RESUMEN
In geographical regions characterized by high pathogen prevalence, it has been shown that human populations tend to be characterized by lower levels of extraversion (E) and openness to experience (OtE). According to the "behavioral immune system" hypothesis, the reduction of extraversion and openness levels represents a behavioral defense against infections. Like the 'classical' immune system, the "behavioral immune system" could also be shaped by its underlying genetic background. Previous studies have shown that the *C allele of the ACP1 gene confers increased susceptibility to infectious/parasitic diseases. We hypothesized that carriers of the ACP1*C allele should likewise be associated with reduced E and OtE. We tested this hypothesis using two samples comprised of 153 students from Southern California (Group 1), and 162 female subjects recruited from an executive health program (Group 2), genotyped for ACP1 polymorphism and evaluated by the NEO Five-Factor Inventory (NEO-FFI). ACP1 was significantly associated with E: we found that carriers of ACP1*C showed reduced scores for E (Group 1: ß=-4.263, P=0.027; Group 2: ß=-8.315, P=0.003; Group 1+Group 2: ß=-5.366, P=0.001). Across groups, ACP1 was only marginally associated with OtE. In conclusion, the present study found that the ACP1*C allele, previously associated with an increased vulnerability to infectious/parasitic diseases may also be able to shape behavioral immune defenses by interaction with the level of E.
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Enfermedades Transmisibles/etiología , Personalidad , Carácter Cuantitativo Heredable , Adulto , Anciano , Alelos , Enfermedades Transmisibles/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteínas Tirosina Fosfatasas/genética , Proteínas Proto-Oncogénicas/genética , Adulto JovenRESUMEN
A large number of studies investigated the genetic modulation of personality with mixed results. As a confirmatory analysis of previous findings, we firstly examined the association between several previously examined single nucleotide polymorphisms (SNPs) and personality traits in a sample of 158 healthy subjects. As a secondary aim, we tested the potential modulation of additional never previously investigated genes on personality. A blood sample was collected and the Temperament and Character Inventory (TCI) has been administered to all participants. Multivariate analysis of covariance, controlling for sex and age, was used to test SNP influence on TCI scores. Examination of previously studied gene variants showed an effect of adrenergic alpha 2B receptor (ADRA2B) on Cooperativeness and of serotonin receptor HTR2A on Self Directedness. Examination of new variants revealed that sex hormone binding protein (SHBG) was associated with reward dependence. Moreover, several additional variants showed a tendency towards association with some TCI traits, confirming previous results. This study suggests that ADRA2B, HTR2A and SHBG genes may be involved in the modulation of personality in healthy subjects. The major limitation of this study was the small sample size.
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Personalidad/genética , Adulto , Carácter , Femenino , Humanos , Masculino , Inventario de Personalidad , Polimorfismo de Nucleótido Simple , Psicometría , TemperamentoRESUMEN
Cytokine gene variants are known to influence both infectious disease susceptibility and harm-avoidant behaviors, suggesting that these risk variants may be pleiotropically linked to instinctual disease-avoidant traits. The gamma-interferon (IFNG) +874 T>A polymorphism (rs2430561) is an ideal candidate gene variant for immune-behavioral studies. It is a functional SNP, regulating IFNG mRNA expression; it is known to modulate serotonergic activity and is therefore capable of modifying behavior; and it has previously been associated with increased susceptibility to malaria, tuberculosis, leprosy and Chagas disease. We hypothesized that the infectious disease-high-risk IFNG +874 A-allele would be associated with four personality traits previously reported as behavioral defenses against infection: Harm Avoidance (HA), Extraversion (E), Exploratory Excitability (Exp E), and Openness to Experience (O). We tested this hypothesis in a sample of 168 healthy university students from Southern California genotyped for IFNG +874 T>A and evaluated by the Temperament and Character Inventory-Revised (TCI-R) and the NEO Five-Factor Inventory (NEO-FFI). We found that the infectious disease-high-risk IFNG +874 A-allele was associated with increased HA (P=0.001) and decreased E (P=0.030) and Exp E (P=0.030). These findings suggest that the IFNG +874 A gene variant is linked both to infectious disease susceptibility and to proactive behavioral defenses that reduce infection risk in healthy subjects.
