RESUMO
Aim: To evaluate the effects of gene polymorphisms in the treatment of erythema nodosum leprosum with prednisone/thalidomide. Patients & methods: A total of 152 patients from different regions of Brazil were included. Generalized estimating equation was used to evaluate the influence of polymorphisms and haplotypes on the drug dose variation throughout the treatment. Results: An association between the genotype tuberculoid of polymorphism ABCB1 3435C>T (rs1045642; p = 0.02) and prednisone dose was found in the recessive model. An association between the haplotypes 1031T/-863C/-857C/-308A/-238G (p = 0.006) and 1031T/-863C/-857T/-308A/-238G (p = 0.040) of the TNF gene and the CYP2C19*2 polymorphism were also identified, in relation to thalidomide dosage variation over the course of treatment. Conclusion: This work presents the first pharmacogenetic report of association between gene polymorphisms and erythema nodosum leprosum treatment with prednisone/thalidomide.
Assuntos
Citocromo P-450 CYP2C19/genética , Eritema Nodoso/tratamento farmacológico , Fator de Necrose Tumoral alfa/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Brasil/epidemiologia , Relação Dose-Resposta a Droga , Eritema Nodoso/genética , Eritema Nodoso/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos/genética , Humanos , Masculino , Polimorfismo Genético , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Receptores de Glucocorticoides/genética , Talidomida/administração & dosagem , Talidomida/efeitos adversosRESUMO
Thalidomide is one of the most potent teratogens known to humans. It is currently used for many clinical situations such as treatment of leprosy reactions and multiple myeloma. However, the teratogenic mechanisms by which it produces morphological defects still remain unclear. One of the hypotheses is the blockage of angiogenesis by reduction of nitric oxide (NO). In this study, we evaluated two functional polymorphisms of the endothelial nitric oxide synthase (eNOS) gene which is a constitutively expressed enzyme responsible for production of NO. The promoter -786T>C exon 7 (896G>T) polymorphisms were genotyped using real-time PCR for 28 individuals with thalidomide embryopathy (TE), 27 first-degree relatives of these individuals, and 68 individuals from the general population. Their allele, genotypic, and haplotypic frequencies were compared. A significant difference was observed in the -786T>C polymorphism genotypes (p=0.03) between the groups affected by TE and those unaffected (non-relatives). The TT genotype of the 896G>T polymorphism was observed in 10.7% of those affected and 2.9% of those unaffected, but the difference was not statistically significant (p=0.09). The haplotypic analysis indicated that the wild haplotype -786T/896G was distributed differently in the affected and unaffected groups (p=0.004). These results indicate that the individuals with TE have a higher frequency of alleles associated with lower expression of eNOS, indicating that this may be a genotype susceptible to TE.