• Helena Bui, Amena Keshawarz, Shih-Jen Hwang, Chen Yao, Gha Young Lee, Kathryn Recto, George T O'Connor, and Daniel Levy.
• Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, 31 Center Drive, Ste 10-7C114, Bethesda, MD 20891, USA; Framingham Heart Study, 73 Mt. Wayte Avenue, Framingham, MA 01702, USA.
• J. Allergy Clin. Immunol. 2021 Dec 30.

BackgroundAsthma is a complex respiratory condition caused by environmental and genetic factors. Although lower concentrations of the anti-inflammatory protein sRAGE have been associated with asthma in humans and mouse models, it is uncertain whether sRAGE plays a causal role in asthma.ObjectiveWe designed a two-stage study of sRAGE in relation to asthma with i) association analysis in FHS participants and ii) causal inference testing using MR.MethodsWe measured plasma levels of sRAGE and performed cross-sectional analysis to examine the association between plasma sRAGE concentration and asthma status in 6,546 FHS participants. We then used sRAGE pQTLs derived from a GWAS of plasma sRAGE levels in ∼7,000 FHS participants with UK Biobank asthma GWAS 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 AGER locus with variants from the UK Biobank asthma GWAS.ResultsAssociation 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 based on self-reported (OR [per 1 SE increment in inverse rank-normalized sRAGE]=0.97, 95% CI 0.95-0.99; p=0.005) and doctor-diagnosed asthma (OR=0.97, 95% CI 0.95-0.99; p=0.011).ConclusionThrough 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.Copyright © 2021. Published by Elsevier Inc.

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