Gender differences in the association between HTR2C gene variants and suicidal behavior in a Mexican population: a case-control study.

BACKGROUND: The aim of this case-control study was to explore the association by gender between the HTR2C gene variants and suicidal behavior in a Mexican population. SUBJECTS AND METHODS: A total of 183 suicide attempters and 208 healthy volunteers were included in this study. We genotyped five polymorphisms of HTR2C (rs547536, rs2192372, rs4272555, rs6318, and rs2428707), then measured the association by genotype, allele, and haplotype. RESULTS: In the female group, we found an association between two polymorphisms of the HTR2C (rs4272555 and rs2428707) and suicide attempts. The C allele of the single-nucleotide polymorphism (SNP) rs4272555 was associated with a decreased risk of suicide attempt (P=0.01, odds ratio =0.26, 95% confidence interval: 0.09-0.79), whereas the G allele of the SNP rs2428707 was associated with an increased risk of suicide attempt (P=0.01, odds ratio =3.68, 95% confidence interval: 1.24-10.90). No significant association was observed between the other polymorphisms studied (rs547536, rs2192372, rs6318) or haplotypes with suicide attempts. CONCLUSION: These findings suggest a possible risk factor of the HTR2C gene in the pathology of suicidal behavior in Mexican population. More studies are necessary to confirm this association.

Potential drug-drug interaction in Mexican patients with schizophrenia.

OBJECTIVE: The aim of this study was to observe potential drug-drug interactions in the medication of Mexican schizophrenic patients. METHODS: We performed a retrospective and cross-sectional study that was carried out in a psychiatric clinic. Only the prescriptions of patients with schizophrenia whose diagnoses were based on the DSM-IV instrument were included in this study. The Drug Interactions Checker software ( http://www.drugs.com/drug_interactions.html ) was used in this study to analyse potential drug-drug interactions. RESULTS: In total, 86 of 126 patients were at risk of potential drug-drug interactions. Haloperidol and biperiden was the most common drug pair of 232 pairs evaluated. In our study, 13.8% of drug-drug interaction showed a major level of severity, whereas in 83.2%, the interaction was moderate. Finally, central nervous system (CNS) depression and anticholinergic effect were the main possible effects of drug-drug interaction. CONCLUSIONS: Our results revealed a high number of patients with schizophrenia receiving two or more drugs. The potential drug-drug interactions observed in the Mexican population are consistent with the concomitant use of antipsychotics, benzodiazepines, and antidepressants prescribed in schizophrenia that could cause central nervous system (CNS) depression and anticholinergic effect. Drug-drug interaction must be considered when the patient with schizophrenia is medicated.

Differences by gender in completed suicides in a Mexican population: A psychological autopsy study.

OBJECTIVE: Using the method of psychological autopsy, we identified differences by gender in socio-demographic aspects, signs and symptoms, and suicide characteristics in a population of the state of Tabasco. Mexico. METHODS: Between the years 2007-2014, 182 psychological autopsies were documented by the Secretary of Health of the State of Tabasco, Mexico. A structured questionnaire was used to obtain information on socio-demographic aspects and suicide characteristics. RESULTS: The sample was mainly formed by males (78%). 84% of the sample used hanging as suicide method. However, in comparison with the male group, females were older on the average (p = 0.002); they were mostly housewives (37.5%) and had more years of schooling (p = 0.004). Other significant differences predominantly present in the male group were: the use of alcohol at the time of suicide (52.1%), job retirement, and increases in apathy (50.7%) and aggressiveness (36.6%) (p < 0.05). CONCLUSION: Our results suggest that there are differences by gender between subjects with completed suicide. Factors such as alcohol consumption, job retirement, aggressiveness and isolation/social apathy certainly render men more vulnerable to suicide in the Mexican population.

No association between ApoE and schizophrenia: Evidence of systematic review and updated meta-analysis.

INTRODUCTION: Schizophrenia affects between 0.3% and 2% of the worldwide population. A genetic contribution has been postulated in the development of this disorder. Genes such as ApoE have been implicated in the neurodevelopment associated with schizophrenia in case-control and meta-analysis studies, but the results remain inconclusive. Due to this, the aim of the present study was to explore the association between ApoE and schizophrenia through a meta-analysis. MATERIAL AND METHODS: We collected all relevant studies by searching PubMed and EBSCO databases. The pooled odds ratios with 95% confidence intervals were calculated to estimate the association. The following models were evaluated: A) ε4 vs ε3, B) ε4 vs ε2, C) ε4 vs ε3+ε2, D) Caucasian population and E) Asian population. Statistical analyses were performed using EPIDAT 3.1 software. RESULTS: The meta-analyses comprised 28 association studies, which included 4703 controls and 3452 subjects with schizophrenia. A significant protective effect was found for allele ε3 in the Asian population (OR=0.73, 95% CI=0.54-0.98). No significant associations were observed in the other models and populations analyzed. CONCLUSIONS: Our meta-analysis suggests a protective association between ApoE allele ε3 and schizophrenia in the Asian population.

