Genetically Determined Inflammation-Related Proteins in Asthma and Type-2 Signatures.

Abstract

Protein quantitative trait loci (pQTLs) remain underexplored in asthma but might provide valuable insights into the underlying molecular mechanisms. This study aimed to investigate associations between genetic variation and inflammation-related plasma proteins and to assess differences in the levels of genetically determined proteins in subjects with signatures of type-2 inflammation and/or asthma. A pQTL mapping of 92 inflammation-related plasma proteins was conducted in young adults from the Swedish BAMSE cohort (n = 1538). Replication of sentinel pQTLs was attempted, and the overlap and colocalization of pQTLs with expression quantitative trait loci (eQTLs) were investigated using publicly available data. Proteins with significant pQTLs were tested for association with type-2 signatures defined as high levels of fractional exhaled nitric oxide, blood eosinophils, and/or sensitization to airborne allergens in subjects with or without asthma in BAMSE. Forty-five sentinel pQTLs (33 cis, 12 trans) for 39 inflammation-related proteins were identified (p ≤ 7.14 × 10^-11), and a high proportion of these were validated in independent populations. A high likelihood for colocalization of cis-pQTLs and cis-eQTLs was observed for 19 proteins in different tissues. Six of the 39 circulating proteins with significant pQTLs were associated with type-2 signatures and/or asthma, and matrix metalloproteinase-10 (MMP-10) showed the most significant associations. These findings underscore the existence of a genetic component influencing the plasma levels of proteins involved in inflammatory processes, including MMP-10, which is suggested to have a role in high type-2 inflammation in asthma subjects.