key: cord-0284900-d8dfss2x
authors: Adamson, W. E.; Noyes, H.; Beckett-Hill, G.; Cooper, A.; MacLeod, A.
title: A combination of variant genotypes at two loci in the APOL1 gene is associated with adverse outcomes in SARS-CoV-2: a UK Biobank study.
date: 2021-11-02
journal: nan
DOI: 10.1101/2021.11.02.21265755
sha: 387b42e0e6689f6afdd5cbe1dfa703cca0e5ae35
doc_id: 284900
cord_uid: d8dfss2x

The risk of hospitalisation or death from Covid-19 in the UK is disproportionately higher in black ethnic populations than others for reasons that are not fully understood (1). In people of African ancestry, variants of the APOL1 gene (G1 and G2) have been associated with risk of a number of non-communicable diseases, such as chronic kidney disease (2,3,4,5) and the infectious disease, African sleeping sickness (6). Here we test the hypothesis that adverse Covid-19 outcomes are also associated with these variants. Using data from Black UK Biobank participants, we used Firth's Bias-Reduced Logistic Regression in R to identify APOL1 genotypes that were associated with either hospitalisation or death. APOL1 G1/G2 compound heterozygotes were associated with hospitalisation (OR = 2.4 95% CI: 1.2-4.5) p = 0.010) and death (OR = 5.4, 95% CI: 1.8-15.4, p = 0.004) compared to individuals not carrying the variants. This support hypotheses proposing APOL1 genotype (specifically G1/G2) is a significant contributory factor in the increased rates of poor Covid-19 outcomes observed in people of African ancestry. This has implications for both at the individual and population level by identifying those at higher risk of severe Covid-19 who would benefit from early vaccination and treatment. This is especially relevant to geographical regions where APOL1 G1/G2 genotypes are common such as West and Central Africa (6) and their diaspora.

Using data from Black UK Biobank participants, we used Firth's Bias-Reduced Logistic Regression in R to identify APOL1 genotypes that were associated with either hospitalisation or death. APOL1 G1/G2 compound heterozygotes were associated with hospitalisation (OR = 2.4 95% CI: 1.2-4.5) p = 0.010) and death (OR = 5.4, 95% CI: 1.8-15.4, p = 0.004) compared to individuals not carrying the variants. This support hypotheses proposing APOL1 genotype (specifically G1/G2) is a significant contributory factor in the increased rates of poor Covid-19 outcomes observed in people of African ancestry. This has implications for both at the individual and population level by identifying those at higher risk of severe Covid-19 who would benefit from early vaccination and treatment. This is especially relevant to geographical regions where APOL1 G1/G2 genotypes are common such as West and Central Africa 6 and their diaspora. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 2, 2021. ; https://doi.org/10.1101/2021.11.02.21265755 doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Walt Adamson, Harry Noyes, Georgia Beckett-Hill, Anneli Cooper, and Annette MacLeod The risk of hospitalisation or death from Covid-19 in the UK is disproportionately higher in black ethnic populations than others for reasons that are not fully understood 1 . In people of African ancestry, variants of the APOL1 gene have been associated with risk of a number of non-communicable diseases such as chronic kidney disease 2,3,4,5 . Here we test the hypothesis that adverse Covid-19 outcomes are also associated with these variants.

Within the last 10,000 years two variants of the APOL1 gene have arisen in the African population, termed G1 (encoding S342G and I384M) and G2 (encoding deletion of N388 and Y389), which are present on different haplotypes and are absent or at very low frequency in non-African derived populations 2 . Individuals who have neither variant are termed G0/G0. As well as being associated with a number of non-communicable diseases, G1 and G2 are associated with alternate outcomes from the infectious disease African sleeping sickness, which is caused by two subspecies of T. brucei, T.b. gambiense and T.b. rhodesiense 6 . G1 is associated with milder T.b. gambiense infection, whereas G2 is associated with more severe T.b. gambiense disease, yet protection from T.b. rhodesiense infection 6 . In G1/G2 compound heterozygotes, G1 mitigates the risk associated with G2 gambiense disease severity 6 . Since the effect of APOL1 genotype on infection by SARS-CoV-2 could not be predicted based on our current knowledge, we tested the six variant combinations that have been detected in African populations.

We used data from the UK Biobank, a large-scale biomedical database and research resource containing genetic, lifestyle, and health information from half a million UK participants from across the UK 7 . The UK Biobank includes 7,643 individuals who self-report as being of black ethnicity, including 7,600 who have unambiguous genotype data for APOL1 variants. Within this cohort there have been 142 hospitalisations and 36 deaths attributed to Covid-19 as of September 2021 (Table 1) . Taking the four most significant UK Biobank principal components as covariates along with risk factors previously associated with Covid-19 (age, sex, chronic kidney disease (CKD), atrial fibrillation, hypertension, depression, chronic obstructive pulmonary disease (COPD), dementia, type 2 diabetes 8 , obesity 9 and Townsend deprivation index 10 ), we used Firth's Bias-Reduced Logistic Regression in R to identify APOL1 genotypes that were associated with either hospitalisation or death. G1/G2 compound heterozygotes were associated with hospitalisation (OR = 2.4 95% CI: 1.2-4.5) p = 0.010) and death (OR = 5.4, 95% CI: 1.8-15.4, p = 0.004) compared to G0/G0 (Table 1) . This association has not been previously detected in genome wide association studies 11,12 as they usually examine individual loci separately rather than consider combinations of loci.

Black UK Biobank participants who have been hospitalised and/or died as a result of SARS-CoV-2 infection represent a relatively small dataset, and verification in a larger cohort is required. However, our observations support hypotheses proposing APOL1 genotype (specifically G1/G2 compound heterozygotes) as a significant contributory factor in the increased rates of poor Covid-19 outcomes observed in people of African ancestry. Indeed, there are anecdotal reports of that APOL1 genotypes may be associated with severe collapsing glomerular nephropathy in SARS-CoV-2 infection 13 and G1/G2 compound heterozygotes have been shown to be associated with HIV-associated nephropathy 14 . The molecular mechanism behind the association of G1/G2 and deleterious SARS-CoV-2 infection outcome is unclear but warrants further investigation. This association could have important implications both at the individual and population level by identifying those at higher risk of severe Covid-19 who would benefit from early vaccination and treatment. This is especially relevant to geographical regions where APOL1 G1/G2 genotypes are common such as West and Central Africa 6 and their diaspora. 

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