Identification of Novel Genetic Risk Factors for Focal Segmental Glomerulosclerosis in Children: Results From the Chronic Kidney Disease in Children (CKiD) Cohort

Abstract

Rationale & objective: Focal segmental glomerulosclerosis (FSGS) is a major cause of pediatric nephrotic syndrome, and African Americans exhibit an increased risk for developing FSGS compared with other populations. Predisposing genetic factors have previously been described in adults. Here we performed genomic screening of primary FSGS in a pediatric African American population.

Study design: Prospective cohort with case-control genetic association study design.

Setting & participants: 140 African American children with chronic kidney disease from the Chronic Kidney Disease in Children (CKiD) cohort, including 32 cases with FSGS.

Predictors: Over 680,000 common single-nucleotide polymorphisms (SNPs) were tested for association. We also ran a pathway enrichment analysis and a human leucocyte antigen (HLA)-focused association study.

Outcome: Primary biopsy-proven pediatric FSGS.

Analytical approach: Multivariate logistic regression models.

Results: The genome-wide association study revealed 169 SNPs from 14 independent loci significantly associated with FSGS (false discovery rate [FDR]<5%). We observed notable signals for genetic variants within the APOL1 (P=8.6×10^-7; OR, 25.8 [95% CI, 7.1-94.0]), ALMS1 (P=1.3×10^-7; 13.0% in FSGS cases vs 0% in controls), and FGFR4 (P=4.3×10^-6; OR, 24.8 [95% CI, 6.3-97.7]) genes, all of which had previously been associated with adult FSGS, kidney function, or chronic kidney disease. We also highlighted novel, functionally relevant genes, including GRB2 (which encodes a slit diaphragm protein promoting podocyte structure through actin polymerization) and ITGB1 (which is linked to renal injuries). Our results suggest a major role for immune responses and antigen presentation in pediatric FSGS through (1) associations with SNPs in PTPRJ (or CD148, P=3.5×10^-7), which plays a role in T-cell receptor signaling, (2) HLA-DRB1∗11:01 association (P=6.1×10^-3; OR, 4.5 [95% CI, 1.5-13.0]), and (3) signaling pathway enrichment (P=1.3×10^-6).

Limitations: Sample size and no independent replication cohort with genomic data readily available.

Conclusions: Our genetic study has identified functionally relevant risk factors and the importance of immune regulation for pediatric primary FSGS, which contributes to a better description of its molecular pathophysiological mechanisms.

Plain-language summary: We assessed the genetic risk factors for primary focal segmental glomerulosclerosis (FSGS) by simultaneously testing over 680,000 genetic markers spread across the genome in 140 children, including 32 with FSGS lesions. Fourteen independent genetic regions were significantly associated with pediatric FSGS, including APOL1 and ALMS1-NAT8, which were previously found to be associated with FSGS and chronic kidney diseases in adults. Novel genes with relevant biological functions were also highlighted, such as GRB2 and FGFR4, which play a role in the kidney filtration barrier and in kidney cell differentiation, respectively. Finally, we revealed the importance of immune regulation in pediatric FSGS through associations involving cell surface proteins presenting antigens to the immune system and interacting with T-cell receptors.

Keywords: ALMS1; APOL1 G1; African American; CCDC7; CDH12; DNAH6; FGFR4; GRB2; HLA; KCNK6; SCNN1G; children; chronic kidney disease (CKD); focal segmental glomerulosclerosis (FSGS); gene-set enrichment analysis; genetic risk marker; genome-wide association study (GWAS); pediatric; single-nucleotide variant (SNV).