Mannose-Binding Lectin Haplotypes and Infection Risk

描述(申请人提供)：甘露糖结合凝集素(MBL)通过识别多种病原体表面的糖部分，在先天性免疫反应中发挥重要作用。MBL结合以非抗体依赖的方式通过调节和/或激活补体途径而导致破坏。因此，MBL缺乏与许多免疫相关疾病有关，包括类风湿性关节炎、系统性红斑狼疮，以及儿童和免疫功能低下的成年人的严重感染。此外，几种疾病的进展，包括囊性纤维化、肝炎、BIC和HIV，也与MBL的表达有关。MBL的转录和功能活性取决于基因的多态和它们的时相或单倍型构型。因此，能够轻松而廉价地确定个体的MBL单倍型将有助于在MBL与疾病易感性和疾病进展之间建立更强的联系，并有助于诊断测试的开发。这项第一阶段的提案应用PolyGenyx的新的分子SNP单倍型方法来开发一种高通量的MBL基因12个多态的分析方法。目前，还没有其他方法可以对SNP基因座进行简单、可靠、准确的高通量单倍型分析。第二阶段研究有望将个体的MBL单倍型与感染风险联系起来。 由于受MBL影响的疾病种类繁多，单倍型分析的潜在商业应用是多样化的，并且在经济上具有吸引力。例如，类风湿性关节炎每年对经济的影响估计为150亿美元的直接医疗成本和600亿美元的间接成本。对于每种疾病，评估患者的MBL状态将是非常有益的。单倍型结构预测疾病/感染风险增加的患者可以采取几个步骤来降低这种风险，改善他们的生活质量，并减少对社会的总体经济影响。

DESCRIPTION (provided by applicant): Mannose-binding lectin (MBL) plays an important role in the innate immune response via its ability to recognize sugar moieties on the surfaces of a great variety of pathogens. MBL binding leads to destruction by opsonization and/or activation of the complement pathway in an antibody-independent manner. Thus, MBL deficiency has been associated with numerous immune-related diseases including rheumatoid arthritis, systemic lupus erythematosus, and severe infections in children and immunocompromised adults. In addition, the progression of several diseases, including cystic fibrosis, hepatitis BIC and HIV, are also associated with MBL expression. The transcription and functional activity of MBL depend upon polymorphisms within the gene and their phase or haplotypic configuration. Therefore, the ability to easily and inexpensively determine an individual's MBL haplotype would help establish a stronger link between MBL and disease susceptibility and progression, and aid in the development of a diagnostic test. This Phase I proposal applies PolyGenyx's novel molecular SNP haplotyping approach to developing a highthroughput assay for 12 polymorphisms within the MBL gene. Currently, no other method allows simple, reliable, accurate high-throughput haplotyping of SNP loci. Phase II studies are expected to associate an individual's MBL haplotype with risk of infection. Due to the wide variety of diseases influenced by MBL, the potential commercial applications for a haplotyping assay are diverse and economically attractive. For instance, the annual economic impact of rheumatoid arthritis is estimated at $15B in direct medical costs and $60B in indirect costs. For each disease, evaluating the patient's MBL status would be extremely beneficial. Patients with a haplotypic configuration predicting increased risk of disease/infection could undergo several steps to reduce this risk, improve their quality of life, and reduce the total economic impact to society.