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INTRODUCTION: Thalassaemia is one of the major health problems in Malaysia. With safe blood transfusion regime, the lifespan of patients with transfusion-dependent thalassaemia (TDT) has improved but at the cost of a higher risk of developing endocrine disorders. It is crucial for us to monitor the iron overload to prevent end organ damage. This study aims to evaluate the iron burden and prevalence of endocrinopathies in patients with TDT in Sarawak. MATERIALS AND METHODS: This retrospective cohort study was conducted between January 2020 to June 2020 in six government hospitals in Sarawak. A total of 89 patients with TDT, aged 10 years and above, were recruited. RESULTS: Out of the 89 patients, there were 54 males (60.7%) and 35 females (39.3%) with a median age of 21 years (range 10.0-65.0). Sixty-seven (75.3%) patients had betathalassaemia major and 15 (16.9%) patients had haemoglobin E beta-thalassaemia (HbE beta-thalassaemia), remaining seven patients had other genotypes. Thirty-one (34.8%) patients had mean serum ferritin 2500ng/ml and above, and 44 (66.6%) had liver iron concentration (LIC) ≥7mg/g. The prevalence of endocrine disorders in our cohort was 69.7%. The most common endocrinopathies were short stature (n=46, 51.7%), followed by hypogonadism (n=24, 26.9%), delayed puberty (n=23, 25.8%), hypothyroidism (n=10, 11.2%), diabetes mellitus (n=9, 10.1%), impaired glucose tolerance (n=6, 6.7%) and hypoparathyroidism (n=3, 3.3%). Endocrinopathies were significantly associated with age (p=0.01), age at initiating regular blood transfusion (p<0.01) and duration of regular blood transfusion (p<0.01). CONCLUSION: Our data shows that the development of endocrinopathies in TDT can be time dependent. Early detection of endocrine-related complications and prompt treatment with iron chelation therapy are important to improve morbidity and mortality. A multidisciplinary approach with good patient-doctor collaboration is the key to improving patient care in our settings.
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Transfusão de Sangue , Doenças do Sistema Endócrino , Sobrecarga de Ferro , Talassemia , Humanos , Masculino , Estudos Retrospectivos , Feminino , Malásia/epidemiologia , Adulto , Criança , Adolescente , Doenças do Sistema Endócrino/epidemiologia , Doenças do Sistema Endócrino/etiologia , Adulto Jovem , Talassemia/terapia , Talassemia/complicações , Talassemia/epidemiologia , Transfusão de Sangue/estatística & dados numéricos , Pessoa de Meia-Idade , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/epidemiologia , Prevalência , Idoso , Ferro/metabolismoRESUMO
INTRODUCTION: Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator is beneficial in acute ischaemic stroke (AIS). We aim to compare the realworld clinical outcomes and service efficiency of IVT in Malaysian primary stroke centres (PSCs) versus acute stroke ready hospitals (ASRHs). MATERIALS AND METHODS: We conducted a multi-centre cohort study involving 5 PSCs and 7 ASRHs in Malaysia. Through review of medical records of AIS patients who received IVT from 01 January 2014 to 30 June 2021, real-world data was extracted for analysis. Univariate and multivariate regression models were employed to evaluate the role of PSCs versus ASRHs in post-IVT outcomes and complications. Statistical significance was set at p<0.05. RESULTS: A total of 313 multi-ethnic Asians, namely 231 from PSCs and 82 from ASRHs, were included. Both groups were comparable in baseline demographic, clinical, and stroke characteristics. The efficiency of IVT delivery (door-toneedle time), functional outcomes (mRS at 3 months post- IVT), and rates of adverse events (intracranial haemorrhages and mortality) following IVT were comparable between the 2 groups. Notably, 46.8% and 48.8% of patients in PSCs and ASRHs group respectively (p=0.752) achieved favourable functional outcome (mRS≤1 at 3 months post-IVT). Regression analyses demonstrated that post-IVT functional outcomes and adverse events were independent of the role of PSCs or ASRHs. CONCLUSION: Our study provides real-world evidence which suggests that IVT can be equally safe, effective, and efficiently delivered in ASRHs. This may encourage the establishment of more ASRHs to extend the benefits of IVT to a greater proportion of stroke populations and enhance the regional stroke care.
