Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Women who have experienced childhood sexual abuse (CSA) have an increased risk of alcoholism and antisocial personality disorder (ASPD). Among male subjects, a functional polymorphism (MAOA-LPR, monoamine oxidase A linked polymorphic region) in the promoter region of the monoamine oxidase A gene (MAOA) appears to moderate the effect of childhood maltreatment on antisocial behavior. Our aim was to test whether MAOA-LPR influences the impact of CSA on alcoholism and ASPD in a sample of 291 women, 50% of whom have experienced CSA; we also tested whether haplotypes covering the region where both MAOA and monoamine oxidase B (MAOB) genes are located predict risk of alcoholism and ASPD better than the MAOA-LPR locus alone. Participants included 168 alcoholics (39 with ASPD (antisocial alcoholics) and 123 controls (no alcoholics, no ASPD). Antisocial behavior was also modeled as a continuous trait: ASPD symptoms count. The MAOA-LPR low activity allele was associated with alcoholism (P=0.005), particularly antisocial alcoholism (P=0.00009), only among sexually abused subjects. Sexually abused women who were homozygous for the low activity allele had higher rates of alcoholism and ASPD, and more ASPD symptoms, than abused women homozygous for the high activity allele. Heterozygous women displayed an intermediate risk pattern. In contrast, there was no relationship between alcoholism/antisocial behavior and MAOA-LPR genotype among non-abused women. The MAOA-LPR low activity allele was found on three different haplotypes. The most abundant MAOA haplotype containing the MAOA-LPR low activity allele was found in excess among alcoholics (P=0.008) and antisocial alcoholics (P=0.001). Finally, a MAOB haplotype, which we termed haplotype C, was significantly associated with alcoholism (P=0.006), and to a lesser extent with antisocial alcoholism (P=0.03). In conclusions, MAOA seems to moderate the impact of childhood trauma on adult psychopathology in female subjects in the same way as previously shown among male subjects. The MAOA-LPR low activity allele appears to confer increased vulnerability to the adverse psychosocial consequences of CSA. Haplotype-based analysis of the MAOA gene appeared to strengthen the association, as compared to the MAOA-LPR locus alone. A MAOB haplotype was associated with alcoholism independently from ASPD.
Mol Psychiatry 2008 Mar
PMID:Interaction between a functional MAOA locus and childhood sexual abuse predicts alcoholism and antisocial personality disorder in adult women. 1759 78

Eleven single-nucleotide polymorphisms (SNPs) spanning OPRD1 were examined in 1063 European Americans (EAs) (620 cases with substance dependence (SD), including 557 with alcohol dependence (AD), 225 with cocaine dependence (CD) and 111 with opioid dependence (OD), and 443 controls). Nominally significant associations (P<0.05) of five SNPs with SD were observed; only the association of the non-synonymous variant G80T with OD remained significant after correction for multiple testing using SNPSpD. Haplotype analyses with six tag SNPs indicated that a specific haplotype GCAACT, which harbors G80T G-allele and C921T C-allele, was significantly associated with AD (chi(2)=14.82, degrees of freedom (d.f.)=1, P<0.001), CD (chi(2)=9.19, d.f.=1, P=0.002) and OD (chi(2)=20.68, d.f.=1, P<0.001). Logistic regression analyses, with sex and age being considered, demonstrated that this haplotype had a risk effect on AD (P=0.03, beta=1.86, odds ratio (OR)=6.43) and especially on OD (P<0.001, beta=3.92, OR=50.57). Moreover, seven SNPs covering OPRK1 were examined in the majority of the above subjects (390 cases, including 327 AD, 177 CD and 97 OD subjects, and 358 controls). Although no significant differences in allele, genotype or haplotype frequency distributions were seen between cases and controls, a specific OPRK1 haplotype, GGCTTCT, was significantly associated with AD (chi(2)=8.12, d.f.=1, P=0.004). Logistic regression analyses also revealed its risk effect on AD (P=0.009, beta=1.06, OR=2.90). Population stratification artifact was not observed in the sample. Taken together, our findings supported a positive association between OPRD1 variants and SD, and a positive haplotypic association between OPRK1 and AD in EAs.
Mol Psychiatry 2008 May
PMID:The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk. 1762 22

There have been many conflicting reports concerning the association of the DRD2 locus with alcohol dependence (AD). To investigate whether these findings could be reconciled by considering the genomic region of DRD2 in greater detail, we conducted two separate association studies of AD in 1220 European-American subjects using family-based (488 subjects) and case-control (318 cases and 414 controls) designs, and 43 single nucleotide polymorphisms mapped to the gene cluster of NCAM1, TTC12, ANKK1 and DRD2. We used a generalized linear model and haplotype score tests for the case-control sample, and the family-based association test for the family sample. Haplotype associations centered on TTC12 exon 3 [rs1893699-rs723077; optimal individual haplotype simulated P-value (P(oihs)) = 0.00021] in both independent samples (family and case-control). Additional AD-associated haplotypes centered around NCAM1 exon 12 in the family sample (P(oihs) = 0.0032), and at exons 2 and 5 of ANKK1 in the case-control sample (P(oihs) = 0.00058). LD contrasts between cases and controls support selection at TTC12 exon 3 and ANKK1 exon 2. The armadillo repeat domains encoded by TTC12 and dopamine interact in the Wnt pathway and may have effects on dopamine cell development in the ventral midbrain. We conclude that risk for AD is attributable in part to variants in four regions within this cluster: exon 3 of TTC12, exon 12/intron13 of NCAM1 and exons 2 and 5 of ANKK1. The complexity of these relationships, many of which replicate between our independent samples, may explain prior inconsistent results.
Hum Mol Genet 2007 Dec 01
PMID:Association of haplotypic variants in DRD2, ANKK1, TTC12 and NCAM1 to alcohol dependence in independent case control and family samples. 1776 87

