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 hospitalization2,3,4 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

Paraoxonase (PON1): from toxicology to cardiovascular medicine

Paraoxonase (PON1) is a liver and plasma enzyme most studied because of its ability to hydrolyze the active metabolites of several organophosphorus insecticides. The discovery that PON1 can also metabolize oxidized phospholipids has spurred research on its possible role in coronary heart disease and atherosclerosis. Additionally, its potential roles in metabolizing pharmaceutical drugs and microbial quorum sensing factors are also being explored. PON1 displays several polymorphisms that influence both its level of expression and its catalytic activity, thus determining the rates at which a given individual will detoxify a specific insecticide, metabolize harmful oxidized lipids, and activate or inactivate specific drugs and quorum sensing factors

Pharmacological and dietary modulators of paraoxonase 1 (PON1) activity and expression: the hunt goes on

Paraoxonase 1 (PON1) is a high density lipoprotein (HDL)-associated enzyme displaying esterase and lactonase activity. PON1 hydrolyzes several organophosphorus (OP) insecticides and nerve agents, a number of exogenous and endogenous lactones, and metabolizes toxic oxidized lipids of low density lipoproteins (LDL) and HDL. As such, PON1 plays a relevant role in determining susceptibility to OP toxicity, cardiovascular diseases and several other diseases. Serum PON1 activity in a given population can vary by at least 40-fold. Most of this variation can be accounted for by genetic polymorphisms in the coding region (Q192R, L55M) and in the promoter region (T-108C). However, exogenous factors may also modulate PON1 activity and/or level of expression. This paper examines various factors that have been found to positively modulate PON1. Certain drugs (e.g. hypolipemic and anti-diabetic compounds), dietary factors (antioxidants, polyphenols), and life-style factors (moderate alcohol consumption) appear to increase PON1 activity. Given the relevance of PON1 in protecting from certain environmental exposure and from cardiovascular and other diseases, there is a need for further mechanistic, animal, and clinical research in this area, and for consideration of possible alternative strategies for increasing the levels and activity of PON1

Paraoxonase 2 (PON2) in the mouse central nervous system: a neuroprotective role?

The aims of this study were to characterize the expression of paraoxonase 2 (PON2) in mouse brain and to assess its antioxidant properties. PON2 levels were highest in the lung, intestine, heart and liver, and lower in the brain; in all tissues, PON2 expression was higher in female than in male mice. PON2 knockout [PON2(-/-)] mice did not express any PON2, as expected. In the brain, the highest levels of PON2 were found in the substantia nigra, the nucleus accumbens and the striatum, with lower levels in the cerebral cortex, hippocampus, cerebellum and brainstem. A similar regional distribution of PON2 activity (measured by dihydrocoumarin hydrolysis) was also found. PON3 was not detected in any brain area, while PON1 was expressed at very low levels, and did not show any regional difference. PON2 levels were higher in astrocytes than in neurons isolated from all brain regions, and were highest in cells from the striatum. PON2 activity and mRNA levels followed a similar pattern. Brain PON2 levels were highest around birth, and gradually declined. Subcellular distribution experiments indicated that PON2 is primarily expressed in microsomes and in mitochondria. The toxicity in neurons and astrocytes of agents known to cause oxidative stress (DMNQ and H2O2) was higher in cells from PON2(-/-) mice than in the same cells from wild-type mice, despite similar glutathione levels. These results indicate that PON2 is expressed in the brain, and that higher levels are found in dopaminergic regions such as the striatum, suggesting that this enzyme may provide protection against oxidative stress-mediated neurotoxicity

Functional genomics of paraoxonase (PON1) polymorphisms: effects on pesticide sensitivity, cardiovascular disease and drug metabolism.