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Noradrenaline and adrenaline are neurotransmitters of the sympathetic nervous system that interact with various adrenergic receptor (ADR) subtypes, and this regulates the basal metabolic rate, thermogenesis and efficiency of energy utilization. We examined a possible role of the gene coding for ADRA1A receptor in weight gain in schizophrenia subjects exposed to antipsychotics. A total of 401 schizophrenia in-patients treated with antipsychotics for >2 years were recruited and a final 394 DNA samples were genotyped. Their body mass indexes (BMIs) were recorded for 12 months and parameterized to be correlated in regression. Among the 58 single-nucleotide polymorphisms (SNPs) genotyped, 44 valid SNPs, which had minor allele frequency > or =0.03, were analyzed in statistics. Linear regression model with age, gender, diabetes, use of typical antipsychotics and use of atypical antipsychotics as covariates, with or without gender interaction, showed evidence of associations between the ADRA1A gene and BMI. Most of the SNPs associated with BMI are located in the promoter and intron regions, and being female appeared to enhance the gene effect. Our study suggests that the ADRA1A gene is involved in weight gain among schizophrenia patients treated with antipsychotics. Further molecular dissection of the ADRA1A gene warrants better understanding on weight gain mechanisms in schizophrenia.
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Antipsicóticos/uso terapêutico , Índice de Massa Corporal , Receptores Adrenérgicos alfa 1/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Feminino , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Obesidade/etiologia , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Esquizofrenia/complicações , Aumento de Peso/genéticaRESUMO
Artificial intelligence has become a possible solution to resolve the problem of loss of information when complexity of a disease increases. Obesity phenotypes are observable clinical features of drug-naive schizophrenic patients. In addition, atypical antipsychotic medications may cause these unwanted effects. Here we examined the performance of neuro-fuzzy modeling (NFM) in predicting weight changes in chronic schizophrenic patients exposed to antipsychotics. Two hundred and twenty inpatients meeting DSMIV diagnosis of schizophrenia, treated with antipsychotics, either typical or atypical, for more than 2 years, were recruited. All subjects were assessed in the same study period between mid-November 2003 and mid-April 2004. The baseline and first visit's physical data including weight, height and circumference were used in this study. Clinical information (Clinical Global Impression and Life Style Survey) and genotype data of five single nucleotide polymorphisms were also included as predictors. The subjects were randomly assigned into the first group (105 subjects) and second group (115 subjects), and NFM was performed by using the FuzzyTECH 5.54 software package, with a network-type structure constructed in the rule block. A complete learned model trained from merged data of the first and second groups demonstrates that, at a prediction error of 5, 93% subjects with weight gain were identified. Our study suggests that NFM is a feasible prediction tool for obesity in schizophrenic patients exposed to antipsychotics, with further improvements required.
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Antipsicóticos/farmacologia , Peso Corporal/efeitos dos fármacos , Pesos e Medidas Corporais/métodos , Lógica Fuzzy , Modelos Biológicos , Esquizofrenia/fisiopatologia , Adulto , Antipsicóticos/uso terapêutico , Peso Corporal/fisiologia , Escalas de Graduação Psiquiátrica Breve , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Esquizofrenia/tratamento farmacológico , Adulto JovemRESUMO
BACKGROUND: Presurgical hand washing is crucial for preventing surgical site infections (SSIs). Chlorhexidine gluconate (CHG) and povidone-iodine (PI) products have been conventionally used as hand scrubs for presurgical hand preparation. However, waterless hand rub (WHR) products have been developed for operating room staff. AIM: The aim of this study was to conduct a systematic review and meta-analysis to compare the antiseptic efficacies of WHR, CHG, and PI in surgical settings. METHODS: PubMed, Embase, and Cochrane Library databases as well as the ClinicalTrials.gov registry were searched for studies published before October 2018. Randomized controlled trials (RCTs) comparing the clinical outcomes of the use of WHRs, CHG, or PI for presurgical hand washing were included. A random effects model was used for meta-analysis. Colony-forming unit (cfu) counts, SSI rates, and preference and compliance were determined to measure efficacies. FINDINGS: Eleven RCTs involving 5135 participants were included. Residual cfu counts were significantly lower in the WHR and CHG groups than in the PI group. The differences in cfu counts between the WHR and CHG groups were non-significant. No significant differences were observed in the SSI rates between the WHR and traditional hand scrub groups. Moreover, WHRs were considered most favourable and were associated with higher compliance rates than the other products. CONCLUSION: WHRs and CHG exhibited higher antiseptic efficacies than PI. However, additional studies with consistent outcome measurements and accurate grouping are required to obtain comprehensive results. Moreover, preference, compliance, and the cost determine the selection of hand wash products.
