d, Three cartoon views of an AlphaFold model of pulmonary surfactant-associated protein D (SFTPD UniProtKB: P35247). Colour shows linkage disequilibrium with the missense variant rs721917. c, Effect-size plot for effect of multiple variants on SFTPD expression (eQTLgen, x axis) against increasing susceptibility to critical COVID-19 ( β xy = 0.16 P xy = 9.7 × 10 −6). Pro474 is predicted to be in a tightly packed environment, and may therefore affect the folding of SLC22A31. The risk variant, P474L (Ala at rs117169628) would be expected to introduce more flexibility to the transmembrane helix and might therefore affect the transport properties of SLC22A31. Pro474 is predicted to be located in the transmembrane helix and point towards a putative transport pathway of a small molecule. A putative channel for small-molecule transport across the cell membrane is indicated by a dashed circle. The side chains of Pro474 and interacting amino acids are shown as connected spheres. b, Three cartoon views of an AlphaFold model of putative solute carrier family 22 member 31 (SLC22A31 UniProtKB: A6NKX4). The colour shows linkage disequilibrium (LD) with the missense variant rs117169628. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).Ī, Effect-size plot for the effect of multiple variants on SLC22A31 expression (eQTLgen, x axis) against increasing susceptibility to critical COVID-19 ( β xy = 0.11 P xy = 1.3 × 10 −9). To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3. GenOMICC Investigators SCOURGE Consortium ISARICC Investigators 23andMe COVID-19 Team Jian YangĬritical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2.
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