Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank
Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank
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DOI：
10.1016/j.jaci.2019.09.035
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发表时间：
2020-02-01
影响因子：
14.2
通讯作者：
Liang, Liming
中科院分区：
文献类型：
--
作者：
Zhu, Zhaozhong;Guo, Yanjun;Liang, Liming
背景：临床和流行病学研究表明，肥胖与哮喘相关，并且这些关联因哮喘亚型而异。关于肥胖和哮喘之间的共同遗传成分知之甚少。目的：我们试图确定成人肥胖相关特征和哮喘亚型之间共同的遗传关联。方法：使用来自英国生物银行的 457,822 名欧洲血统受试者进行了一项跨特征全基因组关联研究 (GWAS)。通过使用肥胖小鼠与瘦小鼠 RNA 测序和 RT-PCR 实验的结果，通过 GWAS 寻找支持与肥胖相关性状和哮喘显着相关的基因作用的实验证据。结果：我们发现体重指数与迟发性哮喘之间存在显着的正向遗传相关性，迟发性哮喘定义为哮喘发病年龄为 16 岁或以上（Rg = 0.25，P = 9.56 X 10(-22)）。孟德尔随机分析提供了强有力的证据支持体重指数会增加哮喘风险。跨性状荟萃分析确定了 3 种肥胖相关性状和 2 种哮喘亚型之间的 34 个共享基因座。 GWAS 功能分析确定了肥胖和哮喘之间共享基因座和基因型组织表达 (GTEx) 数量性状基因座以及共享免疫和细胞分化相关途径之间的潜在因果关系。最后，肥胖小鼠与对照小鼠肺部的 RNA 测序数据发现，跨性状荟萃分析中的 2 个基因（酰基辅酶 A 氧化酶样 [ACOXL] 和肌球蛋白轻链 6 [MYL6]）存在差异表达，并且通过在一组独立的小鼠中使用 RT-PCR 验证了这些发现。结论：我们的工作确定了肥胖相关性状和特定哮喘亚型之间共有的遗传成分，强化了肥胖会增加哮喘风险的假设哮喘并确定可能导致肥胖和哮喘的分子途径。
Background: Clinical and epidemiologic studies have shown that obesity is associated with asthma and that these associations differ by asthma subtype. Little is known about the shared genetic components between obesity and asthma.Objective: We sought to identify shared genetic associations between obesity-related traits and asthma subtypes in adults.Methods: A cross-trait genome-wide association study (GWAS) was performed using 457,822 subjects of European ancestry from the UK Biobank. Experimental evidence to support the role of genes significantly associated with both obesity-related traits and asthma through a GWAS was sought by using results from obese versus lean mouse RNA sequencing and RT-PCR experiments.Results: We found a substantial positive genetic correlation between body mass index and later-onset asthma defined by asthma age of onset at 16 years or greater (Rg = 0.25, P = 9.56 X 10(-22)). Mendelian randomization analysis provided strong evidence in support of body mass index causally increasing asthma risk. Cross-trait meta-analysis identified 34 shared loci among 3 obesity-related traits and 2 asthma subtypes. GWAS functional analyses identified potential causal relationships between the shared loci and Genotype-Tissue Expression (GTEx) quantitative trait loci and shared immune and cell differentiation related pathways between obesity and asthma. Finally, RNA sequencing data from lungs of obese versus control mice found that 2 genes (acyl-coenzyme A oxidase-like [ACOXL] and myosin light chain 6 [MYL6]) from the cross-trait meta-analysis were differentially expressed, and these findings were validated by using RT-PCR in an independent set of mice.Conclusions: Our work identified shared genetic components between obesity-related traits and specific asthma subtypes, reinforcing the hypothesis that obesity causally increases the risk of asthma and identifying molecular pathways that might underlie both obesity and asthma.