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Anti-Infecciosos Locais/farmacologia , Clorexidina/farmacologia , Desinfecção das Mãos/métodos , Povidona-Iodo/farmacologia , Contagem de Colônia Microbiana , Humanos , Cuidados Pré-Operatórios/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Infecção da Ferida Cirúrgica/prevenção & controle , Resultado do TratamentoRESUMO
AIMS: Wound closure after thyroidectomy and parathyroidectomy is associated with patients' satisfaction, perception of cosmetic appearance, and experience of postoperative pain. Subcutaneous sutures, clips, and tissue adhesive are the three major methods of wound closure. In this study, we conducted a meta-analysis of randomized controlled trials to evaluate the outcomes of these methods. METHODS: Relevant studies published before December 2017 were identified from PubMed, Embase, Cochrane Library, Scopus, and the ClinicalTrials.gov registry. Individual effect sizes were standardized, and a meta-analysis was conducted to calculate the pooled effect size by using random-effect models. The primary outcome was the cosmetic appearance, which was evaluated 4 weeks, 6 weeks, and 6 months after surgery. The secondary outcomes were patient satisfaction, postoperative pain, and complications. RESULTS: A total of nine trials with 612 patients were reviewed. No significant difference was observed in patient satisfaction, postoperative pain, and complications among the wound closure methods. However, according to surgeon assessment, the subcutaneous suture method resulted in a significantly more favorable cosmetic appearance than the clip method (mean difference: -1.47, 95% confidence interval: -2.72 to -0.23). CONCLUSION: In the current study, no differences were found in patient satisfaction and postoperative pain among the subcutaneous suture, clip, and tissue adhesive wound closure methods. However, surgeons provided a more favorable appraisal for the subcutaneous suture method because of the improved cosmetic appearance. The choice of the closure method should be based on surgeon's preference and cost.
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Paratireoidectomia , Tireoidectomia , Técnicas de Fechamento de Ferimentos , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Previous population association studies have indicated that certain alleles of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes may reduce the risk of alcoholism in Oriental populations. In this report we determined the genotypes for three genes, ADH2, ADH3, and ALDH2 among subjects with alcohol dependence (n = 159) and ethnically matched normal controls (n = 149) for the four largest aboriginal groups (Atayal, Ami, Bunun, and Paiwan) in Taiwan. The ethnicity matching used in this study was feasible because there are still few intergroup marriages between these aboriginal groups. On a group level, the rare frequencies of ALDH2*2, the inactive allele of ALDH2, among these aborigines may account partially for their vulnerability to alcohol use disorders. On an individual level, however, the genotypes controlling alcohol metabolism did not account for intragroup differences in vulnerability to alcoholism except in the case of ADH2 for the Ami ethnic group.
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Álcool Desidrogenase/genética , Alcoolismo/genética , Aldeído Desidrogenase/genética , Isoenzimas/genética , Adulto , Alelos , Primers do DNA , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Havaiano Nativo ou Outro Ilhéu do Pacífico , Reação em Cadeia da Polimerase , Grupos Raciais , TaiwanRESUMO
OBJECTIVE: The role of monoamine oxidase (MAO) in alcoholism was assessed by genetic association studies separately in five ethnic groups in Taiwan. METHOD: Restriction fragment length polymorphisms (RFLP) and dinucleotide repeat polymorphisms (DNRP) were used to determine MAOA and MAOB alleles in male alcoholic patients and nonalcoholic comparison subjects among Han Chinese and four aboriginal groups. RESULTS: Significant associations of alcohol dependence with MAOA alleles (RFLP and DNRP) were found among the Han Chinese, but not among the aboriginal groups. No significant association with MAOB DNRP alleles was found in any group. CONCLUSIONS: Genetic heterogeneity may underlie alcoholism among different ethnic groups in Taiwan, and MAOA mutations may play a role in susceptibility to alcoholism among Han Chinese.
