RESUMO
Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists of the thiazolidinedione family are used for the treatment of type 2 diabetes mellitus due to their ability to reduce glucose and lipid levels in patients with this disease. Three thiazolidinediones that were approved for treatment are Rezulin (troglitazone), Avandia (rosiglitazone), and Actos (pioglitazone). Troglitazone was withdrawn from the market due to idiosyncratic drug toxicity. Rosiglitazone and pioglitazone are still on the market for the treatment of type 2 diabetes. The authors present data from a gene expression screen that compares the impact these three compounds have in rats, in rat hepatocytes, and in the clone 9 rat liver cell line. The authors monitored the changes in expression in multiple genes, including those related to xenobiotic metabolism, proliferation, DNA damage, oxidative stress, apoptosis, and inflammation. Compared to the other two compounds, troglitazone had a significant impact on many of the pathways monitored in vitro although no major perturbation was detected in vivo. The changes detected predict not only general toxicity but potential mechanisms of toxicity. Based on gene expression analysis, the authors propose there is not just one but multiple ways troglitazone could be toxic, depending on a patient's environment and genetic makeup, including immune response-related toxicity.
Assuntos
Cromanos/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hipoglicemiantes/toxicidade , Tiazolidinedionas/toxicidade , Animais , Linhagem Celular , Células Cultivadas , Perfilação da Expressão Gênica , Hepatócitos/metabolismo , Hipoglicemiantes/farmacologia , Pioglitazona , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rosiglitazona , Tiazolidinedionas/farmacologia , TroglitazonaAssuntos
Leucina/genética , Osteoporose/genética , Polimorfismo Genético/genética , Prolina/genética , Fator de Crescimento Transformador beta/genética , População Branca/genética , Idoso , Sequência de Aminoácidos , Densidade Óssea/genética , Estudos de Coortes , Feminino , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Análise Multivariada , Osteoporose/epidemiologia , Modelos de Riscos Proporcionais , Fatores de Risco , Fator de Crescimento Transformador beta1 , Estados Unidos/epidemiologiaRESUMO
To assess the utility of linkage disequilibrium (LD) as a tool for fine-mapping disease genes in non-isolated populations, we have assessed the linkage disequilibrium strength among a series of single nucleotide polymorphisms (SNPs) in an approximate 1 Mb region of human chromosome 22q11. Nineteen random SNPs were discovered and tested across this region with an average spacing of 57 kb (range=1.4-289 kb). These 19 SNPs were genotyped in a population consisting of 444 unrelated pedigrees that were largely collected in the U.S. and U.K. Haplotypes for all pedigrees were derived from pedigree data and over 1,400 haplotypes from unrelated individuals were evaluated for linkage disequilibrium between marker alleles. In addition, linkage disequilibrium between marker alleles was also evaluated using estimated haplotypes without genealogical information (i.e., without parental genotype information). Every marker pair combination was tested for a total of 171 tests and 2x2 contingency tables were constructed to measure LD strength. In general the haplotypes derived from pedigree data provided a more conservative estimate of LD strength. Using genealogical information for estimates of D', 59% (10/17) of marker pairs less than 50 kb apart had D' values >0.30. Finally, we observed a 60 kb region with non-significant LD, which could reflect increased recombination in this region.
