Common single nucleotide polymorphisms associated with idiopathic pulmonary fibrosis: a systematic review

Abstract

Background: Several genetic variants are associated with the risk of idiopathic pulmonary fibrosis (IPF). These have not been systematically reviewed.

Methods: We searched the PubMed, Embase and GWAS Catalog databases for studies indexed between inception and 15 January 2024 describing genetic variants associated with IPF susceptibility. We included studies describing common associated single nucleotide polymorphisms (SNPs). We excluded studies describing rare variants, non-SNP variants and those without an allelic model analysis. We recorded study type, participant characteristics, genotyping methods, IPF diagnostic criteria, the SNPs and the respective genes, odds ratios, and other details. We also searched databases for functions of the identified genes.

Results: The primary search retrieved 2697 publications; we included 42 studies. There were nine genome-wide association/linkage studies, while 27 were candidate gene studies. The studies included 22-11 160 IPF subjects. 88 SNPs in 58 genes or loci were found associated with IPF susceptibility. MUC5B rs35705950 was the most studied SNP. Most (n=51) SNPs were in the intronic or intergenic regions; only 11 were coding sequence variants. The SNPs had odds ratios ranging from 0.27 to 7.82 for an association with IPF. Only 22 SNPs had moderate-large effects (OR >1.5 or <0.67). Only 49.1% of the associated genes have a known functional role in IPF; the role of G protein-related signalling and transcriptional regulation (zinc-finger proteins) remain unexplored.

Conclusion: Several common SNPs in over 50 genes have been found associated with IPF susceptibility. These variants may inform gene panels for future studies (PROSPERO CRD42023408912).

FIGURE 1

Study selection. GWAS: genome-wide association study; IPF: idiopathic pulmonary fibrosis; SNP: single nucleotide polymorphism.

FIGURE 2

Genes found to be associated with idiopathic pulmonary fibrosis (IPF) in the reviewed studies grouped by their proven or proposed effects on various cellular functions involved in IPF pathogenesis (courtesy of Dr. Dharambir Kashyap).