Genetic Association Studies of Diabetic Nephropathy

糖尿病肾病的遗传关联研究

• 批准号: 8783338
• 负责人: JENNIFER NICHOLSON TODD
• 金额: $ 6.76万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-03 至 2015-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783338
• 关键词: Address; Affect; Albuminuria; Biology; Blood Glucose; Caring; Cataloging; Catalogs; Childhood; Chronic; Chronic Disease; Chronic Kidney Failure; Clinical; Code; Collaborations; Complex; Complication; Complications of Diabetes Mellitus; Cross-Sectional Studies; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Dyslipidemias; End stage renal failure; Endocrinologist; Epidemiology; Etiology; Evaluation; Family; Family Study; Foundations; Frequencies; Funding; Gene Frequency; Genes; Genetic; Genetic Research; Genome; Glomerular Filtration Rate; Goals; Heritability; Hyperglycemia; Hypertension; Incidence; Individual; Inherited; Insulin-Dependent Diabetes Mellitus; International; Investigation; Kidney Diseases; Kidney Failure; Link; Long-Term Survivors; Longitudinal Studies; Measures; Mentors; Meta-Analysis; Methods; Minor; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathogenesis; Patients; Phenotype; Predisposition; Prevention; Proteinuria; Randomized; Renal function; Research; Research Design; Risk; Risk Factors; Role; Sample Size; Scanning; Siblings; Signal Transduction; Smoking; Staging; Survivors; Testing; United States; Variant; base; case control; cohort; density; disease phenotype; disorder control; disorder risk; exome; genetic association; genetic risk factor; genetic variant; genome wide association study; genome-wide; genome-wide analysis; glycemic control; meetings; novel; prevent; protein function; public health relevance; rare variant; risk variant; trait; treatment strategy

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is a devastating complication of diabetes, and the leading cause of end-stage renal disease in the United States. Current treatment strategies only slow progression of, rather than prevent or reverse, this disease. Although tight control of blood glucose reduces the rate of diabetic complications including DN, there is variability in susceptibility to DN that is not explained by glycemic contro alone. Studies of families of siblings with diabetes strongly suggest a role for heritable factors n the development of DN; however, the specific genetic factors influencing DN risk remain largely unknown. Uncovering the genetic basis of DN risk holds the promise of better understanding the biology of the pathogenesis of DN, and identifying novel targets for prevention and treatment. Advances in genetic research have enabled genome-wide analysis studies (GWAS), which offer an unbiased scan of the entire genome, powered to detect effects of modest size. Initial GWAS of DN identified several potential risk loci, but these studies were hindered by low variant densities or sample sizes too small to detect modest effects. The largest GWAS of DN to date, an international consortium of T1D cohorts, was unable to replicate most of the previously associated genetic associations for DN; a subsequent meta-analysis identified several GWAS associations for ESRD. A notable finding of this analysis was that stronger genetic associations were apparent using the more stringent ESRD phenotype compared to the traditional proteinuria-based definition of DN. This project will build on a current expanded GWAS effort, totaling ~20,000 cases and controls, funded by the Juvenile Diabetes Research Foundation, to explore signals uncovered by using alternate phenotype definitions, evaluating quantitative DN- associated traits, and restricting analysis to extreme phenotypes. Additionally, uncommon and rare variants will be evaluated using the most current gene-burden tests, which group all variants within a gene collectively. Finally, the results from our cross-sectional analysis will be integrated with longitudinal data from our collaborators to further explore suggestive signals; thi data will be further leveraged to explore the causality of heritable risk factors (e.g. obesity or hypertension) with epidemiologic association with DN. The advanced analytic approaches outlined in this proposal have the promise to uncover new genetic variants associated with development of renal disease in patients with T1D.

描述（由申请人提供）：糖尿病肾病（DN）是糖尿病的一种毁灭性并发症，是美国终末期肾病的主要原因。目前的治疗策略只能减缓这种疾病的进展，而不是预防或逆转。尽管严格控制血糖可降低糖尿病并发症（包括DN）的发生率，但DN的易感性存在变异性，不能仅用血糖控制来解释。对糖尿病兄弟姐妹家庭的研究强烈提示遗传因素在DN的发展中起作用;然而，影响DN风险的特定遗传因素在很大程度上仍然未知。揭示DN风险的遗传基础有望更好地理解DN发病机制的生物学，并确定预防和治疗的新靶点。遗传学研究的进步使全基因组分析研究（GWAS）成为可能，它提供了对整个基因组的无偏扫描，能够检测到适度大小的影响。DN的初始GWAS确定了几个潜在的风险位点，但这些研究受到低变异密度或样本量太小而无法检测适度影响的阻碍。迄今为止最大的DN GWAS，T1 D队列的国际联盟，无法复制大多数先前与DN相关的遗传关联;随后的荟萃分析确定了ESRD的几个GWAS关联。这项分析的一个值得注意的发现是，与传统的基于蛋白尿的DN定义相比，使用更严格的ESRD表型时，更强的遗传关联是明显的。该项目将建立在目前扩大的GWAS努力的基础上，总计约20，000例病例和对照，由青少年糖尿病研究基金会资助，以探索通过使用替代表型定义发现的信号，评估定量DN相关性状，并将分析限制在极端表型。此外，将使用最新的基因负荷测试评估不常见和罕见的变异，该测试将基因内的所有变异集中在一起。最后，我们的横截面分析结果将是 与我们合作者的纵向数据相结合，进一步探索提示信号;这些数据将进一步用于探索遗传性风险因素（例如肥胖或高血压）与DN流行病学相关性的因果关系。该提案中概述的先进分析方法有望发现与T1 D患者肾脏疾病发展相关的新遗传变异。