Elevated plasma levels of CXCL16 in severe COVID-19 patients.

Genome-wide association studies have recently identified 3p21.31, with lead variant pointing to the CXCR6 gene, as the strongest thus far reported susceptibility risk locus for severe manifestation of COVID-19. In order the determine its role, we measured plasma levels of Chemokine (C-X-C motif) ligand 16 (CXCL16) in the plasma of COVID-19 hospitalized patients. CXCL16 interacts with CXCR6 promoting chemotaxis or cell adhesion. The CXCR6/CXCL16 axis mediates homing of T cells to the lungs in disease and hyper-expression is associated with localised cellular injury. To characterize the CXCR6/CXCL16 axis in the pathogenesis of severe COVID-19, plasma concentrations of CXCL16 collected at baseline from 115 hospitalized COVID-19 patients participating in ODYSSEY COVID-19 clinical trial were assessed together with a set of controls. We report elevated levels of CXCL16 in a cohort of COVID-19 hospitalized patients. Specifically, we report significant elevation of CXCL16 plasma levels in association with severity of COVID-19 (as defined by WHO scale) (P-value < 0.02). Our current study is the largest thus far study reporting CXCL16 levels in COVID-19 hospitalized patients (with whole-genome sequencing data available). The results further support the significant role of the CXCR6/CXCL16 axis in the immunopathogenesis of severe COVID-19 and warrants further studies to understand which patients would benefit most from targeted treatments.

Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus.

To date, the locus with the most robust human genetic association to COVID-19 severity is 3p21.31. Here, we integrate genome-scale CRISPR loss-of-function screens and eQTLs in diverse cell types and tissues to pinpoint genes underlying COVID-19 risk. Our findings identify SLC6A20 and CXCR6 as putative causal genes that modulate COVID-19 risk and highlight the usefulness of this integrative approach to bridge the divide between correlational and causal studies of human biology.

Association of CXCR6 with COVID-19 severity: delineating the host genetic factors in transcriptomic regulation.

The coronavirus disease 2019 (COVID-19) is an infectious disease that mainly affects the host respiratory system with ~ 80% asymptomatic or mild cases and ~ 5% severe cases. Recent genome-wide association studies (GWAS) have identified several genetic loci associated with the severe COVID-19 symptoms. Delineating the genetic variants and genes is important for better understanding its biological mechanisms. We implemented integrative approaches, including transcriptome-wide association studies (TWAS), colocalization analysis, and functional element prediction analysis, to interpret the genetic risks using two independent GWAS datasets in lung and immune cells. To understand the context-specific molecular alteration, we further performed deep learning-based single-cell transcriptomic analyses on a bronchoalveolar lavage fluid (BALF) dataset from moderate and severe COVID-19 patients. We discovered and replicated the genetically regulated expression of CXCR6 and CCR9 genes. These two genes have a protective effect on lung, and a risk effect on whole blood, respectively. The colocalization analysis of GWAS and cis-expression quantitative trait loci highlighted the regulatory effect on CXCR6 expression in lung and immune cells. In the lung-resident memory CD8+ T (TRM) cells, we found a 2.24-fold decrease of cell proportion among CD8+ T cells and lower expression of CXCR6 in the severe patients than moderate patients. Pro-inflammatory transcriptional programs were highlighted in the TRM cellular trajectory from moderate to severe patients. CXCR6 from the 3p21.31 locus is associated with severe COVID-19. CXCR6 tends to have a lower expression in lung TRM cells of severe patients, which aligns with the protective effect of CXCR6 from TWAS analysis.

[A poisoned gift]. / Un cadeau empoisonné - Chroniques génomiques.

GWAS analysis of severe Covid patients implicates a major locus on chromosome 3. The corresponding 50 kb segment appears to originate from Neanderthal/Sapiens crossings, raising interesting evolutionary questions.