A first update on mapping the human genetic architecture of COVID-19

peer reviewe

TNF Blockade Maintains an IL-10+ Phenotype in Human Effector CD4+ and CD8+ T Cells

CD4(+) and CD8(+) effector T cell subpopulations can display regulatory potential characterized by expression of the prototypically anti-inflammatory cytokine IL-10. However, the underlying cellular mechanisms that regulate expression of IL-10 in different T cell subpopulations are not yet fully elucidated. We recently showed that TNF inhibitors (TNFi) promote IL-10 expression in human CD4(+) T cells, including IL-17(+) CD4(+) T cells. Here, we further characterized the regulation of IL-10 expression via blockade of TNF signaling or other cytokine/co-stimulatory pathways, in human T cell subpopulations. Addition of the TNFi drug adalimumab to anti-CD3-stimulated human CD4(+) T cell/monocyte cocultures led to increased percentages of IL-10(+) cells in pro-inflammatory IL-17(+), IFNγ(+), TNFα(+), GM-CSF(+), and IL-4(+) CD4(+) T cell subpopulations. Conversely, exogenous TNFα strongly decreased IL-10(+) cell frequencies. TNF blockade also regulated IL-10 expression in CD4(+) T cells upon antigenic stimulation. Using time course experiments in whole peripheral blood mononuclear cell (PBMC) cultures, we show that TNF blockade maintained, rather than increased, IL-10(+) cell frequencies in both CD4(+) and CD8(+) T cells following in vitro stimulation in a dose- and time-dependent manner. Blockade of IL-17, IFNγ, IL-6R, or CD80/CD86-mediated co-stimulation did not significantly regulate IL-10 expression within CD4(+) or CD8(+) T cell subpopulations. We show that TNF blockade acts directly on effector CD4(+) T cells, in the absence of monocytes or CD4(+) CD25(high)CD127(low) regulatory T cells and independently of IL-27, resulting in higher IL-10(+) frequencies after 3 days in culture. IL-10/IL-10R blockade reduced the frequency of IL-10-expressing cells both in the presence and absence of TNF blockade. Addition of recombinant IL-10 alone was insufficient to drive an increase in IL-10(+) CD4(+) T cell frequencies in 3-day CD4(+) T cell/monocyte cocultures, but resulted in increased IL-10 expression at later time points in whole PBMC cultures. Together, these data provide additional insights into the regulation of IL-10 expression in human T cells by TNF blockade. The maintenance of an IL-10(+) phenotype across a broad range of effector T cell subsets may represent an underappreciated mechanism of action underlying this widely used therapeutic strategy

Making the economic case for prevention – a view from Wales

<p>Abstract</p> <p>Background</p> <p>It is widely acknowledged that adverse lifestyle behaviours in the population now will place an unsustainable burden on health service resources in the future. It has been estimated that the combined cost to the NHS in Wales of overweight and obesity, alcohol and tobacco is in excess of £540 million.</p> <p>In the current climate of financial austerity, there can be a tendency for the case for prevention efforts to be judged on the basis of their scope for cost savings. This paper was prompted by discussion in Wales about the evidence for the cost savings from prevention and early intervention and a resulting concern that these programmes were thus being evaluated in policy terms using an incorrect metric. Following a review of the literature, this paper contributes to the discussion of the potential role that economics can play in informing decisions in this area.</p> <p>Discussion</p> <p>This paper argues that whilst studies of the economic burden of diseases provide information about the magnitude of the problem faced, they should not be used as a means of priority setting. Similarly, studies discussing the likelihood of savings as a result of prevention programmes may be distorting the arguments for public health.</p> <p>Prevention spend needs to be considered purposefully, resulting in a strategic commitment to spending. The role of economics in this process is to provide evidence demonstrating that information and support can be provided cost effectively to individuals to change their lifestyles thus avoiding lifestyle related morbidity and mortality. There is growing evidence that prevention programmes represent value for money using the currently accepted techniques and decision making metrics such as those advocated by NICE.</p> <p>Summary</p> <p>The issue here is not one of arguing that the economic evaluation of prevention and early intervention should be treated differently, although in some instances that may be appropriate, rather it is about making the case for these interventions to be treated and evaluated to the same standard. The difficulty arises when a higher standard of cost saving may be expected from prevention and public health programmes.</p> <p>The paper concludes that it is of vital importance that during times of budget constraints, as currently faced, the public health budgets are not eroded to fund secondary care budget shortfalls, which are more easily identifiable. To do so would diminish any possibility of reducing the future burden faced by the NHS of lifestyle-related illnesses.</p

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

COVID-19 Host Genetics Initiative. A first update on mapping the human genetic architecture of COVID-19

The COVID-19 pandemic continues to pose a major public health threat, especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity, we formed the COVID-19 Host Genetics Initiative1. Here we present a genome-wide association study meta-analysis of up to 125,584 cases and over 2.5 million control individuals across 60 studies from 25 countries, adding 11 genome-wide significant loci compared with those previously identified2. Genes at new loci, including SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.</p