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Genetic dominance of transforming growth factor-β1 polymorphisms in chronic liver disease.

ABSTRACT: Chronic liver disease (CLD) is an extremely common clinical condition accompanied by sustained inflammatory response leading to tissue damage. Transforming growth factor-β1 (TGF-β1) is known as a master immune regulator in CLDs, but the association between TGF-β1 polymorphisms and CLD risk is controversial and inconclusive, and the genetic dominance of CLDs remains unknown. In this study, the relationship between TGF-β1 polymorphisms and CLD susceptibility is systematically analyzed based on 35 eligible studies. Individuals with the TGF-β1-509 allele (TT or CT) or codon 10 allele (Pro/Pro) show an increased risk of CLDs. Subgroup analyses indicate TGF-β1-509C/T has a significant correlation with cirrhosis and chronic hepatitis C, codon 10 is associated with chronic hepatitis B occurrence, and codon 25 exhibits a relationship with autoimmune hepatitis risk. Missense mutations in G29E, A105S, D191N, and F321L of TGF-β1 are the genetic factors of HCC susceptibility. Furthermore, the TGF-β1 gene expression is significantly elevated in CLD patients, and the TGF-β1 codon 263 is located close to the region where the TGF-β1 dimerization interacts, indicating the TGF-β1 codon 263 variant may affect the secretion of TGF-β1 by altering its dimerization. Together, our findings provide new insights into the immune regulator gene TGF-β1 polymorphisms as susceptibility factors for CLD occurrence and regulators for TGF-β1 expression, which have implications for the regulation of immune factors during CLD development.

SUBMITTER: Cai X

PROVIDER: S-EPMC9708878 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Genetic dominance of transforming growth factor-β1 polymorphisms in chronic liver disease.

Cai Xuanyan X Zha Huiyan H Yang Zhaoxu Z Du Yiwen Y Dai Xiaoyang X Yang Bo B Wang Jiajia J He Qiaojun Q Weng Qinjie Q

Frontiers in immunology 20221116

Chronic liver disease (CLD) is an extremely common clinical condition accompanied by sustained inflammatory response leading to tissue damage. Transforming growth factor-β1 (TGF-β1) is known as a master immune regulator in CLDs, but the association between TGF-β1 polymorphisms and CLD risk is controversial and inconclusive, and the genetic dominance of CLDs remains unknown. In this study, the relationship between <i>TGF-β1</i> polymorphisms and CLD susceptibility is systematically analyzed based ...[more]

PMID: 36466817

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Project description:Fabry disease is a lysosomal storage disorder (LSD) caused by deficiency of α-galactosidase A (α-gal A), resulting in deposition of globotriaosylceramide (Gb3; also known as ceramide trihexoside) in the vascular endothelium of many organs. A gradual accumulation of Gb3 leads to cardiovascular, cerebrovascular and renal dysfunction. Endothelial cell dysfunction leads to renal complications, one of the main symptoms of Fabry disease. However, the pathological mechanisms by which endothelial dysfunction occurs in Fabry disease are poorly characterized. The purpose of this study was to investigate whether the expression of transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF) is associated with the renal pathogenesis of Fabry disease. We found that the protein expression levels of renal thrombospondin-1 (TSP-1), TGF-β1 and VEGF were higher in the kidneys from Fabry mice compared to wild-type mice. The expression levels of VEGF receptor 2 (VEGFR2), fibroblast growth factor-2 (FGF-2) and phospho-p38 (P-p38) were also higher in the kidneys from Fabry mice compared with wild-type mice. Activities of cysteine aspartic acid protease (caspase)-6 and caspase-9 were higher in kidneys from Fabry than from the wild-type mice. These results suggest that overexpression of TGF-β1 and VEGF in the Fabry mouse kidney might contribute to Fabry disease nephropathy by inducing apoptosis. To test whether Gb3 accumulation can induce apoptosis, we incubated bovine aortic endothelial cells with Gb3 and found increased expression of TGF-β1, VEGFR2, VEGF, FGF-2 and P-p38. The combination of increased expression of TGF-β1 and VEGF caused by Gb3 accumulation may allow upregulation of FGF-2, VEGFR2 and P-p38 expression, and these changes may be associated with Fabry disease nephropathy by inducing apoptosis.

Dataset Information

Genetic dominance of transforming growth factor-β1 polymorphisms in chronic liver disease.

Publications

Genetic dominance of transforming growth factor-β1 polymorphisms in chronic liver disease.

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