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

ABSTRACT: 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 (?-SMA) levels (fibrogenesis) and total collagen content (fibrosis). The top genetic loci associated with the two markers were BAZA1 and NOL10 for ?-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 ?-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 ?-SMA showed that decreased MIF expression is correlated with increased ?-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.

SUBMITTER: Liu Z

PROVIDER: S-EPMC7500331 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Liu Zhipeng Z Chalasani Naga N Lin Jingmei J Gawrieh Samer S He Yuan Y Tseng Yan J YJ Liu Wanqing W

Journal of bio-X research 20190301 1

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 <i>P</i><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 assoc ...[more]

PMID: 32953199

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Project description:Autistic spectrum disorders are childhood neurodevelopmental disorders characterized by social and communicative impairment and repetitive and stereotypical behavior. Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity that promotes monocyte/macrophage-activation responses by increasing the expression of Toll-like receptors and inhibiting activation-induced apoptosis. On the basis of results of previous genetic linkage studies and reported altered innate immune response in autism spectrum disorder, we hypothesized that MIF could represent a candidate gene for autism spectrum disorder or its diagnostic components.Genetic association between autism spectrum disorder and MIF was investigated in 2 independent sets of families of probands with autism spectrum disorder, from the United States (527 participants from 152 families) and Holland (532 participants from 183 families). Probands and their siblings, when available, were evaluated with clinical instruments used for autism spectrum disorder diagnoses. Genotyping was performed for 2 polymorphisms in the promoter region of the MIF gene in both samples sequentially. In addition, MIF plasma analyses were conducted in a subset of Dutch patients from whom plasma was available.There were genetic associations between known functional polymorphisms in the promoter for MIF and autism spectrum disorder-related behaviors. Also, probands with autism spectrum disorder exhibited higher circulating MIF levels than did their unaffected siblings, and plasma MIF concentrations correlated with the severity of multiple autism spectrum disorder symptoms.These results identify MIF as a possible susceptibility gene for autism spectrum disorder. Additional research is warranted on the precise relationship between MIF and the behavioral components of autism spectrum disorder, the mechanism by which MIF contributes to autism spectrum disorder pathogenesis, and the clinical use of MIF genotyping.

Dataset Information

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

Publications

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

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