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Alcoolismo/etnologia , Povo Asiático/genética , Monoaminoxidase/genética , Alcoolismo/enzimologia , Alelos , Sequência de Bases , China/etnologia , Repetições de Dinucleotídeos/genética , Humanos , Masculino , Dados de Sequência Molecular , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Grupos Raciais , Fatores Sexuais , TaiwanRESUMO
The alternatively spliced 8-amino-acid exon for the GABAA receptor gamma2 subunit gene (GABRC2) has been postulated to mediate behavioral actions of alcohol. A rapid search for splice-junction mutations near the 8-amino-acid exon using restriction enzymes which normally recognize sequences near or in the exon gave negative results among 217 alcoholics in four aboriginal groups (Ami, Atayal, Bunun and Paiwan) and Han Chinese in Taiwan. The role of the GABRC2 gene in alcoholism was further assessed by a comparison of allelic frequencies revealed by a NciI RFLP between case and control groups. No significant association of alcohol dependence with GABRC2 alleles was observed. These results suggest that the GABRC2 gene probably does not play an essential role in predisposition to alcoholism in the sample population.
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Alcoolismo/genética , Alelos , Processamento Alternativo , Éxons , Mutação , Receptores de GABA-A/genética , Alcoolismo/epidemiologia , Povo Asiático/genética , Ligação Genética , Humanos , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Grupos Raciais , Taiwan/epidemiologiaRESUMO
gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system and it acts at the GABA(A) and GABA(B) receptors. A possible role for the GABA(A) receptors in alcohol action has been derived from in vitro cell models, animal studies and human research. GABA(A) subunit mRNA expression in cell models has suggested that the long form of the gamma2 subunit is essential for ethanol enhanced potentiation of GABA(A) receptors, by phosphorylation of a serine contained within the extra eight amino acids. Several animal studies have demonstrated that alterations in drug and alcohol responses may be caused by amino-acid differences at the GABA(A)alpha6 and GABA(A)gamma2 subunits. An Arg(100)/Glu(100) change at the GABA(A)alpha6 subunit conferring altered binding efficacy of the benzodiazepine inverse agonist Ro 15-4513, was found between the AT (alcohol tolerance) and ANT (alcohol non-tolerance) rats. Several loci related to alcohol withdrawal on mouse chromosome 11 which corresponds to the region containing four GABA(A) subunit (beta2, alpha6, alpha1 and gamma2) genes on human chromosome 5q33-34, were also identified. Gene knockout studies of the role of GABA(A)alpha6 and GABA(A)gamma2 subunit genes in mice have demonstrated an essential role in the modulation of other GABA(A) subunit expression and the efficacy of benzodiazepine binding. Absence of the GABA(A)gamma2 subunit gene has more severe effects with many of the mice dying shortly after birth. Disappointingly few studies have examined the effects of response to alcohol in these gene knockout mice. Human genetic association studies have suggested that the GABA(A)beta2, alpha6, alpha1 and gamma2 subunit genes have a role in the development of alcohol dependence, although their contributions may vary between ethnic group and phenotype. In summary, in vitro cell, animal and human genetic association studies have suggested that the GABA(A)beta2, alpha6, alpha1 and gamma2 subunit genes have an important role in alcohol related phenotypes (300 words).
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Alcoolismo/genética , Etanol/farmacologia , Família Multigênica/fisiologia , Isoformas de Proteínas/genética , Receptores de GABA-A/genética , Animais , HumanosRESUMO
Ethanol enhances mesolimbic/cortical dopamine activity in reward and reinforcement circuits. We investigated the hypothesis that risk for alcoholism may be mediated by genes for neurotransmitters associated with the dopamine reward system as well as genes for enzymes involved in ethanol metabolism. DNA was extracted from brain tissue collected at autopsy from pathologically characterized alcoholics and controls. PCR-based assays showed that alcoholism was associated with polymorphisms of the dopamine D2 receptor (DRD2) TaqI B (P = .029) and the GABAA-beta2 subunit C1412T (P = .012) genes, but not with the glutamate receptor subunit gene NMDAR2B (366C/G), the serotonin transporter gene (5HTTL-PR), the dopamine transporter gene DAT1(SLC6A3), the dopamine D2 receptor gene DRD2 TaqI A, or the GABAA alpha1(A15G), alpha6(T1519C), and gamma2(G3145A) subunit genes. The glial glutamate transporter gene EAAT2 polymorphism G603A was associated with alcoholic cirrhosis (P = .048). The genotype for the most active alcohol dehydrogenase enzyme ADH1C was associated with a lower risk of alcoholism (P = .026) and was less prevalent in alcoholics with DRD2TaqIA2/A2 (P = .047), GABAA-beta2 1412C/C (P = .01), or EAAT2 603G/A (P = .022) genotypes. Combined DRD2TaqI A or B with GABAA-beta2 or EAAT2 G603A genotypes may have a concerted influence in the predisposition to alcoholism.
