High-resolution characterization of human leukocyte antigen genes in diverse populations to study the genetics of food allergy

对不同人群中的人类白细胞抗原基因进行高分辨率表征，以研究食物过敏的遗传学

• 批准号: 10665162
• 负责人: Keoki Williams
• 金额: $ 45万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10665162
• 关键词: 6p21; Admixture; Adult; Affect; African American; African American population; Air Pollution; Allergens; Allergic; American; Anaphylaxis; Antigenic Variation; Antigens; Anxiety; Asthma; Characteristics; Child; Code; Cohort Studies; Cytotoxic T-Lymphocytes; DNA sequencing; Data; Effector Cell; Emotional; Environment; Ethnic Origin; Ethnic group; European; Event; Family; Food; Food Hypersensitivity; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic study; Genotype; Goals; HLA Antigens; Helper-Inducer T-Lymphocyte; Heritability; Human Genome; Hypersensitivity; IgE; Immune; Immune Tolerance; Individual; Latino; Latino Population; Length; Life; Linkage Disequilibrium; Major Histocompatibility Complex; Maps; Measures; Mental Depression; Methods; Mexican; Minority Groups; Neighborhoods; Nuts; Participant; Pediatric Hospitals; Pediatric cohort; Perinatal; Pharmacogenomics; Phase; Phenotype; Philadelphia; Play; Population; Population Group; Population Heterogeneity; Prevalence; Proteins; Pseudogenes; Puerto Rican; Race; Reaction; Reporting; Resolution; Risk; Risk Factors; Role; Sampling; Seafood; Social Environment; Surveys; Symptoms; Technology; Telephone; Tobacco smoke; Trees; Twin Studies; Untranslated RNA; Variant; causal variant; cohort; cost; egg; epidemiology study; ethnic difference; food allergen; genetic risk factor; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic data; innovation; insight; multi-ethnic; non-genetic; novel; novel strategies; prevent; racial and ethnic; seafood hypersensitivity; social; study population; vigilance; whole genome

Food allergies are common, costly, and potentially life-threatening. Epidemiologic studies suggest prevalence is growing, particularly among minority populations. Twin studies estimate that food allergies are highly heritable (>80%), underscoring the importance of genetic causes. To date, there has been only a few genome-wide association studies of food allergy and none with African Americans or Latinos in the discovery set. Moreover, the phenotypes used in these studies have been inconsistent. Despite these issues, there have been some consistent findings, such as repeated associations with human leukocyte antigen (HLA) genes. This is not altogether surprising given the role that HLA proteins play in presenting antigens to effectors cells, resulting in either tolerance or sensitization. However, our ability to identify causal variants in HLA genes is hampered by the structural complexity of the major histocompatibility complex (MHC) region (i.e., an exceptionally high degree of polymorphism, numerous pseudogenes, and long-range linkage disequilibrium). In this application, we take a multifaceted approach to better understanding food sensitization, food allergy disparities, and the underlying risk factors. We have assembled three large, diverse study cohorts (combined n=12,882): the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE); the Study of African Americans, Asthma, Genes & Environment (SAGE); and the Genes- Environments & Admixture in Latino Americans (GALA II). These multi-ethnic cohorts have a wealth of existing socio-environmental exposure data and high-depth short-read whole-genome sequencing (WGS). In Aim 1, we will utilize IgE arrays to broadly characterize allergic sensitization for 94 different foods and 77 food allergen components. These data will allow us to identify differences in food sensitization between population groups (i.e., African Americans, Latinos [Mexicans and Puerto Ricans], and European Americans) and to assess the relationship between socio-environmental exposures (e.g., air pollution, tobacco smoke, neighborhood characteristics, and perinatal events) and food allergen sensitization. In Aim 2, we will leverage the large and diverse study population, existing WGS, and IgE sensitization data from Aim 1 to investigate for genetic variants associated with any food sensitization and sensitization to specific common food allergens (e.g., peanut, seafood, tree nut, dairy, and egg). Associations will be replicated in a large pediatric cohort from the Children’s Hospital of Philadelphia. To overcome the aforementioned challenges of the MHC region, in Aim 3 we propose a novel approach, which exploits the benefits of short-read DNA sequencing (high fidelity) and recent advances in ultra-long-read DNA sequencing. The resulting de novo, high-resolution assemblies of the MHC region will be used to look for HLA variants associated with food sensitization in a large sample of African American participants from SAPPHIRE (n=1,860) and SAGE (n=849). These data will provide an unprecedented look at the relationship between HLA variation and both seafood and peanut sensitization.

食物过敏是常见的，昂贵的，可能会威胁生命的。流行病学研究表明患病率 正在增长，尤其是在少数民族中。双研究估计食物过敏是高度的 可遗传的（> 80％），强调了遗传原因的重要性。迄今为止，只有少数 全基因组全基因组协会的食物过敏研究，与非洲裔美国人或拉丁美洲人无关 放。此外，这些研究中使用的表型并不一致。尽管存在这些问题， 已经是一致的发现，例如与人类白细胞抗原（HLA）的重复关联 基因。鉴于HLA蛋白在将抗原展示给 效应细胞，导致耐受性或灵敏度。但是，我们识别因果变异的能力 HLA基因受主要组织相容性复合物（MHC）区域的结构复杂性的阻碍（即 极高的多态性，众多的伪基和远程连接 dissequilibrium）。在此应用程序中，我们采用多方面的方法来更好地了解食物敏感性， 食物过敏分布以及潜在的风险因素。我们组装了三个大型潜水员研究队列 （组合n = 12,882）：种族种族对哮喘表型和药物相互作用的研究 （蓝宝石）;非裔美国人，哮喘，基因与环境（SAGE）的研究；和基因 - 拉丁美洲裔美国人的环境和混合物（晚会II）。这些多种族的队列有很多 现有的社会环境暴露数据和高深度的短阅读全基因组测序（WGS）。 AIM 1，我们将利用IGE阵列来广泛地表征94种不同食物和77种食物的过敏感应化 过敏原成分。这些数据将使我们能够确定人群之间食物敏感性的差异 团体（即非裔美国人，拉丁美洲人[墨西哥人和波多黎各人]和欧洲人）和 评估社会环境暴露之间的关系（例如，空气污染，烟草烟雾， 邻居特征和围产期事件）和食物过敏原敏感性。在AIM 2中，我们将利用 来自AIM 1的大型研究人群，现有的WGS和IGE灵敏度数据调查 与特定常见食物过敏原的任何食物敏感性和敏感性相关的遗传变异 （例如，花生，海鲜，树坚果，乳制品和鸡蛋）。协会将在大的儿科队列中复制 费城儿童医院。为了克服MHC地区的Priore需求挑战， AIM 3我们提出了一种新颖的方法，该方法利用了短阅读DNA测序的好处（高保真） 以及超长读取DNA测序的最新进展。最终的从头开始，高分辨率的组件 MHC区域将用于寻找与食物敏化相关的HLA变体。 来自蓝宝石（n = 1,860）和鼠尾草（n = 849）的非裔美国人参与者。这些数据将提供 前所未有的观察HLA变异与海鲜和花生敏感性之间的关系。