VEGF-related polymorphisms identified by GWAS and risk for major depression.

Depression is a common, severe, disabling mental disease that affects millions of people of all ages worldwide. Various studies have shown that neurotrophic/growth factors have a key role in depression and, more specifically, vascular endothelial growth factor (VEGF) is implicated in the pathogenesis of depression. The purpose of this study was to investigate the potential links between four VEGF-related single-nucleotide polymorphisms (SNPs), previously identified through a genome-wide association study (GWAS) and depression. The direct effects and epistatic interactions of the four VEGF-related SNPs (rs10738760, rs6921438, rs6993770 and rs4416670) on depression were investigated through a case-control study including 437 individuals diagnosed with depression and 477 healthy volunteers as controls. Gender, age and body mass index influence was additionally analyzed. The SNP rs4416670 was associated with increased risk for depression (OR: 1.60, P: 0.010). This result demonstrates the existence of relationships between VEGF genetic determinants and depression. This novel association reveals new molecular mechanisms suggesting the potential role of VEGF in depression development that could help to promote a personalized prediction for this severe common disease.

High frequency of CYP2D6 ultrarapid metabolizers in Spain: controversy about their misclassification in worldwide population studies.

A high frequency (7-10%) of CYP2D6 ultrarapid metabolizers estimated from the genotype (gUMs) has been claimed to exist among Spaniards and Southern Europeans. However, methodological aspects such as the inclusion of individuals carrying non-active multiplied alleles as gUMs may have led to an overestimation. Thus, this study aimed to analyze the gUM frequency (considering only those carrying more than two active genes) in 805 Spanish healthy volunteers studied for CYP2D6*2, *3, *4, *5, *6, *10, *17, *35, *41, and multiplications. Second, all worldwide studies reporting gUM frequencies were reviewed in order to evaluate potential misclassifications. The gUM frequency in this Spanish population was 5.34%, but increased to 8.3% if all individuals with CYP2D6 multiplications were classified as gUMs without considering the activity of the multiplied alleles. Moreover, among all reviewed worldwide studies only 55.6% precisely determined whether the multiplied alleles were active. Present results suggest that the evaluation of CYP2D6 ultrarapid metabolism should be standarized, and that the frequency of gUMs should be reconsidered in Spaniards and globally.

Interethnic differences in the relevance of CYP2C9 genotype and environmental factors for diclofenac metabolism in Hispanics from Cuba and Spain.

The aims of this study were to evaluate the diclofenac metabolism in Hispanics from Cuba and Spain and its relation to ethnicity, CYP2C9 genotypes and environmental factors. Diclofenac hydroxylation capacity (concentration ratios of diclofenac/metabolites in 8-h urine) was studied in 160 Cuban (classified as 76 Cuban-Whites-CWs and 84 Cuban-Mestizos-CMs) and 148 Spaniard (SPs) healthy volunteers. Diclofenac and its main metabolites, 4'-hydroxy (OH), 3'-OH and 5-OH diclofenac, and CYP2C9*2 to *6 and *8 alleles were also determined in 132 and 128 CWs and CMs, respectively. Gender, tobacco, caffeine and ethanol consumption were also evaluated. The mean diclofenac/4'-OH diclofenac ratio was higher in CMs (0.72±0.25) than in CWs (0.64±0.20; P<0.05) and SPs (0.57±0.26; P<0.001). The mean diclofenac/4'-OH diclofenac ratio was higher (P<0.05) in subjects with CYP2C9*1/*3 (0.77±0.19; n=22) and CYP2C9*1/*8 (0.93±0.33; n=4) genotypes than with CYP2C9*1/*1 (0.65±0.24; n=90). Environmental factors did not seem to influence the diclofenac metabolism in these populations. The present findings show for the first time interethnic differences between Hispanic groups in urinary diclofenac/4'-OH diclofenac ratios, and the relevance of CYP2C9*3 and CYP2C9*8 alleles.

Increased risk for major depression associated with the short allele of the serotonin transporter promoter region (5-HTTLPR-S) and the CYP2C9*3 allele.

In the present study, we aimed to analyze the potential relevance of the polymorphism in the promoter region of the serotonin transporter (SERT or 5-HTT) gene (5-HTTLPR) and the risk of suffering major depression (MDD) in a population of patients previously genotyped for CYP2C9. Seventy white European psychiatric outpatients suffering from MDD and a group of 142 healthy volunteers (HVs) were studied. The frequency of subjects carrying the 5-HTTLPR-S allele was higher (P < 0.05) among MDD than in HV. The odds ratio associated with 5-HTTLPR-S allele was 2.03 for the MDD patients in comparison with the HV group. Previously, we found in this population that the CYP2C9*3 allele frequency was higher among this population of MDD patients than in HV. The frequency of subjects with the combination 5-HTTLPR-S and CYP2C9*3 alleles was higher (P < 0.01, odds ratio 3.47) in MDD than in HV. The present findings provide preliminary evidence about the greater risk of suffering MDD for individuals carrying both 5-HTTLPR-S and CYP2C9*3 alleles.

