Inserm U1163, Institut Imagine, University Paris Descartes, Paris, France.
Pediatric Nephrology Department, Necker Hospital, APHP, Paris, France.
Nephrol Dial Transplant. 2019 Nov 1;34(11):1885-1893. doi: 10.1093/ndt/gfy176.
Apolipoprotein L1 (APOL1) risk variants are strongly associated with sporadic focal segmental glomerulosclerosis (FSGS) in populations with African ancestry. We determined the frequency of G1/G2 variants in steroid-resistant nephrotic syndrome (SRNS)/FSGS patients with African or French West Indies ancestry in France and its relationships with other SRNS genes.
In a cohort of 152 patients (139 families), the APOL1 risk variants were genotyped by direct Sanger sequencing and pathogenic mutations were screened by next-generation sequencing with a panel including 35 SRNS genes.
The two risk allele [high-risk (HR)] genotypes were found in 43.1% (66/152) of subjects compared with 18.9% (106/562) in a control population (P < 0.0001): 33 patients homozygous for APOL1 G1 alleles, 4 homozygous for G2 and 29 compound heterozygous for G1 and G2. Compared with patients in the low-risk (LR) group, patients in the HR group were more likely to originate from the French West Indies than from Africa [45/66 (68.2%) versus 30/86 (34.9%); P < 0.0001]. There were more familial cases in the HR group [27 (41.5%) versus 8 (11.4%); P < 0.0001]. However, causative mutations in monogenic SRNS genes were found in only 1 patient in the HR group compared with 16 patients (14 families) in the LR group (P = 0.0006). At diagnosis, patients in the HR group without other mutations were more often adults [35 (53.8%) versus 19 (27.1%); P = 0.003] and had a lower estimated glomerular filtration rate (78.9 versus 98.8 mL/min/1.73 m2; P = 0.02).
The HR genotype is frequent in FSGS patients with African ancestry in our cohort, especially in those originating from the West Indies, and confer a poor renal prognosis. It is usually not associated with other causative mutations in monogenic SRNS genes.
载脂蛋白 L1（APOL1）风险变异与非洲裔人群中的散发性局灶节段性肾小球硬化症（FSGS）密切相关。我们确定了法国具有非洲或法属西印度群岛血统的类固醇耐药性肾病综合征（SRNS）/FSGS 患者中 G1/G2 变异的频率及其与其他 SRNS 基因的关系。
在 152 名患者（139 个家系）的队列中，通过直接 Sanger 测序对 APOL1 风险变异进行基因分型，并通过包括 35 个 SRNS 基因的下一代测序对致病性突变进行筛查。
与对照组（562 人）中 18.9%（106/562）相比，高风险（HR）基因型在 43.1%（66/152）的受试者中发现（P<0.0001）：33 名患者纯合子携带 APOL1 G1 等位基因，4 名纯合子携带 G2 等位基因，29 名复合杂合子携带 G1 和 G2 等位基因。与低风险（LR）组患者相比，HR 组患者更可能来自法属西印度群岛而不是非洲[45/66（68.2%）比 30/86（34.9%）；P<0.0001]。HR 组的家族性病例更多[27（41.5%）比 8（11.4%）；P<0.0001]。然而，在 HR 组中仅发现 1 例患者存在单基因 SRNS 基因突变，而在 LR 组中发现 16 例（14 个家系）（P=0.0006）。在诊断时，没有其他突变的 HR 组患者更常为成年人[35（53.8%）比 19（27.1%）；P=0.003]，估算肾小球滤过率（eGFR）较低[78.9 比 98.8 mL/min/1.73 m2；P=0.02]。
在我们的队列中，具有非洲血统的 FSGS 患者中 HR 基因型很常见，尤其是来自西印度群岛的患者，并且预后不良。它通常不与单基因 SRNS 基因中的其他致病突变相关。