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Alcoolismo/genética , Ligação Genética/genética , Neurotransmissores/genética , Polimorfismo Genético/genética , População Branca/genética , Alcoolismo/patologia , Encéfalo/patologia , Distribuição de Qui-Quadrado , Intervalos de Confiança , Frequência do Gene/genética , Humanos , Razão de ChancesRESUMO
BACKGROUND: Metabolic abnormality is common among schizophrenia patients. Some metabolic traits were found associated with subgroups of schizophrenia patients. OBJECTIVES: We examined a possible relationship between metabolic abnormality and psychosis profile in schizophrenia patients. METHOD: Three hundred and seventy-two chronic schizophrenia patients treated with antipsychotics for more than 2 years were assessed with the Positive and Negative Syndrome Scale. A set of metabolic traits was measured at scheduled checkpoints between October 2004 and September 2006. RESULTS: Multiple regressions adjusted for sex showed negative correlations between body mass index (BMI) and total score and all subscales; triglycerides (TG) was negatively correlated with total score and negative syndrome, while HDLC was positively correlated with negative syndrome. When sex interaction was concerned, total score was negatively correlated with BMI but not with others; negative syndrome was negatively correlated with BMI and positively with HDLC. No metabolic traits were correlated with positive syndrome or general psychopathology. CONCLUSIONS: Loss of body weight is a serious health problem in schizophrenia patients with severe psychosis syndrome, especially the negative syndrome. Schizophrenia patients with severe negative syndrome may have a distinct lipid pathophysiology in comparison with those who were less severe in the domain.
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Transtornos Psicóticos/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Índice de Massa Corporal , HDL-Colesterol/sangue , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/metabolismo , Esquizofrenia/metabolismo , Índice de Gravidade de Doença , Síndrome , Taiwan , Triglicerídeos/sangueRESUMO
GABAA receptor subunit genes clustered on 5q33 play a role in the development of alcoholism and methamphetamine use disorder without psychosis. The present study explored the possible contribution of the same subunit genes to the development of heroin dependence. Single nucleotide polymorphisms (SNPs) of the GABAA receptor subunits GABRB2, GABRA6, GABRA1, and GABRG2 were examined in 178 male Han Chinese heroin-dependent and 170 male control subjects. A significant difference in allele frequency for the SNP rs211014 in the GABAAgamma2 receptor subunit gene between cases and controls was identified (P = 0.015). A possible mechanism for the involvement of the GABA receptor subunit genes on 5q33 in the development of heroin dependence is discussed.
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Povo Asiático/genética , Cromossomos Humanos Par 5/genética , Predisposição Genética para Doença , Dependência de Heroína/genética , Subunidades Proteicas/genética , Receptores de GABA/genética , Adolescente , Adulto , Estudos de Casos e Controles , China , Ordem dos Genes , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-IdadeRESUMO
PRIMARY OBJECTIVE: To investigate jaw movements in children following traumatic brain injury (TBI) during speech using electromagnetic articulography (EMA). METHODS AND PROCEDURES: Jaw movements of two non-dysarthric children (aged 12.75 and 13.08 years) who had sustained a TBI were recorded using the AG-100 EMA system (Carstens Medizineletronik) during word-initial consonant productions. Mean quantitative kinematic parameters and coefficient of variation (variability) values were calculated and individually compared to the mean values obtained by a group of six control children (mean age 12.57 years, SD 1.52). MAIN OUTCOMES AND RESULTS: The two children with TBI exhibited word-initial consonant jaw movement durations that were comparable to the control children, with sub-clinical reductions in speed being offset by reduced distances. Differences were observed between the two children in jaw kinematic variability, with one child exhibiting increased variability, while the other child demonstrated reduced or comparable variability compared to the control group. CONCLUSIONS: Possible sub-clinical impairments of jaw movement for speech were exhibited by two children who had sustained a TBI, providing insight into the consequences of TBI on speech motor control development.
