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

• 批准号: 9129496
• 负责人: ALI G GHARAVI
• 金额: $ 45.48万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129496
• 关键词: 17p13; 1q32; 22q12; 6p21; Address; Alleles; Antigen-Antibody Complex; Asians; Biological Assay; Biopsy; Caucasians; Cells; Characteristics; Chinese People; Clinical; Collaborations; Complex; Data; Deposition; Development; Diagnostic; Disease; European; Gene Frequency; Genetic Risk; Genetic study; 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; Prevalence; Research Personnel; Risk; Sample Size; Sampling; Serum; Signal Transduction; Susceptibility Gene; 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

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（由申请方提供）：免疫球蛋白A肾病是全球肾衰竭的主要原因。它是亚洲人群中肾衰竭的最常见原因，也是高加索人中原发性肾小球肾炎的最常见形式。我们最近完成了IgAN的全基因组关联研究（GWAS），在中国汉族血统的1，194例病例和902例对照中发现，并在中国队列和欧洲队列（1，950例病例和1，920例对照）中进行了有针对性的随访。我们在主要组织相容性复合体（MHC）的Chr. 6p 21上确定了三个独立的基因座，在Chr. 1 q32上CFHR 1和CFHR 3的共同缺失，以及在Chr. 22 q12上的一个基因座，每个基因座都超过了全基因组显著性（相关性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）。这五个位点解释了4-7%的疾病变异和高达10倍的个体间风险变异。 在这项研究中，我们建议跟进最近的全基因组关联研究（GWAS）的IgA肾病，其中确定了五个新的易感基因座。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，以确定潜在的功能变体。接下来我们将研究这些基因座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，我们将在欧洲人群（1440例，1217例对照）中进行第二次GWAS发现，并在剩余样本中进行复制，以确定新的IgAN基因座，并进一步确定疾病的分子途径。最后，我们将在整个队列中完善和验证IgAN的遗传风险评分模型。这些研究将为IgAN的发病机制提供深入了解，为开发肾衰竭这一主要原因的诊断和治疗工具提供新的机会。