Rossetti Sandro, Burton Sarah, Strmecki Lana, Pond Gregory R, San Millán Jośe L, Zerres Klaus, Barratt T Martin, Ozen Seza, Torres Vicente E, Bergstralh Erik J, Winearls Christopher G, Harris Peter C
Division of Nephrology and Section of Biostatistics, Mayo Clinic, Rochester, Minnesota 55905, USA.
J Am Soc Nephrol. 2002 May;13(5):1230-7. doi: 10.1097/01.asn.0000013300.11876.37.
The severity of renal cystic disease in the major form of autosomal dominant polycystic kidney disease (PKD1) is highly variable. Clinical data was analyzed from 324 mutation-characterized PKD1 patients (80 families) to document factors associated with the renal outcome. The mean age to end-stage renal disease (ESRD) was 54 yr, with no significant difference between men and women and no association with the angiotensin-converting enzyme polymorphism. Considerable intrafamilial variability was observed, reflecting the influences of genetic modifiers and environmental factors. However, significant differences in outcome were also found among families, with rare examples of unusually late-onset PKD1. Possible phenotype/genotype correlations were evaluated by estimating the effects of covariants on the time to ESRD using proportional hazards models. In the total population, the location of the mutation (in relation to the median position; nucleotide 7812), but not the type, was associated with the age at onset of ESRD. Patients with mutations in the 5' region had significantly more severe disease than the 3' group; median time to ESRD was 53 and 56 yr, respectively (P = 0.025), with less than half the chance of adequate renal function at 60 yr (18.9% and 39.7%, respectively). This study has shown that the position of the PKD1 mutation is significantly associated with earlier ESRD and questions whether PKD1 mutations simply inactivate all products of the gene.
常染色体显性多囊肾病（PKD1）主要形式的肾囊性疾病严重程度差异很大。对324例已明确突变特征的PKD1患者（80个家系）的临床数据进行分析，以记录与肾脏转归相关的因素。进入终末期肾病（ESRD）的平均年龄为54岁，男性和女性之间无显著差异，且与血管紧张素转换酶多态性无关。观察到显著的家系内变异性，反映了基因修饰因子和环境因素的影响。然而，在不同家系之间也发现了转归的显著差异，有罕见的PKD1异常晚发的例子。通过使用比例风险模型估计协变量对进入ESRD时间的影响，评估可能的表型/基因型相关性。在总体人群中，突变位置（相对于中位位置；核苷酸7812）而非类型与ESRD发病年龄相关。5'区域发生突变的患者疾病严重程度显著高于3'区域突变组；进入ESRD的中位时间分别为53岁和56岁（P = 0.025），60岁时肾功能正常的几率不到一半（分别为18.9%和39.7%）。这项研究表明，PKD1突变位置与较早进入ESRD显著相关，并对PKD1突变是否只是使该基因的所有产物失活提出了疑问。
