Integrative genetics-metabolomics analysis of infant bronchiolitis-childhood asthma link: A multicenter prospective study.
Integrative genetics-metabolomics analysis of infant bronchiolitis-childhood asthma link: A multicenter prospective study.
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DOI：
10.3389/fimmu.2022.1111723
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
患有细支气管炎的婴儿发生儿童哮喘的风险很高。虽然全基因组关联研究表明这些疾病之间存在共同的遗传易感性，但这种联系背后的机制仍不清楚。通过对这一高危人群的综合遗传学-代谢组学分析，我们试图确定与哮喘发展相关的遗传驱动代谢物以及与这些代谢物和哮喘易感性相关的遗传位点。在一项对因毛细支气管炎住院的婴儿进行的多中心前瞻性队列研究中，我们分析了鼻咽部代谢物组，并在住院时进行了全基因组分型。我们从283种测定化合物中鉴定了哮喘相关代谢物，并进行了代谢物数量性状基因座（mtQTL）分析。我们进一步研究了mtQTL的关联，通过共定位分析和基因座与已知哮喘易感基因之间的一致性测试代谢产物和哮喘的共享遗传位点。在744名因细支气管炎住院的婴儿中，28种代谢物（例如，二十二碳五烯酸[DPA]、1，2-二油酰-sn-甘油-3-磷酸甘油、鞘磷脂）与哮喘风险相关。共有349个位点与这些代谢物相关-非西班牙裔白色人161个，非西班牙裔黑人120个，西班牙裔68个。其中，有证据表明16种代谢物与哮喘风险之间存在30个共享位点（共定位后验概率≥0.5）。基因座内的显著SNP与已知的哮喘易感基因（例如，AD0RA1，MUC16）。综合遗传学-代谢组学分析确定了婴儿期与哮喘发展相关的遗传驱动代谢物以及与这些代谢物和哮喘易感性相关的遗传位点。确定这些代谢物和遗传位点应该推进对婴儿细支气管炎-儿童哮喘联系的功能机制的研究。
Infants with bronchiolitis are at high risk for developing childhood asthma. While genome-wide association studies suggest common genetic susceptibilities between these conditions, the mechanisms underlying the link remain unclear. Through integrated genetics-metabolomics analysis in this high-risk population, we sought to identify genetically driven metabolites associated with asthma development and genetic loci associated with both these metabolites and asthma susceptibility. In a multicenter prospective cohort study of infants hospitalized for bronchiolitis, we profiled the nasopharyngeal metabolome and genotyped the whole genome at hospitalization. We identified asthma-related metabolites from 283 measured compounds and conducted metabolite quantitative trait loci (mtQTL) analyses. We further examined the mtQTL associations by testing shared genetic loci for metabolites and asthma using colocalization analysis and the concordance between the loci and known asthma-susceptibility genes. In 744 infants hospitalized with bronchiolitis, 28 metabolites (e.g., docosapentaenoate [DPA], 1,2-dioleoyl-sn-glycero-3-phosphoglycerol, sphingomyelin) were associated with asthma risk. A total of 349 loci were associated with these metabolites—161 for non-Hispanic white, 120 for non-Hispanic black, and 68 for Hispanics. Of these, there was evidence for 30 shared loci between 16 metabolites and asthma risk (colocalization posterior probability ≥0.5). The significant SNPs within loci were aligned with known asthma-susceptibility genes (e.g., ADORA1, MUC16). The integrated genetics-metabolomics analysis identified genetically driven metabolites during infancy that are associated with asthma development and genetic loci associated with both these metabolites and asthma susceptibility. Identifying these metabolites and genetic loci should advance research into the functional mechanisms of the infant bronchiolitis-childhood asthma link.
影响因子：
5.6
作者：
Read JF;Bosco A
通讯作者：
Bosco A