哮喘多基因风险评分的表观基因组划分揭示不同基因驱动疾病的通路
2024/07/30
摘要
背景：支气管哮喘（一种异质性慢性炎症性肺病，以下简称哮喘）易感性的个体差异目前知之甚少。遗传学是否可以预测哮喘风险，以及遗传变异如何调节哮喘复杂的病理生理学，仍存在争议。
目的：本研究旨在建立用于哮喘风险预测的多基因风险评分（PRSs），并从表观遗传学角度将预测性基因变异与病理生理机制相联系。
方法：本研究采用来自全基因组关联研究的单核苷酸变体构建限制性PRS，并采用鹿特丹研究（由14926人组成的荷兰前瞻性队列）中产生的数据进行验证。本研究采用的结局包括哮喘、儿童期发作性哮喘（COA）、成年期发作性哮喘（AOA）、嗜酸性粒细胞性哮喘及哮喘急性加重。本研究将来自19种疾病相关细胞类型的全基因组染色质分析数据用于表观基因组PRS划分。
结果：PRS可预测哮喘及相关结局，且与COA的相关性最强（每PRS标准差2.55倍比值比，曲线下面积为0.760）。PRS将人群分为高风险组和低风险组。通过对表观基因组图谱进行PRS划分，在与特定哮喘相关细胞、基因和生物途径相关的假定基因调控区内确定了5簇变体。
结论：在荷兰前瞻性队列中，PRS与哮喘（相关特征）相关，COA的预测能力明显高于AOA。重要的是，PRS变体可以从表观遗传学上划分为具有不同病理生理关联模式和效应估计的调控变体簇，这可能代表不同基因驱动疾病的途径。本研究结果对个性化风险缓解和治疗策略具有潜在的意义。
Epigenomic partitioning of a polygenic risk score for asthma reveals distinct genetically driven disease pathways.
Stikker B, Trap L, Sedaghati-Khayat B, de Bruijn MJW, van Ijcken WFJ, de Roos E, Ikram A, Hendriks RW, Brusselle G, van Rooij J, Stadhouders R.
Abstract
BACKGROUND:Individual differences in susceptibility to develop asthma, a heterogeneous chronic inflammatory lung disease, are poorly understood. It remains debated whether genetics can predict asthma risk and how genetic variants modulate the complex pathophysiology of asthma.
OBJECTIVE:To build polygenic risk scores (PRSs) for asthma risk prediction and epigenomically link predictive genetic variants to pathophysiological mechanisms.
METHODS:Restricted PRSs were constructed using single nucleotide variants derived from genome-wide association studies and validated using data generated in the Rotterdam Study, a Dutch prospective cohort of 14 926 individuals. Outcomes used were asthma, childhood-onset asthma (COA), adulthood-onset asthma (AOA), eosinophilic asthma, and asthma exacerbations. Genome-wide chromatin analysis data from 19 disease-relevant cell types were used for epigenomic PRS partitioning.
RESULTS:PRSs obtained predicted asthma and related outcomes, with the strongest associations observed for COA (2.55 odds ratios per PRS standard deviation, area under the curve of 0.760). PRSs allowed for the classification of individuals into high and low-risk groups. PRS partitioning using epigenomic profiles identified 5 clusters of variants within putative gene regulatory regions linked to specific asthma-relevant cells, genes, and biological pathways.
CONCLUSION:PRSs were associated with asthma(-related traits) in a Dutch prospective cohort, with substantially higher predictive power observed for COA than for AOA. Importantly, PRS variants could be epigenomically partitioned into clusters of regulatory variants with different pathophysiological association patterns and effect estimates, which likely represent distinct genetically driven disease pathways. Our findings have potential implications for personalized risk mitigation and treatment strategies.
