Genome-wide meta-analysis identifies new candidate genes for sickle cell disease nephropathy

Area of Science:

• Genetics
• Nephrology
• Hematology

Background:

• Sickle cell disease nephropathy (SCDN) is a major complication of sickle cell disease (SCD), significantly increasing mortality risk.
• Previous polygenic risk scores showed poor model fit for predicting proteinuria and declining estimated glomerular filtration rate (eGFR) in SCD, indicating unique genetic factors are involved.

Approach:

• Genome-wide association studies (GWAS) were conducted on two large adult SCD cohorts to identify genetic loci associated with proteinuria and decreased eGFR.
• A meta-analysis identified six novel genome-wide significant associations for SCDN manifestations, independent of APOL1 risk variants.

Key Points:

• Three novel loci (CRYL1, VWF, ADAMTS7) were associated with proteinuria in SCDN.
• Three novel loci (LRP1B, linc02288, FPGT-TNNI3K/TNNI3K) were associated with decreased eGFR in SCDN.
• Genetic variants in CRYL1, VWF, ADAMTS7, and linc02288 show associations with kidney gene expression and relevant biological pathways, suggesting distinct SCDN pathophysiology.

Conclusions:

• These findings identify novel genetic targets for SCDN, distinct from other kidney diseases.
• The identified loci provide potential biomarkers for early risk identification and future therapeutic strategies in patients with sickle cell disease.