Genome-Wide Association Studies of Diabetic Nephropathy

糖尿病肾病的全基因组关联研究

• 批准号: 8117211
• 负责人: JOEL N HIRSCHHORN
• 金额: $ 52.85万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117211
• 关键词: Albuminuria; Amputation; Attention; Biological; Biopsy; Blindness; Blood Glucose; Candidate Disease Gene; Clinical; Clinical Management; Collaborations; Collection; Complication; Complications of Diabetes Mellitus; Controlled Study; Coronary heart disease; DNA; DNA Resequencing; DNA Sequence; Data; Data Analyses; Data Set; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Disease; End stage renal failure; Family Study; Frequencies; Gene Expression; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Health; Heart Diseases; Heterogeneity; Hyperglycemia; Individual; Inherited; Insulin-Dependent Diabetes Mellitus; International; Ireland; Joints; Kidney; Kidney Diseases; Malignant neoplasm of lung; Malignant neoplasm of prostate; Maps; Measures; Meta-Analysis; Multiple Sclerosis; Nephrology; Non-Insulin-Dependent Diabetes Mellitus; Osteoporosis; Pathway interactions; Patients; Plant Roots; Play; Predisposition; Prevention strategy; Preventive; Preventive Intervention; Probability; Process; Public Health; Publications; Renal function; Research Design; Rheumatoid Arthritis; Risk; Risk Factors; Role; Sampling; Sensitivity and Specificity; Severities; Signal Transduction; Single Nucleotide Polymorphism; Source; Staging; Stroke; Technology; Testing; Therapeutic Intervention; United States National Institutes of Health; Validation; Variant; base; biobank; cohort; design; disorder risk; early onset; genetic epidemiology; genetic risk factor; genetic variant; genome wide association study; genome-wide; glycemic control; improved; in vitro Model; in vivo; insight; macrovascular disease; malignant breast neoplasm; novel; public health relevance; success; time interval; trait

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.

描述（由申请人提供）：糖尿病肾病（DN）是全球终末期肾脏疾病的主要原因。虽然严格控制血糖可以降低糖尿病肾病的风险，但许多控制适当的患者会发展为肾病，而其他患者尽管血糖控制不良，但仍无并发症。家庭研究指出，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然未知，限制了我们对这种毁灭性并发症的理解。我们的长期目标是发现影响糖尿病肾病风险的遗传因素，希望通过提高对该疾病的了解，确定新的治疗和预防干预的生物学靶点。直到最近，寻找糖尿病肾病等多因素疾病的因果遗传风险因素一直相当困难。然而，在过去的一年里，遗传学和基因组学的进步使人们能够完成对一系列常见疾病的全基因组关联研究，这些研究成功地发现了对疾病风险影响不大的常见遗传变异。这些成功的关键是对足够动力的样品进行仔细和严格的分析。我们假设糖尿病肾病的风险在一定程度上受到普通遗传变异的影响，这些变异的影响适度，可以通过一项强有力的全基因组关联研究来确定。我们进一步假设，通过这种方法确定的基因位点可能包含多种变异（常见或罕见），这些变异会影响个体对肾病的易感性。我们建议对这些遗传风险因素进行全面的搜索，使用多阶段全基因组关联研究。我们建立了具有互补优势的研究小组之间的国际合作，并收集了来自898例1型糖尿病合并肾病患者（病例）和1091例长期1型糖尿病且无肾病患者（对照组）的DNA样本。我们建议在该样本中生成900,000个单核苷酸多态性（snp）的全基因组基因型数据，并将这些数据与最近公布的类似确定的GoKIND研究（905例/890例对照）的全基因组数据相结合进行分析。联合关联分析将进一步由肾活检生物库的基因表达数据提供信息。具有最佳关联信号的snp将在另外2500名患者的验证小组中进行测试。为了在验证的基因座上搜索其他常见的因果变异，我们将进行精细的制图研究；为了寻找具有更强影响的罕见变异，我们将对早发性肾病患者和50年无并发症的糖尿病患者进行基因重排序。确定肾病的遗传风险因素将突出这种疾病的根本原因的生物学途径，提供新的见解，有助于指导改进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一种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。遗传因素在决定谁会患上这种并发症方面发挥着作用，但这些因素仍然未知，限制了我们开发改进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。