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

说明(申请人提供)：免疫球蛋白A(IgA)是免疫系统的重要组成部分，提供对粘膜病原体的局部防御。呼吸道或胃肠道感染引起的活动性粘膜炎症患者常可观察到免疫球蛋白A的生成增加。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一致。IGAN是世界范围内最常见的原发性肾小球肾炎，高达40%的病例进展为终末期肾病。更具体地说，IgAN患者的IgA1亚类水平升高，主要是半乳糖缺乏。本实验室建立了一种可靠的基于凝集素的半乳糖缺陷型免疫球蛋白A1(Gd-IgA1)生物标志物检测方法。我们之前已经证明了血清Gd-IgA1的高遗传度(50-70%)，这表明这个生物标记物在一定程度上是由遗传决定的。Gd-IgA1促进含有IgA1的免疫复合体的形成和系膜沉积。我们最近的研究表明，血清Gd-IgA1水平升高也可能预测肾脏疾病的进展。此外，我们的数据显示，高Gd-IgA1水平经常出现在IgAN患者的无症状亲属中，以及普通人群中一小部分表面上健康的人。因此，我们推测这一缺陷可能代表了具有很强遗传成分的IgAN的定量危险因素，但其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，目前尚不清楚高Gd-IgA1水平的无症状个体在多大程度上有可能在以后的生活中患上肾脏疾病。我们建议对三个实力雄厚的多种族预期队列，总计6,000人，对血清IgA、IgA1和Gd-IgA1水平进行严格的基于人群的分析。我们将比较这些特征在不同种族的研究参与者中的分布。我们将研究它们与肾功能和心血管预后的关系。利用现有的全基因组SNP数据，我们将对血清IgA、IgA1和Gd-IgA1进行广义遗传分析，以确定这些特征的共同遗传决定因素。我们将在提供给我们的其他复制队列中验证我们的Gwas发现。

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.