Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease
Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease
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DOI：
10.1097/01.asn.0000061774.90975.25
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发表时间：
2003-05-01
影响因子：
13.6
通讯作者：
Pei, Y
中科院分区：
文献类型：
--
作者：
Magistroni, R;He, N;Pei, Y
常染色体显性多囊肾病（ADPKD）是一种常见的孟德尔疾病，大约每1000名活产婴儿中就有1例受到影响。PKD 1和PKD 2两个基因的突变分别占大约80%至85%和10%至15%的病例。ADPKD的显著家族间和家族内肾病变异性已被充分记录。基因座异质性是家族间疾病变异性的主要决定因素（即，与来自PKD 2-连锁家族的患者相比，来自PKD 1-连锁家族的患者具有显著更早的ESRD发作）。最近，两项研究表明等位基因异质性可能影响肾脏疾病的严重程度。目前的研究检查了来自71个已知PKD 2突变的ADPKD家族的461名受影响个体的基因型-肾功能相关性。在这些家族中发现了50种不同的突变，跨越PKD 2的外显子1和14之间。这些突变中的大多数（94%）被预测为失活。分析这些患者的肾脏结局，包括终末期肾病（ESRD）和慢性肾衰竭（CRF;定义为肌酐清除率小于或等于50 ml/min，使用Cockroft和Gault公式计算）的发病年龄。在所有临床评估的受影响个体中，117例（25.4%）患有ESRD，47例（10.2%）死亡，无ESRD，65例（14.0%）患有CRF，232例（50.3%）在末次随访时既无CRF也无ESRD。与男性患者相比，女性患者的ESRD（76. 0 [95% CI，73. 8 - 78. 1] vs 68. 1 [95% CI，66. 0 - 70. 2]岁）和CRF（72. 5 [95% CI，70. 1 - 74. 9] vs 63. 7 [95% CI，61. 4 - 66. 0]岁）的平均发病年龄较晚。线性回归和肾存活分析显示PKD 2突变的位置不影响ESRD的发病年龄。然而，剪接位点突变的患者与其他突变类型的患者相比，肾脏疾病似乎较轻（对数秩检验P < 0.04;调整了性别效应）。在具有相同PKD 2突变的受影响个体中也发现了相当大的肾病变异性。这种变异性可能会混淆等位基因效应的确定，并支持额外的遗传和/或环境因素可能调节ADPKD肾病严重程度的观点。
Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Mutations of two genes, PKD1 and PKD2, account for the disease in approximately 80 to 85% and 10 to 15% of the cases, respectively. Significant interfamilial and intrafamilial renal disease variability in ADPKD has been well documented. Locus heterogeneity is a major determinant for interfamilial disease variability (i.e., patients from PKD1-linked families have a significantly earlier onset of ESRD compared with patients from PKD2-linked families). More recently, two studies have suggested that allelic heterogeneity might influence renal disease severity. The current study examined the genotype-renal function correlation in 461 affected individuals from 71 ADPKD families with known PKD2 mutations. Fifty different mutations were identified in these families, spanning between exon 1 and 14 of PKD2. Most (94%) of these mutations were predicted to be inactivating. The renal outcomes of these patients, including the age of onset of end-stage renal disease (ESRD) and chronic renal failure (CRF; defined as creatinine clearance less than or equal to 50 ml/min, calculated using the Cockroft and Gault formula), were analyzed. Of all the affected individuals clinically assessed, 117 (25.4%) had ESRD, 47 (10.2%) died without ESRD, 65 (14.0%) had CRF, and 232 (50.3%) had neither CRF nor ESRD at the last follow-up. Female patients, compared with male patients, had a later mean age of onset of ESRD (76.0 [95% CI, 73.8 to 78.1] versus 68.1 [95% Cl, 66.0 to 70.2] yr) and CRF (72.5 [95% Cl, 70.1 to 74.9] versus 63.7 [95% CI, 61.4 to 66.0] yr). Linear regression and renal survival analyses revealed that the location of PKD2 mutations did not influence the age of onset of ESRD. However, patients with splice site mutations appeared to have milder renal disease compared with patients with other mutation types (P < 0.04 by log rank test; adjusted for the gender effect). Considerable renal disease variability was also found among affected individuals with the same PKD2 mutations. This variability can confound the determination of allelic effects and supports the notion that additional genetic and/or environmental factors may modulate the renal disease severity in ADPKD.