Association Of Estrogen Receptor Gene Polymorphism And Primary Biliary Cirrhosis

Background: Primary biliary cirrhosis (PBC) is one kind of chronic autoimmunal liver disease, with characteristics of biliary tract epidermic inflammatory and endothelial cells proliferation. Liver cirrhosis will be the end of this disease. Nowadays, it is considered that factors such as heredity, environment, infection and so on play significant roles in PBC etiology, especially genetic contributions. The major auto-antigen recognized by the immune system is defined as E2 component of pyruvate dehydrogenase complex (PDC-E2). The presence of such antibodies and the infiltration of T lymphocytes in the portal areas suggest that immunological disorder has a close relationship with the genesis and progression of PBC. Both female predominancy (F: M ratio 9:1) and the higher incidence of women from pre-menopause to post-menopause raise us the question of some possibility that estrogen attributes to the pathogenesis of PBC. The intracellular action of estrogens is regulated by estrogen receptor (ER). Previous studies demonstrated that estrogen and its receptors cause bile ducts destruction and cholangiocytes proliferation. Nonetheless, there is still no clear relationship between estrogen and PBC. Estrogen receptor genes can alter transcripting level, structure and function of estrogen receptor in the way of changing its nucleotide sequences, which makes it probable that estrogen receptor genes are candidate genes of estrogen causative disease. Several single nucleotide polymorphisms on ESR1 and ESR2 genes have been associated with a range of hormone sensitive diseases, for example, breast cancer and endometriosis. Variations in estrogen receptor genes might also influence the development of PBC, and one case-control study has found an association between two ESR1 polymorphisms and PBC, thus we examined the role of common genetic variants in estrogen receptor genes on the risk of PBC in a case-control study in the northest of China.Aim: To investigate whether the gene polymorphism of estrogen receptor is associated with pathology of primary biliary cirrhosis in the Northeast of China.Methods: 36 primary biliary cirrhosis patients (case group) and 35 healthy people (control group) from northeast of China were studied. The whole genome DNA was extracted from subjects of all participants. Three SNPs (rs2234693, rs2228480, rs3798577) from ESR1 and two (rs1256030, rs1048315) from ESR2 were analyzed. Odds of developing PBC across SNPs were calculated usingχ2 test, and the association between allele frequence and liver function was analyzed in the way of logistic regression.Results: (1) The C/T allele frequency of ESR2 rs1256030 is different between case group and control group (χ2=3.8616,P=0.0495,OR=2.1277,95%CI=1.1872~4.5517). Those with T allele are 1.5 times higher risk in developing PBC than those with C allele. (2) The frequency of genotype TGC (ESR1 rs2234693, rs2228480, rs3798577)in case groups are significantly different from control group(χ2=6.582 , P=0.0103 , OR=3.386 ,95%CI=1.287~8.907). The greauency of genotype TAC in case groups is significantly different from control group(χ2=8.712,P=0.0032,OR=0.152,95%CI=0.038~0.616)。(3)Among PBC patients, the ratio of C/T and the distribution of CC/CT/TT on ESR1 rs2234693 are related with liver function (χ2=6.6498, P=0.0099 andχ2=11.9673, P=0.0025, respectively). The genotypes TGC (P=0.0103, OR=3.386, 95%CI=1.287~8.907) is risk for PBC; but genotype TAC (P=0.0032, OR=0.152, 95%CI=0.038~0.616) may be protective. The genotypes TAC (P=0.0268, OR=7.109, 95%CI=1.004~50.308) are dangerous factors for cholestasis; genotype TGT might be helpful for delivering ALP (P=0.0107, OR=0.250, 95%CI=0.083~0.750); genotype TAT is probably adverse for delivering GGT (P=0.0344, OR=0.002, 95%CI=0.000~0.039).Conclusion:1. The single nucleotide polymorphism of ESR2 is associated with primary biliary cirrhosis.2. ESR2 rs1256030 T allele may be a dangerous factor for primary biliary cirrhosis. 3. ESR1 rs2234693 is associated with liver function of patients with PBC. C allele may be a potential risk factor for primary biliary cirrhosis.4. Among haplotypes of ESR1 rs2234693, rs2228480, rs3798577, genotype TGC is risk for PBC; but genotype TAC may be protective. The genotype TAC is a dangerous factor for cholestasis; genotype TGT might be helpful for delivering ALP (P=0.0107, OR=0.250, 95%CI=0.083~0.750); genotype TAT is probably adverse for delivering GGT (P=0.0344, OR=0.002, 95%CI=0.000~0.039).