位于染色体17q21的基因间长链非编码RNA功能性序列变异与哮喘相关
2025/08/01
摘要
背景：哮喘的遗传与分子基础尚不明确，其基因-环境相互作用机制仍未被完全揭示。本研究旨在识别与哮喘相关的致病性遗传变异及其与环境因素的相互作用。
方法：本研究在台湾生物库中对汉族人群（病例=4877例，正常对照=98,218例）开展病例对照全基因组关联研究（GWAS），以识别哮喘易感位点，并在一项医院人群（N=2595）中进行了验证。评估了累计10至15年的细颗粒物（PM2.5）和多环芳烃（PAHs）的环境暴露水平，以分析基因-环境关系。采用RNA免疫沉淀、RNA pull-down、RT-qPCR和蛋白免疫印迹（Western blot）等技术，研究新发现的长链非编码RNA lncZPBP2-3 的功能及其与PM2.5和PAHs暴露的相互作用。
结果：结果发现，染色体17q12-21是显著的风险区域，包含lncZPBP2-3及其邻近基因的变异体，并且该区域与PM2.5及其吸附的PAHs的暴露水平增加存在相互作用。在哮喘患者的外周血中，lncZPBP2-3及其邻近基因的表达水平均高于对照组。与非风险型lncZPBP2-3相比，风险变异体lncZPBP2-3通过其与转录绝缘子CCCTC结合因子（CTCF）的相互作用，破坏了该风险位点的转录抑制，导致携带风险基因型个体的邻近基因表达水平更高。
结论：lncRNA lncZPBP2-3 的功能性变异与哮喘显著相关，并可被环境中PAHs诱导，提示其可能在哮喘的遗传与分子机制中发挥新型作用。
Functional sequence variants of intergenic long non-coding RNA on Chromosome 17q21 are associated with asthma
Liu, K. Y., Sie, J. J., Gao, Y., Lo, Y. L., Wu, C. C., Wang, C. C., Sheu, C. C., Lai, R. S., Leung, S. Y., Lin, C. C., Wei, Y. F., Lin, C. H., Lin, S. H., Hsu, J. Y., Huang, W. C., Tseng, C. C., Lai, Y. F., Cheng, M. H., Chen, H. C., Yang, C. J., … Huang, S. K. (2025).
Abstract
BACKGROUND:
The genetic and molecular basis of asthma remains unclear and its gene-environment interaction is still enigmatic. In the present study, we aimed to identify asthma-causing genetic variants and their interactions with the environment.
METHODS:
We performed case-control genome-wide association studies on individuals of Han Chinese descent from the Taiwan biobank (case=4877 and control=(98 218) to identify asthma susceptibility loci, validated in a hospital-based population of subjects (N=2595). The 10- to 15-year exposure of cumulative ambient particulate matter with a diameter of less than 2.5 μm (PM2.5) and polycyclic aromatic hydrocarbons (PAHs) were assessed for gene-environment relationships. The function of the newly identified long non-coding RNA, lncZPBP2-3, and its interaction with PM2.5 and PAH exposure were analyzed using RNA immunoprecipitation, RNA pull-down, RT-qPCR, and western blotting.
RESULTS:
Chromosome 17q12-21 was found to be a significant risk region, encompassing variants of lncZPBP2-3 and its neighboring genes, which interacted with increasing exposure to PM2.5 and its adsorbed PAHs. The expression of lncZPBP2-3 was elevated, correlating with the expression of its neighboring genes, in the peripheral blood of asthmatic individuals compared to that in controls. Unlike non-risk lncZPBP2-3, the risk variant of lncZPBP2-3 disrupted the transcriptional suppression of the risk locus via its interaction with the transcription insulator, CCCTC-binding factor (CTCF), concomitant with the higher expression levels of neighboring genes in individuals with the risk genotype.
CONCLUSION:
An functional variant of lncRNA, lncZPBP2-3, was significantly associated with asthma and inducible by environmental PAH, suggesting a potentially novel genetic and molecular mechanism of asthma.
