Population-based study of serum IgA, IgA1, and galactose-deficient IgA1 levels

描述（由申请人提供）：免疫球蛋白A （IgA）是免疫系统的重要组成部分，提供针对粘膜病原体的局部防御。在呼吸道或胃肠道感染引起的活动性粘膜炎症患者中经常观察到IgA的产生增加。在IgA肾病（IgAN）患者中也观察到高水平的IgA，这通常与粘膜感染相吻合。IgAN是世界范围内原发性肾小球肾炎最常见的形式，高达40%的病例发展为终末期肾病。更具体地说，IgAN患者的IgA1亚类水平升高，主要是半乳糖缺乏。我们的实验室已经开发并使用了一种可靠的基于凝集素的生物标志物测定血清半乳糖缺乏IgA1 （Gd-IgA1）。我们之前已经证明了血清Gd-IgA1的高遗传率（50-70%），这表明这种生物标志物在一定程度上是由遗传决定的。Gd-IgA1促进含有IgA1的免疫复合物的形成和系膜沉积。我们最近的研究表明，血清中Gd-IgA1水平升高也可能预测肾脏疾病的进展。此外，我们的数据表明，高水平的Gd-IgA1经常出现在IgAN患者的无症状亲属中，以及一小部分从一般人群中明显健康的个体中。因此，我们假设这种缺陷可能是IgAN的一个定量危险因素，具有很强的遗传成分，但它本身不足以引起肾炎。高Gd-IgA1的遗传原因目前尚不清楚。同样，目前尚不清楚无症状的高水平Gd-IgA1个体在以后的生活中患肾脏疾病的风险有多大。我们建议在三个多民族前瞻性队列中进行严格的基于人群的血清IgA、IgA1和Gd-IgA1水平分析，共6000人。我们将比较这些特征在不同种族的研究参与者之间的分布。我们将研究它们与肾功能和心血管结局的关系。利用现有的全基因组SNP数据，我们将对血清IgA、IgA1和Gd-IgA1进行GWAS，以确定这些性状的共同遗传决定因素。我们将在其他可获得的复制队列中验证我们的GWAS结果。

DESCRIPTION (provided by applicant): Immunoglobulin A (IgA) is an important component of the immune system that provides local defense against mucosal pathogens. Increased production of IgA is frequently observed in patients with active mucosal inflammation due to respiratory or gastrointestinal infections. High levels of IgA are also observed in patients with IgA nephropathy (IgAN), which commonly coincides with mucosal infections. IgAN is the most common form of primary glomerulonephritis worldwide and progresses to end-stage renal disease in up to 40% of cases. More specifically, individuals with IgAN have elevated levels IgA1 subclass that is predominantly galactose-deficient. A reliable lectin-based biomarker assay for quantification of serum galactose-deficient IgA1 (Gd-IgA1) has been developed and used in our laboratory. We have previously demonstrated high heritability of serum Gd-IgA1 (50-70%), suggesting that this biomarker is, in part, genetically determined. Gd-IgA1 promotes formation and mesangial deposition of IgA1- containing immune complexes. Our recent study suggests that elevated serum levels of Gd-IgA1 may also predict renal disease progression. Moreover, our data demonstrate that high Gd-IgA1 levels are frequently present in asymptomatic relatives of patients with IgAN, as well as in a fraction of apparently healthy individuals from the general population. Therefore, we postulate that this defect may represent a quantitative risk factor for IgAN with a strong genetic component, but by itself it is insufficient to cause nephritis. The genetic causes of high Gd-IgA1 are currently not known. Similarly, it is not known to what degree the asymptomatic individuals with high Gd-IgA1 levels are at risk of developing kidney disease later in life. We propose to perform a rigorous population-based analysis of serum IgA, IgA1, and Gd-IgA1 levels in three well-powered multi-ethnic prospective cohorts, totaling 6,000 individuals. We will compare the distributions of these traits between different ethnicities of study participants. We will examine their association with renal function and cardiovascular outcomes. Utilizing available genome-wide SNP data, we will perform a GWAS for serum IgA, IgA1, and Gd-IgA1 to identify common genetic determinants of these traits. We will validate our GWAS findings in additional replication cohorts available to us.