The impact of COMT gene polymorphisms on suicidality in treatment resistant major depressive disorder--a European multicenter study.

Many association studies have reported associations between the catechol-O-methyltransferase (COMT) gene and psychiatric disorders including major depression (MDD). The COMT gene has further been associated with suicidal behaviour, as well as with treatment response, although with conflicting results. In the present study, we further elucidate the impact of COMT in treatment response in MDD patients with suicide risk and/or a personal history of suicide attempts. Two hundred fifty MDD patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for seven SNPs (rs4680, rs2075507, rs737865, rs6269, rs4633, rs4818 and rs165599) within the COMT gene. With regard to suicide risk and personal history of suicide attempts, neither single marker nor haplotypic association was found with any SNP after multiple testing correction. In non-responders, we found significant single marker and haplotypic association with suicide risk, but not in responders. The same holds true for both remitters and non-remitters, and when testing for association with a personal history of suicide attempts and treatment response phenotypes. In conclusion, we found significant association of COMT SNPs with suicide risk in MDD patients not responding to antidepressant treatment. Larger well-defined cohorts will be required to dissect this further.

Catechol-O-methyltransferase (COMT) genetic polymorphism in a Turkish population.

Catechol-O-methyltransferase (COMT) inactivates neurotransmitters, catechol hormones and drugs such as levodopa and methyldopa. A low activity allele has been demonstrated at codon 108/158 of the soluble and membrane-bound COMT, respectively, whereby a G to A transition results in a valine to methionine substitution. Ethnic and inter-individual differences in red blood cell COMT activity have been observed in the different populations studied so far. Since, no information is available on inter-individual variability of COMT genotype in Turkish population, we genotyped 217 healthy, unrelated Turkish individuals. The allelic frequencies of COMT gene in the Turkish population were found to be the same as has been observed in Caucasians, but different from Orientals.

Comparison of genotoxicity of sevoflurane and isoflurane in human lymphocytes studied in vivo using the comet assay.

In the present paper, we report data on the possible genotoxic properties of two inhalation anaesthetics--sevoflurane (SVF) and isoflurane (ISF) - in peripheral blood lymphocytes of patients before, during and after anaesthesia as compared to an unexposed control group. Both anaesthetics were evaluated for genotoxic activity using the comet assay. The exposed groups consisted of 24 ASA grades 1-2 unpremedicated patients (aged 20-66 years, anaesthetized 115-162 min for elective lower abdominal surgery), while the control group consisted of 12 healthy individuals. After induction of anaesthesia (thiopenthone sodium 5-7 mg/kg, fentanyl citrate 0.1mg and vecuronium bromide 0.1mg/kg), anaesthesia was maintained with inhalation of SVF 1-1.5% (n=12) or ISF 1-1.5% (n=12) in oxygen-air mixture. Venous blood samples were obtained before the induction of anaesthesia, at 60 and 120 min of anaesthesia and on the first, third and fifth days following anaesthesia. The comet assay detects DNA damage which includes strand breaks and alkaline labile sites induced directly by genotoxic agents as well as DNA degradation due to cell death. One hundred cells from each sample were examined and graded as no tailed, short and long tailed nuclei. The mean comet response was not different between controls and patients before anaesthesia. However, similar significant increases were observed in the mean comet response in blood sampled from patients at 60 (36.5+/-11.2, 37.8+/-12.1), or 120 min (53.1+/-17.1, 50.0+/-12.2) of anaesthesia and on the first day (37.8+/-15.1, 35.2+/-15.7) after anaesthesia in SVF and ISF treated groups, respectively. Removal of the DNA damage was observed after the third day of anaesthesia and the repair was completed within 5 days. The DNA damage detected in lymphocytes of patients during anaesthesia with SVF or ISF showed similar results as demonstrated by an increased mean comet migration at 120 min of anaesthesia and the cells were able to repair the induced DNA damage completely on the fifth postoperative day.

Influence of GSTM1 genotype on comet assay and chromosome aberrations after induction by bleomycin in cultured human lymphocytes.

Investigators have demonstrated that the mutagen sensitivity assay, based on the quantification of bleomycin (BLM)-induced chromatid breaks in short-term cultured peripheral lymphocytes, can be a marker of cancer susceptibility. Although many factors can contribute to variability in human biomonitoring studies, genetic susceptibility (the influence of polymorphic metabolising genes on response to environmental mutagens) should be considered whenever appropriate. Glutathione-S-transferases (GSTs) encode a family of detoxifying phase II enzymes catalysing the conjugation of glutathione to electrophilic compounds. Studies on Caucasians indicate that about 45% of individuals lack the glutathione-S-transferase M1 (GSTM1, null) enzyme, and are therefore, theoretically at a higher risk to the toxic effects of chemicals. The aim of the present study was to investigate this hypothesis further by evaluating whether the GSTM1 genotype influences the background [corrected] level of DNA damage and the induction of chromosomal aberrations by BLM in peripheral-blood lymphocytes. The alkaline comet assay was used to evaluate background levels of DNA damage in unstimulated lymphocytes while standard cytogenetic techniques were used in mitogen-stimulated lymphocytes treated with BLM. Without BLM treatment, individuals with the GSTM1 null genotype had no significant difference in frequencies of damaged cells by comparison to individuals with the GSTM1 genotype. Also, no significant differences between the two groups of individuals (GSTM1 positive and GSTM1 null) were observed for BLM-induced chromosomal aberrations.