Interethnic differences in drug metabolism: influence of genetic and environmental factors on debrisoquine hydroxylation phenotype.

Genetic and environmental factors are determinants of the interindividual and interethnic variability in drug metabolism. The metabolism of several important drugs (e.g. haloperidol) cosegregates with that of debrisoquine. Thus, interethnic differences in debrisoquine hydroxylation polymorphism (CYP2D6) might be partly responsible for the variation in haloperidol disposition between races. The influence of tobacco, ethanol, caffeine, gender, and oral contraceptive use on the debrisoquine metabolic ratio (MR) has been analyzed in 633 Spanish healthy volunteers. MR was also determined in panels of healthy volunteers. 18 smokers were studied during a tobacco abstinence period, and 31 women three times during the same menstrual cycle. Among EMs, debrisoquine MR was significantly (P < 0.05) lower during smoking cessation (mean antilog +/- SD, 0.48 +/- 0.29) compared to a smoking period (0.61 +/- 0.23). During the lutheal phase of the menstrual cycle, debrisoquine MR was also significantly (P < 0.01) lower (0.33 +/- 0.41) compared to the ovulatory-phase (0.41 +/- 0.34) and the phase before ovulation (0.44 +/- 0.36). Among EMs, it is suggested that debrisoquine MR may be modified by tobacco smoking and sexual hormones. The clinical relevance of these findings remains unclear.

Debrisoquin and mephenytoin hydroxylation phenotypes and CYP2D6 genotype in patients treated with neuroleptic and antidepressant agents.

Debrisoquin and S-mephenytoin hydroxylation phenotypes were determined in 72 Spanish psychiatric patients treated with neuroleptic or antidepressant agents. One patient (1.4%) was classified as a poor metabolizer of S-mephenytoin. Between both neuroleptic- and antidepressant-treated patients, the distribution of the debrisoquin metabolic ratio was shifted toward higher values compared with 54 drug-free healthy subjects. Forty percent of patients treated with neuroleptics and 5% of patients treated with antidepressants were classified as poor metabolizers of debrisoquin. CYP2D6 genotype analysis in 36 neuroleptic-treated patients confirmed that the high metabolic ratios were attributable to inhibition of CYP2D6 and not to overrepresentation of subjects with poor metabolizer genotypes. In 48 selected Spanish drug-free subjects, CYP2D6 genotype predicted the phenotype with 95% accuracy. Neuroleptics and antidepressants interfere at therapeutic doses with phenotyping for CYP2D6 but not for S-mephenytoin hydroxylation capacity. In psychotropic-treated patients, genotyping provides a valuable tool for prediction of the CYP2D6 phenotype.

Relationship between personality and debrisoquine hydroxylation capacity. Suggestion of an endogenous neuroactive substrate or product of the cytochrome P4502D6.

We administered the Karolinska Scales of Personality to 225 healthy subjects in Spain selected from a group of 925 individuals previously phenotyped with regard to their capacity to hydroxylate debrisoquine. A significant relationship was found between the scores in as many as 4 of the 15 subscales (psychic anxiety, psychasthenia, inhibition of aggression and socialization) and the debrisoquine hydroxylation capacity. Poor metabolizers were more anxiety-prone and less successfully socialized than extensive metabolizers of debrisoquine. This and a previous study among subjects in Sweden suggest that there may be a relationship between personality and the activity of the enzyme hydroxylating debrisoquine (cytochrome P4502D6). This polymorphic enzyme may have an endogenous neuroactive substrate or product, such as a biogenic neurotransmitter amine.

Debrisoquine oxidation phenotype during neuroleptic monotherapy.

The debrisoquine oxidation phenotype was determined in 91 schizophrenic patients on monotherapy with different neuroleptics and in 67 untreated healthy volunteers. The prevalence of poor metabolizers of debrisoquine was significantly higher in the patients (46.2%) than in the healthy subjects (7.5%). Treatment with phenothiazine antipsychotics (chlorpromazine, levomepromazine and thioridazine) was associated with a higher debrisoquine metabolic ratio than treatment with haloperidol. On the other hand, treatment with clothiapine appeared not to interfere with debrisoquine oxidation. Oral administration of 50 mg thioridazine daily to 8 healthy subjects resulted in a marked increase in the debrisoquine metabolic ratio and 4 of them were transformed into phenotypically poor metabolizers. The results confirm the fact that phenothiazines, and to a lesser extent haloperidol, inhibit the oxidative metabolism of debrisoquine. They show also that clothiapine administration does not disturb the debrisoquine metabolic ratio.

