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

描述(申请人提供)：在这项研究中，我们建议对免疫球蛋白A肾病(免疫球蛋白A肾病，OMIM%161950)进行第一次全基因组关联研究，这是一种研究不足的疾病，是美国和世界范围内肾衰竭的主要原因。它是亚洲人群中最常见的肾衰竭原因，也是年轻高加索人中最常见的原发肾炎形式。与许多免疫介导性疾病一样，IgAN是一种复杂的遗传特征，疾病的遗传基础尚不清楚。为了进行全球疫苗试验，我们汇集了国际上最大的免疫球蛋白肾病病例/对照队列。研究人群包括从北京和上海招募的中国队列(2,000例有活检记录的IgAN病例和2,000名健康对照)，以及从北美和欧洲招募的高加索/欧洲队列(2,000例有活检记录的病例和2,000名对照)，招募工作在四个研究地点进行。关键的是，这些研究的所有样本都在手中。北京地区551例患者和441例对照的初步基因分型中国(Illumina 610quad芯片)数据分析显示没有显著的分层(？=1.005)，并揭示了全基因组范围内IgAN与人类白细胞抗原-DQA2基因座的显著关联(p=9x10-8)。此外，这个中等大小的队列在染色体7q31(p=7x10-6)、15q13(p=8x10-6)、4q21(p=2x10-5)和3q26.2(p=3x10-5)上发现了几个提示关联，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，以确定对疾病有轻微到较大影响的常见变异。接下来，我们将在上海(750例病例/750例对照)和北美/欧洲高加索人(2000例/2000例对照)的独立队列中重复这些发现。这些研究将提供对IgAN发病机制的洞察，为开发诊断和治疗这一肾功能衰竭的主要原因的工具提供新的机会。 公共卫生相关性：免疫球蛋白A肾病(IgAN，OMIM%161950)，这是一种研究不足的疾病，是美国和世界各地肾衰竭的主要原因。这些遗传学研究将提供对IgAN发病机制的洞察，为开发诊断和治疗这一肾功能衰竭的主要原因的工具提供新的机会。

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.