COVID-19 and Systemic Lupus Erythematosus genetics: A balance between autoimmune disease risk and protection against infection

Abstract

The COVID-19 pandemic presents an unprecedented opportunity to delve into the underlying genetic mechanisms governing the immune response to viral infections. Systemic Lupus Erythematosus (SLE), a multifaceted autoimmune disorder characterized by dysregulated interferon signalling and immune responses, serves as a valuable comparative model for exploring shared genetic factors in population immunological equilibrium. Certain SLE risk alleles potentiate the interferon response, while other susceptibility genes associated with lupus operate within the intracellular viral sensing pathway. The interferon signalling pathway, renowned for its pivotal role in both SLE and the host response to viral infections, emerges as a key player in the shared genetic architecture uncovered by our investigation. By juxtaposing the genetic architecture of severe COVID-19 with SLE, I revelled insights into instances where the autoimmune condition exhibits protective roles against viral infections. To unravel shared associations at genetic loci, I leveraged summary statistics from severe COVID-19 and SLE genome-wide association study (GWAS) data, encompassing 13,769 and 9,302 cases of European descent, respectively. Additionally, SLE Immunochip data comprising 6,748 cases of European descent are utilized. Fine-mapping was performed using individual genotype data from all SLE datasets and a subset of severe COVID-19 data (5,989 cases of European descent).

Through cross-trait meta-analyses, I illuminated both aligned and opposing effects at specific loci. Our investigation identified seven loci, including TYK2, CLEC1A, IL12B, PLCL1-RFTN2, MIR146A, LZTFL1, and BCL2L11, that demonstrated high colocalisation probabilities (PP_H4 > 70.0%), with signals from CLEC1A and TYK2 exhibiting particularly strong colocalisation (PPH4 > 95.0%). TYK2, a central player in the type I interferon, IL-12, and IL-23 signalling pathway, stands out as a focal locus with shared associations, particularly through four independent signals (tagged by rs34536443, rs12720356, rs35018800, and rs12720358) displaying opposing effects in severe COVID-19 and SLE. Colocalization analysis at the TYK2 locus of genetic signals revealed intricate relationships with expression quantitative trait loci (eQTL) signals, where the severe COVID-19 risk allele, which is protective for SLE, showed increased TYK2, ICAM5, and ZGLP1 expression, as well as decreased PDE4A expression. Additionally, the analysis highlighted colocalisation with protein quantitative trait loci (pQTL) signals, indicating decreased interleukin-12 receptor subunit beta-1 (IL12RB1) and interferon alpha/beta receptor 1 (IFNAR1) expressions in human plasma, thus underscoring TYK2's regulatory roles in immune signalling.

The identified genetic correlations and shared loci emphasize the complex interplay between viral infections, autoimmunity, and IFN-I, IL-12, and IL-23 signalling pathways. TYK2, with its intricate genetic architecture, warrants attention in targeted therapeutic interventions in both viral infections and autoimmune disorders. The observed opposing effects at the TYK2 locus align with the hypothesis that certain alleles conferring risk for SLE persist in the general population due to innate immune protection against pathogens, including viruses.

Date of Award	1 Jun 2024
Original language	English
Awarding Institution	King's College London
Supervisor	David Morris (Supervisor) & Timothy Vyse (Supervisor)