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

Die Völkerschlacht bei Leipzig vom 16. bis 19. Oktober 1813

DIE VÖLKERSCHLACHT BEI LEIPZIG VOM 16. BIS 19. OKTOBER 1813 Die Völkerschlacht bei Leipzig vom 16. bis 19. Oktober 1813 ([3]r) Einband ( - ) Das Denkmal der Völkerschlacht bei Leipzig ([1]v) Das Schlachtfeld von Leipzig am Entscheidungstage, den 18. Oktober 1813 ([2]r) Titelseite ([3]r) Widmung ([4]r) Text ([1]) Die Schlacht bei Möckern (100) Stellung der Schlesischen Armee in der Nacht vom 17. zum 18. (123) Stellung der französischen Hauptarmee unter Napoleon zwischen Pleiße und Rietzschkebach südlich Leipzig am 18. (125) Armee-Befehl. (Uebersetzung) (185) Werbung ( -

Diet matters, particularly in pregnancy - results from MoBa studies of maternal diet and pregnancy outcomes

Awareness that maternal diet may influence the outcome of pregnancy as well as the long-term health of mother and child has increased in recent years. A new food frequency questionnaire (FFQ) was developed and validated specifically for the Norwegian Mother and Child Cohort Study (MoBa). The MoBa FFQ is a semi-quantitative tool which covers the average intake of food, beverages and dietary supplements during the first 4 to 5 months of pregnancy. It includes questions about intakes of 255 foods and dishes and was used from 2002 onwards. Data assessed by the MoBa FFQ is available for 87,700 pregnancies. Numerous sub-studies have examined associations between dietary factors and health outcomes in MoBa. The aim of this paper is to summarize the results from 19 studies of maternal diet and pregnancy outcomes, which is the complete collection of studies based on the MoBa FFQ and published before September 2014. The overall research question is whether maternal diet – from single substances to dietary patterns – matters for pregnancy outcome. The pregnancy outcomes studied till now include birth size measures, infants being small and large for gestational age, pregnancy duration, preterm delivery, preeclampsia, as well as maternal gestational weight gain and postpartum weight retention. As a whole, the results from these studies corroborate that the current dietary recommendations to pregnant women are sound and that maternal diet during pregnancy is likely to contribute to reduce the risk of pregnancy complications including preterm birth, preeclampsia, and reduced foetal growth. The results provide supporting evidence for recommending pregnant women to consume vegetables, fruit, whole grain, fish, dairy, and water regularly and lower the intake of sugar sweetened beverages, processed meat products and salty snacks. The results showing negative impact of even low levels of environmental contaminants support the precautionary advice on consumption of foods containing these. New findings are that particularly lean fish explained the positive association between seafood intake and foetal growth, and the indications of a protective effect of probiotic and antimicrobial foods on pregnancy outcomes. This points to the importance of diet composition for a healthy gut flora and the body’s immune response. Although these studies are observational and cannot infer causality, the results identify diet as an important modifiable lifestyle factor, suggesting that healthy eating, defined as following the official recommendations, is particularly important in pregnancy

The selectivity of galardin and an azasugar-based hydroxamate compound for human matrix metalloproteases and bacterial metalloproteases

