Abstract
INTRODUCTION: Preserved ratio impaired spirometry (PRISm) is a new and variable phenotype of spirometry impairment that was first defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2023. The identification of high-risk factors for the progression from PRISm to COPD remains insufficient at present. METHODS: Mendelian randomization (MR) analysis was conducted using genome-wide association study (GWAS) summary statistics. Genetic instruments for smoking behavior were derived from the GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN) (n=607291), while PRISm case-control data were sourced from the UK Biobank (n=296282). The inverse-variance weighted (IVW) method served as the primary analytical approach, supplemented by heterogeneity assessment, pleiotropy evaluation, and sensitivity analyses. For the meta-analysis, PubMed, Embase, Cochrane Library, and Web of Science were systematically searched from inception to 31 December 2024, to identify relevant studies that followed up on the changes in spirometry among individuals with PRISm or studies that reported the possible factors related to the changes in spirometry among individuals with PRISm. The risk of bias and the quality of the included studies were assessed using the Newcastle-Ottawa Scale (NOS). RESULTS: The MR analysis identified 85 SNPs as genetic instruments, revealing a modest causal link between cigarette smoking and PRISm prevalence (IVW: OR=1.01-1.02, p=0.048). The meta-analysis of 14 studies (n=7336 PRISm cases) shows 20.8% (95% CI: 15.6-25.9) progress to COPD at follow-up, with no significant difference by follow-up duration (<5 vs ≥5 years). Persistent PRISm occurs in 41.5% (95% CI: 35.8-47.2), more frequently in long-term follow-up subgroups. Baseline 'chest distress/dyspnea' (OR=3.81; 95% CI: 1.47-9.84) and 'current smoking' (OR=2.18; 95% CI: 1.14-4.15) significantly predict progression, while respiratory symptoms, FEV(1)/FVC ratio, TLC%, and FVC% show no association. CONCLUSIONS: Our findings suggest a modest causal link between cigarette smoking and PRISm prevalence. The progression of PRISm to COPD within 5 years is approximately 20.8%. Among individuals with PRISm at the first visit, 'chest distress or dyspnea' and 'current smoking' are potential clinical risk factors for the progression of PRISm to COPD.