary care practices participating in a cluster-randomized controlled trial of the Clinical Effort Against Secondhand Smoke Exposure (CEASE) intervention was conducted. Parents were considered to be dual users of cigarettes and e-cigarettes if they reported smoking a cigarette, even a puff, in the past seven days and using an e-cigarette within the past 30 days. Parents were asked if they received a prescription for nicotine replacement therapy and referral to the quitline to help them quit from their child's clinician. Multivariable logistic regression examined factors (dual use, insurance status, relationship to the child, race, and education status of the parent) associated with delivery of smoking cessation treatment (receiving prescriptions and/or enrollment in quitline) to smoking parents. Further, we compared the rates of tobacco cessation treatment delivery to dual users in the usual-care control practices vs. intervention practices. RESULTS: Of 1007 smokers or recent quitters surveyed in the five intervention practices, 722 parents reported current use of cigarettes-only and 111 used e-cigarettes. Of these 111 parents, 82 (73.9%) reported smoking cigarettes. Parents were more likely to report receiving any treatment if they were dual users vs. cigarette-only smokers (OR 2.43, 95% CI 1.38, 4.29). Child's insurance status, parents' sex, education, and race were not associated with parental receipt of tobacco cessation treatment in the model. No dual users in the usual-care control practices reported receiving treatment. Discussion. Dual users who visited CEASE intervention practices were more likely to receive treatment than cigarette-only smokers when treatments were discussed. An increased uptake of tobacco cessation treatments among dual users reinforces the importance of discussing treatment options with this group, while also recognizing that cigarette-only smokers may require additional intervention to increase the acceptance rate of cessation assistance. This trial is registered with ClinicalTrials.gov, Identifier: NCT01882348

Global Respiratory Syncytial Virus-Related Infant Community Deaths

Background: Respiratory syncytial virus (RSV) is a leading cause of pediatric death, with >99% of mortality occurring in low- and lower middle-income countries. At least half of RSV-related deaths are estimated to occur in the community, but clinical characteristics of this group of children remain poorly characterized. Methods: The RSV Global Online Mortality Database (RSV GOLD), a global registry of under-5 children who have died with RSV-related illness, describes clinical characteristics of children dying of RSV through global data sharing. RSV GOLD acts as a collaborative platform for global deaths, including community mortality studies described in this supplement. We aimed to compare the age distribution of infant deaths <6 months occurring in the community with in-hospital. Results: We studied 829 RSV-related deaths <1 year of age from 38 developing countries, including 166 community deaths from 12 countries. There were 629 deaths that occurred <6 months, of which 156 (25%) occurred in the community. Among infants who died before 6 months of age, median age at death in the community (1.5 months; IQR: 0.8-3.3) was lower than in-hospital (2.4 months; IQR: 1.5-4.0; P<.0001). The proportion of neonatal deaths was higher in the community (29%, 46/156) than in-hospital (12%, 57/473, P<0.0001). Conclusions: We observed that children in the community die at a younger age. We expect that maternal vaccination or immunoprophylaxis against RSV will have a larger impact on RSV-related mortality in the community than in-hospital. This case series of RSV-related community deaths, made possible through global data sharing, allowed us to assess the potential impact of future RSV vaccines. © 2021 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America.Bill and Melinda Gates Foundation, BMGF: OPP1148988.8; Johnson and Johnson, J&J; Merck; Roche; AbbVieThis publication is based on research funded in part by the Bill & Melinda Gates Foundation (grant number OPP1148988.8). ES reports grants from Bill and Melinda Gates Foundation, during the conduct of the study; grants, personal fees and non-financial support from Astra Zeneca Inc, grants, personal fees and non-financial support from Merck & Co., grants, personal fees and non-financial support from Regeneron Inc, grants, personal fees and non-financial support from Pfizer Inc, personal fees, non-financial support and other from Abbvie Inc, personal fees from Alere Inc, grants, personal fees and non-financial support from Roche Inc, other from GSK Inc, grants from Johnson and Johnson, grants and nonfinancial support from Novavax Inc, outside the submitted work; FP reports grants and personal fees from JANSSEN, grants and personal fees from NOVAVAX, INC, personal fees from BAVARIAN NORDIC A/S, personal fees from PFIZER, personal fees from SANOFI, personal fees from REGENERON, personal fees from MERCK, outside the submitted work