Immune Response Gene Polymorphisms and AMD: Examining HLA-KIR Epistasis

免疫反应基因多态性和 AMD：检查 HLA-KIR 上位性

• 批准号: 8541859
• 负责人: Gregory J. Tranah
• 金额: $ 23.49万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541859
• 关键词: Accounting; Age related macular degeneration; Age-Years; Alleles; Biological Assay; Biological Markers; Blindness; Collection; Copy Number Polymorphism; DNA; DNA Sequence; Databases; Development; Disease; Disease susceptibility; Elderly; Epidemiology; Eye; Eye diseases; Family; Functional disorder; Gene Dosage; Genes; Genetic; Genetic Epistasis; Genetic Polymorphism; Genetic Variation; Genotype; HLA Antigens; Haplotypes; Health; Human Genome; Immune Response Genes; Immune response; Immunologics; Individual; Intervention; Interview; Laboratories; Lead; Ligands; Linkage Disequilibrium; Longevity; Major Histocompatibility Complex; Measures; Methods; Natural Killer Cells; Nested Case-Control Study; Outcome; Pathway interactions; Persons; Population; Positioning Attribute; Predisposition; Quality Control; Quality of life; Receptor Gene; Reporting; Risk; Risk Factors; Role; Sampling; Sampling Studies; Scientist; Single Nucleotide Polymorphism; Source; Statistical Methods; System; Techniques; Testing; Variant; Visual; base; cohort; computerized data processing; cost; design; experience; genome wide association study; genotyping technology; improved; interest; killer immunoglobulin-like receptor; neglect; next generation; osteoporosis with pathological fracture; population based; public health relevance; receptor; response

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of blindness in persons 65 years of age and older in the developed world. Multiple lines of evidence support an immunologic basis and genetic disposition for the development of AMD. In this context, human leukocyte antigen (HLA) polymorphisms, encoded within the major histocompatibility complex (MHC), and killer immunoglobulin-like receptors (KIR) are of particular interest. HLA and KIR genes are among the most polymorphic within the human genome and variation within these regions has not been comprehensively assessed as a risk factor for AMD. We propose to test the hypothesis that genetic variation at the HLA and KIR loci, comprehensively assayed using next generation high-throughput sequencing methods for massively parallel DNA sequencing, modulate susceptibility to AMD both individually and in combination (HLA-KIR epistasis). Because of the complexity of the HLA and KIR regions, standard genotyping techniques including genome- wide association studies do not properly discern the contribution of these regions to disease susceptibility. Our approach will overcome some of the limitations of previous association studies that have incompletely tested HLA and KIR genetic variation and neglected KIR gene copy number as a source of genetic variation. We will employ unique laboratory and statistical methods developed for HLA and KIR that account for the extensive linkage disequilibrium (LD) within these regions. We will assess the association between HLA and KIR sequence and copy number variation and AMD in a case-control study nested within the Study of Osteoporotic Fractures (SOF) cohort; a longitudinal, population-based study. The HLA and KIR regions will be genotyped from 570 AMD cases and 570 controls participating in the SOF-Eye study. Results will be replicated in 855 cases and 855 controls from additional population and family-based samples. The genotyping costs will be minimal compared to the costs of recruitment, interviewing, and DNA collection that already have been accomplished. We have assembled a diverse team of leading scientists and experts in the genetics of eye disease, epidemiology, and HLA-KIR genetics. Our experience with the HLA and KIR genotyping has allowed us to develop quality control measures for the genotyping technologies and databases for processing the data. Understanding the role of HLA and KIR genetic variation in AMD may identify individuals at risk for AMD and ultimately lead to opportunities to modulate these pathways by precise pharmacological means and thus improve visual outcomes in this devastating disease.

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是发达国家65岁及以上人群失明的主要原因。多种证据支持AMD发展的免疫学基础和遗传倾向。在这种情况下，人类白细胞抗原（HLA）多态性，编码内的主要组织相容性复合体（MHC），和杀伤免疫球蛋白样受体（KIR）是特别感兴趣的。HLA和KIR基因是人类基因组中最具多态性的基因之一，这些区域内的变异尚未被全面评估为AMD的风险因素。 我们建议测试的假设，在HLA和KIR基因座的遗传变异，全面分析使用下一代高通量测序方法的大规模并行DNA测序，调节AMD的易感性，无论是单独和组合（HLA-KIR上位性）。由于HLA和KIR区域的复杂性，包括全基因组关联研究的标准基因分型技术不能正确辨别这些区域对疾病易感性的贡献。我们的方法将克服以前的关联研究的局限性，不完全测试HLA和KIR遗传变异和忽略KIR基因拷贝数作为遗传变异的来源。我们将采用为HLA和KIR开发的独特的实验室和统计方法，这些方法解释了这些区域内广泛的连锁不平衡（LD）。 我们将评估HLA和KIR序列和拷贝数变异与AMD之间的关联，这是一项嵌套在骨质疏松性骨折研究（SOF）队列中的病例对照研究;一项纵向的、基于人群的研究。HLA和KIR区域将从参与SOF-Eye研究的570例AMD病例和570例对照中进行基因分型。结果将在来自额外人群和基于家庭的样本的855例病例和855例对照中重复。与已经完成的招募、面试和DNA收集的成本相比，基因分型的成本将是最低的。我们组建了一个由眼科疾病遗传学、流行病学和HLA-KIR遗传学领域的领先科学家和专家组成的多元化团队。我们在HLA和KIR基因分型方面的经验使我们能够为基因分型技术和数据库开发质量控制措施，以处理数据。 了解HLA和KIR遗传变异在AMD中的作用可以识别AMD风险个体，并最终导致通过精确的药理学手段调节这些途径的机会，从而改善这种毁灭性疾病的视力结果。