Genetically Determined Inflammation‐Related Proteins in Asthma and Type‐2 Signatures

• Published in: Allergy (Copenhagen) Vol. 80; no. 6; pp. 1702 - 1714
• Main Authors: Hernandez‐Pacheco, Natalia, Björkander, Sophia, Merid, Simon Kebede, Kere, Maura, Kumar, Ashish, Klevebro, Susanna, Mogensen, Ida, Ekström, Sandra, Janson, Christer, Palmberg, Lena, Hage, Marianne, Mälarstig, Anders, Merritt, Anne‐Sophie, Pershagen, Göran, Bergström, Anna, Kull, Inger, Schwenk, Jochen M., Melén, Erik
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.06.2025; John Wiley and Sons Inc
• Subjects: Adolescent; Adult; Asthma; Asthma - diagnosis; Asthma - genetics; Asthma - immunology; Asthma - metabolism; Biomarkers; Blood Proteins - genetics; Female; Genetic diversity; Genetic Predisposition to Disease; genetics; Humans; Inflammation; Inflammation - genetics; Leukocytes (eosinophilic); Male; Matrix metalloproteinase; Metalloproteinase; Molecular modelling; Nitric oxide; Original; ORIGINAL ARTICLE; Peptide mapping; Plasma levels; Plasma proteins; Polymorphism, Single Nucleotide; Proteins; Quantitative Trait Loci; Sweden; type-2 signatures; Young Adult; Young adults; Sweden; asthma; genetics; inflammation; proteins; type‐2 signatures
• DOI: 10.1111/all.16608
• ISSN: 0105-4538; 1398-9995

ABSTRACT Background 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. Methods 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. Results 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. Conclusions 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. This study investigates the association between genetic variation and inflammation‐related plasma proteins, and the differences in the proteins genetically determined between subjects with type‐2 signatures and/or asthma. Our findings suggest a strong contribution of genetic variation to the inflammation‐related proteome. MMP‐10 was demonstrated to be involved in type‐2 signatures in young adults with and without asthma. BAMSE, Swedish abbreviation for Child (Barn), Allergy, Milieu, Stockholm, Epidemiology; bEos, blood eosinophils; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E against at least one common airborne allergen; MMP‐10, matrix metalloproteinase‐10; SNP, single nucleotide polymorphism.