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

描述(申请人提供)：老年性黄斑变性(AMD)是发达国家65岁及以上人群失明的主要原因。多条证据支持AMD发生的免疫学基础和遗传倾向。在这种背景下，编码在主要组织相容性复合体(MHC)和杀伤免疫球蛋白样受体(KIR)中的人类白细胞抗原(HLA)基因多态尤其令人感兴趣。HL A和KIR基因是人类基因组中最多态的基因之一，这些区域内的变异尚未被全面评估为AMD的危险因素。我们建议检验这样一种假设，即使用下一代大规模并行DNA测序的高通量测序方法综合分析的HLA和KIR基因座的遗传变异，分别和联合调节AMD的易感性(HLA-KIR上位症)。由于人类白细胞抗原和KIR区域的复杂性，包括全基因组关联研究在内的标准基因分型技术不能正确识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一些局限性，这些研究没有完全测试人类白细胞抗原和KIR的遗传变异，并忽略了KIR基因拷贝数作为遗传变异的一个来源。我们将使用为人类白细胞抗原和KIR开发的独特的实验室和统计方法，来解释这些区域内广泛的连锁不平衡(LD)。我们将在一项嵌套在骨质疏松性骨折(SOF)队列研究中的病例对照研究中，评估人类白细胞抗原和KIR序列与拷贝数变异和AMD之间的关联；这是一项基于人群的纵向研究。参与SOF-Eye研究的570名AMD患者和570名对照将进行人类白细胞抗原和KIR区的基因分型。结果将在855个病例和855个对照中复制，这些结果来自额外的人口和基于家庭的样本。与已经完成的招聘、面试和DNA收集的成本相比，基因分型的成本将是最低的。我们已经组建了一支由眼病遗传学、流行病学和人类白细胞抗原-KIR遗传学领域的顶尖科学家和专家组成的多元化团队。我们在人类白细胞抗原基因分型和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。了解人类白细胞抗原和KIR基因变异在AMD中的作用可能会识别AMD的风险个体，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觉结果。 公共卫生相关性：老年性黄斑变性(AMD)是发达国家65岁及以上人群失明的主要原因。该项目将评估人类白细胞抗原(HLA)和杀伤免疫球蛋白样受体(KIR)区域的遗传变异与AMD风险的关系。识别影响AMD风险的人类白细胞抗原和KIR变异可以建立AMD的生物标记物，并导致对改善老年人口的健康、生活质量和寿命具有非常显著影响的干预措施。

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.