The TYK2 gene associated with lupus provides protection against SARS-CoV-2 infection

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Researchers from King’s College London – United Kingdom have discovered that the gene TYK2 that is associate with systemic lupus erythematosus (SLE) provides protection against SARS-CoV-2 infections and also prevents COVID-19 severity but increases the risk for autoimmune diseases.

The study findings were published in the peer reviewed journal: PLOS Genetics
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010253
 

Our results indicate that there are shared genetic effects between the autoimmune disease SLE and the clinical consequences of COVID-19.

The locus with the most evidence of shared effects was the Janus kinase (JAK), TYK2, that promotes IL-12 and IFN-I signaling. Here there are two separate genetic association signals (designated A and B) shared between severe COVID-19 and SLE. Importantly for both, the genetic factors for SLE risk mitigate the outcome following SARS-Cov2 infection.

In seeking to uncover the mechanisms underlying these relationships it was apparent that the functional effects of the risk alleles are complex. Signal-A at TYK2 is likely driven by a coding P1104A variant (rs34536443) whose COVID-19 risk allele has been shown to impair TYK2 target phosphorylation [13].

This is further supported by the therapeutic effect of a TYK2 inhibitor in psoriasis [18], and by observed risk in other infectious disease such as tuberculosis where it has been found that homozygosity for the minor allele (C) of rs34536443 is risk, in line with severe COVID-19, and strongly impairs IL-23 signaling in T cells and IFN-γ production in PBMC [19,20].

Signal-A, led by rs34536443, was also found to colocalize with an eQTL for nearby PDE4A, which encodes a phosphodiesterase that regulates cAMP. This enzyme has multiple potential roles, however PDE4A inhibitors have been shown to have anti-inflammatory activity and are being studied in AID and inflammatory lung diseases [21].

The severe COVID-19 risk alleles are associated with decreased expression of PDE4A, while they are protective for SLE. The PDE4A eQTL cell type is heterogeneous however and the relevance to SLE is unclear. Signal-B includes another missense variant in TYK2, namely rs2304256 (V362F) in exon 8, but this also acts as a splicing mutation and the missense variant is missing from the spliced transcript.

The severe COVID-19 risk allele promotes inclusion of exon 8 in TYK2 that is essential for TYK2 binding to cognate receptors [15]. Therefore signal-B comprises evidence for two functional effects with respect to COVID-19 risk alleles, one of which increases function of TYK2 through altered splicing (rs2304256 (V362F)) and one that is correlated with increased expression of TYK2 (rs11085727).

It may be that the overall reduction of TYK2 activity caused by the COVID-19 risk alleles in signal-A evokes a compensatory effect on overall gene expression, which is designed to mitigate the deleterious effect of the missense variants–an example of regulatory variants modifying the penetrance of coding variants [15,22]. This conjecture is supported by the lack of epigenetic marks in the signal-B region of TYK2.

The severe COVID-19 risk allele for signal-B at TYK2 is associated with reduced SERPING1 and CXCL10 protein expression, implying that the minor allele at signal-B in the TYK2 locus reduces some aspect of TYK2 function. CXCL10 (IP-10) is a chemokine that acts on Th1 cells and is key regulator of the cytokine storm immune response to COVID-19 infection [23].

SERPING1, an inhibitor of complement 1 (C1-inh), is known to be reduced by infection and this reduction correlates with more severe COVID-19 [24]. Therefore genetic predisposition to low SERPING1 expression may increase risk for COVID-19 through the same dynamics as reduced levels due to infection. This and the effect of reduced levels of CXCL10 are likely just two examples of altered IFN induced activity that affects risk for disease.

We found agreement in direction of effect of association in CLEC1A. CLEC1A is interesting as C-type Lectin receptors are involved in fungal recognition and fungal immunity. Genetic variation in CLEC1A is a risk factor for the development of Aspergillosis in immunosuppression [25]. CLEC1A is a negative regulator of dendritic cells [26].

Therefore the SLE and severe COVID-19 risk allele, being associated with reduced expression of CLEC1A, would be expected to exert a pro-inflammatory effect. We also found agreement in direction of effect of associations in 3 other loci (IL12B, PLCL1-RFTN2, MIR146A) that showed relatively strong evidence of colocalization.

The modest p-values and relatively high colocalisation possibilities support them as good candidates to follow up in larger studies. At both IRF8 and TNFSF4 the evidence for association in severe COVID is moderate yet the signals do show some evidence of colocalizing with opposing effects in systemic lupus erythematosus (SLE, Lupus).

With prominent roles in the pro-inflammatory IFN response these two loci should be a focus when larger data in severe COVID-19 are available. IRF8 provides more evidence that the IFN pathway is important in the balance between SLE risk and infection as mutations that impair IRF8 transcriptional activity have been found to cause immunodeficiency [27].

Interferons constitute one of the main means of host defense against viruses and hence have been well studied in the context of COVID-19 [28–30]. In systemic lupus erythematosus (SLE, Lupus), evidence for interferon activity is present in about half of the patients and is often present in those with more severe disease [31–33].

Although elevated interferon has been implicated in other AID, the role is prominent in SLE. This has been exploited with therapeutic agents designed to antagonize type I interferon activity showing benefit in SLE [34]. Parallels between SLE and viral infection extend beyond interferon activation though.

As stated above there are SLE risk genes that act in the intracellular viral sensing pathways. SLE is characterized by an immune response against host nucleic acids. The means by which the immune system loses tolerance to these structures appears to involve aberrant exposure of self through the pathways that are designed to sense foreign nucleic acids, as happens during viral infection [35]. Further investigation into the genetic correlation between systemic lupus erythematosus (SLE, Lupus) and severe COVID-19 will help explain the genetic basis of both diseases, which may be in part due to variation in response to viral infection.

Risk alleles for SLE, that are also risk for severe COVID-19, may persist in the population due to protective effects against other exposures such as fungal infection. The opposing effects we find at the TYK2 locus is compatible with the hypothesis that there are alleles in the general population that, while represent a risk for SLE, persist possibly due to an innate immune protection against pathogens [36–41] including viruses.

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