Genetic coding variants in APOL1, which encodes apolipoprotein L1 (APOL1), were identified in 2010 and are relatively common among individuals of sub-Saharan African ancestry. Approximately 13% of African Americans carry two APOL1 risk alleles. These variants, termed G1 and G2, are a frequent cause of kidney disease — termed APOL1 nephropathy — that typically manifests as focal segmental glomerulosclerosis and the clinical syndrome of hypertension and arterionephrosclerosis. Cell culture studies suggest that APOL1 variants cause cell dysfunction through several processes, including alterations in cation channel activity, inflammasome activation, increased endoplasmic reticulum stress, activation of protein kinase R, mitochondrial dysfunction and disruption of APOL1 ubiquitinylation. Risk of APOL1 nephropathy is mostly confined to individuals with two APOL1 risk variants. However, only a minority of individuals with two APOL1 risk alleles develop kidney disease, suggesting the need for a ‘second hit’. The best recognized factor responsible for this ‘second hit’ is a chronic viral infection, particularly HIV-1, resulting in interferon-mediated activation of the APOL1 promoter, although most individuals with APOL1 nephropathy do not have an obvious cofactor. Current therapies for APOL1 nephropathies are not adequate to halt progression of chronic kidney disease, and new targeted molecular therapies are in clinical trials.

APOL1中编码载脂蛋白 L1 (APOL1) 的遗传编码变体于2010 年被鉴定，并且在撒哈拉以南非洲血统的个体中相对常见。大约 13% 的非裔美国人携带两个APOL1风险等位基因。这些变异，称为 G1 和 G2，是肾脏疾病（称为 APOL1 肾病）的常见原因，通常表现为局灶节段性肾小球硬化以及高血压和动脉肾硬化的临床综合征。细胞培养研究表明APOL1变异通过几个过程引起细胞功能障碍，包括阳离子通道活性的改变、炎症小体的激活、内质网应激增加、蛋白激酶 R 的激活、线粒体功能障碍和 APOL1 泛素化的破坏。APOL1 肾病的风险主要局限于具有两种APOL1风险变异的个体。然而，只有少数具有两个APOL1风险等位基因的个体会患上肾脏疾病，这表明需要“第二次打击”。造成这种“第二次打击”的最公认因素是慢性病毒感染，尤其是 HIV-1，导致干扰素介导的APOL1激活启动子，尽管大多数 APOL1 肾病患者没有明显的辅助因子。目前针对 APOL1 肾病的疗法不足以阻止慢性肾病的进展，新的靶向分子疗法正在临床试验中。