Genetic ancestry differences in IgE- mediated peanut allergy in African Americans

摘要 食物过敏(FA)的负担在少数族裔儿童中不成比例地高，特别是流行率 非洲裔美国人(AA)的FA是欧洲裔美国人(EA)儿童的4倍。花生过敏(PA)是 最常见和最严重的FA形式。就像在总体而言，PA在AA之间表现出相同的种族差异 和EA。尽管人们对遗传血统在PA风险中的作用达成了普遍共识，但 血统对种族差异的影响或解释在很大程度上仍然不为人知。我们的长期目标是确定 混合AA儿童中导致总IgE差异和花生特异性IgE差异的遗传祖先决定因素。 我们的总体目标是确定花生特异性IgE风险在多大程度上由遗传祖先决定 AA混血个体具有不同的非洲血统比例。我们的表型良好的PA队列收集了 DNA样本，以及包含定制SNP集的高密度全基因组多种族全局阵列(MEGA) 向混合血统发展为识别特定血统的PA风险变异提供了一个独特的机会。我们 假设非洲血统和欧洲血统中等位基因频率差异较大的遗传变异 人口可能是目前PA风险差异的部分原因。提出了两个具体目标，以 测试我们的假设并实现我们提出的计划：目标1)确定基因祖先和行为 使用多种族基因分型阵列的混合作图；以及目标2)复制AM中最有希望的变体 使用独立复制队列的高峰区。拟议的研究具有非常重要的意义(考虑到 AA儿童的PA负担)和高度创新(这是第一个混合分析)来揭开基因 与PA相关的祖先特有的风险变量。最重要的是，结果将针对少数族裔人口 并将有助于我们了解和早期预测、诊断和治疗PA-a路线图 走向精准诊断。因此，我们相信，这项研究以及未来的研究将揭示根本 关于遗传血统是否会影响PA风险和预测的信息，从而减轻PA的负担 对患者及其家人的关注，并提高他们的生活质量。 1

Abstract The burden of food allergy (FA) is disproportionately high among minority children, in particular the prevalence of FA is 4 times higher in African American (AA) than European American (EA) children. Peanut allergy (PA) is the most common and serious form of FA. As in FA in general, PA exhibits the same racial disparity between AA and EA. Although there is a general consensus about the role of genetic ancestry in PA risk, the extent to which ancestry contributes or explains racial disparities remains largely unknown. Our long-term goal is to determine genetic ancestry determinants that contribute to total and peanut specific IgE disparities in admixed AA children. Our overall objective is to determine to what extent peanut specific IgE risk is determined by genetic ancestry in AA admixed individuals with varying African ancestry proportion. Our well-phenotyped PA cohorts with collected DNA samples, and high-density genome-wide Multi-Ethnic Global Array (MEGA) that contains SNP sets tailored towards admixed ancestry presents a unique opportunity to identify ancestry-specific PA risk variants. We hypothesize that genetic variants with large allele frequency differences between African and European ancestry population may be partly responsible for the current difference in PA risk. Two Specific Aims are proposed to test our hypothesis and achieve our proposed plan: Aim 1) Determine the genetic ancestry and conduct admixture mapping using multi-ethnic genotyping array; and Aim 2) Replicate the most promising variants in AM peak regions using independent replication cohorts. The proposed study is highly significant (given the high burden of PA among AA children) and highly innovative (it is the first admixture analysis) to unravel genetic ancestry-specific risk variants associated with PA. Most importantly, the results will be on minority population and will contribute to our knowledge and to the early prediction, diagnosis and treatment of PA—a road map towards precision diagnosis. We therefore believe that this study along with future studies will uncover fundamental information about whether genetic ancestry can affect PA risk and prediction, thereby reducing the burden of PA on patients and their families and improving their quality of life. 1