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

描述（由申请方提供）：免疫球蛋白A（伊加）是免疫系统的重要组成部分，可提供针对粘膜病原体的局部防御。在由于呼吸道或胃肠道感染而具有活动性粘膜炎症的患者中经常观察到伊加的产生增加。伊加肾病（IgAN）患者中也观察到高水平的伊加，其通常与粘膜感染同时发生。IgAN是世界范围内最常见的原发性肾小球肾炎，在高达40%的病例中进展为终末期肾病。更具体地说，IgAN患者的IgA 1亚类水平升高，主要是半乳糖缺乏。一个可靠的凝集素为基础的生物标志物测定血清半乳糖缺乏型IgA 1（Gd-IgA 1）的定量已被开发和使用在我们的实验室。 我们以前已经证明了血清Gd-IgA 1的高遗传性（50-70%），表明该生物标志物部分由遗传决定。Gd-IgA 1促进含IgA 1免疫复合物的形成和系膜沉积。我们最近的研究表明，血清Gd-IgA 1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Gd-IgA 1水平经常出现在IgAN患者的无症状亲属，以及在一小部分明显健康的个人从一般人群。因此，我们推测，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-IgA 1的遗传原因目前尚不清楚。同样，目前尚不清楚高Gd-IgA 1水平的无症状个体在多大程度上有在以后的生活中发展为肾脏疾病的风险。 我们建议在三个具有良好功效的多种族前瞻性队列中对血清伊加、IgA 1和Gd-IgA 1水平进行严格的基于人群的分析，共计6,000人。我们将比较这些特征在不同种族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，我们将对血清伊加、IgA 1和Gd-IgA 1进行GWAS，以确定这些性状的共同遗传决定因素。我们将在其他可用的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.