SURFACTANT PATHWAY GENE VARIANTS AMONG INFANTS WITH RESPIRATORY DISTRESS SYNDROME

呼吸窘迫综合征婴儿的表面活性剂途径基因变异

• 批准号: 8190268
• 负责人: Jennifer Wambach
• 金额: $ 12.55万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190268
• 关键词: 1 year old; ATP-Binding Cassette Transporters; Accounting; Adult; Affect; African; Age-Years; Algorithms; Alveolar; Biological; Biological Assay; Candidate Disease Gene; Cause of Death; Cells; Child; Clinical; Complex; Complex Mixtures; Computational algorithm; Computer software; Control Groups; Counseling; DNA; DNA Resequencing; Development; Diagnostic; Discipline of obstetrics; Disease; Ethnic Origin; Ethnic group; European; Frequencies; Gender; Genes; Genetic; Genetic Variation; Goals; Health; Healthcare; Heritability; Heterogeneity; In Vitro; Infant; Informed Consent; Laboratories; Linkage Disequilibrium; Linkage Disequilibrium Mapping; Logic; Mentors; Metabolism; Methods; Missouri; Modeling; Morbidity - disease rate; Mutation; Newborn Infant; Newborn Respiratory Distress Syndrome; Outcome; Pathway interactions; Phenotype; Phospholipids; Production; Proteins; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactant-Associated Protein C; Pulmonary Surfactants; Regression Analysis; Reporting; Research; Research Personnel; Resolution; Risk; Sampling; Surface Tension; System; Technology; Testing; Therapeutic; Time Management; Training; Translating; Twin Studies; United States; Variant; Work; alveolar type II cell; base; career; case control; clinical care; cohort; cost; experience; expiration; fitness; genetic epidemiology; genetic variant; genome wide association study; improved; mortality; next generation; novel; novel diagnostics; novel therapeutics; population based; reproductive; respiratory; respiratory distress syndrome; skills; surfactant; tool

DESCRIPTION (provided by applicant): Neonatal respiratory distress syndrome (RDS) is the most common respiratory cause of mortality and morbidity among infants in the United States. While RDS is most commonly attributed to a developmental immaturity of pulmonary surfactant production, a genetic mechanism is suggested by studies of twins, ethnicity, gender, and lethal mutations in surfactant-related genes (SFTPB, SFTPC, and ABCA3). Prior research to define the genetic mechanisms underlying neonatal RDS has focused on common genetic variants within single candidate genes and explains only a small proportion of disease heritability. Research in complex adult diseases that reduce reproductive fitness suggests that combinations of rare, highly penetrant variants in multiple genes account for disease heritability. Our laboratory has identified statistical and functional associations of rare variants in surfactant-related genes with neonatal RDS. The goals of this proposal are to identify gene loci with excess, rare, functional variants that statistically account for the missing heritability of RDS and to develop methods to test the biologic mechanisms by which genetic variants disrupt surfactant metabolism. First, we will use next generation sequencing to determine the population-based frequencies of rare genetic variants among five surfactant-related genes (SFTPC, ABCA3, LPCAT, CHPT, and PCYT1B) using 1,116 infant samples obtained from the Missouri Department of Health. Second, we will determine whether excess, rare, functionally disruptive variants in these five genes are overrepresented among infants with RDS compared to infants without RDS in already available DNA samples with informed consent (N=940 infants of African and European descent). Third, we will use cell-based functional assays to investigate the underlying biologic mechanisms of these disruptive variants. This comprehensive research strategy is novel because we will study candidate genes with higher resolution, use software based algorithms to assess variant functionality, use traditional (regression) and novel (Collapsing Methods, BimBam, logic regression) statistical approaches to evaluate variant interactions, and use cell-based assays to study the functionality of identified variants and combinations of variants. The development of cell-based assays will permit mechanistic study of variants identified through statistical associations and provide the basis for the long-term development of diagnostic and therapeutic approaches for affected infants. The combination of my clinical experience, prior didactic and mentored training in genetic epidemiology, and an integrated training plan that allows me to develop skills in the use of surrogate cell systems will enable me to develop into an independent investigator that can bridge statistical observation with functional mechanism and translate these findings into specific therapeutic approaches for infants with RDS. PUBLIC HEALTH RELEVANCE: Respiratory distress syndrome (RDS) is the most frequent respiratory cause of death and morbidity in infants less than 1 year of age in the United States; studies of ethnic groups, gender, and clinical reports of single gene causes of lethal neonatal RDS strongly suggest that genetic mechanisms contribute to the risk for RDS. This proposal will discover statistical and functional associations and interactions between/among five pulmonary surfactant-related genes with risk for neonatal RDS. Understanding the genetic mechanisms that underlie RDS is critical for improving outcomes of children in the United States and reducing the costs of their health care.

描述（由申请人提供）：新生儿呼吸窘迫综合征 (RDS) 是美国婴儿死亡和发病的最常见呼吸系统原因。虽然 RDS 最常见的原因是肺表面活性物质产生的发育不成熟，但对双胞胎、种族、性别和表面活性剂相关基因（SFTPB、SFTPC 和 ABCA3）的致命突变的研究提示了一种遗传机制。先前定义新生儿 RDS 遗传机制的研究主要集中在单个候选基因内的常见遗传变异，并且仅解释了一小部分疾病遗传性。对降低生殖健康的复杂成人疾病的研究表明，多个基因中罕见、高渗透性变异的组合导致了疾病的遗传性。我们的实验室已经确定了表面活性剂相关基因的罕见变异与新生儿 RDS 的统计和功能关联。 该提案的目标是识别具有过量、罕见的功能变异的基因位点，这些变异在统计上解释了 RDS 遗传性的缺失，并开发方法来测试遗传变异破坏表面活性剂代谢的生物学机制。首先，我们将使用从密苏里州卫生部获得的 1,116 个婴儿样本，利用下一代测序来确定五个表面活性剂相关基因（SFTPC、ABCA3、LPCAT、CHPT 和 PCYT1B）中罕见遗传变异的人群频率。其次，我们将确定在知情同意的现有 DNA 样本中（N = 940 名非洲和欧洲血统婴儿），与无 RDS 的婴儿相比，这 5 个基因中过量、罕见、功能破坏性变异是否在 RDS 婴儿中出现过多。第三，我们将使用基于细胞的功能测定来研究这些破坏性变异的潜在生物学机制。 这种综合研究策略是新颖的，因为我们将以更高分辨率研究候选基因，使用基于软件的算法来评估变异功能，使用传统（回归）和新颖（折叠方法、BimBam、逻辑回归）统计方法来评估变异相互作用，并使用基于细胞的检测，用于研究已识别变体和变体组合的功能。基于细胞的检测的发展将允许对通过统计关联确定的变异进行机制研究，并为受影响婴儿的诊断和治疗方法的长期开发提供基础。我的临床经验、先前在遗传流行病学方面的教学和指导培训，以及使我能够培养使用替代细胞系统的技能的综合培训计划相结合，将使我能够发展成为一名独立调查员，能够将统计观察与功能联系起来。机制并将这些发现转化为 RDS 婴儿的具体治疗方法。 公共卫生相关性：呼吸窘迫综合征 (RDS) 是美国 1 岁以下婴儿死亡和发病最常见的呼吸系统原因；对种族、性别的研究以及致死性新生儿 RDS 的单基因原因的临床报告强烈表明，遗传机制会导致 RDS 的风险。该提案将发现五个肺表面活性物质相关基因与新生儿 RDS 风险之间的统计和功能关联以及相互作用。了解 RDS 背后的遗传机制对于改善美国儿童的预后和降低其医疗保健成本至关重要。