Genetic regulation of gene expression of MIF family members in lung tissue

Laura Florez-Sampedro,Barbro N Melgert,Maarten Van Den Berge,Maaike De Vries,Philippe Joubert,Cornelis J Vermeulen,Alen Faiz,Corry-Anke Brandsma,David C Nickle,Gerrit J Poelarends,Ma’En Obeidat,Wim Timens,Rene Bults

doi:10.1038/s41598-020-74121-w

Abstract

Macrophage migration inhibitory factor (MIF) is a cytokine found to be associated with chronic obstructive pulmonary disease (COPD). However, there is no consensus on how MIF levels differ in COPD compared to control conditions and there are no reports on MIF expression in lung tissue. Here we studied gene expression of members of the MIF family MIF, D-Dopachrome Tautomerase (DDT) and DDT-like (DDTL) in a lung tissue dataset with 1087 subjects and identified single nucleotide polymorphisms (SNPs) regulating their gene expression. We found higher MIF and DDT expression in COPD patients compared to non-COPD subjects and found 71 SNPs significantly influencing gene expression of MIF and DDTL. Furthermore, the platform used to measure MIF (microarray or RNAseq) was found to influence the splice variants detected and subsequently the direction of the SNP effects on MIF expression. Among the SNPs found to regulate MIF expression, the major LD block identified was linked to rs5844572, a SNP previously found to be associated with lower diffusion capacity in COPD. This suggests that MIF may be contributing to the pathogenesis of COPD, as SNPs that influence MIF expression are also associated with symptoms of COPD. Our study shows that MIF levels are affected not only by disease but also by genetic diversity (i.e. SNPs). Since none of our significant eSNPs for MIF or DDTL have been described in GWAS for COPD or lung function, MIF expression in COPD patients is more likely a consequence of disease-related factors rather than a cause of the disease.

Highlights

Sputum, and in macrophages present in bronchoalveolar lavage of COPD patients compared to healthy smokers and c ontrols[10,11]
The primary objective of this study was to evaluate gene expression of the migration inhibitory factor (MIF) family members MIF, DDT and DDTL in lung tissue of COPD patients compared to non-COPD subjects and to elucidate whether MIF expression in lung tissue is regulated genetically by SNPs
We found higher gene expression levels of MIF and DDT in lung tissue samples of COPD patients, compared to non-COPD subjects

Summary

Introduction

Sputum, and in macrophages present in bronchoalveolar lavage of COPD patients compared to healthy smokers and (non-smoker) c ontrols[10,11]. It was reported that the MIF-794 CATT5 allele was associated with a lower diffusion capacity in COPD patients[15]. Genetic variation may explain some of the differences found for MIF expression in COPD and may influence disease severity as defined by the level of diffusion capacity. To date, nothing is known about the biological function of DDTL or its expression in lung tissue. It is important to attain more clarity on the levels and regulation of MIF and other MIF family members in lung tissue in COPD. We aimed to investigate the gene expression levels of the MIF family members MIF, DDT and DDTL in lung tissue of patients with and without COPD and to assess whether their gene expression is regulated by single nucleotide polymorphisms (SNPs)

Objectives

Methods

Results

Conclusion