背景：哮喘的遗传与分子基础尚不明确，其基因-环境相互作用机制仍未被完全揭示。本研究旨在识别与哮喘相关的致病性遗传变异及其与环境因素的相互作用。
方法：本研究在台湾生物库中对汉族人群（病例=4877例，正常对照=98,218例）开展病例对照全基因组关联研究（GWAS），以识别哮喘易感位点，并在一项医院人群（N=2595）中进行了验证。评估了累计10至15年的细颗粒物（PM2.5）和多环芳烃（PAHs）的环境暴露水平，以分析基因-环境关系。采用RNA免疫沉淀、RNA pull-down、RT-qPCR和蛋白免疫印迹（Western blot）等技术，研究新发现的长链非编码RNA lncZPBP2-3 的功能及其与PM2.5和PAHs暴露的相互作用。
结果：结果发现，染色体17q12-21是显著的风险区域，包含lncZPBP2-3及其邻近基因的变异体，并且该区域与PM2.5及其吸附的PAHs的暴露水平增加存在相互作用。在哮喘患者的外周血中，lncZPBP2-3及其邻近基因的表达水平均高于对照组。与非风险型lncZPBP2-3相比，风险变异体lncZPBP2-3通过其与转录绝缘子CCCTC结合因子（CTCF）的相互作用，破坏了该风险位点的转录抑制，导致携带风险基因型个体的邻近基因表达水平更高。
结论：lncRNA lncZPBP2-3 的功能性变异与哮喘显著相关，并可被环境中PAHs诱导，提示其可能在哮喘的遗传与分子机制中发挥新型作用。
Functional sequence variants of intergenic long non-coding RNA on Chromosome 17q21 are associated with asthma
Liu, K. Y., Sie, J. J., Gao, Y., Lo, Y. L., Wu, C. C., Wang, C. C., Sheu, C. C., Lai, R. S., Leung, S. Y., Lin, C. C., Wei, Y. F., Lin, C. H., Lin, S. H., Hsu, J. Y., Huang, W. C., Tseng, C. C., Lai, Y. F., Cheng, M. H., Chen, H. C., Yang, C. J., … Huang, S. K. (2025).
Abstract
BACKGROUND:
The genetic and molecular basis of asthma remains unclear and its gene-environment interaction is still enigmatic. In the present study, we aimed to identify asthma-causing genetic variants and their interactions with the environment.
METHODS:
We performed case-control genome-wide association studies on individuals of Han Chinese descent from the Taiwan biobank (case=4877 and control=(98 218) to identify asthma susceptibility loci, validated in a hospital-based population of subjects (N=2595). The 10- to 15-year exposure of cumulative ambient particulate matter with a diameter of less than 2.5 μm (PM2.5) and polycyclic aromatic hydrocarbons (PAHs) were assessed for gene-environment relationships. The function of the newly identified long non-coding RNA, lncZPBP2-3, and its interaction with PM2.5 and PAH exposure were analyzed using RNA immunoprecipitation, RNA pull-down, RT-qPCR, and western blotting.
RESULTS:
Chromosome 17q12-21 was found to be a significant risk region, encompassing variants of lncZPBP2-3 and its neighboring genes, which interacted with increasing exposure to PM2.5 and its adsorbed PAHs. The expression of lncZPBP2-3 was elevated, correlating with the expression of its neighboring genes, in the peripheral blood of asthmatic individuals compared to that in controls. Unlike non-risk lncZPBP2-3, the risk variant of lncZPBP2-3 disrupted the transcriptional suppression of the risk locus via its interaction with the transcription insulator, CCCTC-binding factor (CTCF), concomitant with the higher expression levels of neighboring genes in individuals with the risk genotype.
CONCLUSION:
An functional variant of lncRNA, lncZPBP2-3, was significantly associated with asthma and inducible by environmental PAH, suggesting a potentially novel genetic and molecular mechanism of asthma.
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