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

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

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 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

Efficacy and safety of tacrolimus in Crohn's disease: a nationwide, multi-centric study from GETECCU

Background: Crohn's disease (CD) is chronic inflammatory disease of the gastrointestinal tract. Tacrolimus (TCR) is a calcineurin inhibitor drug commonly used for prophylaxis of rejection in renal and liver transplantation. There is some evidence on the short- and medium-term efficacy and safety of TCR in CD, but data are still scarce. The primary aim of our study was to evaluate the efficacy and safety of TCR in CD in clinical practice in Spain. Methods: We performed a retrospective, multi-centric study in 22 inflammatory bowel disease Units in Spain. We included all adult patients with an established diagnosis of CD in whom oral TCR was prescribed for this condition. Clinical response was assessed by Harvey?Bradshaw index (H-B) and physician global assessment after 3 months. Perianal disease was evaluated by fistula drainage assessment (FDA) at the same time point. Follow-up period was considered until the last visit during therapy or 12 months after stopping the drug. Descriptive statistics and non-parametric tests were used in the statistical analysis. Results: Between January 2000 and November 2017 a total of 85 patients received TCR (mean age 36 years; 55% female; 69% perianal disease; mean CRP 14 mg/l). The most common indications for TCR were refractory luminal disease (57%) and perianal disease (32%). Most patients (81%) had previously received at least one anti-TNF agent and 61% ?2. Blood drug levels were 5?10 ng/ml during induction (34%) and maintenance (47%). In 25% of cases, TCR was started concomitantly with systemic steroids, in 11% with an anti-TNF agent and in 6% with vedolizumab. The drug was maintained for a median time of 6 months (2.7?18) and the median follow?up was 28 months (15?56). We found statistically significant differences in H-B after 3 months (median 7.4 (SD 4.4), p = 0.014). FDA showed a complete response in 8%, while 34% had partial response. In the univariate analysis, concomitant thiopurines were significantly associated with short-term clinical response (OR 5.53 95% CI 1.36?22.5, p = 0.017). We observed statistically significant differences in CRP levels 1, 3, 6, and 12 months when compared with baseline (p < 0.03). The drug was stopped in 86% of patients after a median time of 6 months (2?17): 62% requiring a new immunomodulator, 44% hospitalisation and 42% surgery. A total of 34% patients suffered adverse events related to the drug (45% tremor, 28% acute kidney injury), and in 37% they led to the discontinuation of the drug. Conclusions: Tacrolimus shows a clinical benefit in CD in the short-term, but its lower long-term effectiveness and frequent adverse events remain relevant issues in clinical practice