Risk factors for idiopathic pulmonary fibrosis: an umbrella review of meta-analyses and mendelian randomization analyses

Background: The incidence of idiopathic pulmonary fibrosis (IPF) is rising globally. Existing meta-analyses and Mendelian randomization (MR) studies have yielded inconsistent findings with uncertain evidence quality. Objectives: This study aimed to synthesize available evidence and assess its credibility for potential risk factors of IPF. Methods: We systematically searched 8 databases and selected meta-analyses and MR studies related to IPF risk factors from inception to March 11, 2025. We assessed the quality of meta-analyses using the AMSTAR-2 tool and evaluated MR studies using the STROBE-MR guidelines. We categorized the evidence into four levels and performed pooled analysis for risk factors reported in at least two MR studies. Results: A total of 8 meta-analyses were included, reporting 22 associations, mainly involving genetics, infections, occupational and environmental exposures, lifestyle, and clinical variables. According to the grading of evidence credibility, 12 were rated as suggestive associations, and 10 as weak associations. The overall credibility of the evidence is relatively low. The 36 MR studies investigated a total of 124 associations, with evidence grading showed 13 as robust, 90 as possible, 17 as suggestive, and 4 as insufficient. The pooled analysis identified 108 associations covering lifestyle, diet and nutrition, anthropometric indices, biomarkers, and clinical variables. The quality level of the included meta-analyses was low and critically low, while the MR studies strictly adhered to STROBE-MR, demonstrating good reporting quality. Conclusions: This umbrella review uncovers the evidence regarding the associations between IPF risk and factors such as genetics, viral infections, occupational and environmental exposures, lifestyle, and clinical variables through a comprehensive analysis of meta-analyses and MR studies. These findings provide an evidence base for IPF risk factor research and support clinical decisions and public health strategies. PROSPERO registration number: CRD42024575341.