APOL1 Risk Variants Associated with Serum Albumin in a Population-Based Cohort Study

Abstract

Introduction: The association of apolipoprotein L1 (APOL1) nephropathy risk variants (APOL1), unique to African-ancestry (African-American [AA]) populations, with systemic inflammation, a contributor to chronic kidney disease (CKD) and end-stage kidney disease (ESKD) is ill-defined. This study aimed to describe the role of inflammatory markers in the relationship between APOL1 and incident kidney outcomes using a prospective cohort study.

Methods: APOL1 high-risk status under a recessive genetic model was studied in 10,605 AA adults aged ≥45 years from the Reasons for Geographic and Racial Differences in Stroke study. The primary variables of interest were inflammatory markers: C-reactive protein (mg/dL), white blood cell count (cells/mm3), and serum albumin (sALB) (mg/dL). High inflammation status was defined if at least one of these inflammatory markers exceeded clinical threshold. The association between APOL1 and biomarkers were assessed using regression models adjusting for age, sex, ancestry, hypertension, lipid medications, albumin-to-creatinine ratio, and estimated glomerular filtration rate (eGFR). Models were stratified by diabetes status. We identified incident ESKD using USRDS linkage, and we defined incident CKD as an eGFR <60 mL/min/1.73 m2 and ≥25% decline in the eGFR and normal baseline eGFR and tested for mediation of APOL1 and outcomes by biomarkers using the causal inference approach.

Results: Among 7,151 participants with data available on all inflammation markers, 4,479 participants had ≥1 marker meeting the clinical threshold. APOL1 high-risk status was associated with lower adjusted odds of reduced sALB {odds ratio (OR) (95% confidence interval [CI]): 0.59 [0.36, 0.96])}, and this association was significant in people with diabetes (OR [95% CI]: 0.40 [0.18, 0.89]) but not in those without diabetes. There was no association of APOL1 high-risk status with other markers or high inflammation status. APOL1 was independently associated with ESKD (OR [95% CI] = 1.78 [1.28, 2.48]) and CKD (OR [95% CI] = 1.38 [1.00, 1.91]). On mediation analysis, the direct effect between APOL1 and ESKD strengthened after accounting for sALB, but the estimated mediated effect was not statistically significant (OR [95% CI]: 0.98 [0.92, 1.05], p = 0.58).

Conclusion: APOL1 high-risk variants were associated with sALB. However, sALB did not statistically mediate the association between APOL1 and incident ESKD.

Keywords: APOL1; End-stage kidney disease; Inflammation; Mediation; Serum albumin.