Development of Polygenic Risk Score for Persistent Albuminuria in Children and Adults With Sickle Cell Anemia

Albuminuria is associated with high-risk apolipoprotein-L1 variants (APOL1 G1/G2) in patients with sickle cell anemia (SCA). However, this gene variant does not account for all chronic kidney disease (CKD) risk. We hypothesized that we could develop a polygenic risk score (PRS) for CKD in SCA, combining APOL1 G1/G2 with other candidate genes that modify SCA severity and further stratify patients into risk categories based on this risk score. Variants in APOL1, HMOX1 (rs743811), BCL11A (rs1424407), and α-thalassemia (α ^-3.7) were identified in children with SCA enrolled in the Sickle Cell Clinical Research and Intervention Program longitudinal cohort (SCCRIP). We individually tested the association of these variants with persistent albuminuria, tested a three-variant PRS (PRS-3) (APOL1, BCL11A (rs1424407), and α^-3.7), and developed a four-variant PRS (PRS-4) after adding HMOX1 (rs743811) to PRS-3 using the summation of high-risk alleles. An adult SCA cohort from the University of Illinois, Chicago (UIC), was used for validation. Persistent albuminuria was defined as having a urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g on at least 2 of 3 consecutive measurements. In both cohorts, APOL1 risk variants increased the risk while α-thalassemia protected against persistent albuminuria. PRS-4 was significantly associated with persistent albuminuria (SCCRIP: p = 0.004; UIC: p = 0.00016). When stratifying patients into three and four risk categories based on the PRS, 58% and 86% of the high-risk (PRS-3) and 54% and 89% of very high-risk (PRS-4) categories developed persistent albuminuria cases in the SCCRIP and UIC cohorts, respectively. A PRS may identify high-risk SCA patients for albuminuria. Applying this PRS to guide the early implementation of disease modifiers and renoprotective therapies may help reduce the burden of SCA-related CKD. Trial Registration: NCT02098863.