APOL1 in an ethnically diverse pediatric population with nephrotic syndrome: implications in focal segmental glomerulosclerosis and other diagnoses

Author(s):Show less -

Watanabe, Andreia ^{[1, 2]} ; Guaragna, Mara Sanches ^[3] ; Santoro Belangero, Vera Maria ^[4] ; Serafim Casimiro, Fernanda Maria ^[5] ; Pesquero, Joao Bosco ^[5] ; Feltran, Luciana de Santis ^[6] ; Pereira Palma, Lilian Monteiro ^[4] ; Varela, Patricia ^[5] ; Miranda de Menezes Neves, Precil Diego ^{[2, 7]} ; Lerario, Antonio Marcondes ^[8] ; de Souza, Marcela Lopes ^[3] ; de Mello, Maricilda Palandi ^[3] ; Gervasio de Brito Lutaif, Anna Cristina ^[4] ; Ferrari, Cassio Rodrigues ^[4] ; Sampson, Matthew Gordon ^{[9, 10, 11]} ; Onuchic, Luiz Fernando ^{[2, 7]} ; Koch Nogueira, Paulo Cesar ^[12]

Affiliation:Show less -

^[1] Univ Sao Paulo, Dept Pediat, Sch Med, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Div Mol Med, Sch Med, Sao Paulo - Brazil

^[3] Univ Estadual Campinas, Ctr Mol Biol & Genet Engn, Campinas - Brazil

^[4] Univ Estadual Campinas, Dept Pediat, Campinas - Brazil

^[5] Univ Fed Sao Paulo, Ctr Diag & Res Genet Dis, Dept Biophys, Sch Med, Sao Paulo - Brazil

^[6] Univ Fed Sao Paulo, Dept Nephrol, Sch Med, Sao Paulo - Brazil

^[7] Univ Sao Paulo, Div Nephrol, Sch Med, Sao Paulo - Brazil

^[8] Univ Michigan, Div Endocrinol, Ann Arbor, MI - USA

^[9] Harvard Med Sch, Boston, MA 02115 - USA

^[10] Boston Childrens Hosp, Div Pediat Nephrol, Boston, MA - USA

^[11] Broad Inst, Cambridge, MA - USA

^[12] Univ Fed Sao Paulo, Dept Pediat, Sch Med, Sao Paulo - Brazil

• Document type: Journal article
• Source: Pediatric Nephrology; v. 36, n. 8, SI, p. 2327-2336, AUG 2021.
• Web of Science Citations: 0

Abstract

Background APOL1 high-risk genotypes (HRG) are associated with increased risk of kidney disease in individuals of African ancestry. We analyzed the effects of APOL1 risk variants on an ethnically diverse Brazilian pediatric nephrotic syndrome (NS) cohort. Methods Multicenter study including 318 NS patients, categorized as progressors to advanced CKD {[}estimated glomerular filtration rate (eGFR)] < 30 mL/min/1.73 m(2)] and slow/non-progressors (eGFR > 30 mL/min/1.73 m(2) through the study). We employed Cox regression with progression time as the outcome and APOL1 genotype as the independent variable. We tested this association in the entire cohort and three subgroups; (1) focal segmental glomerulosclerosis (FSGS), (2) steroid-resistant NS (SRNS), and (3) those who underwent kidney biopsy. Results Nineteen patients (6%) had an HRG. Of these, 47% were self-reported White. Patients with HRG manifested NS at older ages and presented higher frequencies of FSGS and SRNS. HRG patients progressed to advanced CKD more often than low-risk-genotype (LRG) children in the whole NS cohort (p = 0.001) and the three subgroups. In SRNS and biopsied patients, a single risk variant was associated with trends of higher CKD progression risk. Conclusions Novel discoveries include a substantial prevalence of HRG among patients self-reported White, worse kidney outcomes in HRG versus LRG children in the FSGS subgroup, and a trend of higher CKD progression risk associated with a single risk variant in the SRNS cohort. These findings suggest APOL1-associated NS extends beyond patients self-reported non-White, the HRG effect is independent of FSGS, and a single risk variant may have a detrimental impact in children with NS. (AU)

• FAPESP's process: 13/02162-8 - Molecular pathogenesis and characterization of monogenic developmental diseases: a route to translational medicine
• Grantee: Berenice Bilharinho de Mendonça
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/27198-8 - Establishment of a center of genetic and molecular research for clinical challenges
• Grantee: João Bosco Pesquero
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/20502-6 - Whole Exome Sequencing in Brazilian Children and Adolescents with Steroid Resistant Nephrotic Syndrome
• Grantee: Maricilda Palandi de Mello
• Support Opportunities: Regular Research Grants