APOL1 variant risk may extend to poorer outcomes from SARS-CoV-2 infection

By Dr. Priyom Bose, Ph.D.Nov 4 2021

The rapid outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 has caused widespread havoc claiming more than 5 million lives worldwide. There is a wide range of hospitalization rates and mortality risks associated with COVID-19.

Black ethnic populations are at a disproportionately high risk of hospitalization or death from COVID-19 in the UK for reasons that are not entirely understood.

Now, a new study published on the medRxiv* preprint server tests the hypothesis that adverse COVID-19 outcomes are associated with the variants of the APOL1 gene.

Study: 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. Image Credit: Gopixa / Shutterstock

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

African Ancestry and Risk of Severe COVID-19 Outcomes

In individuals having African ancestry, variants of the APOL1 gene (G1 and G2) are present. These variants have been associated with the risk of a number of non-communicable diseases such as chronic kidney disease, African sleeping sickness, etc.

Variants of the APOL1 gene (G1 and G2)

Variants of the APOL1 gene are rare, and in the last 10,000 years, two variants have arisen in the African population. These are termed G1 (encoding S342G and I384M) and G2 (encoding deletion of N388 and Y389). These variants are present on different haplotypes and are absent (or at very low frequency) in non-African populations. G0/G0 is the name given to individuals who have neither variant. G1 and G2 are associated with alternate outcomes from the infectious disease African sleeping sickness that is caused by two subspecies of Trypanosoma sp, i.e., Trypanosoma brucei, Trypanosoma brucei gambiense, and Trypanosoma brucei rhodesiense.

Study: 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. Image Credit: Kateryna Kon / Shutterstock

Researchers have observed that G1 is associated with milder T.b. gambiense infection, whereas G2 is associated with more severe T.b. gambiense disease. In relation to G1/G2 compound heterozygotes, G1 mitigates the risk associated with G2 gambiense disease severity.

In the current study, scientists tested the six variant combinations that have been detected in African populations to understand the effect of the APOL1 genotype on SARS-CoV-2 infection.

UK Biobank

Researchers used data from the UK Biobank, a large-scale biomedical database and research resource. UK Biobank contains genetic, lifestyle, and health information of half a million UK participants. It also includes 7,643 individuals who self-report as being of black ethnicity. This includes 7,600 individuals who have unambiguous genotype data for APOL1 variants. As of September 2021, there were 142 hospitalizations and 36 deaths in this cohort associated with COVID-19.

Scientists used Firth's Bias-Reduced Logistic Regression to identify APOL1 genotypes associated with either hospitalization or death. In this analysis, they considered the four most significant UK Biobank principal components as covariates. Other risk factors associated with COVID-19 include age, sex, chronic kidney disease (CKD), atrial fibrillation, hypertension, depression, chronic obstructive pulmonary disease (COPD), dementia, type 2 diabetes, obesity, and Townsend deprivation index, were considered.

It was observed that G1/G2 compound heterozygotes were associated with hospitalization and death compared to G0/G0. This finding is novel as this association has not been detected in genome-wide association studies. Such studies usually examine individual loci separately rather than combinations of loci.

Conclusion

The study has a novel finding in that the APOL1 genotype (specifically G1/G2 compound heterozygotes) is a significant contributory factor in the increased rates of adverse COVID-19 outcomes in people of African ancestry. It must, however, be noted that the sample of black UK Biobank participants, who have been hospitalized and/or died as a result of COVID-19, is relatively small. Therefore, verification of the result with a more extensive cohort study is required.

The molecular mechanism behind the association of G1/G2 and SARS-CoV-2 infection outcome is unclear and this issue requires further research. Results from such studies would be immensely valuable both at the individual and population level. They will aid in identifying individuals at a higher risk of contracting the infection and may, therefore, benefit from early vaccination and treatment. This is particularly relevant to countries where the APOL1 G1/G2 genotypes are common such as West and Central Africa.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.