There is an extra sequence in the middle of the sFxr ligand binding domain (LBD) compared with the LBD of FXR␣. Luciferase reporter assays demonstrated that sFxr responds weakly to scymnol sulfate, bile salts, and synthetic FXR␣ ligands, in striking difference from human FXR␣ (hFXR␣). Interestingly, all-trans retinoic acid was capable of transactivating both hFXR␣ and sFxr. When the extra amino acids in the sFxr LBD were deleted and replaced with the corresponding sequence from hFXR␣, the mutant sFxr gained responsiveness to ursodeoxycholic acid, GW4064, and fexaramine. Surprisingly, chenodeoxycholic acid antagonized this activation. Together, these results indicate that FXR is an ancient nuclear receptor and suggest that FXR␣ may have acquired ligand specificity for bile acids later in evolution by deletion of a sequence from its LBD. Acquisition of this property may be an example of molecular exploitation, where an older molecule is recruited for a new functional role. nuclear receptor; structure/function relationship NUCLEAR RECEPTORS PLAY CRITICAL roles in development and physiology by sensing cellular levels of steroid hormones and dietary metabolites, although the true ligands for many of these receptors have not yet been identified or may even not exist. It has been demonstrated that nuclear receptors have shifted or gained their ligand specificity during evolution (4, 10); however, it remains to be determined how most nuclear receptors have acquired their ligand specificity and when this occurred in the course of evolution.FXR␣ (NR1H4) and FXR␤ (NR1H5) represent two forms of the farnesoid X receptor (FXR) in mammals, although FXR␤ is a pseudogene in humans and other primates (23). FXR␣ and FXR␤ are members of the class I nuclear receptors, which heterodimerize with the retinoid X receptors (RXR, NR2B) and regulate gene expression. FXRs share the typical structure of other members in this family, including an activation function domain 1 (AF1) at the N-terminus, followed by a conserved DNA binding domain (DBD), a ligand binding domain (LBD) that also contains an activation function domain 2 (AF2) at the C-terminus, as well as a hinge region that links the DBD and LBD (11). FXR␣ and FXR␤ share ϳ50% amino acid identity, but their ligand specificity does not overlap (23).

Single-nucleotide polymorphisms in the human leukocyte antigen (HLA)-DQB1 gene are associated with chronic inflammatory and immunological diseases. Host genetic factors have a key role in the development of chronic hepatitis B (CHB). The aim of the present study was to investigate the association between the HLA-DQB1 polymorphisms and the susceptibility to CHB. PubMed, Embase, CNKI and Wanfang databases were searched for the studies that reported the association of the HLA-DQB1 polymorphisms with CHB between January 1, 1966 and July 30, 2015. HLA-DQB1 polymorphism-specific odds ratio (OR) and 95% confidence intervals (95% CI) were pooled and calculated in the fixed effects model using the Mantel-Haenszel method. Q-test and I2 test were performed to examine the heterogeneity. Begg's funnel test and Egger's test were conducted to assess publication bias. All the statistical tests were two-tailed. Subsequent to searching the databases and screening according to the inclusion criteria, 7 case-control studies were available in the present meta-analysis, including 815 CHB patients and 731 control subjects for the HLA-DQB1 polymorphisms. In conclusion, the statistically significant pooled OR of the HLA-DQB1 polymorphisms were obtained for the HLA-DQB1 loci (*0201, case vs. control: I2=36.5%; P-value of heterogeneity=0.15; OR, 1.29; 95% CI, 1.02–1.64; P=0.0301; *0301, case vs. control: I2=0%; P-value of heterogeneity=0.899; OR, 1.37; 95% CI, 1.12–1.69; P=0.002; *0502, case vs. control: I2=24.9%; P-value of heterogeneity=0.239; OR, 1.50; 95% CI, 1.02–2.20; P=0.04), which were associated with an increased risk of CHB. Similar significant results were observed and acquired in the following HLA-DQB1 loci (*0303, case vs. control: I2=0%; P-value of heterogeneity=0.986; OR, 0.77; 95% CI, 0.62–0.95; P=0.017; *0604, case vs. control: I2=0%; P-value of heterogeneity=0.594; OR, 0.38; 95% CI, 0.20–0.74; P=0.003), which were associated with a decreased risk of CHB. No significant association was observed for the other HLA-DQB1 family loci. The present meta-analysis demonstrated that the HLA-DQB1 loci (*0201, *0301 and *0502) polymorphisms were significantly associated with an increased risk of CHB. However, HLA-DQB1 loci polymorphisms (*0303 and *0604) were associated with a decreased risk of CHB. These results support the hypothesis that polymorphisms of the HLA-DQB1 allele families may affect the susceptibility or resistance to CHB.