Association between Variations in Cell Cycle Genes and Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating and progressive lung disease. Its aetiology is thought to involve damage to the epithelium and abnormal repair. Alveolar epithelial cells near areas of remodelling show an increased expression of proapoptotic molecules. Therefore, we investigated the role of genes involved in cell cycle control in IPF. Genotypes for five single nucleotide polymorphisms (SNPs) in the tumour protein 53 (TP53) gene and four SNPs in cyclin-dependent kinase inhibitor 1A (CDKN1A), the gene encoding p21, were determined in 77 IPF patients and 353 controls. In peripheral blood mononuclear cells (PBMC) from 16 healthy controls mRNA expression of TP53 and CDKN1A was determined.Rs12951053 and rs12602273, in TP53, were significantly associated with survival in IPF patients. Carriers of a minor allele had a 4-year survival of 22% versus 57% in the non-carrier group (p = 0.006). Rs2395655 and rs733590, in CDKN1A, were associated with an increased risk of developing IPF. In addition, the rs2395655 G allele correlated with progression of the disease as it increased the risk of a rapid decline in lung function. Functional experiments showed that rs733590 correlated significantly with CDKN1A mRNA expression levels in healthy controls.This is the first study to show that genetic variations in the cell cycle genes encoding p53 and p21 are associated with IPF disease development and progression. These findings support the idea that cell cycle control plays a role in the pathology of IPF. Variations in TP53 and CDKN1A can impair the response to cell damage and increase the loss of alveolar epithelial cells.

Familial pulmonary fibrosis

“…Numerous other polymorphisms, for example on TLR9, have been associated with IPF [93][94][95]. More recently, genome-wide pulmonary fibrosis association studies have not only confirmed the association between IPF and MUC5B, TERT or TERC but have also revealed several new locations of interest [96][97].…”

“…De nombreux autres polymorphismes par exemple sur TLR9 ont été associés à la FPI [93][94][95]. Plus récemment des études d'association génome entier-fibrose pulmonaire ont d'abord confirmé l'association entre la FPI et MUC5B, TERT ou TR mais ont aussi mis en évidence plusieurs nouveaux locus d'intérêt [96][97].…”

Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease

“…associated with rapid progression of idiopathic pulmonary fibrosis, 32 increased risk of death in non-small cell lung cancer, 33 and joint involvement in systemic lupus erythematosus. 34 It is plausible that variants in CDKN1A might play a similar role in disease progression of NAFLD.…”

Genetic susceptibility and pulmonary fibrosis

“…Prior studies have indicated that the abnormalities in the ability of epithelial cells to divide and replace epithelia could be central to the pathophysiology of disease [34-36*], and correspondingly genetic variants in cell cycle genes have been associated with IPF and disease progression [37]. …”