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、昂贵的且可能危及生命的流行病学研究表明其普遍存在。 正在增长，特别是在少数族群中，双胞胎研究估计食物过敏率很高。 遗传性（>80%），强调了遗传原因的重要性，迄今为止，只有少数原因。 食物过敏的全基因组关联研究，但没有发现与非裔美国人或拉丁美洲人相关的研究 此外，尽管存在这些问题，但这些研究中使用的表型仍然不一致。 一些发现是一致的，例如与人类白细胞抗原（HLA）的重复关联 考虑到 HLA 蛋白在呈递抗原中所发挥的作用，这并不完全令人惊讶。 效应细胞，导致耐受或致敏，然而，我们有能力因果地识别变异。 HLA 基因受到主要组织相容性复合体 (MHC) 区域（即， 异常高度的多态性、大量假基因和长程连锁 不平衡）。在此应用中，我们采取多方面的方法来更好地了解食物过敏， 我们收集了三个大型、多样化的研究队列。 （合并 n=12,882）：按种族-民族划分的哮喘表型和药物基因组相互作用的研究 （SAPPHIRE）；非裔美国人、哮喘、基因与环境研究（SAGE）； 拉丁美洲人的环境与混合（GALA II）。这些多种族群体拥有丰富的知识。 现有的社会环境暴露数据和深度短读长全基因组测序（WGS）。 目标 1，我们将利用 IgE 阵列广泛表征 94 种不同食物和 77 种食物的过敏致敏性 这些数据将使我们能够确定人群之间食物过敏的差异。 群体（即非裔美国人、拉丁裔[墨西哥人和波多黎各人]和欧洲裔美国人） 评估社会环境暴露之间的关系（例如空气污染、烟草烟雾、 在目标 2 中，我们将利用（社区特征和围产期事件）和食物过敏原致敏。 来自目标 1 的大量且多样化的研究人群、现有的 WGS 和 IgE 致敏数据，用于调查 与任何食物过敏和对特定常见食物过敏原过敏相关的遗传变异 （例如，花生、海鲜、木本坚果、乳制品和鸡蛋的关联将在大型儿科队列中复制）。 费城儿童医院 为了克服 MHC 地区的挑战， 目标 3 我们提出了一种新方法，该方法利用短读长 DNA 测序（高保真度）的优势 以及超长读长 DNA 测序的最新进展。 MHC 区域将用于在大量样本中寻找与食物过敏相关的 HLA 变异 来自 SAPPHIRE (n=1,860) 和 SAGE (n=849) 的非裔美国参与者这些数据将提供一个结果。 对 HLA 变异与海鲜和花生过敏之间的关系进行了前所未有的研究。