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

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.

Maternal variants within the apolipoprotein L1 gene are associated with preeclampsia in a South African cohort of African ancestry.

OBJECTIVE: Preeclampsia (PE) is a complex pregnancy-specific medical disorder arising from an ischaemic placenta releasing factors causing widespread endothelial damage involving multiple organs systems, such as the renal system. Two variant alleles, termed G1 and G2, of the APOL1 gene are strongly associated with progressive renal disease and preeclampsia in the recessive or compound heterozygous state. Hence, we investigated the role of maternal APOL1 genotype in the pathogenesis of preeclampsia in South African women of African ancestry. STUDY DESIGN: This case-control study comprised three groups of South African pregnant women of African ancestry attending a regional hospital in Durban, South Africa: mothers experiencing normotensive pregnancies, early onset preeclampsia and late onset preeclampsia underwent APOL1 genotyping. Differences in G1 and G2 allele and genotype frequencies were analysed for the three groups. RESULTS: Our study revealed a significant association between the maternal APOL1 G1 risk allele and early-onset PE development (OR 2.2, p = 0.03). Among the EOPE group, 5 % [OR(95 %CI) 0.94 (0.29-3.12)] of the study population carried two risk alleles, 49 % [OR(95 %CI) 1.34 (0.77-2.3)] carried at least one risk allele, while 46 % of the participants did not carry either risk allele, compared to the normotensive pregnant group, where 52 % carried no risk allele, 42 % had at least one risk allele and 6 % of the women had both risk alleles. CONCLUSION: Our results suggest that maternal APOL1 G1 risk allele may contribute to the development of early-onset PE in South African pregnant women of African ancestry either directly or by transmission of a APOL1 risk allele to the foetus.