Shared genetic effects between the autoimmune disease systemic lupus erythematosus and the clinical consequences of COVID-19

In a recent study published in PLOS Genetics, researchers identified a genetic association signal, via genome-wide association (GWA) studies, between severe coronavirus disease 2019 (COVID-19) with systemic lupus erythematosus (SLE), an autoimmune disease (AID). They tested this association formally using genetic correlation analysis via linkage disequilibrium (LD) score regression.

Study: COVID-19 and systemic lupus erythematosus genetics: A balance between autoimmune disease risk and protection against infection. Image Credit: MiniStocker/Shutterstock
Study: COVID-19 and systemic lupus erythematosus genetics: A balance between autoimmune disease risk and protection against infection. Image Credit: MiniStocker/Shutterstock

Background

The COVID-19 outbreak presented an unprecedented opportunity to investigate the genetics of response to viral infection. Previous GWA studies of severe COVID-19 pointed to the involvement of a genetic component in the heterogeneity of the clinical outcomes. As expected, some of the genetic loci identified in this pursuit pointed towards the involvement of host immune pathways. Thus, a comparative analysis of the genetics of severe COVID-19 and AIDs, such as SLE, could be insightful.

About the study

In the present study, researchers downloaded summary-level GenOMICC GWAS data of 1676 critically ill COVID-19 patients of European ancestry from 208 intensive care units (ICUs) and 8380 ancestry-matched controls from the UK Biobank. Further, they gathered an SLE meta-analysis of three previously published European GWASs. They used a standard fixed effects inverse variance approach for meta-analysis.

Furthermore, the researchers evaluated the genetic correlation between SLE and severe COVID-19 using conventional cross-trait LD score regression (LDSC) to calculate genome-wide genetic correlation (rg). They retained all the overlapping single nucleotide polymorphisms (SNPs) between the SLE meta-analysis and the COVID-19 GenOMICC data. The team added SLE Immunochip data from a previous study to increase the local genetic correlation detection power.

They also used Immunochip study data for the meta-analysis of 1,559,546 genome-wide overlapped NSNPs (fine-mapping). This dataset had 2,970 cases and 2,452 controls from African Americans and 1,872 cases, and 2,016 controls of Hispanic origin.

The team performed two cross-trait meta-analyses between the SLE meta-analysis. In both meta-analyses, they retained and plotted p-values for only those SNPs that had p< 0.01 in both diseases and shared the direction of effects concerning each meta-analysis. Any SNPs that passed a significance threshold of P < 5 × 10−08 in meta-analysis in both traits were considered candidates for the shared association. They declared a locus shared if its colocalization probability was more than 0.9. Likewise, they followed these by fine mapping in traits- and colocalization analysis.

Study findings

The researchers identified multiple shared loci between SLE and COVID-19, some of which even exerted opposing effects. Though it had a negative local genetic correlation, the locus with the most evidence of shared association was tyrosine-protein kinase (TYK2), a gene critical to the type I interferon (IFN) pathway. 

They identified two separate genetic association signals shared between severe COVID-19 and SLE, designated as signals A and B. Importantly for A and B, the genetic factors for SLE risk mitigated the outcome following COVID-19. A coding P1104A variant (rs34536443) drove signal-A at TYK2, whose COVID-19 risk allele has shown to impair TYK2 target phosphorylation. While this allele is associated with decreased expression of phosphodiesterase 4A (PDE4A), it is protective against SLE. The PDE4A cis-expression quantitative trait locus (eQTL) cell type is heterogeneous; however, the relevance to SLE is yet unclear.

Signal B includes TYK2 rs2304256 (V362F) missense variant (in exon 8) that also acts as a splicing mutation. The severe COVID-19 risk allele promotes the inclusion of exon 8 in TYK2, which is essential for TYK2 binding to cognate receptors. The evidence for two functional effects concerning COVID-19 risk alleles in signal B suggests that the COVID-19 risk alleles in signal-A compensate for the overall reduction of TYK2 activity. It mitigates the deleterious effect of the missense variants, an example of how regulatory variants modify the penetrance of coding variants. Perhaps this is why the epigenetic marks in the signal B region of TYK2 are missing.