Association analysis of TPH-1 and TPH-2 genes with suicidal behavior in patients with attempted suicide in Mexican population.

BACKGROUND: Suicidal behavior is a worldwide health problem. Tryptophan hydroxylase (TPH) is a rate limiting enzyme in the biosynthesis of serotonergic neurotransmission. TPH-1 and TPH-2 genes encode for TPH isoforms and have been implicated as candidate genes for suicidal behavior. The aim of this study was to evaluate the association between the genetic variants of the TPH-1 (rs21102 and 1607395) and TPH-2 (rs4290270, rs7305115 and rs1007023) genes and suicidal behavior in a Mexican population. METHODS: We conducted a case-control study including 200 cases with suicide attempt and 263 controls. Patients were evaluated by a trained psychiatrist or clinical psychologists. Five polymorphisms were genotyped and assessed for allele, genotype and haplotype association with suicide attempt. RESULTS: The rs7305115 polymorphism of the TPH-2 gene was associated with suicidal behavior in a Mexican population in genotype (χ(2)=6.02, df=2, p=0.04) and allele (OR=1.39, 95%IC=1.06-1.81, p=0.01) frequencies. The THP-2 haplotypes GTA (χ(2)=5.68, p=0.01) and ATT (χ(2)=5.0, p=0.02) were associated with risk for suicide attempt. CONCLUSION: Our results provide evidence for an association between the rs7305115 polymorphism of the TPH-2 gene and suicidal behavior in a Mexican population. However, more studies are necessary to replicate these results using larger samples.

The role of brain-derived neurotrophic factor (BDNF) Val66Met genetic polymorphism in bipolar disorder: a case-control study, comorbidities, and meta-analysis of 16,786 subjects.

OBJECTIVES: The aim of this study was to evaluate the association of Val66Met brain-derived neurotrophic factor (BDNF) polymorphism with bipolar disorder in (i) a meta-analysis and (ii) a case-control study in a Mexican population. We also investigated the possible association of this polymorphism with clinical features. METHODS: We performed a keyword search of the PubMed and Web of Science databases. A total of 22 studies that have investigated the association of Val66Met (rs6265) with bipolar disorder were selected for inclusion and combined with random effects meta-analysis, using allelic, additive, dominant, and recessive models. Finally, the single nucleotide polymorphism (rs6265) Val66Met in the BDNF gene was genotyped and compared between 139 patients with bipolar disorder and 141 healthy volunteers in a Mexican population. RESULTS: The pooled results from the meta-analysis (9,349 cases and 7,437 controls) did not show a significant association in any of the models. The same results were obtained in our case-control study when analyzing the distribution of the genotypic frequencies of the Val66Met polymorphism in patients with bipolar disorder. However, when we analyzed the association between rs6265 and lifetime history of suicidal behavior, we found an association between genotype Val-Val and suicide attempt (p = 0.02). CONCLUSIONS: Although the present study has some limitations, the results indicate a lack of association between the Val66Met polymorphism and bipolar disorder. However, in our case-control study in a Mexican population, the Val66Met polymorphism was associated with suicidal behavior in patients with bipolar disorder. Nevertheless, it is important to consider potential interactions of the BDNF gene, the environment, and different inheritance patterns, when carrying out future genetic studies with larger samples.

Study on genes of the serotonergic system and suicidal behavior: protocol for a case-control study in Mexican population.