Asunto(s)
Reacción de Prevención/fisiología , Predisposición Genética a la Enfermedad/genética , Infecciones/genética , Interferón gamma/fisiología , Adulto , Carácter , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/psicología , Humanos , Infecciones/inmunología , Infecciones/psicología , Interferón gamma/genética , Interferón gamma/inmunología , Masculino , Persona de Mediana Edad , Personalidad/genética , Personalidad/fisiología , Inventario de Personalidad , Polimorfismo de Nucleótido Simple/genética , Polimorfismo de Nucleótido Simple/fisiología , Temperamento , Adulto JovenRESUMEN
Glycogen synthase kinase-3 beta (GSK3ß) is a ubiquitous kinase that is part of multiple signaling pathways. It has neurotrophic/neuroprotective effects by mediating the actions of neurotrophic molecules in the brain, thus providing neuroprotection through modulation of energy metabolism. Notably, it has been demonstrated that GSK3ß is involved in Wnt-beta-catenin signaling, which contributes to the inhibition of myelination and remyelination processes in mammals. Three-hundred nineteen patients with MS and 294 age-matched controls were genotyped by allelic discrimination for four common GSK3ß variants (rs2199503, rs9826659, rs334558 and rs6438552) tagging about 100% of GSK-3ß variability. A statistically significant increased frequency of the rs334558 GG genotype was observed in patients as compared with controls (25.4% versus 17.7%, P=0.02; OR:1.58, 95%CI: 1.07-2.34). Stratifying MS patients according to the disease subtype, a statistically significant difference of rs334558 GG frequency was found between Relapsing Remitting (RR), but not Primary Progressive or Secondary MS, and controls (27.0% versus 17.7%, P=0.01; OR: 1.72, 95%CI: 1.13-2.61). GSK3ß rs334558 is a susceptibility factor for MS. As it is located in the promoter region, a possible explanatory mechanism could be an influence of the variant on the gene transcription rate.
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Predisposición Genética a la Enfermedad , Glucógeno Sintasa Quinasa 3/genética , Esclerosis Múltiple/genética , Femenino , Genotipo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
UNLABELLED: Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the "brain reward cascade," a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). METHODOLOGY: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. RESULTS: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. CONCLUSIONS: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific "reward" phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates.
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Conducta Adictiva/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Dopamina beta-Hidroxilasa/genética , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Recompensa , Alelos , Femenino , Genotipo , Humanos , Masculino , Linaje , Fenotipo , Polimorfismo GenéticoRESUMEN
Conflicting results have been reported as to whether genetic variations (Val66Met and C270T) of the brain-derived neurotrophic factor gene (BDNF) confer susceptibility to Alzheimer's disease (AD). We genotyped these polymorphisms in a Japanese sample of 657 patients with AD and 525 controls, and obtained weak evidence of association for Val66Met (P = 0.063), but not for C270T. After stratification by sex, we found a significant allelic association between Val66Met and AD in women (P = 0.017), but not in men. To confirm these observations, we collected genotyping data for each sex from 16 research centers worldwide (4,711 patients and 4,537 controls in total). The meta-analysis revealed that there was a clear sex difference in the allelic association; the Met66 allele confers susceptibility to AD in women (odds ratio = 1.14, 95% CI 1.05-1.24, P = 0.002), but not in men. Our results provide evidence that the Met66 allele of BDNF has a sexually dimorphic effect on susceptibility to AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Predisposición Genética a la Enfermedad , Metionina/genética , Caracteres Sexuales , Valina/genética , Anciano , Secuencia de Bases , Estudios de Casos y Controles , Cartilla de ADN , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND AND HYPOTHESIS: Based on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential blocking of postsynaptic Nucleus Accumbens (NAc) dopamine receptors (D1-D5), whereas long term activation of the mesolimbic dopaminergic system should