APOL1 Risk Variants, Acute Kidney Injury, and Death in Participants With African Ancestry Hospitalized With COVID-19 From the Million Veteran Program

Abstract

IMPORTANCECoronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates.OBJECTIVE Individuals with African ancestry with 2 copies of apolipoprotein L1 (APOL1) variants G1 or G2 (high-risk group) have significantly increased rates of kidney disease. We tested the hypothesis that the APOL1 high-risk group is associated with a higher-risk of COVID-19-associated AKI and death. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study included 990 participants with African ancestry enrolled in the Million Veteran Program who were hospitalized with COVID-19 between March 2020 and January 2021 with available genetic information.EXPOSURES The primary exposure was having 2 APOL1 risk variants (RV) (APOL1 high-risk group), compared with having 1 or 0 risk variants (APOL1 low-risk group). MAIN OUTCOMES AND MEASURESThe primary outcome was AKI. The secondary outcomes were stages of AKI severity and death. Multivariable logistic regression analyses adjusted for preexisting comorbidities, medications, and inpatient AKI risk factors; 10 principal components of ancestry were performed to study these associations. We performed a subgroup analysis in individuals with normal kidney function prior to hospitalization (estimated glomerular filtration rate Ն60 mL/min/1.73 m 2 ). RESULTSOf the 990 participants with African ancestry, 905 (91.4%) were male with a median (IQR) age of 68 (60-73) years. Overall, 392 (39.6%) patients developed AKI, 141 (14%) developed stages 2 or 3 AKI, 28 (3%) required dialysis, and 122 (12.3%) died. One hundred twenty-five (12.6%) of the participants were in the APOL1 high-risk group. Patients categorized as APOL1 high-risk group had significantly higher odds of AKI (adjusted odds ratio [OR], 1.95; 95% CI, 1.27-3.02; P = .002), higher AKI severity stages (OR, 2.03; 95% CI, 1.37-2.99; P < .001), and death (OR, 2.15; 95% CI, 1.22-3.72; P = .007). The association with AKI persisted in the subgroup with normal kidney function (OR, 1.93; 95% CI, 1.15-3.26; P = .01). Data analysis was conducted between February 2021 and April 2021. CONCLUSIONS AND RELEVANCEIn this cohort study of veterans with African ancestry hospitalized with COVID-19 infection, APOL1 kidney risk variants were associated with higher odds of AKI, AKI severity, and death, even among individuals with prior normal kidney function.

Adverse outcomes in SARS-CoV-2 infections are associated with a combination of variant genotypes at two loci in the APOL1 gene: a UK Biobank study

“…In African Americans infected with SARS-CoV-2, carriage of two APOL1 variants is associated with collapsing glomerulopathy 15 , acute kidney injury (AKI), persistent AKI, and requirement for kidney replacement therapy 16 . Among African Americans hospitalised with COVID-19, carriage of two high-risk APOL1 variants has been associated with increased AKI severity and death 17 . These investigations followed the precedent set by previous studies on APOL1 -associated non-communicable diseases by considering the number of variant alleles carried rather than the individual genotypes.…”

“…There is growing evidence that APOL1 genotype also influences outcomes in COVID-19 15,16,17 . These investigations followed the precedent set by previous studies on APOL1 -associated non-communicable diseases by considering the number of variant alleles carried rather than the complete genotype.…”

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“…Chauss and colleagues [ 99 ] demonstrated that severe COVID-19 may result from a dysfunction of type I immune response, that involves the vitamin D receptor (VDR) signaling. Similarly, it is interesting to observe how individuals with African descent, homozygous for the G1 or G2 variant of apolipoprotein L1 ( APOL1 ), have an increased risk of acute kidney disease compared to subjects with low-risk variants [ 100 ]. A recent study revealed an association of phenotype severity and polymorphisms of the MBL2 gene, which encodes a mannose-binding lectin (MBL) secreted by the liver and involved in innate immune defense [ 101 ].…”

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“…Is there a set of COVID-19 gene products that converges pro-fibrotic and other pathways in diverse kidney cells and structures? African Americans develop COVID-19 associated with stronger AKI more often than other racial and ethnic groups ( Hung et al., 2022 ). Are socioeconomic factors the sole drivers of these disparities, or is there a role for other genetic factors and environmental factors?…”