OBJECTIVE: To explore the contribution of gene variants and derived haplotypes of the pregnane X receptor (NR1I2) to the severity of nonalcoholic fatty liver disease (NAFLD). METHODS: A total of 290 individuals were evaluated in a case-control association study, including 188 NAFLD patients with different stages of disease severity and 102 healthy individuals. Four tag single nucleotide polymorphisms (SNPs; rs12488820 C/T, rs2472671 C/T, rs2461823 A/G, and rs1054191 A/G) encompassing 36 kb in chromosome 3 and representing 33 polymorphic sites (r2>0.8) were genotyped. Four additional SNPs (rs3814055, rs3814057, rs6785049, and rs7643645) were also included because they showed earlier evidence of functionality. RESULTS: Genotypic tests for single SNPs showed that rs7643645 and rs2461823 were significantly associated with disease severity by ordinal multinomial analysis (P<0.0015 and 0.039, respectively). A significant association was also observed under the additive model for both variants (P<0.00038 and 0.012, respectively). Consistent with the analysis of individual markers, we observed that the multimarker composed of rs2461823/A-rs7643645/G was significantly associated with disease severity (P<6.9 x 10(-5), beta: 0.45). In addition, the rs7643645/G variant was significantly associated with ALT level (P<0.026), a surrogate marker of severe liver injury. Finally, in univariate analysis rs7643645/G was significantly associated with fatty liver disease (P<0.04), with an odds ratio of 1.457 (95% confidence interval: 1.018-2.086). CONCLUSION: Our study suggests that pregnane X receptor polymorphisms and related haplotypes may contribute to disease severity in NAFLD by influencing the individual susceptibility to progress to more severe stages of the disease.
OBJECTIVE: To explore the contribution of gene variants and derived haplotypes of the pregnane X receptor (NR1I2) to the severity of nonalcoholic fatty liver disease (NAFLD). METHODS: A total of 290 individuals were evaluated in a case-control association study, including 188 NAFLD patients with different stages of disease severity and 102 healthy individuals. Four tag single nucleotide polymorphisms (SNPs; rs12488820 C/T, rs2472671 C/T, rs2461823 A/G, and rs1054191 A/G) encompassing 36 kb in chromosome 3 and representing 33 polymorphic sites (r2>0.8) were genotyped. Four additional SNPs (rs3814055, rs3814057, rs6785049, and rs7643645) were also included because they showed earlier evidence of functionality. RESULTS: Genotypic tests for single SNPs showed that rs7643645 and rs2461823 were significantly associated with disease severity by ordinal multinomial analysis (P<0.0015 and 0.039, respectively). A significant association was also observed under the additive model for both variants (P<0.00038 and 0.012, respectively). Consistent with the analysis of individual markers, we observed that the multimarker composed of rs2461823/A-rs7643645/G was significantly associated with disease severity (P<6.9 x 10(-5), beta: 0.45). In addition, the rs7643645/G variant was significantly associated with ALT level (P<0.026), a surrogate marker of severe liver injury. Finally, in univariate analysis rs7643645/G was significantly associated with fatty liver disease (P<0.04), with an odds ratio of 1.457 (95% confidence interval: 1.018-2.086). CONCLUSION: Our study suggests that pregnane X receptor polymorphisms and related haplotypes may contribute to disease severity in NAFLD by influencing the individual susceptibility to progress to more severe stages of the disease.
Authors: Tasmin Reuter; Rolf Warta; Dirk Theile; Andreas D Meid; Juan Pablo Rigalli; Carolin Mogler; Esther Herpel; Niels Grabe; Bernd Lahrmann; Peter K Plinkert; Christel Herold-Mende; Gerhard Dyckhoff; Walter Emil Haefeli; Johanna Weiss Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2015-07-04 Impact factor: 3.000
Authors: Heather B Clair; Christina M Pinkston; Shesh N Rai; Marian Pavuk; Nina D Dutton; Guy N Brock; Russell A Prough; Keith Cameron Falkner; Craig J McClain; Matthew C Cave Journal: Toxicol Sci Date: 2018-07-01 Impact factor: 4.849
Authors: Matthew C Cave; Heather B Clair; Josiah E Hardesty; K Cameron Falkner; Wenke Feng; Barbara J Clark; Jennifer Sidey; Hongxue Shi; Bashar A Aqel; Craig J McClain; Russell A Prough Journal: Biochim Biophys Acta Date: 2016-03-04
Authors: Krisstonia Spruiell; Ricardo M Richardson; John M Cullen; Emmanuel M Awumey; Frank J Gonzalez; Maxwell A Gyamfi Journal: J Biol Chem Date: 2013-12-20 Impact factor: 5.157