Genome-Wide Association Studies of Diabetic Nephropathy

描述(申请人提供)：糖尿病肾病是全球终末期肾病的主要原因。虽然严格控制血糖可以降低糖尿病肾病的风险，但许多控制充分的患者会发展成肾病，而其他患者尽管血糖控制不佳，但仍然没有并发症。家族研究表明，遗传因素在肾病的发展中起着重要作用，但相关的遗传变异仍不清楚，限制了我们对这种毁灭性并发症的了解。我们的长期目标是发现影响糖尿病肾病风险的遗传因素，希望对疾病的更好理解将为治疗和预防干预找到新的生物学靶点。直到最近，寻找糖尿病肾病等多因素疾病的致因遗传危险因素一直是相当困难的。然而，在过去的一年里，遗传学和基因组学的进步使一系列常见疾病的全基因组关联研究得以完成，这些疾病成功地发现了对疾病风险影响不大的常见基因变异。这些成功的关键是对足够强大的样品进行了仔细和严格的分析。我们假设糖尿病肾病的风险在一定程度上受到普通基因变异的影响，这些基因变异的影响程度不大，可以通过一项强有力的全基因组关联研究来识别。我们进一步假设，通过这种方法确定的遗传位点可能含有多种变异(常见或罕见)，影响个体对肾病的易感性。我们建议使用多阶段全基因组关联研究，对这些遗传风险因素进行全面研究。我们已经建立了一个由优势互补的研究小组组成的国际合作，并收集了898名1型糖尿病和肾病患者(病例)和1091名长期存在的1型糖尿病和无肾病患者(对照组)的DNA样本。我们建议在这个样本中生成900,000个单核苷酸多态(SNPs)的全基因组基因数据，并结合最近发布的来自类似确定的GoKIND研究(905例/890例对照)的全基因组数据来分析这些数据。联合关联分析将由来自肾活检生物库的基因表达数据进一步提供信息。具有最佳关联信号的SNPs将在由另外H2500名患者组成的验证小组中进行测试。为了在已验证的基因座上寻找其他常见的因果变异，我们将进行精细的作图研究；为了寻找影响更强的罕见变异，我们将对早发性肾病患者和50年来无并发症的糖尿病患者的基因进行重新测序。确定肾病的遗传风险因素将突出作为该疾病根本原因的生物途径，提供新的见解，有助于指导改进的治疗或预防措施的开发或应用。公共卫生相关性：肾脏疾病是糖尿病的常见和破坏性并发症，是世界范围内的一个主要公共卫生问题。遗传的遗传因素在决定谁会患上这种并发症方面发挥了作用，但这些因素仍然未知，限制了我们开发改进的治疗和预防措施的能力。我们建议使用一种新的、强大的遗传方法(全基因组关联研究)来寻找影响糖尿病肾病发展的遗传因素。

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Although tight control of blood sugar can decrease the risk of diabetic kidney disease, many patients with adequate control develop nephropathy, while others remain complication-free despite poor glycemic control. Family studies point to a strong role for inherited factors in the development of nephropathy, but the relevant genetic variants remain unknown, limiting our understanding of this devastating complication. Our long term goal is to discover the genetic factors that influence the risk of diabetic nephropathy, with the hope that improved understanding of the disease will identify novel biological targets for therapeutic and preventive intervention. The search for causal genetic risk factors for multifactorial diseases such as diabetic nephropathy has until recently been quite difficult. In the past year, however, advances in genetics and genomics have enabled the completion of genome-wide association studies for an array of common diseases, which have successfully discovered common genetic variants with modest effects on disease risk. Critical to these successes has been careful and rigorous analysis of adequately powered samples. We hypothesize that the risk of diabetic nephropathy is influenced in part by common genetic variants of modest effect that can be identified by a well-powered genome-wide association study. We further hypothesize that genetic loci identified by this approach may harbor multiple variants (common or rare) that influence individual susceptibility to nephropathy. We propose a comprehensive search for these genetic risk factors, using a multistage genome-wide association study. We have established an international collaboration spanning investigative groups with complementary strengths, and assembled DNA samples from 898 patients with type 1 diabetes and nephropathy (cases) and 1,091 patients with long-standing type 1 diabetes and no nephropathy (controls). We propose to generate genome-wide genotype data at 900,000 single nucleotide polymorphisms (SNPs) in this sample and analyze these data in combination with recently released genome- wide data from the similarly ascertained GoKIND study (905 cases/890 controls). The combined association analysis will be further informed by gene expression data from a biobank of kidney biopsies. SNPs with the best signals of association will be tested in a validation panel of H2,500 additional patients. To search for additional common causal variants at validated loci, we will perform fine mapping studies; to search for rare variants with stronger effects we will resequence genes in patients with early-onset nephropathy and in patients with diabetes for 50 years but no complications. Identification of genetic risk factors for nephropathy would highlight biological pathways that are root causes of this disease, providing new insights that could help guide the development or application of improved treatments or preventive measures. PUBLIC HEALTH RELEVANCE: Kidney disease is a common and devastating complication of diabetes, and represents a major public health problem worldwide. Inherited, genetic factors play a role in determining who will get this complication, but these factors remain unknown, limiting our ability to develop improved treatments and preventive measures. We propose to use a new, powerful genetic approach (genome-wide association studies) to search for the genetic factors that influence the development of diabetic kidney disease.