Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion. Objectives:To improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations. Methods and measurements:We performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Main results:We identified and replicated three new genome-wide significant (P<5×10 −8 ) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility. Conclusions:Novel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

Identification of a novel missense variant inSPDL1associated with idiopathic pulmonary fibrosis

“…2), with a case frequency of 6.9% and a control frequency of 3.0% (p = 9.97 x 10 -16 ; OR, 3.13). Taking Despite its relatively strong effect size, the SPDL1 locus has not been previously reported in IPF through prior GWAS with larger sample sizes (Table S3) 4 . Because of known Mendelian genetics contribution to IPF genetic architecture, we tested whether the SPDL1 missense variant may have independently arisen multiple times in Europeans or whether it resides on a common haplotype.…”

“…Furthermore, an improved understanding of genetic risk factors associated with IPF may enable stratification of patients in clinical trials 3 . Genome-wide association studies (GWAS) have implicated common variants at several loci 4 , with the strongest signal mapping to the promoter region of MUC5B 5 .…”

Familial Interstitial Lung Disease

“…Family-based cohort studies have focused primarily on rare genetic variants of large effect in families; however, common genetic variation also contributes to FIP risk. [118][119][120] The available data suggest that common genetic variants linked to IPF risk by linkage 118 or genome-wide association studies, 119 including the MUC5B promoter polymorphism and more than 15 additional loci 119,[121][122][123] have similar effect sizes in familial and sporadic IPF patients. 119,120 As common genetic variants follow complex rather than Mendelian inheritance patterns, genetic testing for common genetic variants does not currently have a role in the clinical evaluation or care of patients with FIP.…”

Sirt1 antisense long non-coding RNA attenuates pulmonary fibrosis through sirt1-mediated epithelial-mesenchymal transition

“…The pathogenesis of IPF is mostly attributed to the fibroblast/myofibroblast trans-differentiation [2] and excessive deposition of extracellular matrix (ECM) components [3]. However, the etiology of IPF is complex [4] and no effective medication is currently available for managing its progression [5]. The pathophysiological mechanisms of its occurrence and development of novel therapeutic strategies is urgently needed.…”