BACKGROUND: Suicidal behavior is a leading cause of injury and death worldwide. Several studies have provided a possible relationship between genetic factors and suicidal behavior. Also, these studies have shown evidence for altered serotonergic neural transmission in the pathogenesis of suicidal behavior. In addition, genes pertaining to the serotonergic system have been proposed as candidates to establish biological correlates between suicidal behavior and the serotonergic system. The most studied genes are SCL6A4, HTR2A, HTR2C, HTR1A, HTR1B, TPH-1, and TPH-2. To get a comprehensive understanding of the association with suicidal behavior we will conduct genotype assays studies in a Mexican population. METHODS/DESIGN: We will conduct a case-control study. The population sample will comprise adolescent and adult patients admitted for attempted of suicide and diagnosed by a psychiatrist. A peripheral blood sample will be taken from all the subjects (cases and controls). Genomic DNA from the leukocytes blood sample will be extracted. The genotypes of interest are distributed in the following genes: SCL6A4, HTR2A, HTR1A, HTR1B, HTR2C, TPH-2 and TPH-1. All the samples will be analyzed using a polymerase chain reaction (PCR) end-point method. We will evaluate the Hardy-Weinberg Equilibrium. The chi-squared test or Fisher's exact test will be used to compare genotype and allele frequencies between control and case groups. The Quanto 1.2 software will measure the sample size of the association. For all the association analyses the level of significance will be set at p = 0.05 and the confidence interval at 95%. DISCUSSION: Suicidal behavior has been increase in Mexico, principally in young population. Our study will demonstrate the association between serotoninergic genes and suicide behavior in Mexican population.

Association of 5HTR1A gene variants with suicidal behavior: case-control study and updated meta-analysis.

INTRODUCTION: The gene encoding the serotonin 1A receptor (5HTR1A) has been a candidate gene associated with suicidal behavior in case-control and meta-analysis studies. We carried out a meta-analysis and a case-control study on the 5HTR1A gene to examine the association of this gene with suicidal behavior. METHODS: We performed a systematic search in electronic databases to study meta-analytically the association of 5HTR1A gene with suicidal behavior; we found 9 published genetic association studies concerning the rs6295 polymorphism. To get a comprehensive knowledge of this association we conducted a case-control study on the following polymorphisms: rs1423691, rs6295, and rs878567 in a Mexican population; the sample was composed of 152 suicide attempters and 264 healthy subjects. RESULTS: The meta-analysis revealed that the rs6295 polymorphism is not associated with suicidal behavior. Similarly, no significant association for polymorphisms rs6295 and rs878567 was found in the case-control study. The polymorphism rs1423691 was excluded of the association analysis because cases and control groups were in Hardy-Weinberg disequilibrium. CONCLUSION: The meta-analysis of functional rs6295 polymorphisms produced no association. Likewise, the analysis in our case-control study in a Mexican population resulted in lack of association of polymorphisms rs6295 and rs878567 with suicidal behavior. However, further studies assessing different populations, as well as larger samples are necessary to obtain conclusive outcomes.

Distribution of the Val108/158Met polymorphism of the COMT gene in healthy Mexican population.

Catechol-O-methyltransferase (COMT) inactivates the catecholamines adrenaline, noradrenaline and dopamine. On the other hand, some studies have reported that the enzymatic activity of COMT is partly genetically determined. With regard to the COMT gene, the most studied polymorphism is the functional variant Val108/158Met (rs4680), which results in substantial three- to four-fold variations in enzyme activity. To date, the rs4680 polymorphism of COMT has been associated with a number of disorders. In addition, this polymorphism has been found to have important differences in frequency according to the studied population. Therefore, the aim of the present study was to evaluate the frequency of a common single nucleotide polymorphism (SNP) Val108/158Met of the COMT gene in the Mexican population. Accordingly, we recruited 431 healthy volunteers. Our sample consisted of 111 healthy individuals from Mexico City and 320 individuals from the state of Tabasco, Mexico. We observed that Met was the most common allele, ranging from 57% (Tabasco) to 85% (Mexico City). In addition, we analyzed the frequency of Val108/158Met polymorphism of Caucasian (54% Met allele), Asian (29% Met allele) and African (34% Met allele) populations separately and also in comparison with Mexican (63% Met allele) population. In conclusion, the distribution of the Val108/158Met polymorphism distinguishes the Mexican population studied from other populations, but it is necessary to increase the size of the sample to get more conclusive results.

Association of the 5HTR2A gene with suicidal behavior: case-control study and updated meta-analysis.

