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

食物过敏很常见，代价很高，而且可能危及生命。流行病学研究表明流行率 正在增长，特别是在少数族裔人口中。双胞胎研究估计，食物过敏非常严重。 可遗传性(&gt；80%)，强调了遗传原因的重要性。到目前为止，只有几个 在这一发现中，对食物过敏的全基因组关联研究与非裔美国人或拉美裔美国人无关 准备好了。此外，这些研究中使用的表型也是不一致的。尽管存在这些问题，但 已经有一些一致的发现，例如反复发现与人类白细胞抗原(HL A)有关 基因。这并不完全令人惊讶，因为人类白细胞抗原蛋白在将抗原呈递给 效应器细胞，导致耐受或致敏。然而，我们识别因果变量的能力 人类白细胞抗原基因受到主要组织相容性复合体(MHC)区域结构复杂性的阻碍(即， 异常高度的多态、众多的假基因和远距离连锁 不平衡)。在这项应用中，我们采取了多方面的方法来更好地了解食物致敏作用， 食物过敏差异，以及潜在的风险因素。我们已经召集了三个不同的大型研究队列 (联合n=12,882)：按种族-民族对哮喘表型和药物基因组相互作用的研究 (蓝宝石)；对非裔美国人、哮喘、基因和环境的研究(SAGE)；以及基因- 拉美裔美国人的环境和混合体(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……里面 目标1，我们将利用IgE阵列来广泛表征94种不同食物和77种食物的过敏性致敏作用 过敏原成分。这些数据将使我们能够确定不同人群之间食物敏感度的差异 团体(即非洲裔美国人、拉丁裔[墨西哥人和波多黎各人]和欧洲裔美国人)和 评估社会环境暴露(例如，空气污染、烟草烟雾、 社区特征、围产期事件)和食物过敏原敏感性。在目标2中，我们将利用 目标1中要调查的大量和多样化的研究人群、现有的WGS和IgE敏感性数据 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 (例如，花生、海鲜、坚果、乳制品和鸡蛋)。相关关系将在一个大型儿科队列中复制 费城儿童医院。为了克服上述MHC区域的挑战，在 目的3我们提出了一种新的方法，它利用了短读dna测序(高保真)的优点。 以及超长阅读DNA测序的最新进展。由此产生的从头开始的、高分辨率的 MHC区域将被用来在大样本中寻找与食物致敏相关的人类白细胞抗原变异 来自蓝宝石(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 史无前例地研究人类白细胞抗原变异与海鲜和花生致敏之间的关系。

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.