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

Area of Science:

• Genetics
• Nephrology
• Hematology

Background:

• Albuminuria is a risk factor for chronic kidney disease (CKD) in sickle cell anemia (SCA).
• High-risk apolipoprotein-L1 (APOL1) variants (G1/G2) are associated with CKD in SCA but do not explain all risk.
• Other genetic factors influencing SCA severity may also impact CKD risk.

Purpose of the Study:

• To develop and validate a polygenic risk score (PRS) for predicting persistent albuminuria in patients with SCA.
• To combine APOL1 risk variants with other candidate genes (HMOX1, BCL11A, α-thalassemia) into a PRS.
• To stratify SCA patients into risk categories for albuminuria based on the PRS.

Main Methods:

• Genotyping of APOL1, HMOX1 (rs743811), BCL11A (rs1424407), and α-thalassemia (α^-3.7) in children with SCA (SCCRIP cohort).
• Development of a three-variant PRS (PRS-3) and a four-variant PRS (PRS-4) by summing high-risk alleles.
• Validation of PRS-4 in an adult SCA cohort (UIC).
• Association analysis of variants and PRS with persistent albuminuria (defined as UACR ≥ 30 mg/g on ≥ 2 of 3 measurements).

Main Results:

• APOL1 risk variants increased albuminuria risk, while α-thalassemia conferred protection in both cohorts.
• The PRS-4 was significantly associated with persistent albuminuria in both SCCRIP (p=0.004) and UIC (p=0.00016) cohorts.
• High-risk PRS categories showed high rates of persistent albuminuria (54-89% across PRS-3 and PRS-4, and both cohorts).

Conclusions:

• A PRS incorporating APOL1 and other genetic variants effectively identifies SCA patients at high risk for albuminuria.
• PRS-based risk stratification can aid in early detection and management of CKD in SCA.
• Implementing targeted renoprotective therapies based on PRS may mitigate the burden of SCA-related CKD.