Effect of a Single Apolipoprotein L1 Gene Nephropathy Variant on the Risk of Advanced Lupus Nephritis in Brazilians

Abstract

Objective Apolipoprotein L1 gene (APOL1) G1 and G2 renal risk alleles (RRA) are associated with endstage renal disease in blacks with lupus nephritis (LN). The present study determined frequencies of APOL1 RRA in nonwhite Brazilian patients with LN and controls to assess association with renal outcomes. MethodsAPOL1 RRA were genotyped in 222 healthy blood donors (controls) and 201 cases with LN from 3 outpatient clinics. Two single-nucleotide polymorphisms in the G1 (rs73885319 and rs60910145) and an indel for the G2 (rs71785313) variant were genotyped. Results The frequency of APOL1 RRA in nonwhite Brazilian LN cases did not differ significantly from healthy controls, and few participants had 2 RRA. In the sample, 84.6% of LN cases and 84.2% of controls had 0 RRA, 13.4% and 15.3% had 1 RRA, and 2.0% and 0.4% had 2 RRA, respectively. LN cases with ≥ 1 APOL1 RRA had similar baseline characteristics and renal responses to treatment, yet faced higher risk for progressive chronic kidney disease (CKD) to an estimated glomerular filtration rate < 30 ml/min/1.73 m2 compared to those with 0 RRA (11.2% with 0, 29.6% with 1; 50% with 2 RRA, p = 0.005). Although glomerular lesions and activity scores on initial kidney biopsy did not differ significantly between individuals based on APOL1 genotype, chronicity scores, tubular atrophy, and interstitial fibrosis were more severe in those with ≥ 1 RRA (p = 0.011, p = 0.002, p = 0.018, respectively). Conclusion Although initial kidney lesions and treatment responses were similar, a single APOL1 RRA in nonwhite Brazilians with LN was associated with increased risk of advanced CKD and possibly more tubulointerstitial damage.

Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes

“…(38) Consistently, progressive nephritis was worsened with every copy of risk allele in Brazilian AA/H lupus patients. (39) In this context, our data implicating a role for APOL1 within T cells involved in adaptive immune responses against a donor organ, demonstrate that previous data regarding R-nAPOL1 and allograft outcomes need to be reinterpreted, and its role in infiltrating inflammatory mononuclear cells in native kidney glomerulonephritis investigated.…”

Kidney Disease-Associated APOL1 Variants Have Dose-Dependent, Dominant Toxic Gain-of-Function

“…Similarly, our observation that moderate expression of G0G1 or G0G2 caused cytotoxicity could help explain the elevated risk of APOL1 nephropathy in some carriers of one RRVs relative to carriers of G0G0. 13,14,26 Our results also raise new questions. We observed that tet induced a lower level of G0 protein relative to G2 protein in G0G2-containing HEK293 cells.…”

The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases

“…While single polymorphisms may not be sufficient to cause autoimmunity alone, accumulating numbers of risk variants may cause the immune system to become overwhelmed, leading to immune dysregulation [ 24 , 75 ]. Furthermore, interferon signaling upregulation inpatients with LN may trigger nephropathy associated with apolipoprotein L1 ( APOL1 ) risk-alleles (which are prevalent in individuals with Sub-Saharan African ancestry) by upregulating APOL1 mRNA expression and increasing genotype-associated disease severity [ 76 ]. Risk-associated variants in interferon-related genes have also been identified for other autoimmune diseases, including SSc, for which family history remains the strongest known risk factor [ 32 ].…”