involve activation and/or release of Dopamine (DA) at the NAc site. Failure to do so will result in abnormal mood, behavior and potential suicide ideation. Individuals possessing a paucity of serotonergic and/or dopaminergic receptors, and an increased rate of synaptic DA catabolism due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate DA release, including alcohol, opiates, psychostimulants, nicotine, gambling, sex, and even excessive internet gaming. Acute utilization of these substances and/or stimulatory behaviors induces a feeling of well being. Unfortunately, sustained and prolonged abuse leads to a toxic" pseudo feeling" of well being resulting in tolerance and disease or discomfort. Thus, a reduced number of DA receptors, due to carrying the DRD2 A1 allelic genotype, results in excessive craving behavior; whereas a normal or sufficient amount of DA receptors results in low craving behavior. In terms of preventing substance abuse, one goal would be to induce a proliferation of DA D2 receptors in genetically prone individuals. While in vivo experiments using a typical D2 receptor agonist induce down regulation, experiments in vitro have shown that constant stimulation of the DA receptor system via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic antecedents. In essence, D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression causing proliferation of D2 receptors. PROPOSAL AND CONCLUSION: The authors propose that D2 receptor stimulation can be accomplished via the use of Synapatmine, a natural but therapeutic nutraceutical formulation that potentially induces DA release, causing the same induction of D2-directed mRNA and thus proliferation of D2 receptors in the human. This proliferation of D2 receptors in turn will induce the attenuation of craving behavior. In fact as mentioned earlier, this model has been proven in research showing DNA-directed compensatory overexpression (a form of gene therapy) of the DRD2 receptors, resulting in a significant reduction in alcohol craving behavior in alcohol preferring rodents. Utilizing natural dopaminergic repletion therapy to promote long term dopaminergic activation will ultimately lead to a common, safe and effective modality to treat Reward Deficiency Syndrome (RDS) behaviors including Substance Use Disorders (SUD), Attention Deficit Hyperactivity Disorder (ADHD), Obesity and other reward deficient aberrant behaviors. This concept is further supported by the more comprehensive understanding of the role of dopamine in the NAc as a "wanting" messenger in the meso-limbic DA system.
Asunto(s)
Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/metabolismo , Recompensa , Animales , Antagonistas de Dopamina , Genómica , Humanos , Trastornos Mentales/genética , Trastornos Mentales/psicología , Síndrome , Factores de TiempoRESUMEN
Molecular genetic studies have identified several genes that may mediate susceptibility to attention deficit hyperactivity disorder (ADHD). A consensus of the literature suggests that when there is a dysfunction in the "brain reward cascade," especially in the dopamine system, causing a low or hypo-dopaminergic trait, the brain may require dopamine for individuals to avoid unpleasant feelings. This high-risk genetic trait leads to multiple drug-seeking behaviors, because the drugs activate release of dopamine, which can diminish abnormal cravings. Moreover, this genetic trait is due in part to a form of a gene (DRD(2) A1 allele) that prevents the expression of the normal laying down of dopamine receptors in brain reward sites. This gene, and others involved in neurophysiological processing of specific neurotransmitters, have been associated with deficient functions and predispose individuals to have a high risk for addictive, impulsive, and compulsive behavioral propensities. It has been proposed that genetic variants of dopaminergic genes and other "reward genes" are important common determinants of reward deficiency syndrome (RDS), which we hypothesize includes ADHD as a behavioral subtype. We further hypothesize that early diagnosis through genetic polymorphic identification in combination with DNA-based customized nutraceutical administration to young children may attenuate behavioral symptoms associated with ADHD. Moreover, it is concluded that dopamine and serotonin releasers might be useful therapeutic adjuncts for the treatment of other RDS behavioral subtypes, including addictions.
