SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Risk Assessment and Implications of Schoolchildren Exposure to Classroom Heavy Metals Particles in Jeddah, Saudi Arabia

Classrooms Air Conditioner Filter (CACF) particles represent all of the exposed particles that have migrated to the interior environment. This study was conducted to assess the heavy metals contamination in CACF particles from Jeddah primary schools located in urban, suburban and residential areas; and to evaluate their health risks of children exposure (non-carcinogenic and carcinogenic). Heavy metals levels in CACF particles of schools were in the following order: urban schools > suburban schools > residential schools. Fe, Mn and Zn were the dominant species. Geo-accumulation index (Igeo), contamination factor (CF) and pollution load index (PLI) values indicated that the contamination levels was in the following order Cd > Pb > Zn > As > Cu > Ni > Mn > Cr > Co >V > Fe. School CACF particles was moderately contaminated with As and Zn and moderately to heavily contaminated with Pb and Cd. Enrichment factors (EFs) indicated that Zn, Cd, Pb, As and Cu in CACF particles were severe enriched. The hazard quotient (HQs) and hazards index (HI) values for heavy metals were lower than the acceptable level of one. As, Pb, Cr and Mn were exhibited high non-cancer effects for children. The lifetime cancer risk (LCR) and total lifetime cancer risk (TLCR), HQs and HI values for the different exposure pathways of heavy metals decreased in the following order: ingestion > dermal contact > inhalation. Carcinogenic and non-carcinogenic risk rank order of schools were urban schools > suburban schools > residential schools. The LCR and TLCR of heavy metals was in the following order: Co > Ni >Cr > Cd > As > Pb. The ingestion lifetime cancer risk (LCRing) and TLCR values from exposure to Ni and Cr in urban and suburban schools, Cd in urban schools, and Co in all Jeddah schools only exceed the acceptable range (1 × 10−6–1 × 10−4) Only LCRing and TLCR values from exposure to ∑ carcinogens exceed the acceptable level

Classroom Dust-Bound Polycyclic Aromatic Hydrocarbons in Jeddah Primary Schools, Saudi Arabia: Level, Characteristics and Health Risk Assessment

Data concerning polycyclic aromatic hydrocarbons (PAHs) in Jeddah’s schools, Saudi Arabia, and their implications for health risks to children, is scarce. Classroom air conditioner filter dusts were collected from primary schools in urban, suburban and residential areas of Jeddah. This study aimed to assess the characteristics of classroom-dust-bound PAHs and the health risks to children of PAH exposure. Average PAH concentrations were higher in urban schools than suburban and residential schools. Benzo (b)fluoranthene (BbF), benzo(ghi)perylene (BGP), chrysene (CRY) and Dibenz[a,h]anthracene (DBA) at urban and suburban schools and BbF, BGP, fluoranthene (FLT) and indeno (1, 2, 3, −cd)pyrene (IND) at residential schools were the dominant compounds in classroom dust. PAHs with five aromatic rings were the most abundant at all schools. The relative contribution of the individual PAH compounds to total PAH concentrations in the classroom dusts of schools indicate that the study areas do share a common source, vehicle emissions. Based on diagnostic ratios of PAHs, they are emitted from local pyrogenic sources, and traffic is the significant PAH source, with more significant contributions from gasoline-fueled than from diesel cars. Based on benzo[a]pyrene equivalent (BaPequi) calculations, total carcinogenic activity (TCA) for total PAHs represent 21.59% (urban schools), 20.99% (suburban schools), and 18.88% (residential schools) of total PAH concentrations. DBA and BaP were the most dominant compounds contributing to the TCA, suggesting the importance of BaP and DBA as surrogate compounds for PAHs in this schools. Based on incremental lifetime cancer risk (ILCingestion, ILCRinhalation, ILCRdermal) and total lifetime cancer risk (TLCR)) calculations, the order of cancer risk was: urban schools > suburban schools > residential schools. Both ingestion and dermal contact are major contributors to cancer risk. Among PAHs, DBA, BaP, BbF, benzo(a)anthracene (BaA), benzo(k)fluoranthene (BkF), and IND have the highest ILCR values at all schools. LCR and TLCR values at all schools were lower than 10−6, indicating virtual safety. DBA, BaP and BbF were the predominant contributors to cancer effects in all schools

Oncological outcomes of elective versus emergency surgery for colon cancer: A tertiary academic center experience

Background: In this study, we aimed to identify the oncological outcomes in colon cancer patients who underwent elective versus emergency curative resection. Methods: All patients who underwent curative resection for colon cancer between July 2015 and December 2019 were retrospectively reviewed and analyzed. Patients were divided into two groups based on the presentation into elective and emergency groups. Results: A total of 215 patients with colon cancer were admitted and underwent curative surgical resection. Of those, 145 patients (67.4%) were elective cases, and 70 (32.5%) were emergency cases. Family history of malignancy was positive in 44 patients (20.5%) and significantly more common in the emergency group (P = 0.016). The emergency group had higher T and TNM stages (P = 0.001). The 3-year survival rate was 60.9% and significantly less in the emergency group (P = 0.026). The mean duration from surgery to recurrence, 3-year disease-free survival, and overall survival were 1.19, 2.81, and 3.11, respectively. Conclusion: Elective group was associated with better 3-year survival, longer overall, and 3-year disease-free survival compared to the emergency group. The disease recurrence rate was comparable in both groups, mainly in the first two years after curative resection

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

COVID-19 Host Genetics Initiative. A first update on mapping the human genetic architecture of COVID-19

The COVID-19 pandemic continues to pose a major public health threat, especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity, we formed the COVID-19 Host Genetics Initiative1. Here we present a genome-wide association study meta-analysis of up to 125,584 cases and over 2.5 million control individuals across 60 studies from 25 countries, adding 11 genome-wide significant loci compared with those previously identified2. Genes at new loci, including SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.</p

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially