Genetics of Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease. IPF is a complex disease, with environmental and genetic factors variably contributing to disease susceptibility and outcomes. A host of common gene variants with modest effect size impart disease risk in patients with sporadic IPF, while rare variants with large effect size influence disease risk in those with familial interstitial pneumonia. In this review, we highlight several common and rare variants underpinning IPF risk and call attention to recently published studies informing our understanding of this risk.

Keywords: Genetics, Medical; Idiopathic pulmonary fibrosis; familial interstitial pneumonia.

Figure 1:

Kaplan-Meier Survival Curves by MUC5B Genotypes, Chicago Cohort. Reproduced from (16). Reprinted with permission from American Medical Association via the Copyright Clearance Center: [JAMA] Peljto AL, Zhang Y, Fingerlin TE, et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. American Medical Association, 2013.

Figure 2:

Composite endpoint-free survival between NAC and placebo groups after stratification by rs3750920 (TOLLIP) genotype. In those with a CC genotype (a), NAC therapy is associated with worse survival than placebo (Plogrank ¼ 0.01; hazard ratio, 3.23; 95% confidence interval, 0.79–13.16; P¼0.10). In those with a CT genotype (b), survival is similar between groups (Plogrank ¼ 0.82; HR 0.76; 95% CI 0.27–2.19; P ¼ 0.62). In those with a TT genotype (c), NAC therapy is associated with improved survival compared with placebo (Plogrank ¼ 0.06; HR 0.14; 95% CI 0.02–0.83; P ¼ 0.03). Multivariable Cox regression models adjusted for age, sex, FVC (percentage predicted), and diffusion capacity of the lung for carbon monoxide (percentage predicted) at time of study enrollment. Reprinted with permission of the American Thoracic Society. Copyright (c) 2018 American Thoracic Society. Oldham JM, Ma SF, Martinez FJ, et al. 2015. TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 192(12):1475. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. Abbreviations: CI, confidence interval; FVC, forced vital capacity; HR, hazard ratio; NAC, N acetylcysteine.