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Lesões Encefálicas/fisiopatologia , Arcada Osseodentária/fisiopatologia , Movimento , Fala , Adolescente , Fenômenos Biomecânicos , Lesões Encefálicas/psicologia , Criança , Feminino , Humanos , Masculino , Testes de Articulação da Fala/métodosRESUMO
Family and twins studies have suggested that genetic factors are involved in the development of substance use disorders. Several unrelated case/control association studies have reported associations of the GABA(A) subunit genes on 5q33 with the development of alcohol dependence. We hypothesized that these particular GABA(A) subunit genes also contribute to the development of methamphetamine use disorder. To test our hypothesis, we recruited cases using a series of questionnaires. Among the polymorphic SNPs, significant differences between cases and controls were identified in the female sample in the rs2279020 of the GABA(A)alpha1 subunit gene, and the novel SNP rs4480617 in the GABA(A)gamma2 subunit gene. No associations were found in the male sample. Further haplotype analysis identified several marker blocks significantly associated with methamphetamine use disorder in females; each block consists of the rs4480617. Our study provides preliminary evidence that the GABA(A) subunit genes on 5q33 may preferentially contribute to methamphetamine use disorder in females.
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Cromossomos Humanos Par 5/genética , Metanfetamina , Receptores de GABA-A/genética , Caracteres Sexuais , Transtornos Relacionados ao Uso de Substâncias/genética , Adolescente , Adulto , Distribuição de Qui-Quadrado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Polimorfismo de Nucleotídeo Único/genética , Subunidades Proteicas/genéticaRESUMO
Recent investigations suggest that genetic susceptibility to alcohol dependence may be conferred by GABA(A) receptor subunit genes. In this study, three RFLPs at the GABA(A)beta2, GABAAalpha6, GABA(A)alpha1 and two at the GABA(A)gamma2 receptor subunit genes, were examined for association with alcohol dependence in 189 subjects meeting DSM-III-R criteria for this disorder and 152 unrelated controls from a Japanese population. The results demonstrated no association between the AlwNI RFLP at the GABA(A)alpha6 receptor subunit gene and alcohol dependence (P = 0.059). However, the NciI RFLP at the GABA(A)gamma2 receptor subunit gene was associated with alcohol dependence comorbid with antisocial personality disorder (P = 0.021). This supports a recent finding reporting an association between the GABA(A)gamma2 receptor subunit gene and alcohol dependence with criminal record in a Finnish population. Taking into account the effects of multiple comparisons, this result should be interpreted with caution pending replication.
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Alcoolismo/genética , Transtorno da Personalidade Antissocial/genética , Cromossomos Humanos Par 5 , Família Multigênica , Polimorfismo de Fragmento de Restrição , Receptores de GABA-A/genética , Adulto , Povo Asiático/genética , Mapeamento Cromossômico , Feminino , Humanos , Japão , Masculino , Receptores de GABA-A/química , Valores de ReferênciaRESUMO
A role for the GABA/benzodiazepine receptor complex in alcohol dependence syndrome has been suggested by several lines of evidence. To elucidate the role of GABAA subunits in human alcohol dependence syndrome, we identified polymorphisms in the GABAAbeta2 and GABAAalpha6 receptor subunit genes on 5q33 and assessed their potential contribution in an association study, together with a NciI RFLP at the GABAAgamma2 receptor subunit gene. One hundred and eight alcohol-dependent subjects and 54 unrelated controls were recruited from Scotland. Two novel genetic markers were identified at the GABAAbeta2 and GABAAalpha6 receptor subunit genes and examined for association with the alcohol dependence syndrome and subgroups of subjects with Korsakoff's psychosis and without Korsakoff's psychosis, together with a NciI RFLP at the GABAAgamma2 receptor subunit gene. The chi2 tests demonstrated associations between all alcohol-dependent subjects (not stratified) and the BanI RFLP at the GABAAbeta2 receptor subunit gene (P = 0.015), and the AlwNI RFLP at the GABAAalpha6 receptor gene (P = 0.013). Significant associations were also found between the alcohol-dependent subjects with Korsakoff's psychosis and the BanI RFLP (P = 0.039) and the AlwNI RFLP (P = 0.003). Haplotype analysis also provided evidence of association when all alcohol-dependent subjects (P = 0.013) and the subjects with Korsakoff's psychosis (P = 0.007) were compared with controls. Our findings provide evidence for a role for the GABAA receptor subunit cluster on chromosome 5q33 in susceptibility to the alcohol dependence syndrome and Korsakoff's psychosis.