RESUMEN
The identification of the genes for complex, polygenic disorders has proven difficult. This is due to the small effect size of each gene and genetic heterogeneity. An additional important factor could be the presence of unidentified epistatic factors. In the broad definition of epistasis, the effect of one unit is not predicable unless the value of another unit is known and one of the units may not be a gene. We have previously identified maternal age as an epistatic factor for the effect of the LEP gene on the age of onset of menarche. We report here the effect of maternal age and the age of the mother at the birth of her first child (maternal age 1st) as epistatic factors for the interaction of the dopamine D1 gene (DRD1) with obsessive-compulsive behaviors and with stuttering. The epistatic effects of maternal age 1st were stronger than maternal age. This type of epistatic factor may be generalizable to many other gene-trait interactions.
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Epistasis Genética , Edad Materna , Herencia Multifactorial/genética , Adolescente , Adulto , Análisis de Varianza , Femenino , Genotipo , Humanos , Trastorno Obsesivo Compulsivo/genética , Parto , Polimorfismo Genético , Embarazo , Receptores de Dopamina D1/genéticaRESUMEN
BACKGROUND: Attention Deficit Hyperactivity Disorder, commonly referred to as ADHD, is a common, complex, predominately genetic but highly treatable disorder, which in its more severe form has such a profound effect on brain function that every aspect of the life of an affected individual may be permanently compromised. Despite the broad base of scientific investigation over the past 50 years supporting this statement, there are still many misconceptions about ADHD. These include believing the disorder does not exist, that all children have symptoms of ADHD, that if it does exist it is grossly over-diagnosed and over-treated, and that the treatment is dangerous and leads to a propensity to drug addiction. Since most misconceptions contain elements of truth, where does the reality lie? RESULTS: We have reviewed the literature to evaluate some of the claims and counter-claims. The evidence suggests that ADHD is primarily a polygenic disorder involving at least 50 genes, including those encoding enzymes of neurotransmitter metabolism, neurotransmitter transporters and receptors. Because of its polygenic nature, ADHD is often accompanied by other behavioral abnormalities. It is present in adults as well as children, but in itself it does not necessarily impair function in adult life; associated disorders, however, may do so. A range of treatment options is reviewed and the mechanisms responsible for the efficacy of standard drug treatments are considered. CONCLUSION: The genes so far implicated in ADHD account for only part of the total picture. Identification of the remaining genes and characterization of their interactions is likely to establish ADHD firmly as a biological disorder and to lead to better methods of diagnosis and treatment.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/psicología , Predisposición Genética a la Enfermedad , Humanos , Herencia Multifactorial/genética , Neurotransmisores/uso terapéuticoRESUMEN
We hypothesize that pathological aggression, a complex behavioral disorder, in adolescents may in part involve polymorphisms of the dopaminergic system. While a number of neurotransmitter systems must be involved, due to polygenic inheritance, one major pathway should involve the dopaminergic system. Advances in our knowledge of the neurobiology of aggression and violence have given rise to rational pharmacological treatments for these behaviors. The main biological systems that are known to be involved are certain reward neurotransmitters including: serotonin, opioid peptides, gamma-aminobutyric acid, and the catecholamines (dopamine and norepinephrine). It is our notion that pathological aggressive behavior is in part similar mechanistically to other forms of impulsive behaviors such as pathological gambling. By analogy to drug dependence, it has been speculated that the underlying pathology in pathological gambling is a reduction in the sensitivity of the reward system. While studying pathological gamblers and controls during a guessing game using functional Magnetic Resonance Imaging, Reuter et al. observed a reduction of ventral striatal and ventromedial prefrontal activation in the pathological gamblers that were negatively correlated with gambling severity. Subsequently, linking hypo activation of these areas to disease severity. A positive correlation of both the dopamine D2 receptor gene (DRD2) and the dopamine transporter gene (DAT1) polymorphisms were observed with pathological violence in adolescents in a blinded clinical trial. Thus, this and other cited work preliminary suggest a role for both the DRD2 and DAT genes in pathological aggressive behavior. We further hypothesize that follow-up gene research in this area, albeit premature, resulting in confirmation of positive correlations with dopaminergic polymorphisms, and utilizing highly screened controls (eliminating any addictive, compulsive and impulsive behaviors in both proband and family) may have important ramifications in our young population.
