Association Study for 26 Candidate Loci in Idiopathic Pulmonary Fibrosis Patients from Four European Populations.

Amit Kishore,Gernot Zissel,Jana Petrkova,Vladimíra Loštáková,Martin Petrek,Dominique Valeyre,Joachim Müller-Quernheim,Veronika Žižková,Evangelos Bouros,Demosthenes Bouros,Hilario Nunes,Vitezslav Kolek,Lenka Kocourková

doi:10.3389/fimmu.2016.00274

Abstract

Idiopathic pulmonary fibrosis (IPF) affects lung parenchyma with progressing fibrosis. In this study, we aimed to replicate MUC5B rs35705950 variants and determine new plausible candidate variants for IPF among four different European populations. We genotyped 26 IPF candidate loci in 165 IPF patients from four European countries, such as Czech Republic (n = 41), Germany (n = 33), Greece (n = 40), France (n = 51), and performed association study comparing observed variant distribution with that obtained in a genetically similar Czech healthy control population (n = 96) described in our earlier data report. A highly significant association for a promoter variant (rs35705950) of mucin encoding MUC5B gene was observed in all IPF populations, individually and combined [odds ratio (95% confidence interval); p-value as 5.23 (8.94–3.06); 1.80 × 10−11]. Another non-coding variant, rs7934606 in MUC2 was significant among German patients [2.85 (5.05–1.60); 4.03 × 10−4] and combined European IPF cases [2.18 (3.16–1.50); 3.73 × 10−5]. The network analysis for these variants indicated gene–gene and gene–phenotype interactions in IPF and lung biology. With replication of MUC5B rs35705950 previously reported in U.S. populations of European descent and indicating other plausible polymorphic variants relevant for IPF, we provide additional reference information for future extended functional and population studies aimed, ideally with inclusion of clinical parameters, at identification of IPF genetic markers.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive form of fibrosing interstitial pneumonia of unknown cause that predominantly affects lung parenchyma, leading to progressive worsening of dyspnea and lung function [1]
Besides characterizing their major functions, e.g., in regulating production of mucins (MUC5B and MUC2) or of pro-inflammatory cytokines (IL-1, IL-8) and in cell signaling and innate immunity processes (TLR3 and TOLLIP) involved in inflammatory and profibrotic pathways, we have described the approach for their simultaneous investigation using a novel mass spectrometry based matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) multiplexed genotyping assay and reported their gene frequencies in healthy Czech (European) population [15]
There, we suggested the wider application of the data from this report for association studies among genetically homogenous populations following the recommendation of STrengthening the REporting of Genetic Association studies (STREGA) [16]

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive form of fibrosing interstitial pneumonia of unknown cause that predominantly affects lung parenchyma, leading to progressive worsening of dyspnea and lung function [1]. Recent bioinformatics approaches yielded a genomic model that accurately predicted high- and low-risk IPF patients using a list of 118 IPF prognostic predictor genes, many of those with immune-, T-cell-related functions [14] In aggregate, these reports implicated involvement of multiple genetic factors in IPF development and emphasized the need for their evaluation in different populations to decipher the plausible pathobiological mechanism of IPF. In context of the above efforts, we have recently identified and reported 26 IPF-associated candidate loci [15] Besides characterizing their major functions, e.g., in regulating production of mucins (MUC5B and MUC2) or of pro-inflammatory cytokines (IL-1, IL-8) and in cell signaling and innate immunity processes (TLR3 and TOLLIP) involved in inflammatory and profibrotic pathways (http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4585032/table/T1/), we have described the approach for their simultaneous investigation using a novel mass spectrometry based matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) multiplexed genotyping assay and reported their gene frequencies in healthy Czech (European) population [15]. In our decision we reflected recommendations of HLA-NET network group for usage of geographical and/or cultural criteria to describe human populations [19] and our own observations of substantial degree of homogeneity in distribution of immune-related gene variants within European populations, including Greeks [20]

Objectives

Methods

Results

Discussion

Conclusion