Another shared locus identified between SLE and COVID-19 was C-Type Lectin Domain Family 1 Member A (CLEC1A), where the direction of effects aligned. It encodes a lectin involved in cell signaling and anti-fungal immunity. CLEC1A is a negative regulator of dendritic cells. Additionally, its genetic variation increases the risk factor for aspergillosis in immunosuppression. Thus, overall, the reduced expression of CLEC1A exerts a pro-inflammatory effect.

Conclusions

The current study findings demonstrated that some genetic alleles in the human genome confer protection against viral infections while accentuating the risk for autoimmune disease. TYK2, for instance, involved in IFN production, is crucial for processes combating viral infections but is dysregulated in SLE patients.

IFNs, the primary host defense weaponry against viruses, have been studied in detail in the context of COVID-19. Also, studies have evidenced IFN activity in about half of the SLE patients, especially those with more severe disease. Although elevated IFN levels have been implicated in several AIDs, their role is more prominent in SLE. Thus, therapeutics designed to antagonize type I IFN activity show benefits in SLE.

Risk alleles for SLE, which also accentuate the risk for severe COVID-19, may persist in the general population due to their protective effects against fungal infections. It calls for more extensive investigations into the genetic correlation between SLE and severe COVID-19.

The researchers also found agreement in the effects of associations at three other genetic loci, all of which emerged as hotshot candidates to follow up in future studies due to strong evidence supporting their relatively high colocalization. These were interleukin 12B (IL12B), phospholipase C Like 1 (PLCL1)-raftlin family member 2 (RFTN2), and microRNA 146a (MIR146A).

Despite a moderate association with severe COVID-19, two other genetic loci, IFN regulatory factor 8 (IRF8), and tumor necrosis factor-superfamily member 4 (TNF-SF4) showed colocalizing evidence for SLE in a different direction. Also, mutations that impair IRF8 transcriptional activity have been shown to cause immunodeficiency. As larger datasets on severe COVID-19 become available, studies should also focus on these two loci.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

Citations

Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Mathur, Neha. (2022, November 07). Shared genetic effects between the autoimmune disease systemic lupus erythematosus and the clinical consequences of COVID-19. News-Medical. Retrieved on December 10, 2024 from https://www.news-medical.net/news/20221107/Shared-genetic-effects-between-the-autoimmune-disease-systemic-lupus-erythematosus-and-the-clinical-consequences-of-COVID-19.aspx.

  • MLA

    Mathur, Neha. "Shared genetic effects between the autoimmune disease systemic lupus erythematosus and the clinical consequences of COVID-19". News-Medical. 10 December 2024. <https://www.news-medical.net/news/20221107/Shared-genetic-effects-between-the-autoimmune-disease-systemic-lupus-erythematosus-and-the-clinical-consequences-of-COVID-19.aspx>.

  • Chicago

    Mathur, Neha. "Shared genetic effects between the autoimmune disease systemic lupus erythematosus and the clinical consequences of COVID-19". News-Medical. https://www.news-medical.net/news/20221107/Shared-genetic-effects-between-the-autoimmune-disease-systemic-lupus-erythematosus-and-the-clinical-consequences-of-COVID-19.aspx. (accessed December 10, 2024).

  • Harvard

    Mathur, Neha. 2022. Shared genetic effects between the autoimmune disease systemic lupus erythematosus and the clinical consequences of COVID-19. News-Medical, viewed 10 December 2024, https://www.news-medical.net/news/20221107/Shared-genetic-effects-between-the-autoimmune-disease-systemic-lupus-erythematosus-and-the-clinical-consequences-of-COVID-19.aspx.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
Post

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
Researchers develop diabetes prediction system using clinical and genetic data