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

基本信息

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
项目类别：
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

项目摘要

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）：年龄相关性黄斑变性 (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 发生的免疫学基础和遗传倾向。在这种情况下，主要组织相容性复合物（MHC）内编码的人类白细胞抗原（HLA）多态性和杀伤性免疫球蛋白样受体（KIR）特别令人感兴趣。 HLA 和 KIR 基因是人类基因组中多态性最高的基因之一，这些区域内的变异尚未被全面评估为 AMD 的危险因素。我们建议检验以下假设：使用下一代高通量测序方法进行大规模并行 DNA 测序进行全面分析，HLA 和 KIR 位点的遗传变异可单独或组合调节 AMD 易感性（HLA-KIR 上位性）。由于 HLA 和 KIR 区域的复杂性，标准基因分型技术（包括全基因组关联研究）无法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关联研究的一些局限性，这些研究未完全测试 HLA 和 KIR 遗传变异，并忽略了 KIR 基因拷贝数作为遗传变异的来源。我们将采用为 HLA 和 KIR 开发的独特实验室和统计方法，解释这些区域内广泛的连锁不平衡 (LD)。我们将在骨质疏松性骨折研究 (SOF) 队列中的病例对照研究中评估 HLA 和 KIR 序列以及拷贝数变异与 AMD 之间的关联；一项基于人群的纵向研究。将对参与 SOF-Eye 研究的 570 名 AMD 病例和 570 名对照者进行 HLA 和 KIR 区域的基因分型。结果将在来自其他人群和家庭样本的 855 个病例和 855 个对照中得到复制。与已经完成的招聘、面试和 DNA 采集的成本相比，基因分型成本将是最低的。我们组建了一支多元化的团队，由眼病遗传学、流行病学和 HLA-KIR 遗传学领域的顶尖科学家和专家组成。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用于处理数据的数据库开发质量控制措施。了解 HLA 和 KIR 遗传变异在 AMD 中的作用可能会识别出有 AMD 风险的个体，并最终有机会通过精确的药理学手段调节这些途径，从而改善这种破坏性疾病的视力结果。