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Agresión , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Trastornos Mentales/genética , Polimorfismo Genético , Receptores de Dopamina D2/genética , Adolescente , Genética Conductual , HumanosRESUMEN
We examined the frequency of the T allele of the C270T polymorphism of the brain-derived nerve growth factor (BDNF) gene in a test and replication test design. Our objective was to determine if there is an association between the BDNF gene and Alzheimer's Disease (AD) in a US population. There were 106 autopsy-proven AD cases and 101 controls of similar ages in each test for a total of 212 AD cases and 202 controls. We found that there was a significant increase in the T allele in both the initial set (p=.04) and in the replication set (p=.018). For both groups combined p=.0008. Odds ratio=3.28, 95% CI=1.69-6.34. There were 54 cases of early-onset AD (EOAD) and 159 cases of late-onset AD (LOAD). The results were only significant for LOAD, p=.0002, odds ratio=3.81, 95% CI=1.93-7.52. The r2 or fraction of the variance attributed to the BDNF gene for the LOAD cases was .046. The results were independent of the APOE epsilon4 allele. When the younger controls were removed, providing a close age match to the AD subjects, the frequency of the T allele was even lower and the differences were still significant for both total AD and LOAD cases. In a logistic regression analysis including APOE, age, sex and BDNF, BDNF was significant at p<.0001. We concluded that BDNF gene variants are significant risk factors for late onset AD.
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Enfermedad de Alzheimer/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Polimorfismo Genético , Edad de Inicio , Anciano , Anciano de 80 o más Años , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Factores de RiesgoRESUMEN
UNLABELLED: Regulated upon activation, normal T-cell expressed and secreted (RANTES) is a beta-chemokine and has been detected in brain lesions of multiple sclerosis (MS) patients. Considering its potential role in MS, we screened two functional polymorphisms in the proximal promoter region of the RANTES in MS patients versus controls. METHODS: We examined 140 postmortem brain samples from subjects with a primary diagnosis of MS, and peripheral blood samples from 216 control subjects. The RANTES-28C/G and -403G/A promoter polymorphisms were examined. All subjects were non-Hispanic Caucasians. RESULTS: MS cases differed from controls showing a significant association with the 403G/A polymorphism (odds ratio, 2.359, [1.465-3.799]; P=0.0001), but not the -28C/G (P=NS) polymorphism. There was a significant association of the -28G allele with both early onset (P=0.031) and longer survival (P=0.006). CONCLUSION: There is a significant but complex association of the RANTES gene with MS.
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Quimiocina CCL5/genética , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/genética , Adulto , Anciano , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad/epidemiología , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Regiones Promotoras Genéticas , Factores de RiesgoRESUMEN
PURPOSE: The interaction between chemokines and their receptors is extremely important in controlling T cell migration into sites of CNS inflammation. Because trafficking of inflammatory T cells into the central nervous system (CNS) is a key player in the pathogenesis of multiple sclerosis (MS), we investigated the possible association of CCR5 delta32 deletion in this disorder. METHODS: DNA isolated from postmortem brain tissue samples of 132 patients with MS and from blood tissue samples of 163 gender and ethnicity-matched healthy controls was used to screen for the CCR5 delta32 deletion allele. RESULTS: An increased frequency of 32-bp deletion allele was found to be associated with early death (P = 0.00005) and with a progressive reduction in the years of survival (onset to death). The death hazard ratio of CCR5 with deletion versus no deletion was 2.12, suggesting that MS patients with the 32-bp deletion have twice the mortality rate of patients with the normal genotype. This effect was more significant in females (hazard ratio 3.58). CONCLUSION: A strong association of the CCR5delta32 deletion with early death could serve as a prognostic marker for MS.
