Discovery and fine mapping of susceptibility loci for IgA nephropathy

IgA 肾病易感位点的发现和精细定位

基本信息

批准号：
8458387
负责人：
ALI G GHARAVI
金额：
$ 61.82万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8458387
关键词：
17p13 1q32 22q12 6p21 Address Alleles Antigen-Antibody Complex Asians Biological Assay Biopsy Caucasians Caucasoid Race Cells Characteristics Chinese People Clinical Collaborations Complex Data Deposition Development Diagnostic Disease European Gene Frequency Genetic Genetic Risk Genetic Variation Genotype Glomerulonephritis Immune Immune system Immunoglobulin A Immunoglobulins Injury Kidney Kidney Diseases Kidney Failure Major Histocompatibility Complex Maps Mediating Meta-Analysis Minor Modeling Molecular Odds Ratio Online Mendelian Inheritance In Man Outcome Pathogenesis Pathway interactions Patients Phase Population Predisposition Prevalence Research Personnel Risk Sample Size Sampling Serum Signal Transduction Therapeutic Variant base case control cohort complement pathway experience falls follow-up genetic risk factor genome wide association study genome-wide insight novel tool

项目摘要

DESCRIPTION (provided by applicant): Immunoglobulin A Nephropathy is a major cause of kidney failure worldwide. It is the most common cause of kidney failure among Asian populations, and the most common form of primary glomerulonephritis among Caucasians. We recently completed a genome-wide association study (GWAS) of IgAN, with discovery in 1,194 cases and 902 controls of Chinese Han ancestry, and targeted follow-up in Chinese cohorts and European cohorts (1,950 cases and 1,920 controls). We identified three independent loci in the major histocompatibility complex (MHC) on Chr. 6p21, a common deletion of CFHR1 and CFHR3 at Chr. 1q32 and a locus at Chr. 22q12 that each surpassed genome-wide significance (p-values for association between 1.6 x 10-26 and 4.8 x 10-9 and minor allele odds ratios of 0.63-0.80). These five loci explain 4-7% of the disease variance and up to a 10-fold variation in interindividual risk. In this study, we propose to follow-up recent genome-wide association study (GWAS) for IgAN, which identified five new susceptibility loci. We propose to refine the five newly discovered risk loci using the Immunochip, targeted genotyping and MPLA to identify underlying functional variants. We will next examine the impact of these loci on immunological and clinical parameters. Our initial GWAS also suggested that there are yet-undiscovered risk loci in Europeans. In addition, we have tripled our sample size, totaling 7,203 biopsy documented IgAN cases and 8,069 healthy controls of Asian and European ancestry. We will therefore perform a second GWAS with discovery in a European population (1440 cases, 1217 controls) and replication in the remaining samples to identify new IgAN loci and further define molecular pathways underlying disease. Finally, we will refine and validate a genetic risk score model for IgAN in the full cohort. 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.

描述（由申请人提供）：免疫球蛋白 A 肾病是全世界肾衰竭的主要原因。它是亚洲人群肾衰竭的最常见原因，也是白种人原发性肾小球肾炎最常见的形式。我们最近完成了一项 IgAN 全基因组关联研究 (GWAS)，发现了 1,194 例中国汉族血统的病例和 902 名对照者，并对中国队列和欧洲队列（1,950 例病例和 1,920 名对照）进行了有针对性的随访。我们在 Chr 上的主要组织相容性复合体 (MHC) 中确定了三个独立位点。 6p21，Chr. 上 CFHR1 和 CFHR3 的常见缺失。 1q32 和 Chr. 的一个基因座。 22q12，每个都超过全基因组显着性（关联的 p 值在 1.6 x 10-26 和 4.8 x 10-9 之间，次要等位基因比值比为 0.63-0.80）。这五个基因座解释了 4-7% 的疾病变异以及高达 10 倍的个体间风险变异。在这项研究中，我们建议对最近的 IgAN 全基因组关联研究 (GWAS) 进行后续研究，该研究确定了 5 个新的易感位点。我们建议使用免疫芯片、靶向基因分型和 MPLA 来完善五个新发现的风险位点，以识别潜在的功能变异。接下来我们将检查这些位点对免疫学和临床参数的影响。我们最初的 GWAS 还表明，欧洲人中存在尚未发现的风险位点。此外，我们的样本量增加了两倍，共有 7,203 例活检记录的 IgAN 病例和 8,069 例亚洲和欧洲血统的健康对照。因此，我们将进行第二次 GWAS，在欧洲人群（1440 例病例，1217 例对照）中进行发现，并在其余样本中进行复制，以识别新的 IgAN 位点并进一步定义疾病潜在的分子途径。最后，我们将完善并验证整个队列中 IgAN 的遗传风险评分模型。这些研究将深入了解 IgAN 的发病机制，为开发针对肾衰竭这一主要原因的诊断和治疗工具提供新的机会。公共卫生相关性：免疫球蛋白 A 肾病（IgAN，OMIM %161950）是一种尚未得到充分研究的疾病，是美国和全世界肾衰竭的主要原因。这些遗传学研究将深入了解 IgAN 的发病机制，为开发针对肾衰竭这一主要原因的诊断和治疗工具提供新的机会。