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：
8719093
负责人：
ALI G GHARAVI
金额：
$ 45.77万
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/8719093
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 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 genetic variant genome wide association study genome-wide insight novel public health relevance risk variant 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.

描述（由申请人提供）：免疫球蛋白A肾病是全球肾衰竭的主要原因。这是亚洲人群中肾衰竭的最常见原因，也是高加索人中最常见的原发性肾小球肾炎形式。我们最近完成了一项全基因组协会研究（GWAS）的IGAN，在1,194例中发现了中国汉族的1,194例和902例对照，并针对中国同伙和欧洲同类群（1,950例和1,920例对照）进行了随访。我们在Chr上确定了主要组织相容性复合物（MHC）中的三个独立基因座。 6p21，Chr1的常见缺失和Chr3的CFHR3。第1季度和Chr的基因座。 22Q12每个人都超过了全基因组显着性（1.6 x 10-26和4.8 x 10-9之间的关联p值，而次要等位基因优势比为0.63-0.80）。这五个基因座解释了4-7％的疾病差异，并且个体跨性别风险的差异高达10倍。在这项研究中，我们建议对IGAN进行近期全基因组关联研究（GWAS），该研究确定了五个新的易感位点。我们建议使用靶向基因分型和MPLA来完善五个新发现的风险基因座，以识别潜在的功能变体。接下来，我们将研究这些基因座对免疫和临床参数的影响。我们最初的GWAS还建议欧洲人尚未发现风险基因座。此外，我们的样本量增加了两倍，总共有7,203个活检记录了IGAN病例和8,069个亚洲和欧洲血统的健康对照。因此，我们将在欧洲人群（1440例，1217个对照组）中进行第二次GWA，并在其余样品中复制，以鉴定新的Igan基因座并进一步定义了疾病的分子途径。最后，我们将在整个队列中完善并验证IGAN的遗传风险评分模型。这些研究将为Igan的发病机理提供洞察力，为这一主要原因的诊断和治疗工具提供新的机会。