Abstract
Variants in the Apolipoprotein L1 (APOL1) gene (G1-rs60910145, rs73885319, G2-rs71785313) are common in Africans and in individuals of recent African ancestry and are associated with an increased risk of non-diabetic chronic kidney disease (CKD) and in particular of HIV associated nephropathy (HIVAN). In light of the significantly increased risk of HIVAN in carriers of two APOL1 risk alleles, a role in HIV infectivity has been postulated in the mechanism of APOL1 associated kidney disease. Herein, we aim to explore the association between HIV viremia and APOL1 genotype. In addition, we investigated interaction between BK and JC viruria, CKD and HIV viremia. A total of 199 persons living with HIV/AIDS (comprising 82 CKD cases and 117 controls) from among the participants in the ongoing Human Heredity and Health in Africa (H3Africa) Kidney Disease Research Network case control study have been recruited. The two APOL1 renal risk alleles (RRA) genotypes were associated with a higher risk of CKD (OR 12.6, 95% CI 3.89–40.8, p < 0.0001). Even a single APOL1 RRA was associated with CKD risk (OR 4.42, 95% CI 1.49–13.15, p = 0.007). The 2 APOL1 RRA genotypes were associated with an increased probability of having HIV viremia (OR 2.37 95% CI 1.0–5.63, p = 0.05). HIV viremia was associated with increased CKD risk (OR 7.45, 95% CI 1.66–33.35, P = 0.009) and with a significant reduction of JC virus urine shedding (OR 0.35, 95% CI 0.12–0.98, p = 0.046). In contrast to prior studies, JC viruria was not associated with CKD but was restricted in patients with HIV viremia, regardless of CKD status. These findings suggest a role of APOL1 variants in HIV infectivity and emphasize that JC viruria can serve as biomarker for innate immune system activation.
Highlights
Two variants at the APOL1 gene, encoding Apolipoprotein L1, account for more than 70% of the increased risk for non-diabetic chronic kidney disease (CKD) in individuals of African ancestry [1,2,3]
Multivariate logistic regression with a stepwise, forward and backward model selection showed that even a single APOL1 RRA was associated with CKD, OR 4.429
As we previously reported [14], there was no correlation between BK and JC viruria (Pearson correlation coefficient: 0.43, p=0.23). In this genetic epidemiological study of HIV infected individuals living in Ghana and Nigeria [26], we observed an association between 2 APOL1 RRA and HIV viremia and CKD
Summary
Two variants at the APOL1 gene, encoding Apolipoprotein L1, account for more than 70% of the increased risk for non-diabetic chronic kidney disease (CKD) in individuals of African ancestry [1,2,3]. The ancestral non-renal risk allele has been designated G0 and the two risk alleles (renal risk alleles, RRA) have been designated as G1 (encoding S342G and I384M substitutions) and G2 (encoding the combined N388 and Y389 deletions), respectively [1, 3] These variants have risen to high allele frequency due to a dominant selective advantage that restores trypanolytic activity against T. b. Gambiense is endemic, despite the observed G2 association with symptomatic chronic sleeping sickness This raises the likelihood of a broader role in pathogen resistance by the RRA, extending beyond trypanosomes [4,5,6]. APOL1 was identified as one of the HIV restriction proteins, by using genome-wide scans for human genes sharing molecular and evolutionary signatures of known restriction factors These findings were validated using in vitro studies demonstrating anti-HIV- activity [9]. We examined the association between JC and BK viruria in all participants, in light of previous findings demonstrating reduced JC viruria in CKD patients and the expected increased BK urine shedding in immunocompromised HIV infected patients [12,13,14,15,16,17]
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