Bui Helena, Keshawarz Amena, Hwang Shih-Jen, Yao Chen, Lee Gha Young, Recto Kathryn, O'Connor George T, Levy Daniel
Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md; Framingham Heart Study, Framingham, Mass.
Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md; Framingham Heart Study, Framingham, Mass; Harvard Medical School, Boston, Mass.
J Allergy Clin Immunol. 2022 Jun;149(6):1992-1997.e12. doi: 10.1016/j.jaci.2021.11.027. Epub 2021 Dec 30.
Asthma is a complex respiratory condition caused by environmental and genetic factors. Although lower concentrations of the anti-inflammatory protein soluble receptor for advanced glycation end products (sRAGE) have been associated with asthma in humans and mouse models, it is uncertain whether sRAGE plays a causal role in asthma.
We designed a 2-stage study of sRAGE in relation to asthma with association analysis in FHS participants as well as causal inference testing using Mendelian randomization (MR).
We measured plasma levels of sRAGE and performed cross-sectional analysis to examine the association between plasma sRAGE concentration and asthma status in 6546 FHS participants. We then used sRAGE protein advanced glycation end products (pQTLs) derived from a genome-wide association study of plasma sRAGE levels in ∼7000 FHS participants with UK Biobank asthma genome-wide association study in MR to consider sRAGE as a putatively causal protein for asthma. We also performed replication MR using an externally derived sRAGE pQTL from the INTERVAL study. Last, we conducted colocalization using cis-pQTL variants at the advanced glycosylation end-product specific receptor (AGER) locus with variants from the UK Biobank asthma genome-wide association study.
Association analysis revealed that each 1 SD increment in sRAGE concentration was associated with a 14% lower odds of asthma in FHS participants (95% CI 0.76-0.96). MR identified sRAGE as putatively causal for and protective against asthma on the basis of self-reported (odds ratio [per 1 SE increment in inverse-rank-normalized sRAGE] = 0.97, 95% CI 0.95-0.99; P = .005) and doctor-diagnosed asthma (odds ratio = 0.97, 95% CI 0.95-0.99; P = .011).
Through this genomic approach, we identified sRAGE as a putatively causal, biologically important, and protective protein in relation to asthma. Functional studies in cell/animal models are needed to confirm our findings.
哮喘是一种由环境和遗传因素引起的复杂呼吸系统疾病。尽管在人类和小鼠模型中，较低浓度的抗炎蛋白可溶性晚期糖基化终产物受体（sRAGE）与哮喘有关，但尚不确定sRAGE在哮喘中是否起因果作用。
我们设计了一项关于sRAGE与哮喘关系的两阶段研究，在弗雷明汉心脏研究（FHS）参与者中进行关联分析，并使用孟德尔随机化（MR）进行因果推断测试。
我们测量了6546名FHS参与者的血浆sRAGE水平，并进行横断面分析，以检验血浆sRAGE浓度与哮喘状态之间的关联。然后，我们使用从约7000名FHS参与者的血浆sRAGE水平全基因组关联研究中得出的sRAGE蛋白晚期糖基化终产物（pQTL），以及英国生物银行哮喘全基因组关联研究中的MR，将sRAGE视为哮喘的一种可能的因果蛋白。我们还使用来自INTERVAL研究的外部衍生sRAGE pQTL进行了重复MR。最后，我们使用晚期糖基化终产物特异性受体（AGER）基因座的顺式pQTL变体与英国生物银行哮喘全基因组关联研究中的变体进行共定位。
关联分析显示，在FHS参与者中，sRAGE浓度每增加1个标准差，哮喘的患病几率就降低14%（95%CI 0.76-0.96）。基于自我报告的哮喘（优势比[每1个标准化逆秩sRAGE增加1个标准误]=0.97，95%CI 0.95-0.99；P=.005）和医生诊断的哮喘（优势比=0.97，95%CI 0.95-0.99；P=.011），MR确定sRAGE可能是哮喘的病因并具有保护作用。
通过这种基因组方法，我们确定sRAGE是一种与哮喘相关的可能具有因果关系、生物学上重要的保护蛋白。需要在细胞/动物模型中进行功能研究以证实我们的发现。