BACKGROUND: The polymorphism rs6313 (T102C) has been associated with suicidal behavior in case-control and meta-analysis studies, but results and conclusions remain controversial. The aim of the present study was to examine the association between T102C with suicidal behavior in a case-control study and, to assess the combined evidence - this case-control study and available data from other related studies - we carried out a meta-analysis. METHODS: We conducted a case-control study that included 161 patients with suicide attempts and 244 controls; we then performed a meta-analysis. The following models were evaluated in the meta-analysis: A) C allele vs T allele; B) T allele vs C allele; C) Caucasian population, D) Asian population, and E) suicide attempters with schizophrenia. RESULTS: We found an association between attempted suicide and control participants for genotype (χ2=6.28, p=0.04, df=2) and allele (χ2=6.17, p=0.01, df=1, OR 1.48 95% IC: 1.08-2.03) frequencies in the case-control study. The meta-analysis, comprising 23 association studies (including the present one), showed that the rs6313 polymorphism is not associated with suicidal behavior for the following comparisons:T allele vs C allele (OR: 1.03; 95% CI 0.93-1.13; p(Z)=0.44); C allele vs T allele: (OR:0.99; 95% CI: 0.90-1.08; p(Z)=0.22); Caucasians (OR:1.09; 95% CI: 0.96-1.23), and Asians (OR:0.96; 95% CI: 0.84-1.09). CONCLUSION: Our results showed association between the rs6313 (T102C) polymorphism and suicidal behavior in the case-control study. However, the meta-analysis showed no evidence of association. Therefore, more studies are necessary to determine conclusively an association between T102C and suicidal behavior.

No association between catechol-o-methyltransferase Val108/158Met polymorphism and schizophrenia or its clinical symptomatology in a Mexican population.

The gene coding for catecol-o-methyltransferase (COMT), participant in the metabolism of catecholamines, has long been implicated as a candidate gene for schizophrenia. We determined the relation of the COMT Val108/158Met polymorphism with schizophrenia or its symptomatology (negative, disorganized and psychotic dimension). We conducted a case-control study comprising 186 patients with schizophrenia and 247 controls. The diagnosis of schizophrenia was established using the DSM-IV criteria for this illness. The clinical symptomatology was assessed through the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. No significant differences were found in the distribution of alleles (χ2 = 0.01, df = 1, p = 0.90) or genotypes (χ2 = 1.66, df = 2, p = 0.43) between schizophrenic patients and the control group. Multivariate analysis showed that the COMT Val108/158Met polymorphism has no influence in the clinical symptomatology of schizophrenia. Our results showed no association between COMT Val108/158Met and schizophrenia or evidence for an association between COMT and the clinical symptomatology of this illness. This suggests that the COMT gene may not contribute to the risk for schizophrenia among the Mexican population.

The role of clinical variables, neuropsychological performance and SLC6A4 and COMT gene polymorphisms on the prediction of early response to fluoxetine in major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) is treated with antidepressants, but only between 50% and 70% of the patients respond to the initial treatment. Several authors suggested different factors that could predict antidepressant response, including clinical, psychophysiological, neuropsychological, neuroimaging, and genetic variables. However, these different predictors present poor prognostic sensitivity and specificity by themselves. The aim of our work is to study the possible role of clinical variables, neuropsychological performance, and the 5HTTLPR, rs25531, and val108/58Met COMT polymorphisms in the prediction of the response to fluoxetine after 4weeks of treatment in a sample of patient with MDD. METHODS: 64 patients with MDD were genotyped according to the above-mentioned polymorphisms, and were clinically and neuropsychologically assessed before a 4-week fluoxetine treatment. Fluoxetine response was assessed by using the Hamilton Depression Rating Scale. We carried out a binary logistic regression model for the potential predictive variables. RESULTS: Out of the clinical variables studied, only the number of anxiety disorders comorbid with MDD have predicted a poor response to the treatment. A combination of a good performance in variables of attention and low performance in planning could predict a good response to fluoxetine in patients with MDD. None of the genetic variables studied had predictive value in our model. LIMITATIONS: The possible placebo effect has not been controlled. Our study is focused on response prediction but not in remission prediction. CONCLUSIONS: Our work suggests that the combination of the number of comorbid anxiety disorders, an attentional variable, and two planning variables makes it possible to correctly classify 82% of the depressed patients who responded to the treatment with fluoxetine, and 74% of the patients who did not respond to that treatment.

Using msa-2b as a molecular marker for genotyping Mexican isolates of Babesia bovis.

Variable merozoite surface antigens of Babesia bovis are exposed glycoproteins having a role in erythrocyte invasion. Members of this gene family include msa-1 and msa-2 (msa-2c, msa-2a(1), msa-2a(2) and msa-2b). To determine the sequence variation among B. bovis Mexican isolates using msa-2b as a genetic marker, PCR amplicons corresponding to msa-2b were cloned and plasmids carrying the corresponding inserts were purified and sequenced. Comparative analysis of nucleotide and deduced amino acid sequences revealed distinct degrees of variability and identity among the coding gene sequences obtained from 16 geographically different Mexican B. bovis isolates and a reference strain. Clustal-W multiple alignments of the MSA-2b deduced amino acid sequences performed with the 17 B. bovis Mexican isolates, revealed the identification of three genotypes with a distinct set each of amino acid residues present at the variable region: Genotype I represented by the MO7 strain (in vitro culture-derived from the Mexico isolate) as well as RAD, Chiapas-1, Tabasco and Veracruz-3 isolates; Genotype II, represented by the Jalisco, Mexico and Veracruz-2 isolates; and Genotype III comprising the sequences from most of the isolates studied, Tamaulipas-1, Chiapas-2, Guerrero-1, Nayarit, Quintana Roo, Nuevo Leon, Tamaulipas-2, Yucatan and Guerrero-2. Moreover, these three genotypes could be discriminated against each other by using a PCR-RFLP approach. The results suggest that occurrence of indels within the variable region of msa-2b sequences can be useful markers for identifying a particular genotype present in field populations of B. bovis isolated from infected cattle in Mexico.

Phylogenetic analysis of Mexican Babesia bovis isolates using msa and ssrRNA gene sequences.

Variable merozoite surface antigens of Babesia bovis are exposed glycoproteins having a role in erythrocyte invasion. Members of this gene family include msa-1 and msa-2 (msa-2c, msa-2a(1), msa-2a(2), and msa-2b). Small subunit ribosomal (ssr)RNA gene is subject to evolutive pressure and has been used in phylogenetic studies. To determine the phylogenetic relationship among B. bovis Mexican isolates using different genetic markers, PCR amplicons, corresponding to msa-1, msa-2c, msa-2b, and ssrRNA genes, were cloned and plasmids carrying the corresponding inserts were sequenced. Comparative analysis of nucleotide and deduced amino acid sequences revealed distinct degrees of variability and identity among the coding gene sequences obtained from 12 geographically different B. bovis isolates and a reference strain. Overall sequence identities of 47.7%, 72.3%, 87.7%, and 94% were determined for msa-1, msa-2b, msa-2c, and ssrRNA, respectively. A robust phylogenetic tree was obtained with msa-2b sequences. The phylogenetic analysis suggests that Mexican B. bovis isolates group in clades not concordant with the Mexican geography. However, the Mexican isolates group together in an American clade separated from the Australian clade. Sequence heterogeneity in msa-1, msa-2b, and msa-2c coding regions of Mexican B. bovis isolates present in different geographical regions can be a result of either differential evolutive pressure or cattle movement from commercial trade.

msa-1 and msa-2c gene analysis and common epitopes assessment in Mexican Babesia bovis isolates.

Babesia bovis msa-1 and msa-2c genes belong to the variable merozoite surface antigen gene family. These genes code for antigenic proteins present on the merozoite surface (MSA) and are involved in the parasite invasion to the bovine erythrocyte. Previous studies carried out on MSA-1 have evidenced antigen allelic variation in B. bovis isolates from similar endemic regions, as well as in isolates from different geographic regions of the world (Argentina, Australia, Israel). Studies conducted on MSA-2c, however, have shown that this antigen is widely conserved on isolates from distinct geographic regions. In this study, it was hypothesized that MSA-1 and MSA-2c antigens would contain common epitopes despite the presence of nucleotide sequence differences found in 13 B. bovis isolates and strains collected in geographically distant regions of Mexico. Bioinformatics analysis of the primary structure from DNA fragments derived from PCR amplification, cloning, and sequencing of msa-1 and msa-2c genes from the 13 B. bovis populations revealed that the msa-1 gene product present in the various isolates tested is less conserved among isolates obtained within a similar geographic region in Mexico (51-99.7% sequence identity). Results obtained by immunoblot analysis of B. bovis protein extracts reacted with a monoclonal antibody to MSA-1 42-kDa antigen, conclusively showed cross-reactive common epitopes only in Mexican isolates having high sequence identity (>/=99%, eight isolates). Sequence analysis and multiple alignment of deduced MSA-2c demonstrated a high degree of sequence identity (90-100%) among the Mexican B. bovis isolates and strains. Immunoblot results using a polyclonal antibody to MSA-2c reacted against the protein extracts recognized conserved epitopes in at least nine of the B. bovis isolates. The results obtained in this study agree with those previously reported by other researchers and confirm that, based in sequence identity conservation in Mexican B. bovis isolates and strains so far collected and analyzed, MSA-2c represents an ideal antigen worth evaluating as a vaccine candidate.