A GWAS for IgA Nephropathy, the Most Common form of Glomerulonephritis

描述（由申请人提供）：在这项研究中，我们建议对免疫球蛋白A肾病（IgAN, OMIM %161950）进行第一个全基因组关联研究（GWAS），这是一种在美国和世界范围内未被充分研究的疾病，是肾衰竭的主要原因。它是亚洲人群肾衰竭最常见的原因，也是年轻白种人中原发性肾小球肾炎最常见的形式。与许多免疫介导的疾病类似，IgAN是一种复杂的遗传性状，疾病的遗传基础尚不清楚。为了进行GWAS，我们收集了最大的IgAN国际病例/对照队列。本研究人群包括从北京和上海招募的中国队列（bb2000活检记录的IgAN病例和bb1000健康对照）和从北美和欧洲招募的高加索/欧洲队列（bb2000活检记录的病例和2000对照），招募工作正在四个研究地点进行。至关重要的是，这些研究的所有样本都在手。采用Illumina 610quad芯片对来自中国北京的551例病例和441例对照进行初步基因分型。数据分析显示没有显著的分层（?=1.005），并显示IgAN与HLA-DQA2位点的全基因组显著关联（p=9x10-8）。此外，这个中等规模的队列揭示了染色体7q31 （p=7x10-6）、15q13 （p=8x10-6）、4q21 （p=2x10-5）和3q26.2 （p=3x10-5）上的一些暗含关联，突出了新的疾病候选基因。在这个项目中，我们建议完成北京队列（总共1200例IgAN病例/1200例对照）的基因分型，以确定对疾病有中等到较大影响的常见变异。接下来，我们将在来自上海的独立队列（750例/750例对照）和来自北美/欧洲的白种人（2000例/2000例对照）中重复这些发现。这些研究将深入了解IgAN的发病机制，为开发诊断和治疗工具提供新的机会，以治疗这一肾衰竭的主要原因。

DESCRIPTION (provided by applicant): In this study, we propose to perform the first genome-wide association study (GWAS) for Immunoglobulin A Nephropathy (IgAN, OMIM %161950), an understudied disease that is a major cause of kidney failure in the U.S. and worldwide. It is the most common cause of kidney failure among Asian populations, and the most common form of primary glomerulonephritis among young Caucasians. Similar to many immune mediated disorders, IgAN is a genetically complex trait and genetic basis for disease is not known. To perform a GWAS, we have assembled the largest international case/control cohort of IgAN. This study population consists of a Chinese cohort recruited from Beijing and Shanghai ( >2,000 biopsy-documented cases of IgAN and >2,000 healthy controls) and a Caucasian/European cohort recruited the North America and Europe (>2000 biopsydocumented cases and 2000 controls), with the recruitment ongoing at four study sites. Critically, all the samples for these studies are in hand. Initial genotyping of 551 cases and 441 controls from Beijing, China (Illumina 610quad chip). Analyses of the data demonstrated absence of significant stratification (?=1.005) and revealed genome-wide significant association of IgAN with the HLA-DQA2 locus (p=9x10-8). In addition, In addition, this modest-sized cohort revealed several suggestive associations on chromosomes 7q31 (p=7x10-6), 15q13 (p=8x10-6), 4q21 (p=2x10-5), and 3q26.2 (p=3x10-5), highlighting novel candidate genes for disease. In this project, we propose to complete the genotyping of the Beijing cohort (total of 1200 IgAN cases/1200 controls) to identify common variants with modest to large effects on disease. We will next replicate these findings in independent cohorts from Shanghai (750 cases/750 controls) and Caucasians from North America/Europe (2000 cases/2000 controls). These studies will provide insight into the pathogenesis of IgAN, providing novel opportunities for development of diagnostic and therapeutic tools for this major cause of kidney failure. PUBLIC HEALTH RELEVANCE: Immunoglobulin A Nephropathy (IgAN, OMIM %161950), an understudied disease that is a major cause of kidney failure in the U.S. and worldwide. These genetic studies will provide insight into the pathogenesis of IgAN, providing novel opportunities for development of diagnostic and therapeutic tools for this major cause of kidney failure.