Polymorphic oxidation of debrisoquine in lung cancer patients.

Oxidative polymorphism of debrisoquine (DBQ) was assessed in 84 patients (81 male) with histologically proven bronchogenic carcinoma and in 143 healthy male smokers. 80 (95%) patients and 133 (93%) controls, with a metabolic ratio (MR) below 12.6, were classified as extensive metabolisers of DBQ (no significant difference between patients and controls). Only 1 of the 73 patients with epidermoid or microcytic carcinomas was classified as a poor metaboliser (PM) (P = 0.031 compared with controls). 63 patients (75%) and 110 controls (77%) showed a very fast oxidative rate, with MR values under 1 (not significant). The EM phenotype of DBQ might be a secondary genetic risk factor for developing bronchogenic carcinoma in male smokers.

Polymorphic oxidation of debrisoquine in bladder cancer.

The oxidative polymorphism of debrisoquine has been determined in 125 patients with bladder cancer and in 556 healthy control subjects; 96.6% of patients and 93.9% of controls with a metabolic ratio of debrisoquine less than 12.6 were classified as extensive metabolizers of debrisoquine (P = NS). The distribution of frequencies of metabolic ratio values tended to have lower values in the patients (P less than 0.05), reflecting a higher oxidative rate of debrisoquine in urothelioma patients that cannot be explained solely in terms of enzymatic induction by drugs, tobacco or alcohol. Patients with a high occupational risk for urothelioma had lower metabolic ratio values (P = 0.03). Our results suggest that oxidative polymorphism of debrisoquine might be related to the pathogenesis of bladder cancer.

Oxidative polymorphism of debrisoquine in Parkinson's disease.

Oxidative phenotype and metabolic ratio (MR) of debrisoquine (DBQ) have been determined in 87 patients with Parkinson's disease and in 556 healthy control subjects. Three patients (3.45%) and 34 control subjects (6.12%), having an MR greater than 12.6, were classified as poor metabolisers (PM) of DBQ (ns). The distribution of MR values in the 84 Parkinsonian patients classified as extensive metabolisers (EM) showed a less efficient oxidative rate when compared with controls of the same phenotype (p less than 0.001). This difference may be due to enzymatic inhibition caused by drug treatment in 40 of these patients. As in patients not taking any drug known to inhibit the oxidation of DBQ, distribution of MR values was not different from that in controls. A negative correlation (r = -0.36, p less than 0.02) was found between MR of DBQ and age at onset of disease in patients free of drugs known to interact with DBQ metabolism. A higher rate of DBQ oxidation could be a genetic factor that delays the clinical onset of Parkinson's disease in predisposed people.

Assessment of the debrisoquin and dextromethorphan phenotyping tests by gaussian mixture distributions analysis.

From a sample of 149 unrelated Spaniards, individuals were phenotyped for their ability to hydroxylate debrisoquin and O-demethylate dextromethorphan. The distribution of urinary metabolic ratios for each test was analyzed by univariate gaussian mixture distributions analysis to determine the number of populations, the mean and standard deviation of the metabolic ratios for each population, and the proportion belonging to each population. For the 124 subjects phenotyped with both the debrisoquin and dextromethorphan tests a bivariate analysis was performed. The results demonstrate that both tests similarly separated this sample into two populations, with 10% belonging to poor metabolizer phenotypes. In addition, the correlation between the metabolic ratios from each test is significant, indicating that they are measuring the same biologic trait and the certainty of correctly identifying the debrisoquin oxidation phenotype of an individual is improved by using the results of both tests.

Acetylator polymorphism in Parkinson's disease.

Acetylator phenotype has been determined using sulphamethazine in 100 patients with Parkinson's disease and in 93 age-matched normal control subjects. Sixty-nine patients and 54 control subjects were classified as slow acetylators (NS). No relation was found among acetylator polymorphism and age at onset or clinical stage of disease. Amongst slow acetylators, the percentage of acetylated sulphamethazine in plasma was significantly lower in patients than in controls. Despite this finding, the results do not support any relationship between acetylator polymorphism and the risk of developing Parkinson's disease.

Debrisoquin oxidation polymorphism in a Spanish population.

The capacity for debrisoquin metabolism was determined in 377 healthy Spanish volunteers by measuring the amount of debrisoquin and its main metabolite, 4-hydroxydebrisoquin, in urine after an oral dose of debrisoquin. Debrisoquin oxidation was polymorphic, with 25 subjects (6.6%) phenotyped as poor metabolizers whereas 352 subjects (93.4%) were classified as extensive metabolizers. The metabolic ratio between debrisoquin and 4-hydroxydebrisoquin (percent of dose) in 6-hour urine samples ranged from 0.03 in extensive metabolizers to 93.5 in poor metabolizers. The proportion of poor metabolizers found is in the range observed in other white populations studied.