Genetic landscape of idiopathic pulmonary fibrosis: A systematic review, meta-analysis and epidemiological evidence of case-control studies

Background: Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disorder of unknown cause, affecting about three million people worldwide. Being a multifactorial disease, complex genetic and environmental factors contribute to its susceptibility. Therefore, we conducted a two-staged systematic literature search and meta-analyses of published genetic association studies on IPF. Methods: The first search was performed using PubMed and Web of Science, retrieving a total of 5642 articles, of which 57 publications were eligible for inclusion in the first stage. The Second search was performed using PubMed, Web of Science and Scopus for all genetic variants, identified from the first search, with 2 or more studies. Thus, six variants [rs35705950 (MUC5B), rs2736100 (TERT), rs2609255 (FAM13A), rs2076295 (DSP), rs12610495 (DPP9) and rs1800470 (TGF-β1)] from this search qualified for meta-analyses. Additionally, the epidemiological credibility of these six variants was evaluated using the Venice criteria. Results: In this systematic review, 291 polymorphisms were found to be associated with IPF susceptibility. Meta-analyses findings revealed significant (p < 0.05) risk association of rs35705950 [T vs C; OR = 3.85(3.24-4.47)], rs2609255 [G vs T; OR = 1.37(1.27-1.47)], rs2076295 [G vs T; OR = 1.31(1.00-1.63)], rs12610495 [G vs A; OR = 1.29(1.21-1.37)] and rs1800470 [T vs C; OR = 1.08(0.82-1.34)] and protective association of rs2736100 [C vs A; OR = 0.70(0.61-0.79)] with IPF susceptibility. Cumulative epidemiological evidence was graded as strong for rs35705950, moderate for rs2736100, rs2609255 and rs12610495, and weak for rs2076295 and rs1800470. Conclusions: Our findings present the most prominent IPF-associated genetic risk variants involved in alveolar epithelial injuries (MUC5B, TERT, FAM13A, DSP, DPP9) and epithelial-mesenchymal transition (TGF-β1), providing genetic and biological insights into IPF pathogenesis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Council of Scientific and Industrial Research (CSIR) [grant numbers OLP 1154] ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript