Interaction between three stress-related gene polymorphisms and food addiction increases the risk to develop obesity in a sample of Mexican people attending a nutrition clinic.

Chronic stress exposure impacts negatively in individuals leading to food addiction, overweight or obesity. Stress-genes and their translation products are responsible for the responses of humans to adverse environments. Alterations in stress-genes expression or protein function may induce behaviors as compulsive eating of high-energy containing food, which decreases stress-induced negative feelings. However, chronic stress is not assessed in Mexican population. We analyzed here the association between polymorphisms of CRH, CRHR2 and glucocorticoids (GR, NR3C1) receptor genes with food addiction and obesity and overweight in Mexican patients of a Nutrition Clinic. We recruited 508 individuals of both genders, who accepted to participate in the study at their first visit to the clinic, obtaining their fat mass percentage and a blood sample for the genetic analysis. Participants answered the Yale's food addiction scale and were subjected to a Trier social test, as an acute stressful stimulus. Pre and post-test saliva samples were obtained to evaluate cortisol levels and adrenal axis' response to the acute stress. The 63% of participants classified as stressed (S); 6.5% of normal-weight individuals showed food-addiction, whereas 63% of participants with food-addiction were also stressed. The fat mass percentage was greater in stress-addiction than in stressed non-addiction participants. The best interaction model for obesity development risk comprehended the presence of polymorphisms of the three genes that in combination with food addiction increased the risk for developing obesity 2.8-4-fold. Thus, frequent stress exposure favors food-addiction, which along with genetic susceptibility seems to add up to Mexican obesity/overweight rates.

Effect of CRHR1 and CRHR2 gene polymorphisms and childhood trauma in suicide attempt.

Family, twin, and adoption studies have suggested that genetic factors might be involved in suicidal behavior. Corticotropin-releasing receptor type 1 (CRHR1) and 2 (CRHR2) genes play a key role in the activation and modulation of the hypothalamic-pituitary-adrenal (HPA) axis, which is considered a major stress regulator. Childhood trauma is an environmental risk factor associated with suicide attempt (SA) and it has been related to HPA axis dysregulation. This study aimed at analyzing the relationship of CRHR1 and CRHR2 genes with childhood trauma concerning the development of SA. In this study, we included 366 affective disorder patients. Among them, 183 patients had SA at least once and 183 had not SA. Information regarding SA and childhood trauma was obtained from medical records. Multifactor Dimensionality Reduction program was used to detect gene-environment interactions between CRHR1 (rs110402, rs242924, and rs16940665) and CRHR2 (rs2190242, rs2284217, and rs2014663) with childhood trauma in SA. The analysis showed an interaction of CRHR1 and CRHR2 with childhood trauma, thus conferring increased risk of having presented at least one SA (OR 7.44; 95% CI 4.58-12.07; p < 0.0001). In addition, we observed the following in the trauma subtypes analysis: physical negligence (OR 4.72; 95% CI 3.01-7.40; p < 0.0001), emotional abuse (OR 5.76; 95% CI 3.67-9.05; p < 0.0001), and sexual abuse (OR 5.70; 95% CI 3.62-8.97; p < 0.0001). Our results suggested that genetic variants of CRHR1 and CRHR2 genes in addition to physical negligence, and emotional and sexual abuse, contribute to increase risk of presented at least one SA.

The serotonin transporter 5-HTTPR polymorphism is associated with current and lifetime depression in persons with chronic psychotic disorders.

OBJECTIVE: Variation in the serotonin transporter gene (SLC6A4) promoter region has been shown to influence depression in persons who have been exposed to a number of stressful life events. METHOD: We evaluated whether genetic variation in 5-HTTLPR, influences current depression, lifetime history of depression and quantitative measures of depression in persons with chronic psychotic disorders. This is an association study of a genetic variant with quantitative and categorical definitions of depression conducted in the southwest US, Mexico and Costa Rica. We analyzed 260 subjects with a history of psychosis, from a sample of 129 families. RESULTS: We found that persons carrying at least one short allele had a statistically significant increased lifetime risk for depressive syndromes (P < 0.02, odds ratio 2.18, 95% CI 1.10-4.20). CONCLUSION: The 'ss' or 'sl' genotype at the 5-HTTLPR promoter polymorphic locus increases the risk of psychotic individuals to develop major depression during the course of their illness.

[Effect to the serotonin transporter gene (5-HTT) on personality dimensions in individuals without psychopathology]. / Efecto del gen transportador de la serotonina (5-HTT) sobre las dimensiones de la personalidad en individuos sin psicopatología.

INTRODUCTION: The aim of the present study was to assess the association between the serotonin transporter gene and the Temperament and Character Inventory (TCI) personality dimensions in subjects without psychopathology. METHOD: Fifty seven individuals without psychiatric symptoms were assessed with the SCL-90, and the TCI. In all subjects a peripheral blood sample was taken to determine their genotypes, after informed consent. Three groups were formed according to the 5-HTT genotype: SS, SL and LL, and the TCI results were compared. RESULTS: There was no association among the 5-HTT genotypes and any of the TCI subscales. There were also no statistical differences among any of the three groups divided by genotype only according to the TCI scores, as well as when compared with historical controls. CONCLUSIONS: These results are consistent with other studies that have not found associations among the different measurements of personality and 5-HTT genotypes. Likewise, our data suggest that our sample can be useful as a source of controls for later studies. This is the first study assessing TCI dimensions and the 5-HTT gene in the Mexican population.

Efecto del gen del transportador de la serotonina (5-HTT) sobre las dimensiones de la personalidad en individuos sin psicopatología / Effect to the serotonin transporter gene (5-HTT) on personality dimensions in individuals without psychopathology

Introducción. El presente estudio se realizó con el fin de estudiar el efecto de los genotipos moleculares del transportador de la serotonina (5-HTT) sobre las dimensiones de la personalidad basadas en el Inventario de Temperamento y Carácter (ITC) en personas sin presencia de psicopatología. Métodos. Participaron 57 individuos sin sintomatología psiquiátrica evaluados mediante el SCL-90 y que respondieron además el ITC. A todos se les tomó una muestra de sangre periférica para la determinación de sus genotipos previo consentimiento informado. Se formaron tres grupos según el genotipo del 5-HTT: SS, SL y LL, y se compararon los resultados del ITC entre cada grupo. Resultados. No se encontró relación entre los genotipos del 5-HTT y ninguna de las subescalas del ITC. Tampoco se pudieron demostrar diferencias entre ninguno de los tres grupos de acuerdo únicamente a las puntuaciones del ITC en comparación con ellos mismos, ni con un grupo de controles históricos publicados anteriormente. Conclusiones. Los resultados son consistentes con otros estudios en los que no se han encontrado asociaciones entre las diferentes medidas de la personalidad y los genotipos del 5-HTT. Asimismo, los datos sugieren que la muestra que participó en el presente estudio puede utilizarse como una fuente de controles para estudios posteriores. Éste es el primer estudio de asociación entre la personalidad y el gen del 5-HTT que se hace en la población mexicana

Introduction. The aim of the present study was to assess the association between the serotonin transporter gene and the Temperament and Character Inventory (TCI) personality dimensions in subjects without psychopathology. Method. Fifty seven individuals without psychiatric symptoms were assessed with the SCL-90, and the TCI. In all subjects a peripheral blood sample was taken to determine their genotypes, after informed consent. Three groups were formed according to the 5-HTT genotype: SS, SL and LL, and the TCI results were compared. Results. There was no association among the 5-HTT genotypes and any of the TCI subscales. There were also no statistical differences among any of the three groups divided by genotype only according to the TCI scores, as well as when compared with historical controls. Conclusions. These results are consistent with other studies that have not found associations among the different measurements of personality and 5-HTT genotypes. Likewise, our data suggest that our sample can be useful as a source of controls for later studies. This is the first study assessing TCI dimensions and the 5-HTT gene in the Mexican population

Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism.

Allelic variants in the promoter region of the serotonin transporter (5-HTT) gene have been implicated in several psychiatric disorders and personality traits. In particular, two common alleles in a variable repeat sequence of the promoter region (SLC6A4) have been differentially associated with a display of abnormal levels of anxiety and affective illness in individuals carrying the "s" allele. The aim of this study was to compare the basal cerebral metabolic activity of non-psychiatric subjects in fronto-limbic structures to determine whether differences exist in basal metabolic activity within this functional polymorphism. PET scans with fluorine-18 fluorodeoxyglucose as radiotracer were performed in 71 non-psychiatric subjects previously screened for psychopathology and subsequently genotyped for SLC6A4; PET images were compared with SPM2 according to s/s (n = 27), s/l (n = 25), and l/l (n = 19) groups considering a significance threshold in a priori selected areas of P < 0.001 and an extent threshold > or =5 voxels. The analysis showed an effect of interest among the three genotype groups in right anterior cingulate gyrus (ACC), left middle frontal gyrus, and left posterior cingulate gyrus (PCC). Comparison between l/l vs. s/s showed increased metabolism for l/l in left middle frontal gyrus and an increase for s/s in right ACC and left PCC. Comparison between s/s vs. s/l showed an increase for s/s in left PCC and right ACC. Increased basal metabolism in fronto-limbic structures for the s/s group may be conceived as an "overactive metabolic state" of these structures, possibly related to an increased susceptibility for developing an anxiety-depression spectrum disorder.

Mu opioid receptor gene as a candidate for the study of obsessive compulsive disorder with and without tics.

Obsessive compulsive disorder (OCD) is a complex psychiatric disease characterized by recurring obsessions or compulsions that cause significant distress to the patient. The etiology of this disorder remains largely unknown, although a genetic component has been suggested. Many candidates genes have been evaluated based on a possible serotoninergic and dopaminergic brain dysfunction. We postulate the micro opioid receptor (MOR) gene as a candidate because some observations support a role of the opioid system in OCD. The opioid antagonist, naloxone, rapidly exacerbates OCD symptoms and the opioid agonist, tramadol, was reported to be effective in the treatment of some patients. We studied two single nucleotide polymorphisms (C17T and A118G) in 51 trios with OCD. Genotyping was analyzed with transmission desequilibrium test (TDT). The allelic variant +17T of the C17T polymorphism had a low frequency (1%) in our population that did not allow for statistic analysis. However, for the allelic variant +G of the A118G polymorphism we were able to performed statistical comparisons. Our results showed a trend toward significance (chi(2) McNemar = 3.6, P = 0.065) for TDT in patients with comorbid tics. It is an interesting finding that should be tested in a larger sample of OCD patients with tics.

Association study of the serotonin transporter gene polymorphism in obsessive-compulsive disorder.

The hypothesis implicating the serotonergic system in the pathophysiology of obsessive-compulsive disorder (OCD) is supported by the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs). Since SSRIs act on the serotonin transporter (5-HTT), it has been suggested that the 5-HTT gene (SCL6A4) could be a good candidate for OCD. The SCL6A4 gene has a 44-bp insertion/deletion polymorphism in its promoter region (5-HTTLPR). Previous studies have revealed an association between OCD and the l allele. We analysed the 5-HTTLPR polymorphic system in 115 Mexican OCD patients and 136 controls. No significant association was found between l allele and OCD (chi2 = 1.54, d.f. = 1, p = 0.21). Furthermore, we assessed alternative methods that employ family-based designs in a sample of 43 trios. Haplotype-based haplotype relative risk and transmission disequilibrium analysis did not show a preferential transmission of l allele to OCD probands. Our results indicate the need to analyse larger samples using family-based methods.

Additional evidence that genetic variation of MAO-A gene supports a gender subtype in obsessive-compulsive disorder.

Studies have recently reported a sexually dimorphic association between obsessive-compulsive disorder (OCD) and a polymorphism related with variations in MAO-A activity. These observations suggest the possibility of gender differences in genetic susceptibility for OCD. We thus reexamined the MAO-A/EcoRV polymorphism in a sample of 122 OCD patients and 124 healthy subjects. An excess of allele 1 in OCD females with major depression disorder was confirmed as previously reported. This difference was more strongly associated with OCD females than males in the total sample. Finally, we analyzed a sample of 51 OCD trios. Haplotype-based haplotype relative risk (HHRR) analysis of the inheritance of the MAO-A variants revealed in the female probands that 14 out of 19 transmitted the allele 1, providing significant evidence for an allelic association between OCD and MAO-A gene. In conclusion, our findings may provide molecular evidence to identify a clinically meaningful gender subtype. However, an effort should be made to replicate the analysis in larger samples of informative parents using strategies such as transmission disequilibrium test to allow definite conclusions.

Dopamine D4 receptor (DRD4) gene polymorphism in the first psychotic episode.

BACKGROUND: Dopamine D4 receptor (DRD4) has shown some interesting properties at genetic and possibly functional levels. It has been suggested that some molecular variants of the DRD4 gene (e.g., four and seven alleles) could be implicated in the pathogenesis of psychotic disorders. Additionally, the VNTR polymorphism could be implicated in part of the response to treatment with neuroleptics. This study tested the possible association between the 48-bp tandem repeats in exon 3 of the DRD4 gene and patients experiencing their first psychotic episode. METHODS: Patients with a first psychotic episode (FPE, n = 37) were diagnosed and compared with a matched control group (n = 37). The FPE group was subdivided into two categories: those with nonaffective and those with affective psychoses. The variable number of tandem repeats (VNTR) region of the DRD4 gene was amplified by PCR procedures. Chi-square statistics and appropriate corrections and adjustments were used for data analysis. CONCLUSIONS: A significantly lower frequency of the four repeat (4-R) carriers in the FPE group was observed. This association was sustained mainly by the affective psychotic group (chi2 = 9.99 df = 2, p = 0.0073). Although these results require testing with stringent methods, it is suggested that the DRD4-4R allele may confer some protection against psychosis, mainly of the affective subtype.

Lack of association of apolipoprotein E polymorphism in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) could be considered a neurodevelopmental disorder, from several lines of evidence. One of the most widely studied genes in these disorders is the apolipoprotein E gene, particularly allele 4. We analyzed for association among patients with OCD versus normal controls and cognitively impaired patients. There were no significant differences between OCD probands compared with population controls. However, the cognitively impaired group showed a higher frequency of allele apolipoprotein E gene compared with normal controls and patients with OCD.

[Dopamine D2 and D4 receptor genes distinguish the clinical presence of tics in obsessive-compulsive disorder]. / Los genes de los receptores a dopamina D2 y D4 distinguen la presencia clínica de tics en el trastorno obsesivo-compulsivo.

An allelic association study between dopamine receptor gene polymorphisms D2 (DRD2) and D4 (DRD4), in obsessive-compulsive patients (OCD) with or without chronic motor or vocal tics (OCD+ or OCD-) was performed. Molecular genotypes were obtained using the polymerase chain reaction method (PCR) in 66 patients diagnosed according DSMIV criteria, 12/66 OCD patients presented tics, 54 Control subjects were also typed. OCD patients with tics compared to control had a higher frequency of TaqI A2 allele (p = 0.014); and an excess of homozygous individuals A2A2 (p = 0.001). In DRD4 genes polymorphisms, allele 7 showed a higher prevalence and frequency in those OCD+ tics compared to OCD- tics (91% vs. 48%). Most of the OCD patients with tics compared to those without tics showed an increased frequency of the DRD2-A2 (58% vs 27% respectively, p = 0.048) as well as an increased frequency of the DRD4-7-fold variant (48% in OCD with tics vs 9% in OCD without tics, p = 0.018). Similarly, when both alleles were combined (at least one copy of DRD2-A2 and DRD4-R7), patients with tics showed a higher frequency of this haplotype (83.3% vs. 40%, p = 0.016). OCD patients with tics may represent a different clinical and genetic subtype of the disorder.

Repercusión internacional de los programas de vacunación / International impact of vaccination programs

En este artículo se revisan distintos aspectos de los programas internacionales de vacunación de mayor impacto, entre ellos los de la OMS, UNICEF y Banco Mundial. Se comtemplan los porcentajes de inmunización alcanzados hasta ahora, así como las zonas geografícas prioritarias. Los objetivos para el año 2000 son analizados, incluyendo costos y beneficios

Increased prevalence of the seven-repeat variant of the dopamine D4 receptor gene in patients with obsessive-compulsive disorder with tics.

The polymorphism characterized by a varying number of 48 bp repeats (VNTR) in the dopamine D4 receptor (DRD4) gene was examined in 61 obsessive-compulsive disorder (OCD) probands with and without tics. Most of the OCD patients with tics showed at least one copy of the 7-fold variant compared to those affected subjects without tics (91 vs. 48%, respectively, Yates corrected chi2 = 5.54, P = 0.018). Similarly, a higher number of copies of this common variant were detected in the group of probands displaying tics compared to those OCD's without tics (Yates corrected chi2 = 4.66, P = 0.03). Our study suggests that the seven-repeat allele of the DRD4 gene could be a factor in the phenotypic variance of tics among OCD individuals.

DRD2, DRD3 and 5HT2A receptor genes polymorphisms in obsessive-compulsive disorder.

We performed an association analysis of the DRD2, DRD3 and 5HT2A genes polymorphisms in 67 Obsessive-Compulsive Disorder (OCD) patients and 54 healthy controls. There were no statistically significant differences in genotype or allele frequencies for any of the polymorphisms studied between OCD subjects and controls. For the subgrouped analysis, no results were significant after correction for multiple testing, although homozygosity of DRD2/A2A2 in subjects displaying vocal or motor tics approached significance compared to controls (Fisher exact test, P = 0.008). Our results may follow the notion that OCD patients with tics represent a different genetic subtype of the disease.

Molecular analysis of the phenylalanine hydroxylase gene in Mexican phenylketonuric patients.

The molecular analysis of the human phenylalanine hydroxylase (PAH) gene in Mexican phenylketonuric (PKU) patients is described. We analyzed the restriction fragment length polymorphism (RFLP) haplotypes of five probands and ten non-affected relatives, belonging to four unrelated PKU families. Twenty-nine alleles were typified, corresponding to 12 different haplotypes. Eight RFLP haplotypes corresponded to those described in other populations, while the remaining were unreported haplotypes, appearing both on normal and PKU chromosomes. Using the polymerase chain reaction (PCR) and the allele-specific oligonucleotide assay (ASO), we also screened for the IVS10 mutation, one of the most common PAH gene mutations in Mediterranean countries. Forty-two percent of the PKU chromosomes analyzed bore the IVS10 mutation, although it was present in the heterozygous state in all cases. Our data show an important genetic heterogeneity at the PAH locus in the Mexican population, and report the genetic influence of the Spanish immigration to the American continent.

The dopamine D2 receptor gene TaqI A1 polymorphism and alcoholism in a Mexican population.

The suggested association between the TaqI A1 allele of the dopamine D2 receptor (DRD2) gene with alcoholism was studied comparing the genotypes of 38 controls and 38 ethnic matched alcoholics, drawn from the Mexican population. The alcoholics in our sample suffered from one of the following conditions: delirium tremens, alcohol hallucinosis or uncomplicated alcohol withdrawal. Eighty-eight percent of the controls carried the A1 allele. The frequency of the DRD2 A1 allele in the Mexican sample was higher than reported in Caucasians, but similar to those described in Amerindian groups. There was not any difference in the prevalence or allele frequency between alcoholics and controls. Also, there was no significant differences when alcoholics were subtyped according to severity, age of onset, or positive family history. Alcoholics showed higher scores than controls in the neuroticism and psychoticism subscales on the Eysenck Personality Inventory. However, no relationship between personality traits and genotypes was found. Our results do not support a consistent association between the D2 receptor gene and alcoholism.

[Dopaminergic system genes in Mexican schizophrenics]. / Evaluación de genes del sistema dopaminérgico en esquizofrénicos mexicanos.

This investigation reports an association study with alleles of the dopaminergic system genes (tyrosine hydroxylase (TH), D2 and D4 receptors) in schizophrenic patients and non-schizophrenic subjects. The genotypes were typed using a polymerase chain reactions PCR-based CA repeat polymorphisms. There were no significant associations between the studied alleles and schizophrenia. Also, a linkage analysis was performed using the same genes (TH, D2 and D4) in two multiple affected schizophrenic families. There was no linkage among any of three genes and schizophrenia. The maximum lod score (Z = 0.43, theta = 0.10 penetrance 100%) was for the tyrosine hydroxylase gene. Linkage analysis significantly excluded the D2 receptor gene (Z = 5.6, theta = 0.01), assuming an autosomal dominant pattern and complete penetrance, However, when the lod scores were calculated with other penetrance values, they lost significance.