The Significance of Vitamin D Receptor Gene Polymorphisms for Susceptibility to Hepatocellular Carcinoma in Subjects Infected with Hepatitis C Virus

Abstract

Introduction Vitamin D has pivotal immunomodulatory actions and emerging roles in hepatic pathophysiology, inflammatory and metabolic liver diseases. It is considered as a systemic hormone that is involved in metabolism, immune regulation, fibrogenesis and cancer development through its actions on Vitamin D receptor (VDR), an intracellular nuclear hormone receptor; subfamily 1, group1, member 1 (NR111) which interacts with target genes producing a variety of biological conformational changes [1]. VDR gene is located on chromosome 12q13.11; highly polymorphic contains eleven exons and spans about 75kb [2]. Also, it has been previously well established that vitamin D exerts an array of tissue and cell specific antitumor activities [e.g. cell cycle arrest, cell adhesions, inhibition of cancer cell invasion, anti-proliferation, pro-apoptosis, anti-angiogenesis, pro-differentiation] on many cancer cells expressing VDR [3]. Vitamin D-binding protein (DBP) and 25-hydroxy-vitamin D3 (25-OHD3) are mainly synthesized in the liver. Vitamin D has many direct effects on the liver (e.g. anti-fibrotic and expression of detoxifying enzymes). An association has been established between low levels of vitamin D3 and several diseases including viral hepatitis and cancer development. Low serum levels of 25-OHD3 were proved to be associated with increased liver fibrosis in patients with non-alcoholic steatohepatitis [4] and type 2 diabetes mellitus [5] and reported to be associated with high risk of HCC development [6]. Moreover, the serum level of 25-OHD3 had been reported to affect the natural course and treatment response of chronic hepatitis C [7]. Higher vitamin D concentrations were proved to be associated with better prognosis and improved outcomes of adverse health problems [8]. Despite the reported mechanisms supporting the beneficial effects of Vitamin D3 supplementation, the total benefits of its supplementation remain ambiguous. Abstract Background: Vitamin D has emerging roles in fibrogenesis, cell cycle arrest, immune modulation, and tumorigenesis. Several single nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR) gene are associated with tumorigenesis in various organs.