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Alelos , Esclerosis Múltiple/genética , Esclerosis Múltiple/mortalidad , Receptores CCR5/genética , Eliminación de Secuencia/genética , Estudios de Casos y Controles , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Valor Predictivo de las Pruebas , Pronóstico , Tasa de Supervivencia , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
The orexin-2/hypocretin-2 (OX2R) receptor gene is mutated in canine narcolepsy and disruption of the prepro-orexin/hypocretin ligand gene results in both an animal model of narcolepsy and sporadic cases of the human disease. This evidence suggests that the structure of the OX2R gene, and its homologue, the OX1R gene, both members of the G protein-coupled receptor (GPCR) family, and the gene encoding the peptide ligands, the prepro-orexin/hypocretin gene, may be variables in the etiology of sleep disorders. We report a single stranded conformational polymorphism (SSCP) analysis of the coding regions of these genes in idiopathic sleep disorder patients diagnosed with excessive daytime sleepiness (EDS) (n = 28), narcolepsy (n = 28), Tourette's syndrome/chronic vocal or motor tic disorder (n = 70), and control subjects (n = 110). Two EDS patients showed a Pro11Thr change. One Tourette's syndrome patient was found to have a Pro10Ser alteration. The Pro10Ser and Pro11Thr variants were not found in non-disease populations. Analysis of the ability of the mutant receptors to mobilize calcium compared to the wild-type receptor in response to orexin agonists indicated that they resulted in decreased potency at high (etaM) concentrations of orexin ligands. Further work is warranted to study the variability of the orexin/hypocretin system in a variety of disorders characterized by EDS.
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Trastornos de Somnolencia Excesiva/genética , Receptores de Neuropéptido/genética , Síndrome de Tourette/genética , Secuencia de Aminoácidos , Animales , Células COS , Calcio/metabolismo , Chlorocebus aethiops , Comorbilidad , ADN/química , ADN/genética , Análisis Mutacional de ADN , Trastornos de Somnolencia Excesiva/epidemiología , Relación Dosis-Respuesta a Droga , Humanos , Péptidos y Proteínas de Señalización Intracelular/farmacología , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Mutación , Mutación Missense , Neuropéptidos/farmacología , Receptores de Orexina , Orexinas , Polimorfismo Conformacional Retorcido-Simple , Receptores Acoplados a Proteínas G , Receptores de Neuropéptido/agonistas , Receptores de Neuropéptido/fisiología , Síndrome de Tourette/epidemiologíaRESUMEN
We report that a single-nucleotide polymorphism (SNP) in the gene (PTPN22) encoding the lymphoid protein tyrosine phosphatase (LYP), a suppressor of T-cell activation, is associated with type 1 diabetes mellitus (T1D). The variants encoded by the two alleles, 1858C and 1858T, differ in a crucial amino acid residue involved in association of LYP with the negative regulatory kinase Csk. Unlike the variant encoded by the more common allele 1858C, the variant associated with T1D does not bind Csk.
