Discovery and fine mapping of susceptibility loci for IgA nephropathy

描述(由申请人提供)：免疫球蛋白A肾病是全球肾衰竭的主要原因。它是亚洲人群中最常见的肾衰竭原因，也是高加索人中最常见的原发性肾小球肾炎。我们最近完成了对IgAN的全基因组关联研究，发现了1,194例中国汉族人和902名对照，并对中国队列和欧洲队列(1,950例和1,920名对照)进行了有针对性的随访。我们在Chr的主要组织相容性复合体(MHC)上发现了三个独立的基因座。6p21，CFHR1和CFHR3的共同缺失。1q32和Chr.22q12均超过全基因组意义(关联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)。这五个基因座可以解释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，我们建议对最近的IgAN全基因组关联研究(GWAS)进行后续研究，发现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来提炼新发现的五个风险基因座，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还表明，在欧洲人中存在尚未发现的风险基因。此外，我们的样本量增加了两倍，总共有7203例活检记录的IgAN病例和8069名亚洲和欧洲血统的健康对照。因此，我们将在欧洲人群中发现(1440例，1217例对照)，并在其余样本中复制，以确定新的IgAN基因座，并进一步确定疾病的分子途径。最后，我们将完善和验证全队列中IgAN的遗传风险评分模型。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): 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.