Proteomic associations with forced expiratory volume: a Mendelian randomisation study.

Area of Science:

• Proteogenomics
• Respiratory Medicine
• Biomarker Discovery

Background:

• Declining forced expiratory volume (FEV1) is a key indicator of respiratory diseases, particularly impacting the elderly.
• Existing research on biomarkers related to FEV1 is limited, necessitating a systematic investigation into causal relationships.

Purpose of the Study:

• To systematically analyze the causal relationships between serum protein biomarkers and forced expiratory volume (FEV1).
• To identify novel circulating protein markers associated with lung function.

Main Methods:

• Utilized data from the AGES-Reykjavik study, including proteomic measurements (SOMAmers) and spirometric data from 1479 participants.
• Employed linear regression for observational association analysis and bi-directional two-sample Mendelian randomization (MR) to assess causality.
• Integrated genotype and SOMAmer data from 5368 participants with publicly available GWAS data for FEV1 (n=400,102).

Main Results:

• Observational analyses identified 530 SOMAmers associated with FEV1, with RARRES2, RSPO4, and ALPPL2 being most significant.
• Mendelian randomization analyses revealed eight SOMAmers associated with FEV1, with THBS2, ERO1B, and APOM showing directional consistency with observational findings.
• THBS2 association was further supported by colocalization analysis; no significant reverse causal associations were found.

Conclusions:

• Large-scale proteogenomic analysis identified circulating protein markers linked to FEV1.
• Several proteins, including THBS2, ERO1B, and APOM, demonstrate potential causal roles in lung function.
• These findings contribute to understanding the molecular underpinnings of respiratory health and disease.