This review focuses on the functional genomics of the human paraoxonase (PON1) polymorphisms. Levels and genetic variability of the PON1 position 192 isoforms (Gln/Arg) influence sensitivity to specific insecticides or nerve agents and risk for. cardiovascular disease. A more recent area of investigation, the role of PON1 in drug metabolism, is also discussed. We emphasize the importance of considering both PON1 isoforms and PON1 levels in disease/sensitivity association studies

Measurement of paraoxonase (PON1) status as a potential biomarker of susceptibility to organophosphate toxicity

Organophosphorus (OP) compounds are still among the most widely used insecticides, and their main mechanism of acute toxicity is associated with inhibition of acetylcholinesterase. Measurements of urine metabolites and of blood cholinesterase activity are established biomarkers of exposure to OPs and of early biological effects. In recent years, increasing attention has been given to biomarkers of susceptibility to OP toxicity. Here we discuss the polymorphisms of paraoxonase (PON1), a liver and serum enzyme that hydrolyzes a number of OP compounds, and its role in modulating the toxicity of OPs. We stress the importance of determining PON1 status, which encompasses the PON1(192)Q/R polymorphism (that affects catalytic ability toward different substrates) and PON1 levels (which are modulated in part by a C-108T polymorphism) over straight genotyping. Epidemiological studies on OP-exposed workers that include assessment of PON1 status to validate in human populations the role of PON1 as a determinant of susceptibility to OPs, as indicated by animal studies, are needed. Documentation of exposure and of early health effects would be most relevant to increase the predictive value of the tes

Paraoxonase polymorphisms and toxicity of organophosphates

In 1946, it was found that certain organophophorus (OP) insecticides could be enzymatically hydrolyzed by plasma (Mazur, 1946). Seminal studies by Aldridge (1953) indicated that A-esterases were capable of hydrolyzing OPs, whereas B-esterases [such as acetylcholinesterase (AChE)] reacted with a single OP molecule and were thus inhibited by this “suicide reaction”. Aldridge's proposal that an A-esterase hydrolyzed both phenylacetate and paraoxon was conclusively proven several decades later, when it was shown that recombinant paraoxonase/arylesterase catalyzed both activities (Gan et al., 1991). Studies in the late 1970s and early 1980s indicated that the plasma hydrolytic activity toward paraoxon was polymorphically distributed in human populations (Playfer, 1976; Eckerson et al., 1993; Mueller et al., 1983), suggesting a genetically based differential susceptibility to OP toxicity

Paraoxonase 1 (PON1) modulates the toxicity of mixed organophosphorus compounds

A transgenic mouse model of the human hPON1(Q192R) polymorphism was used to address the role of paraoxonase (PON1) in modulating toxicity associated with exposure to mixtures of organophosphorus (OP) compounds. Chlorpyrifos oxon (CPO), diazoxon (DZO), and paraoxon (PO) are potent inhibitors of carboxylesterases (CaE). We hypothesized that a prior exposure to these OPs would increase sensitivity to malaoxon (MO), a CaE substrate, and the degree of the effect would vary among PON1 genotypes in the OP was a physiologically significant PON1 substrate in vivo. CPO and DZO are detoxified by PON1. For CPO hydrolysis, hPON1(R192) has a higher catalytic efficiency than hPON1(Q192R). For DZO hydrolysis, the two alloforms have nearly equal catalytic efficiencies. For PO hydrolysis, the catalytic efficiency of PON1 is too low to be physiologically relevant. When wild-type mice were exposed dermally to CPO, DZO, or PO followed 4-h later by increasing doses of MO, toxicity was increased compared to mice receiving MO alone, presumably due to CaE inhibition. Potentiation of MO toxicity by CPO and DZO was greater in PON1(-/-) mice, which have greatly reduced capacity to detoxify CPO and DZO. Potentiation by CPO was more pronounced in hPON1(Q192) mice than in hPON1(R192) mice due to the decreased efficiency of hPON1(Q192) for detoxifying CPO. Potentiation by DZO was similar in hPON1(Q192) and hPON1(R192) mice, which are equally efficient at hydrolyzing DZO. Potentiation by PO was equivalent among all four genotypes. These results indicate that PON1 status can have a major influence on CaE-mediated detoxication of OP compound