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

食物过敏是常见的，昂贵的，并可能危及生命。流行病学研究表明， 尤其是在少数民族中。双胞胎研究估计，食物过敏是高度 遗传性（>80%），强调遗传原因的重要性。到目前为止，只有少数 食物过敏的全基因组关联研究，没有发现非洲裔美国人或拉丁美洲人 集此外，这些研究中使用的表型不一致。尽管存在这些问题， 已经有一些一致的发现，如与人类白细胞抗原（HLA）的重复关联 基因.考虑到HLA蛋白在将抗原呈递给人中所起的作用，这并不奇怪。 效应细胞，导致耐受或致敏。然而，我们识别因果变异的能力， HLA基因受到主要组织相容性复合体（MHC）区域的结构复杂性（即， 异常高度的多态性、大量的假基因和长距离连锁 不平衡）。在这个应用程序中，我们采取多方面的方法来更好地理解食物致敏， 食物过敏差异和潜在的风险因素。我们已经组建了三个大型、多样化的研究队列 （合并n= 12，882）：不同种族的哮喘表型和药物基因组学相互作用研究 （SAPPHIRE）;非裔美国人，哮喘，基因和环境研究（SAGE）;和基因- 拉丁美洲人的环境与混合物（GALA II）。这些多民族群体拥有丰富的 现有的社会环境暴露数据和高深度短读全基因组测序（WGS）。在 目的1，我们将利用IgE芯片广泛表征94种不同食物和77种食物的过敏性致敏性。 过敏原成分。这些数据将使我们能够确定不同人群之间的食物致敏性差异 组（即，非洲裔美国人、拉丁美洲人[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， 邻里特征和围产期事件）和食物过敏原致敏。在目标2中， 来自目标1的大型和多样化的研究人群、现有WGS和IgE致敏数据，以研究 与任何食物致敏和对特定常见食物过敏原致敏相关的遗传变异 (e.g.,花生、海鲜、树坚果、乳制品和鸡蛋）。相关性将在一个大型儿科队列中进行复制， 费城儿童医院为了克服MHC区域的上述挑战， 目的3：我们提出了一种新的方法，它利用了短读段DNA测序（高保真）的好处。 以及超长读段DNA测序的最新进展由此产生的从头，高分辨率的组装， MHC区域将用于在大样本中寻找与食物致敏相关的HLA变体， 来自SAPPHIRE（n= 1，860）和SAGE（n=849）的非裔美国人参与者。这些数据将提供一个 这是一个前所未有的关于HLA变异与海鲜和花生致敏之间关系的研究。

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.