非裔美国患者哮喘的遗传结构。

Genetic architecture of asthma in African American patients.

机构信息

Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pa.

Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pa.

出版信息

J Allergy Clin Immunol. 2023 Apr;151(4):1132-1136. doi: 10.1016/j.jaci.2022.09.001. Epub 2022 Sep 8.

DOI:10.1016/j.jaci.2022.09.001

PMID:36089080

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9992439/

Abstract

BACKGROUND

Asthma is a chronic inflammatory disorder with a strong genetic inheritance. Although more than 100 loci were reported through the genome-wide association study of European populations, the genetic underpinning of asthma in African American individuals remains largely elusive.

OBJECTIVE

We aimed to identify genetic loci associated with asthma in African American individuals.

METHODS

Three cohorts were genotyped at the Children's Hospital of Philadelphia by using the Illumina single-nucleotide polymorphism array platform. Genotype imputation was performed by using the Trans-Omics for Precision Medicine (TOPMed) reference panel, which includes whole genome sequencing data from more than 100,000 individuals. A meta-analysis of 3 Children's Hospital of Philadelphia cohorts and 10 Consortium on Asthma among African Ancestry Populations in the Americas cohorts, totaling 19,628 subjects, was conducted to identify genetic loci associated with asthma in African American individuals.

RESULTS

Our study identified 12 loci surpassing the classical genome-wide significance threshold (5 × 10). Of those loci, 8 reached the stricter significance threshold (3 × 10). The 9p24.1 locus (rs10975467 [P = 1.63 × 10]) has previously been associated with asthma in European individuals. Six loci are associated with enhancer activities, 2 loci are in DNase I-hypersensitive regions, and all of them are associated with regulatory motifs. Moreover, the locus 11q13.4 (rs7480008) is an expression quantitative trait locus of XRRA1 in lung (P = 9.4 × 10), and the locus 13q14.3 (rs1543525) is a splicing quantitative trait locus of DHRS12 in lung (P = 1.1 × 10).

CONCLUSIONS

Our findings provide candidate genetic loci for therapeutic target identification and prioritization for African populations.

摘要

背景

哮喘是一种具有强烈遗传遗传的慢性炎症性疾病。尽管通过全基因组关联研究在欧洲人群中报告了 100 多个位点，但非洲裔美国人的哮喘遗传基础在很大程度上仍未被发现。

目的

我们旨在确定与非洲裔美国人哮喘相关的遗传位点。

方法

三个队列在费城儿童医院通过 Illumina 单核苷酸多态性芯片平台进行基因分型。通过使用包括超过 100,000 个人的全基因组测序数据的 Trans-Omics for Precision Medicine（TOPMed）参考面板进行基因型推断。对三个费城儿童医院队列和 10 个美洲非洲裔人群哮喘联盟队列进行荟萃分析，总计 19628 例，以鉴定与非洲裔美国人哮喘相关的遗传位点。

结果

我们的研究确定了 12 个超过经典全基因组显著阈值（5×10）的位点。其中 8 个达到了更严格的显著阈值（3×10）。9p24.1 位点（rs10975467 [P=1.63×10]）先前与欧洲人群的哮喘有关。6 个位点与增强子活性有关，2 个位点位于 DNA 酶 I 超敏区域，所有这些都与调节基序有关。此外，11q13.4 位点（rs7480008）是 XRRA1 在肺部的表达数量性状基因座（P=9.4×10），13q14.3 位点（rs1543525）是 DHRS12 在肺部的剪接数量性状基因座（P=1.1×10）。