Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease.
Yask GuptaDavid J FriedmanMichelle McNultyAtlas KhanBrandon LaneChen WangJuntao KeGina JinBenjamin WoodenAndrea L KnobTze Y LimGerald B AppelKinsie HugginsLili LiuAdele MitrottiMegan C StanglAndrew BombackRik WestlandMonica BodriaMaddalena MarasaNing ShangDavid J CohenRussell J CrewWilliam MorelloPietro CanettaJai RadhakrishnanJeremiah MartinoQingxue LiuWendy K ChungAngelica EspinozaYuan LuoWei-Qi WeiQiPing FengChunhua WengYilu FangIftikhar J KulloMohammadreza NaderianNita LimdiMarguerite R IrvinHemant TiwariSumit MohanMaya RaoGeoffrey DubeNinad S ChaudharyOrlando M GutiérrezSuzanne E JuddMary CushmanLeslie A LangeEthan M LangeDaniel L BivonaMiguel VerbitskyCheryl A WinklerJeffrey B KoppDominick SantorielloIbrahim BatalSérgio Veloso Brant PinheiroEduardo Araújo OliveiraAna Cristina Dos Santos LopesIsabella PisaniEnrico FiaccadoriFangming LinLoreto GesualdoAntonio AmorosoGian Marco GhiggeriVivette D D'AgatiRiccardo MagistroniEimear E KennyRuth J F LoosGiovanni MontiniFriedhelm HildebrandtDirk S PaulSlavé PetrovskiDavid B GoldsteinMatthias KretzlerRasheed GbadegesinAli G GharaviKrzysztof KirylukMatthew Gordon SampsonMartin R PollakSimone Sanna-CherchiPublished in: medRxiv : the preprint server for health sciences (2023)
Black Americans have a significantly higher risk of developing chronic kidney disease (CKD), especially focal segmental glomerulosclerosis (FSGS), than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of Black Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1 -associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.