<b><i>APOL1</i></b> Risk Variants Associated with Serum Albumin in a Population-Based Cohort Study

Abstract

<b><i>Introduction:</i></b> The association of apolipoprotein L1 (<i>APOL1</i>) nephropathy risk variants (<i>APOL1</i>), 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 <i>APOL1</i> and incident kidney outcomes using a prospective cohort study. <b><i>Methods:</i></b> <i>APOL1</i> 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 <i>APOL1</i> 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 &#x3c;60 mL/min/1.73 m² and ≥25% decline in the eGFR and normal baseline eGFR and tested for mediation of <i>APOL1</i> and outcomes by biomarkers using the causal inference approach. <b><i>Results:</i></b> Among 7,151 participants with data available on all inflammation markers, 4,479 participants had ≥1 marker meeting the clinical threshold. <i>APOL1</i> 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 <i>APOL1</i> high-risk status with other markers or high inflammation status. <i>APOL1</i> 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 <i>APOL1</i> 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], <i>p</i> = 0.58). <b><i>Conclusion:</i></b> <i>APOL1</i> high-risk variants were associated with sALB. However, sALB did not statistically mediate the association between <i>APOL1</i> and incident ESKD.