Discovery and fine mapping of susceptibility loci for IgA nephropathy

描述（由申请人提供）：免疫球蛋白A肾病是世界范围内肾衰竭的主要原因。它是亚洲人群肾衰竭最常见的原因，也是高加索人群原发性肾小球肾炎最常见的形式。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1194例和902例对照中发现了IgAN，并对中国队列和欧洲队列（1950例和1920例对照）进行了有针对性的随访。我们在Chr. 6p21的主要组织相容性复合体（MHC）中发现了三个独立的位点，Chr. 1q32的CFHR1和CFHR3的共同缺失和Chr. 22q12的位点，每个位点都超过了全基因组显著性（关联的p值在1.6 × 10-26和4.8 × 10-9之间，次要等位基因优势比为0.63-0.80）。这5个基因座解释了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IgAN全基因组关联研究（GWAS），该研究发现了五个新的易感位点。我们建议使用免疫芯片、靶向基因分型和MPLA来完善这五个新发现的风险位点，以确定潜在的功能变异。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也表明欧洲人有尚未发现的风险位点。此外，我们的样本量增加了两倍，共有7203例活检记录的IgAN病例和8069例亚洲和欧洲血统的健康对照。因此，我们将在欧洲人群（1440例病例，1217例对照）中进行第二次GWAS，并在其余样本中进行复制，以确定新的IgAN位点，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): 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.