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: 8143431
• 负责人: Gregory J. Tranah
• 金额: $ 58.15万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8143431
• 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. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the leading cause of blindness in persons 65 years of age and older in the developed world. This project will assess the role of genetic variation in the human leukocyte antigen (HLA) and killer immunoglobulin-like receptor (KIR) regions in relation to AMD risk. Identifying HLA and KIR variants that impact AMD risk could establish biomarkers for AMD and lead to interventions that have a very significant impact on improving health, quality of life and longevity on the elderly population.

描述（由申请人提供）：与年龄相关的黄斑变性（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处理。在这种情况下，人类白细胞抗原（HLA）多态性在主要的组织相容性复合物（MHC）和杀手型免疫球蛋白样受体（KIR）中尤为有趣。 HLA和KIR基因是人类基因组中最多的多态性，这些区域内的变异尚未被全面评估为AMD的危险因素。 我们建议测试以下假设：HLA和KIR基因座的遗传变异，使用下一代高通量测序方法对大量平行的DNA测序进行了全面测定，调节了单独和组合AMD的易感性（HLA-KIR EPISTASIS）。由于HLA和KIR区域的复杂性，包括基因组广泛关联研究在内的标准基因分型技术无法正确识别这些地区对疾病易感性的贡献。我们的方法将克服先前的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。我们将采用针对HLA和KIR开发的独特实验室和统计方法，这些方法是这些区域内广泛的连锁不平衡（LD）。 我们将评估HLA和KIR序列与拷贝数变化与AMD之间的关联，并在嵌套在骨质疏松骨折研究（SOF）同时的病例对照研究中；一项基于人群的纵向研究。 HLA和KIR区域将从570例AMD病例和570个参与SOF-EYE研究的对照中进行基因分型。结果将在855例病例和855个对照中复制，来自其他人群和基于家庭的样本。与已经完成的招聘，访谈和DNA收集成本相比，基因分型成本将是最低的。我们组建了一个领先的科学家和专家团队，这些团队在眼部疾病，流行病学和HLA-KIR遗传学方面。我们对HLA和KIR基因分型的经验使我们能够为处理数据的基因分型技术和数据库制定质量控制措施。 了解HLA和KIR遗传变异在AMD中的作用可能鉴定出有AMD风险的个体，并最终导致有机会通过精确的药理手段调节这些途径，从而改善这种破坏性疾病的视觉结果。 公共卫生相关性：与年龄相关的黄斑变性（AMD）是发达国家65岁及以上人群失明的主要原因。该项目将评估遗传变异在人类白细胞抗原（HLA）和杀手型免疫球蛋白样受体（KIR）区域与AMD风险有关的作用。确定影响AMD风险的HLA和KIR变体可以为AMD建立生物标志物，并导致干预措施对改善健康，生活质量和寿命对老年人口产生非常重大的影响。