Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis

Abstract

Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are immune-mediated chronic inflammatory diseases of the liver of unknown etiology. Genetic factors appear to be involved in the pathogenesis of both diseases. 1,25-Dihydroxyvitamin D 3 has been implicated as an immunomodulator, which acts through its own receptor (VDR). Polymorphisms of the VDR have been linked to a variety of autoimmune diseases. In this study VDR polymorphisms were analyzed in 123 patients with AIH, 74 patients with PBC, and 214 controls. VDR polymorphisms were assessed by BsmI, TaqI, ApaI, and Fok endonuclease digestion after specific polymerase chain reaction (PCR) amplification. We found a significant association between the BsmI polymorphisms in PBC patients in comparison with controls ( 2 ‫؍‬ 9.49, P ‫؍‬ .009). Furthermore we detected a significant association of the Fok polymorphims in AIH patients in comparison to controls ( 2 ‫؍‬ 9.71, P ‫؍‬ .008) indicating a genetic link of VDR polymorphisms to autoimmune liver diseases such as PBC and AIH in German patients. These findings contribute to the knowledge of the complex events determining immunologic tolerance in the liver. Further studies are needed to elucidate the mechanisms by which the vitamin D receptor contributes to the development of autoimmune diseases. (HEPATOLOGY 2002;35:126-131.) A utoimmune hepatitis (AIH) is an immune-mediated chronic inflammation of the liver of unknown etiology, which is characterized by elevated serum transaminase levels, hypergammaglobulinemia, serum autoantibodies, histologic signs of interface hepatitis, and a response to immunosuppressive treatment. 1,2 Genetic factors appear to be involved in the pathogenesis of AIH. However, a conclusive role of a single genetic locus capable of explaining the etiology of AIH has not been identified thus far, and the genetic background of AIH is therefore considered to be polygenic. In previous studies human leukocyte antigens (HLA) DRB1*0301and DRB*0401 have been identified as independent determinants of susceptibility to AIH. 3,4 In addition, tumor necrosis factor ␣ (TNF-␣) and complement C4 alleles have been associated with AIH, despite the observation that both genes exhibit a strong linkage disequilibrium with the HLA A1-B8-DR3 haplotype. [5][6][7] Polymorphisms of the cytotoxic T-lymphocyte antigen 4 (CTLA4*2) have been identified as non-major histocompatibility complex (MHC) susceptibility determinants in AIH type 1. 8 In a recent analysis we have shown a lack of genetic association between idiopathic autoimmune liver diseases and hepatitis as part of the autoimmune polyendocrine syndrome type 1, which is caused by mutations in the autoimmune regulator (AIRE) gene. 9 In primary biliary cirrhosis (PBC) similar genetic factors have been analyzed to elucidate genetic susceptibility. The genetic typing of HLA class II and III alleles revealed a highly significant increase of HLA DRw8 and C4A-Q0 alleles in patients with PBC compared with controls. 10

1,25-dihydroxyvitamin D3 and its receptor inhibit the chenodeoxycholic acid-dependent transactivation by farnesoid X receptor

“…This may release the suppression of CYP7A1 gene, resulting in the consumption of cholesterol from which D3 is synthesized. The association with BsmI polymorphism was reported in primary biliary cirrhosis (PBC) (Halmos et al 2000, Vogel et al 2002. This polymorphism correlates with the length of singlet (A) repeat in the 3 untranslated region of the VDR gene and affects the expression level of its mRNA (Whitfield et al 2001).…”

Genetic background of autoimmune hepatitis in Japan

“…The vitamin D receptor was reported to be another candidate gene of AIH susceptibility in Germany [33] and China [34], but no such reports have surfaced in Japan.…”

Genes and (auto)immunity in primary biliary cirrhosis

“…We note in fact that accelerated bone loss rates in patients with prolonged cholestasis (as in PBC) have been repeatedly reported, sometimes with conflicting results and in some cases with less than rigorous experimental designs. A significant association between BsmII polymorphisms of VDR and PBC was reported in patients with PBC from Germany, Hungary, and China, 61,[65][66][67] while the proposed association with bone loss 68 was not reproduced. 69 We believe that differences in the VDR gene might unravel further potential scenarios to help explain the infrequency of PBC in African-American women, 70 and could in turn support a possible role for sunlight exposure in PBC onset.…”