<div><p>Inhibitors targeting bacterial enzymes should not interfere with enzymes of the host, and knowledge about structural determinants for selectivity is important for designing inhibitors with a therapeutic potential. We have determined the binding strengths of two hydroxamate compounds, galardin and compound <b>1b</b> for the bacterial zinc metalloproteases, thermolysin, pseudolysin and auerolysin, known to be bacterial virulence factors, and the two human zinc metalloproteases MMP-9 and MMP-14. The active sites of the bacterial and human enzymes have huge similarities. In addition, we also studied the enzyme-inhibitor interactions by molecular modelling. The obtained <i>K</i>_i values of galardin for MMP-9 and MMP-14 and compound <b>1b</b> for MMP-9 are approximately ten times lower than previously reported. Compound <b>1b</b> binds stronger than galardin to both MMP-9 and MMP-14, and docking studies indicated that the diphenyl ether moiety of compound <b>1b</b> obtains more favourable interactions within the S´₁-subpocket than the 4-methylpentanoyl moiety of galardin. Both compounds bind stronger to MMP-9 than to MMP-14, which appears to be due to a larger S´₁-subpocket in the former enzyme. Galardin, but not <b>1b</b>, inhibits the bacterial enzymes, but the galardin <i>K</i>_i values were much larger than for the MMPs. The docking indicates that the S´₁-subpockets of the bacterial proteases are too small to accommodate the diphenyl ether moiety of <b>1b</b>, while the 4-methylpentanoyl moiety of galardin enters the pocket. The present study indicates that the size and shape of the ligand structural moiety entering the S´₁-subpocket is an important determinant for selectivity between the studied MMPs and bacterial MPs.</p></div

Purification and activation of proMMP-9.

<p>(<b>A</b>) Imperial stained SDS-PAGE showing the purity of purified recombinant human full length proMMP-9 expressed in Sf9 cells (rproMMP-9) and of proMMP-9 purified from THP-1 cells (proMMP-9) as described in the Materials and Methods section. PT is the pass through fraction from Gelatin-Sepharose Chromatography of the recombinant enzyme, and 4 times more protein was loaded to the gel in the lanes labelled PT(2) compared to the lanes labelled PT(1). Std. 1 is the molecular size marker Spectra^TM Mulitcolor High Range Protein Ladder and sb is sample buffer. Prior to electrophoresis, samples were either treated (+) or not treated (-) with DTT. Gelatin (<b>B-D</b>) and real-time gelatin (<b>E</b>) zymography of purified proMMP-9, trypsin activated (MMP-9) proMMP-9 from THP-1 cells, purified rproMMP-9, AMPA (rMMP-9(A)), trypsin (rMMP-9(T)) and MMP-3 (rMMP-9(M3)) activated recombinant proMMP-9. Std.2 in (<b>B-E</b>) is a mixture of proMMP-9 from THP-1 cells and proMMP-2 from human skin fibroblasts. Std. 3 is the 37 kDa catalytic domain of human MMP-9.</p

The selectivity of galardin and an azasugar-based hydroxamate compound for human matrix metalloproteases and bacterial metalloproteases - Fig 1

<p><b>Domain structure of MMPs (A) and schematic representation of galardin and compound 1b (B).</b> All MMPs contain a signal peptide (cleaved off in the endoplasmatic reticulum), a pro-peptide domain and a catalytic domain. In addition, most MMPs contain a linker (hinge-region) and a hemopexin (HPX) like domain. The hinge region in MMP-9 differs from the other MMPs as it is longer and heavily O-glycosylated, and therefore also called the OG-domain. Three secreted (MMP-11, -21, -28) and all membrane-anchored MMPs have a basic RX[K/R]R motif at the C-terminal end of their pro-domain. This motif can be cleaved inside the cells by furin-like proteases. The two gelatinases (MMP-2, -9) contain three fibronectin II like repeats (FnII module) in their catalytic domain, located N-terminal to the catalytic Zinc-binding site. Four of the six membrane-type (MT)-MMPs are anchored to the cell membranes through a type I transmembrane domain and the other two through a glycosylphosphatidylinosityl (GPI) moiety.</p

Galardin and compound 1b docked into the catalytic site of MMP-9 and MMP-14.

<p>The figure shows close ups of the active site region with the compound structures (xsticks), secondary structure elements and the most important amino acids for ligand binding (xsticks) indicated. Colour coding of atoms of amino acids and ligands: oxygen; red, nitrogen; blue, hydrogen; white, sulphur; yellow, carbon atoms of ligands; yellow, carbon atoms of amino acid side chains; pink, the zinc ion; light blue. The secondary structures elements are coloured from the N- to the C-terminal such that corresponding secondary elements of MMP-9 and MMP-14 obtain similar colour.</p