Genetic associations with onset and progression of focal segmental glomerulosclerosi (FSGS) i black Southern African children

Abstract

Introduction - In children who present clinically with nephrotic syndrome (NS), the most common type of primary glomerular disease causing end stage kidney disease (ESKD) is focal segmental glomerulosclerosis (FSGS). Internationally, there is evidence of a more rapid progression of FSGS to ESKD and higher rates of steroid resistance in black patients compared to other ethnic groups and few studies have been performed in black South African children. The aim of this study was to determine genetic associations with apolipoprotein L1 (APOL1) risk variants and podocin (NPHS2) variants in black children with FSGS. Methods – Thirty-two black South African children with biopsy proven FSGS from 30 families were recruited from two clinics in Johannesburg. Three APOL1 risk variants were genotyped and the exons of the NPHS2 gene sequenced in the cases and healthy ethnically matched controls. Genetic association analyses with APOL1 risk variants and NPHS2 variants were performed. The NPHS2 V260E variant was correlated with kidney function and treatment in all FSGS cases. Two families were examined for allelic segregation with FSGS. Results – There was a weak association between FSGS cases without V260E and APOL1 risk alleles for the dominant model (OR=2.97; 95% CI, 1.01 – 8.75; p= 0.048), but not the recessive model. Steroid resistant nephrotic syndrome (SRNS) and steroid sensitive nephrotic syndrome (SSNS) was present in 22 (69%) (including two sib-pairs) and 10 (31%) of the cases respectively. The OR of having SRNS increased from 36.8 (95% CI, 3.4 - 396.7; p=0.002) when carrying one copy of NPHS2 V260E to 101.2 (95% CI, 10.7 - 955.9; p=7.76e-8) when carrying two copies. The presence of the NPHS2 V2 0E variant was associated with a more rapid decline in kidney function (p= 0.026). Conclusion - The NPHS2 V260E variant is African-origin and is strongly associated with SRNS in black South African children, segregating as an autosomal recessive trait. Genotyping the V260E variant in black children with FSGS could provide useful information in a clinical setting to guide treatment, may prevent the need for renal biopsy and avoid side effects of glucocorticoid and other immunosuppressive therapies, and facilitate genetic counselling in families.