RESUMO
BACKGROUND: Traditionally, medication dosage was based on clinical and demographic parameters, but drug metabolism was recently recognized as an important factor for proper dosing and prediction of side effects. Metabolic considerations are crucial when administering drugs with a narrow therapeutic index, such as those of the thioguanides family (azathioprine and 6-MP). These can cause life-threatening myelosuppression due to low activity of a critical metabolic enzyme, thiopurine S-methyl transferase. A number of single nucleotide substitutions encoding variant enzymes account for most enzyme deficiencies. OBJECTIVES: To determine the frequency of individuals from different Israeli ethnic groups who may be at risk for drug toxicity from drugs of the thioguanide family due to enzymatic variants. METHODS: DNA analysis was performed using polymerase chain reaction methods. We tested TPMT allelic variants TPMT*3A (G460A, A719G), TPMT*3B (G460A) and TPMT*3C (A719G) in five subpopulations in Israel: mixed-origin Israeli Jews, Arabs, Druze, Jews of Kurdish extraction, and Ethiopian Jews. RESULTS: The Druze (P = 0.0002) and Ethiopian Jewish (P = 0.015) subpopulations had a significantly unique distribution of allelic variants compared to the rest of the Israeli population. The Druze subpopulation showed a high number of TPMT variants with decreased activity, and a homozygote for TPMT*3A/ *3A was detected. Ethiopian Jews were found to carry mainly the TPMT*3C variant, also observed in other studies of African populations. CONCLUSIONS: It is advisable that Druze patients be tested for the TPMT enzyme before starting treatment with 6-MP or azathioprine. Such testing may also be considered for other Israeli ethnic subgroups.
Assuntos
Etnicidade/genética , Frequência do Gene/genética , Metiltransferases/genética , Reação em Cadeia da Polimerase/métodos , Humanos , IsraelRESUMO
Drug metabolism/disposition and transporter genes may influence predisposition or prognosis of AML (acute myeloid leukemia) patients. We analyzed polymorphisms in 3 transporters and 4 drug metabolism genes in 293 Israeli individuals (112 AML patients and 181 controls). We analyzed: ABCC3 (MRP3) C-211T; ABCG2 (BCRP) C421A; CNT1 (SLC28A1) G565A and NAT1, NAT2, and GSTT1 and GSTM1 null alleles for influence on predisposition, as well as treatment response and survival. We found that the ABCC3 C-211T polymorphism and GSTM1 null genotype have adverse prognostic significance in AML. None of the other polymorphisms studied were found to influence either predisposition or prognosis in Israeli AML patients.
Assuntos
Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/genética , Proteínas de Membrana Transportadoras/genética , Polimorfismo Genético/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Arilamina N-Acetiltransferase/genética , Primers do DNA , Feminino , Predisposição Genética para Doença , Genótipo , Glutationa Transferase/genética , Humanos , Isoenzimas/genética , Israel/epidemiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Recent studies have examined the relationship between polymorphic alleles of the MDR1 gene and the course of HIV. Such polymorphisms may alter the metabolism of antiretroviral medications or influence susceptibility to HIV infectivity. We therefore studied a polymorphism in MDR1 (C3435T), and the CYP3A4*1B variant allele, the latter of which has not been previously studied in HIV. Ninety-six patients of either Ethiopian (57) or Caucasian (39) ethnicity and 276 controls were studied including serial CD4 counts, clinical course, and AIDS-defining illnesses. For both ethnic groups, the C allele of MDR1 C3435T was highly associated with being infected with HIV (p < 0.0001) compared to controls, but genotype did not influence change in CD4 counts over time in the patients, whether or not they were treated with antiretrovirals. CYP3A4*1B was also significantly associated with being infected with HIV (p < 0.0001) both in heterozygotes and in homozygotes for the polymorphism, but only for Ethiopians (p < 0.023 compared to Caucasians, p = 0.44). CYP3A4*1B did not influence CD4 count or AIDS defining illnesses. We conclude that in Israeli patients, polymorphisms in drug metabolism and disposition genes may influence infectivity of HIV but do not influence the course of the disease. Larger studies are needed to confirm these findings.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Sistema Enzimático do Citocromo P-450/genética , Soropositividade para HIV/genética , Polimorfismo Genético , Adulto , Idoso , Contagem de Linfócito CD4 , Citocromo P-450 CYP3A , Progressão da Doença , Etnicidade , Feminino , Soropositividade para HIV/sangue , Humanos , Israel , Masculino , Pessoa de Meia-IdadeRESUMO
NAD(P)H:quinone oxidoreductase (NQO1) detoxifies quinones. The NQO1*2 variant enzyme (codon 609 C-->T, encoding a proline to serine substitution) with greatly reduced activity has been reported to predispose to acute myeloid leukemia (AML). Our aim was to examine the relationship between NQO1*2 and AML in Israeli patients. We analyzed for NQO1*2 in 262 adult Israeli patients with de novo AML and 688 controls of the same ethnic groups (Arabs, and Caucasian and Ethiopian Jews). Our analysis showed significant differences in the frequencies of NQO1*2 by ethnic group (p=0.000068). However, NQO1*2 frequencies did not differ between AML patients and controls. Karyotype was not found to be associated with NQO1*2. In Israeli patients, NQO1*2 does not predispose to de novo AML.
Assuntos
Variação Genética , Leucemia Mieloide/genética , NAD(P)H Desidrogenase (Quinona)/genética , Doença Aguda , Frequência do Gene , Israel/epidemiologia , Israel/etnologia , Epidemiologia MolecularRESUMO
The optimal tyrosine kinase inhibitor for any individual patient with chronic myeloid leukemia (CML) is not predictable. Pharmacogenetic parameters and trough levels of imatinib (IM) have each been independently correlated with response. We therefore studied the human organic cation transporter (hOCT1) and multidrug resistance (MDR1) single nucleotide polymorphisms (SNPs) and correlated these with IM levels and major molecular response (MMR) (3-log reduction) in 84 patients with CML, the first such study performed in Caucasians. We studied MDR1 G2677T and C3435T, and for hOCT1, C480G and A1222G. IM levels varied significantly with dose (< or > 400 mg/day) (p = 0.038) and were significantly lower in 20 patients who lost MMR (p = 0.042). Adjusting for dose, trough IM levels were not significantly correlated with SNPs. Patients with MDR1 3435 TT had significantly longer times to MMR compared to CC/CT genotypes (p = 0.047). Genotypes did not predict treatment failure when controlling for IM levels. We conclude that IM levels, but not the SNPs studied here, determine IM failure.