背景：支气管哮喘（一种异质性慢性炎症性肺病，以下简称哮喘）易感性的个体差异目前知之甚少。遗传学是否可以预测哮喘风险，以及遗传变异如何调节哮喘复杂的病理生理学，仍存在争议。
目的：本研究旨在建立用于哮喘风险预测的多基因风险评分（PRSs），并从表观遗传学角度将预测性基因变异与病理生理机制相联系。
方法：本研究采用来自全基因组关联研究的单核苷酸变体构建限制性PRS，并采用鹿特丹研究（由14926人组成的荷兰前瞻性队列）中产生的数据进行验证。本研究采用的结局包括哮喘、儿童期发作性哮喘（COA）、成年期发作性哮喘（AOA）、嗜酸性粒细胞性哮喘及哮喘急性加重。本研究将来自19种疾病相关细胞类型的全基因组染色质分析数据用于表观基因组PRS划分。
结果：PRS可预测哮喘及相关结局，且与COA的相关性最强（每PRS标准差2.55倍比值比，曲线下面积为0.760）。PRS将人群分为高风险组和低风险组。通过对表观基因组图谱进行PRS划分，在与特定哮喘相关细胞、基因和生物途径相关的假定基因调控区内确定了5簇变体。
结论：在荷兰前瞻性队列中，PRS与哮喘（相关特征）相关，COA的预测能力明显高于AOA。重要的是，PRS变体可以从表观遗传学上划分为具有不同病理生理关联模式和效应估计的调控变体簇，这可能代表不同基因驱动疾病的途径。本研究结果对个性化风险缓解和治疗策略具有潜在的意义。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Eur Respir J. 2024 Jun 20:2302059. doi: 10.1183/13993003.02059-2023. Epub ahead of print.)
(Eur Respir J. 2024 Jun 20:2302059. doi: 10.1183/13993003.02059-2023. Epub ahead of print.)
Epigenomic partitioning of a polygenic risk score for asthma reveals distinct genetically driven disease pathways.
Stikker B, Trap L, Sedaghati-Khayat B, de Bruijn MJW, van Ijcken WFJ, de Roos E, Ikram A, Hendriks RW, Brusselle G, van Rooij J, Stadhouders R.
Abstract
BACKGROUND:Individual differences in susceptibility to develop asthma, a heterogeneous chronic inflammatory lung disease, are poorly understood. It remains debated whether genetics can predict asthma risk and how genetic variants modulate the complex pathophysiology of asthma.
OBJECTIVE:To build polygenic risk scores (PRSs) for asthma risk prediction and epigenomically link predictive genetic variants to pathophysiological mechanisms.
METHODS:Restricted PRSs were constructed using single nucleotide variants derived from genome-wide association studies and validated using data generated in the Rotterdam Study, a Dutch prospective cohort of 14 926 individuals. Outcomes used were asthma, childhood-onset asthma (COA), adulthood-onset asthma (AOA), eosinophilic asthma, and asthma exacerbations. Genome-wide chromatin analysis data from 19 disease-relevant cell types were used for epigenomic PRS partitioning.
RESULTS:PRSs obtained predicted asthma and related outcomes, with the strongest associations observed for COA (2.55 odds ratios per PRS standard deviation, area under the curve of 0.760). PRSs allowed for the classification of individuals into high and low-risk groups. PRS partitioning using epigenomic profiles identified 5 clusters of variants within putative gene regulatory regions linked to specific asthma-relevant cells, genes, and biological pathways.
CONCLUSION:PRSs were associated with asthma(-related traits) in a Dutch prospective cohort, with substantially higher predictive power observed for COA than for AOA. Importantly, PRS variants could be epigenomically partitioned into clusters of regulatory variants with different pathophysiological association patterns and effect estimates, which likely represent distinct genetically driven disease pathways. Our findings have potential implications for personalized risk mitigation and treatment strategies.
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局部受体相互作用蛋白激酶2抑制减轻HDM诱导的哮喘
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合并功能性消化不良反映了 IL-33 介导的哮喘气道神经元功能障碍
