A genomic approach identifies sRAGE as a putatively causal protein for asthma

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.