167. Interplay between demographic, clinical and polygenic risk factors for severe COVID-19
Creators: name: Chaddock1, Natalie
name: SSR Crossfield1
name: MM Iles1
name: M Pujades-Rodriguez1
name: AW Morgan1, 2
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> Hospitalization and death from COVID-19 is an ongoing threat to public health and medical systems worldwide. We aimed to identify clinico-demographic and genetic risk factors for severe COVID-19 (hospitalization, critical care admission or death) utilising the population-based UK Biobank cohort from the pre-SARS-CoV-2 vaccination era. To improve biological understanding, we aimed to summarise the genetic risk for severe COVID-19 by developing a polygenic risk score (PRS) and applying this across ethnicities. <strong>Methods: </strong>We identified UK Biobank participants diagnosed with COVID-19 in 2020. We derived and optimised a PRS for severe COVID-19 using publicly-available European and trans-ethnic COVID19-hg consortium GWAS summary statistics<sup>1</sup> and UK Biobank data. The performance of our PRS was evaluated in different ethnic subgroups. We estimated the risk of hospital or critical care admission within 28 days or death within 100 days following COVID-19 diagnosis (i.e., severe COVID-19), and assessed associations with demographic factors, immunosuppressant use, morbidities and PRS. Pathway analysis was performed using genetic variants from the final PRS. <strong>Results: </strong>We included 9,560 patients followed for a median of 61 (interquartile range=34-88) days since COVID-19 diagnosis. The risk of severe COVID-19 increased with age and was higher in men, former or current smokers, those living in socio-economically deprived areas, for each additional 5 kg/m² increment of BMI between 25 and 40 kg/m², immunosuppressant users and individuals with morbidities, including autoimmune diseases, or a higher comorbidity count. An optimised PRS consisting of 133 genetic variants was independently associated with risk in both European and transethnic populations after adjustment for clinico-demographic risk factors; the highest PRS quintile compared with the lowest: adjusted odds ratio 1.32, 95% confidence interval 1.11-1.58, <em>R<sup>2</sup></em>=2.35 x 10<sup>-3</sup>, <em>P</em>= 6.23x10<sup>-4</sup>. The magnitude of risk for the highest PRS quintile was equivalent to that reported for well-known risk factors, such as living in the most deprived areas or having cardiovascular disease. Pathway analysis revealed that our PRS was enriched for genetic variants in multiple immune-related pathways, including the “OAS antiviral response” and “Interleukin-10 signalling” pathways. <strong>Conclusions: </strong>We provide evidence for targeted public health interventions, such as vaccine campaigns, for those with identified clinical and sociodemographic risk factors. This study conducted in the pre-SARS-CoV-2 vaccination era, emphasizes the novel insights to be gained from using genomic data alongside commonly considered sociodemographic and clinical factors in developing an understanding of severe COVID-19 outcomes. Our optimized PRS was independently associated with risk of severe COVID-19 and bioinformatic analysis demonstrated that host genetic variation in antiviral and immunoregulatory immune pathways may contribute to COVID-19 severity. Genetic variation in immune pathways offers the opportunity for guiding therapeutic strategies in severe COVID-19 and ultimately risk stratification for patients with autoimmune diseases requiring immunosuppressant therapy. <strong>Disclosures: </strong>AWM has received research grant and educational funding or undertaken consultancy for the following pharmaceutical companies in the last 5 years: AstraZeneca, Kiniska Pharmaceuticals, Regeneron, Roche/Chugai, Sanofi and Vifor. MPR is employed by UCB Biopharma.