Identifying genetic modifiers of severity in ADPKD

描述(由申请人提供)： 与孟德尔病常染色体显性遗传性多囊肾病(ADPKD)相关的表型是高度可变的。临床上最重要的是肾囊性疾病的严重程度。以往的研究表明，基因(PKD_1或PKD_2)和等位基因因素(在较小程度上)影响表型，但最重要的调节因素之一是遗传背景。识别显著影响疾病严重程度的数量性状基因座(QTL)将有助于了解疾病的发病机制，对预后有重要意义，并可能指导治疗。高密度SNP阵列的发展提供了一种方法，利用全基因组关联研究(GWAS)在大型、临床和遗传特征良好的人群中定位这些QTL。NIDDK资助的CRISP和HALT PKD研究有1,000名ADPKD患者，他们具有高度的临床和遗传学特征；&gt；700有肾脏磁共振成像数据。MR计算的总肾脏体积(TKV)已被证明是一个很好的疾病严重程度的衡量标准，在GFR下降可以检测到之前提供信息。此外，UCHSC、Emory、Mayo、KUMC、多伦多、剑桥和牛津大学提供了具有良好特性的PKD1群体，以帮助发现、复制和验证区分真正的QTL和假阳性关联所需的步骤。在这里，我们提出了一个在1600名PKD1高加索人(目标1)中使用Illumina Human 660W-四个基因芯片(658,000个SNPs)的GWA。其中约1100名患者将获得肾脏总体积(TKV)数据，约900名患者将获得信息丰富的EGFR数据。在1600名具有TKV和EGFR表型终点的重复人群中，将使用定制的阵列进一步检测与这些终点最有可能相关的7600个SNPs(目标2)。最后的验证步骤将分析具有相同终点的1216名患者群体中最有希望的30个基因座(目标3)。将用~12个SNPs(总共348个)对这30个基因座进行测试，以提炼QTL并突出可能的致病基因。为了最大限度地发挥研究的力量，我们将以人口和家庭为基础的关联研究相结合的方式来分析数据。综上所述，这个小组的联盟将在ADPKD中进行第一次GWA，以确定疾病严重程度的修饰物。设计分为三个阶段：发现、复制和验证步骤，以最大限度地增加识别QTL的机会，并将假阳性降至最低。 公共卫生相关性：该项目建议确定人类基因组中影响常染色体显性遗传性多囊肾病(ADPKD)肾脏疾病严重程度的基因变异。这项研究将使用新的基于阵列的基因组图谱方法，并详细分析来自美国和世界各地的大量ADPKD人群，这些人群已经具有临床和遗传学特征。阳性结果将对预后具有重要意义，并确定治疗干预的靶点。

DESCRIPTION (provided by applicant): The phenotype associated with the Mendelian disease autosomal dominant polycystic kidney disease (ADPKD) is highly variable. Of paramount importance clinically is the severity of the renal cystic disease. Previous studies have shown that genic (PKD1 or PKD2) and (to a less extent) allelic factors influence the phenotype, but one of the most important modulating factors is genetic background. Identifying quantitative trait loci (QTL) that significantly influence the severity of disease would help understand pathogenesis, be of prognostic importance and may guide therapeutics. The development of high-density SNP arrays provides a means to map these QTL in large, clinically and genetically well-characterized populations, employing a genome-wide association study (GWAS). The NIDDK-funded CRISP and HALT PKD studies have a combined cohort of >1,000 ADPKD patients who are highly characterized clinically and genetically; >700 have renal MR imaging data. MR calculated total kidney volume (TKV) has been shown to be a good measure of disease severity, informative before a decline in GFR is detectable. Additionally, well characterized PKD1 populations are available at UCHSC, Emory, Mayo, KUMC, Toronto, Cambridge and Oxford to aid the discovery, replication and verification steps that are required to differentiate genuine QTL from false positive associations. Here, we propose a GWAS employing the Illumina Human660w-quad Genotyping BeadChip (658,000 SNPs), in 1600 PKD1 Caucasians (Aim 1). Total kidney volumes (TKV) data will be available in ~1100 of these patients and informative eGFR data in ~900 cases. The 7600 most likely associated SNPs detected with these endpoints will be further assayed using a customized array in a replicate population of 1600 PKD1 patients with the TKV and eGFR phenotypic endpoints, as above (Aim 2). A final verification step will analyze the 30 most promising loci in a population of 1216 patients with the same endpoints (Aim 3). The 30 loci will each be tested with ~12 SNPs (total of 348) to refine the QTL and highlight possible causative genes. To maximize the power of the study we will analyze the data as a combined population and family-based association study. In summary, this consortium of groups will perform the first GWAS in ADPKD to identify modifiers of disease severity. A three-stage design; discovery, replication and verification steps are to be employed to maximize the chance to identify QTL and minimize false positives. PUBLIC HEALTH RELEVANCE: This project proposes to identify genetic variants in the human genome that influence the severity of the kidney disease in the genetic disease autosomal dominant polycystic kidney disease (ADPKD). The study will use new array-based genomic mapping methods and analyze a number of large ADPKD populations from US and around the world that have been clinical and genetically characterized in detail. Positive results will be of prognostic importance and identify targets for therapeutic intervention.