Shared SNPs regulating gene expression of MIF And DDTL in lung tissue
Cellular and molecular mechanisms (English)The macrophage migration inhibitory factor (MIF) family, which includes MIF and D-dopachrome tautomerase (DDT or MIF-2), has been associated with chronic lung diseases. Presence of its best-known member, MIF, was shown to be significantly higher in bronchoalveolar lavage and lung tissue of patients with chronic obstructive pulmonary disease (COPD) compared to control individuals. However, it is still unclear whether MIF and its family members, as well as associated receptors, are involved in COPD pathology and whether they are genetically regulated. Additionally, there is a gene coding for a protein known as DDT-like (DDTL) that has a high sequence identity with DDT and shares properties with the MIF family, but its function is still unknown. Our aim was to investigate whether single nucleotide polymorphisms (SNPs) regulate gene expression of MIF family members, including DDTL, and associated receptors.
We performed an expression quantitative trait loci (eQTL) analysis for MIF, DDT, DDTL, and MIF receptors CD74 and CXCR4 in 1087 lung tissue samples from the Lung eQTL consortium from the University Medical Center Groningen, University of British Columbia and University of Laval. The stepwise approach of the eQTL analysis and replication in the Lung GTEx dataset is shown in the diagram (Figure 1).
Significant eQTL SNPs (eSNPS) (FDR < 0.05) were found for MIF (72 SNPs covering 7 LD blocks) and DDTL (134 SNPs covering 11 LD blocks), with FDR values as low as 2.1E10-56 and 0, respectively. We replicated these 206 eSNPs with the online GTEx database and confirmed 57 of 72 eSNPs for MIF and 34 of 134 eSNPs for DDTL in lung tissue. When comparing the eSNPs for both genes, it was apparent that all 34 eSNPs confirmed for DDTL were also confirmed eSNPs for MIF. Among these 34 eSNPs there were at least three large LD blocks and independent signals for rs140188 and rs1006771.
Our results show that both MIF and DDTL gene expression in lung tissue is strongly regulated by genetic variants. The large overlap in genetic variants suggests a common regulatory mechanism for MIF and DDTL. Future studies are necessary to determine whether these eSNPs are present in COPD patients and to elucidate the biological function of DDTL.
Stepwise approach of the eQTL analysis and replication in the Lung GTEx dataset