Integrative omics analysis identifies macrophage migration inhibitory factor signaling pathways underlying human hepatic fibrogenesis and fibrosis.

The genetic basis underlying liver fibrosis remains largely unknown. We conducted a study to identify genetic alleles and underlying pathways associated with hepatic fibrogenesis and fibrosis at the genome-wide level in 121 human livers. By accepting a liberal significance level of P<1e-4, we identified 73 and 71 candidate loci respectively affecting the variability in alpha-smooth muscle actin (α-SMA) levels (fibrogenesis) and total collagen content (fibrosis). The top genetic loci associated with the two markers were BAZA1 and NOL10 for α-SMA expression and FAM46A for total collagen content (P<1e-6). We further investigated the relationship between the candidate loci and the nearby gene transcription levels (cis-expression quantitative trait loci) in the same liver samples. We found that 44 candidate loci for α-SMA expression and 44 for total collagen content were also associated with the transcription of the nearby genes (P<0.05). Pathway analyses of these genes indicated that macrophage migration inhibitory factor (MIF) related pathway is significantly associated with fibrogenesis and fibrosis, though different genes were enriched for each marker. The association between the single nucleotide polymorphisms, MIF and α-SMA showed that decreased MIF expression is correlated with increased α-SMA expression, suggesting that variations in MIF locus might affect the susceptibility of fibrogenesis through controlling MIF gene expression. In summary, our study identified candidate alleles and pathways underlying both fibrogenesis and fibrosis in human livers. Our bioinformatics analyses suggested MIF pathway as a strong candidate involved in liver fibrosis, thus further investigation for the role of the MIF pathway in liver fibrosis is warranted. The study was reviewed and approved by the Institutional Review Board (IRB) of Wayne State University (approval No. 201842) on May 17, 2018.