Polimorfismos genéticos relacionados à via da vitamina D em pacientes com cirrose com ou sem carcinoma hepatocelular

Abstract

Cirrhosis, liver disease characterized by fibrosis, may progress to hepatocellular carcinoma (HCC). Vitamin D deficiency has been linked to the severity of chronic liver disease. It is also worth mentioning the involvement of genetic factors in the transport and metabolism of vitamin D, which should be clarified in cirrhosis and HCC. Objective - To evaluate the association of genetic polymorphisms of the vitamin D binding protein (DBP-rs4588 and DBP-rs7041) and the cytochrome P450 family 24 subfamily A member 1 (CYP24A1-rs6013897), in patients with cirrhosis with or without CHC, considering profile clinical-demographic, serum vitamin D and survival. Casuistic and Methods - We studied 383 subjects, including Group Total patients (GTotal: N=158) with cirrhosis with or without CHC, distributed in Group 1 (G1): 60 with cirrhosis and CHC and Group 2 (G2): 98 with cirrhosis, and the control group without hepatopathies (G3: N=225). Genetic polymorphisms were analyzed by real-time PCR. Clinical-demographic profile and life habits were obtained by questionnaire and medical record. A 5% error was acepted. Results – Male gender was highlighted in all groups. For DBP-rs4588, the wild homozygous genotype (C/C) prevailed in the groups, particularly in woman G3 (56.1%; G1=20%; P=0.0440). Also, for this polymorphism, in G1, genotypes with at least one polymorphic allele (_/A: 80%; G3=43.9%, P=0.0440), as well as allele A (G1=0.50 versus G2=0.21, P=0.0346). The frequency of DBP-rs7041 polymorphism was similar in the groups (P>0.05). For CYP24A1-rs6013897, the wild-type homozygous (A/A) genotype predominated in G2 (11.2%; G1=1.7%; P=0.0309), in which patients genotypes highlight with at least one allele polymorphic (_/T: G1=98.3%; G2=88.8%, P=0.0309). Linkage disequilibrium showed allelic association between DBP-rs4588-DBP-rs7041 pairs in patients and controls (P=0.00000). CG haplotype was observed in patients (45.9%) and controls (51.3%), followed by AT and CT (P>0.05). Subgroups of patients and controls showed similarity to serum levels of vitamin D and parathyroid hormone (PTH) (P>0.05). Genotypes of DBP-rs4588 with at least one polymorphic allele (_/A) were associated with reduced levels of vitamin D in patients (77.8%; controls=14.3%, P=0.0406), and increased vitamin D in controls (76.9%) compared to the wild-type genotype (C/C: 23.1%, P=0.0166). There was a moderate positive correlation between vitamin D and PTH only in GTotal (R2=0.3273). Highlight as cirrhosis independent factors smoking, alcoholism and diabetes mellitus (DM), as well as for cirrhosis with CHC, except smoking, also adding age advancement, male gender, polymorphic allele of CYP24A1-rs6013897 (_/T), viral hepatitis and altered serum levels of gamma-glutamyl transpeptidase (GGT), alpha-fetoprotein (AFP) and creatinine. Survival increase in GTotal was observed in the presence of the polymorphic allele of DBP-rs7041, however, with significance (P=0.0282) only in the general group (with or without transplantation). Conclusion - DBP-rs4588 (in women) and CYP24A1-rs6013897 polymorphisms are associated with cirrhosis and CHC, also confirm possible predictors of alcoholism, DM, advanced age, CYP24A1-rs6013897, increased level of GGT, AFP, creatinine and viral hepatitis; while smoking, alcoholism and DM for isolated cirrhosis. DBP-rs4588 polymorphism is associated with reduced levels of vitamin D in patients and increased in controls, whereas DBP-rs7041 confers increase survival in patients with cirrhosis with or without CHC.