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Alcoolismo/genética , Cromossomos Humanos Par 5 , Variação Genética , Família Multigênica/genética , Receptores de GABA-A/genética , Adulto , Idoso , Alelos , Saúde da Família , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Síndrome de Korsakoff/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Polimorfismo Conformacional de Fita Simples , EscóciaRESUMO
Gamma-amminobutyric acid (GABA) is a major inhibitory neurotransmitter. Two alternatively spliced forms of the gamma2 subunit of GABAA receptor (gamma2L and gamma2S), which differ by an exon of eight amino acids, show different sensitivities to modulatory effects of ethanol on receptor activities. A 2.7 kb DNA fragment and an 1.7 kb DNA fragment covering respectively the introns upstream and downstream from the 8-amino-acid exon were obtained through PCR-amplification of human genomic DNA using primers derived from cDNA sequences. Total sequencing of these fragments showed a composite 4.2 kb segment containing the 8-amino-acid exon and consensus sequences for RNA splice junctions. Restriction fragment length polymorphisms (RFLP) based on NciI restriction digestion were found among Chinese in Taiwan. This RFLP provides a useful DNA marker for allelic association or linkage analyses of the role of GABAA receptors in predisposition to alcoholism or other neuropsychiatric disorders.
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Éxons/genética , Íntrons/genética , Polimorfismo Genético , Receptores de GABA-A/genética , Processamento Alternativo , Sequência de Bases , DNA Complementar/genética , DNA Complementar/isolamento & purificação , Humanos , Dados de Sequência MolecularRESUMO
BACKGROUND: Previous population association studies have indicated that certain alleles of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) may reduce the risk of alcoholism in Asian populations. The association of ALDH2 and ADH2 with the development of alcoholism was found to be independent of each other and has been replicated in different Asian populations, while the effect of ADH3 is less studied. METHOD: We genotyped the alcohol metabolism genes among Han men with alcohol dependence (n = 46) and their ethnically matched normal controls (n = 63) in Taiwan. Multiple logistic regression was then applied to assess the contribution of ADH3 to alcoholism by controlling the effect of ALDH2 and ADH2. RESULTS: The results of multivariate analyses demonstrated that the odds ratios for an increment of one allele of ADH2*1, ADH3*2 and ALDH2*1 in the development of alcoholism were 4.18, 3.82, and 6.89, respectively. CONCLUSIONS: These findings clearly indicate that all three alcohol-metabolising genes contribute to susceptibility to alcoholism.
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Álcool Desidrogenase/genética , Alcoolismo/genética , Aldeído Desidrogenase/genética , Etanol/farmacocinética , Etnicidade/genética , Isoenzimas/genética , Adulto , Idoso , Alcoolismo/enzimologia , Alelos , Regulação Enzimológica da Expressão Gênica/fisiologia , Frequência do Gene/genética , Genética Populacional , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Razão de Chances , TaiwanRESUMO
There has been considerable recent debate concerning the distances over which levels of allelic association useful for genomic quantitative trait locus (QTL) scans can be detected. We have examined simple sequence repeat (SSR) polymorphisms and two single nucleotide polymorphisms (SNPs) in the region flanking the aldehyde dehydrogenase 2 locus, ALDH2, in populations of Japanese alcoholics and controls. These groups differ significantly in the allele frequencies for the functional SNP in exon XII of this gene located on chromosome 12. The results obtained with SSR markers complement recent investigations with SNPs over similar distances at the TCR alpha/delta locus. Significant allelic association with this marker could be detected for SSRs over distances up to 400 kb and over 37 kb for the SNP thereby extending the distance over which LD at this locus could be detected by an order of magnitude. Furthermore, as a proof of principle, we show that comparisons of allele frequency differences for the SSR markers in the case (alcoholics) and control populations would have detected the ALDH2 marker as a putative QTL. Extending the tests to include alleles at two or three flanking loci suggests that the power to detect QTLs through association can be enhanced significantly.