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Diabetes Mellitus Tipo 1/genética , Proteínas Tirosina Fosfatasas/metabolismo , Diabetes Mellitus Tipo 1/enzimología , Marcadores Genéticos , Humanos , Polimorfismo de Nucleótido Simple , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteínas Tirosina Fosfatasas/genéticaRESUMEN
BACKGROUND: Although the identification of the BRCA1 and BRCA2 genes have been of great interest, these genes account for less than 5% of all breast carcinoma cases. The remaining cases are sporadic. Reanalysis of a large twin study suggested that genetic factors may play a significant role in sporadic breast and other carcinomas. Sporadic breast carcinoma is polygenically inherited. Multiple genes are likely to have an additive effect, each gene accounting for a fraction of the variance. One factor that may have an impact on the development of hormonally responsive breast tumors is the duration of exposure of the breast to estrogen. Therefore, one of the demographic risk factors for breast carcinoma is an early age of onset of menarche. The current study was based on the hypothesis that genes that play a role in demographic risk factors may be breast carcinoma risk genes in their own right. The authors hypothesized that six genes relevant to the timing of the onset of menarche and related risk factors might be candidate genes for breast carcinoma. These were the leptin gene (LEP), the leptin receptor gene (LEPR), the catechol-0-methyltransferase gene (COMT), the dopamine D(2) receptor gene (DRD2), the estrogen 1 receptor gene (ESR1), and the androgen receptor gene (AR). METHODS: The authors examined 67 women with postmenopausal sporadic breast carcinoma and 145 gender and race-matched controls. RESULTS: Five of these genes accounted for a significant percent of the variance (r(2)) of breast carcinoma. The following r(2) and P values were calculated: LEP: 0.073, P < or = 0.0001; LEPR: 0.064, P < or = 0.0002; COMT: 0.073, P < or = 0.0001; AR: 0.040, P < or = 0.0035; and DRD2: 0.018, P < or = 0.05. When evaluated in a multivariate regression analysis, they accounted collectively for 24% of the variance of breast carcinoma (P < or = 0.0001). These genes accounted for 40% of the variance (P < or = 0.00001) in a subset of age-matched cases. Individual gene scores were added to form a breast carcinoma risk score (BCRS) that ranged from 0 to 17. When the BCRS was evaluated in a receiver operator characteristic plot, the area under the curve was 0.80 for the full set and 0.869 for the age-matched set. The relative breast carcinoma risk for the different BCRS scores ranged from 0.10 to 11.9. CONCLUSIONS: These results demonstrate a potentially powerful method of evaluating the additive effect of multiple breast carcinoma risk genes to form a potentially clinically useful assessment of women's risk for sporadic breast carcinoma.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Leptina/genética , Proteínas de Neoplasias/genética , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/etiología , Estudios de Casos y Controles , Catecol O-Metiltransferasa/genética , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Polimorfismo Genético , Curva ROC , Receptores Androgénicos/genética , Receptores de Superficie Celular/genética , Receptores de Dopamina D2/genética , Receptores de Estrógenos/genética , Receptores de Leptina , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: To understand the impact of the phenylethanolamine N-methyltransferase (PNMT) G-148A gene and nutritional variables on weight loss in obese women. RESEARCH METHODS AND PROCEDURES: One hundred forty-nine women, ages 45 to 65 with a body mass index of >30 kg/m(2), participated in a 6-month, open-label intervention that included sibutramine (15 mg/d) and a monthly health-education class. Anthropometric measurements, vital signs, food frequency, exercise log, medication compliance, and psychological and sociological questionnaires were completed each month. Genetic polymorphisms of PNMT were determined. RESULTS: Univariate analysis of G/G, G/A, and A/A genotypes against tertiles of percentage of weight loss were significant at 3 but not at 6 months (Pearson chi(2): p < 0.006; homozygous/heterozygosity: p < 0.002, p < 0.253, and p < 0.122, respectively). A regression model that included the PNMT genetic variation and certain nutrition and exercise variables demonstrated that only the PNMT gene (beta = 0.360, SE 0.585, and p = 0.003) was statistically significant at 6 months, and the total calories (beta = -0.925, SE = 0.004, and p = 0.009), fiber intake (beta = 0.621, SE = 0.124, and p = 0.000), and PNMT (beta = 0.262, SE = 1.415, and p = 0.024) were significant. DISCUSSION: The homozygosity/heterozygosity of the PNMT gene was highly predictive of significant weight loss with sibutramine during the first 3 months, which highlights the need for specific pharmacotherapy. The early weight-loss success of those subjects who were homozygous for PNMT may have motivated and selected those that would make further dietary changes, which then augmented their final weight loss.