Neurexins are cell adhesion molecules that help to specify and stabilize synapses and provide receptors for neuroligins, neurexophilins, dystroglycans and alpha-latrotoxins. We previously reported significant allele frequency differences for single nucleotide polymorphisms (SNPs) in the neurexin 3 (NRXN3) gene in each of two comparisons between individuals who were dependent on illegal substances and controls. We now report work clarifying details of NRXN3's gene structure and variants and documenting association of NRXN3 SNPs with alcohol dependence. We localize this association signal with the vicinity of the NRXN3 splicing site 5 (SS#5). A splicing site SNP, rs8019381, that is located 23 bp from the SS#5 exon 23 donor site displays association with P = 0.0007 (odds ratio = 2.46). Including or excluding exon 23 at SS#5 produces soluble or transmembrane NRXN3 isoforms. We thus examined expression of these NRXN3 isoforms in postmortem human cerebral cortical brain samples from individuals with varying rs8019381 genotypes. Two of the splice variants that encode transmembrane NRXN3 isoforms were expressed at significantly lower levels in individuals with the addiction-associated rs8019381 'T' allele than in CC homozygotes. Taken together with recent reports of NRXN3 association with nicotine dependence and linkage with opiate dependence, these data support roles for NRXN3 haplotypes that alter expression of specific NRXN3 isoforms in genetic vulnerabilities to dependence on a variety of addictive substances.
Hum Mol Genet 2007 Dec 01
PMID:Neurexin 3 polymorphisms are associated with alcohol dependence and altered expression of specific isoforms. 1780 23

(1) Circadian clocks have been localized to discrete sites within the nervous system of several organisms and in mammals to the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. The SCN controls and regulates the production and discharge of melatonin (hormonal message of darkness) from the pineal gland via a multisynaptic efferent pathway. The nocturnal rise in melatonin production from serotonin results due to an increased activity of serotonin N-acetyl transferase (NAT). (2) The complex interaction between alcohol and biological clock need to be understood as alcoholism results in various clock linked neuronal disorders especially loss of memory and amnesia like state of consciousness, sleep disorders, insomnia, dementia etc. (3) Serotonin, 5-Hydroxy-tryptamine (5-HT) plays an important role in mediating alcohol's effects on the brain. Understanding the impact of alcohol consumption on circadian system is a pre-requisite to help in treatment of alcohol induced neurological disorders. We, therefore, studied the effect of ethanol drinking and ethanol withdrawal on daily rhythms of serotonin and its metabolite, 5-hydroxy-indole acetic acid (5-HIAA) in SCN and Pineal of adult male Wistar rats maintained under light-dark (LD, 12:12) conditions. (4) Curcumin is well known for its protective properties such as antioxidant, anti-carcinogenic, anti-viral and anti-infectious etc. Hence, we studied the effect of curcumin on ethanol induced changes on 5-HT and 5-HIAA levels and rhythms in SCN and Pineal. (5) Ethanol withdrawal could not restore either rhythmicity or phases or levels of 5-HT and 5-HIAA. Curcumin administration resulted in partial restoration of daily 5-HT/5-HIAA ratio, with phase shifts in SCN and in Pineal. Understanding the impact of alcohol consumption on circadian system and the role of herbal medication on alcohol withdrawal will help in treatment of alcohol induced neurological disorders.
Cell Mol Neurobiol 2007 Dec
PMID:The effect of curcumin on ethanol induced changes in suprachiasmatic nucleus (SCN) and pineal. 1784 84

Drugs of abuse including nicotine and alcohol elicit their effect by stimulating the mesocorticolimbic dopaminergic system. There is a high incidence of nicotine dependence in alcoholics. To date only limited data is available on the molecular mechanism underlying the action of alcohol and nicotine in the human brain. This study utilized gene expression screening to identify genes sensitive to chronic alcohol abuse within the ventral tegmental area (VTA) of the human brain. Alcohol-responsive genes encoded proteins primarily involved in structural plasticity and neurotransmitter transport and release. In particular, genes involved with brain-derived neurotrophic factor signalling and glutamatergic transmission were found to be affected. The possibility that glutamate transport was a target of chronic alcohol and/or tobacco abuse was further investigated in an extended case set by measurement of mRNA and protein expression. Expression levels of vesicular glutamate transporters SLC17A6 and SLC17A7 were robustly induced by smoking, an effect that was reduced by alcohol co-exposure. Glutamatergic transmission is vital for the control of the VTA and may also be critical to the weighting of novelty and importance of a stimulus, an essential output of this brain region. We conclude that enduring plasticity within the VTA may be a major molecular mechanism for the maintenance of smoking addiction and that alcohol, nicotine and co-abuse have distinct impacts on glutamatergic transmission with important implications for the control of this core mesolimbic structure.
Hum Mol Genet 2008 Jan 01
PMID:Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area. 1792 4

Several lines of preclinical evidence indicate the ability of the prototypic cannabinoid CB(1) receptor antagonist, rimonabant, to suppress various alcohol-related behaviors, including alcohol drinking and seeking behavior and alcohol self-administration in rats and mice. Together, these data-synthetically reviewed in the present paper-suggest (a) the involvement of the cannabinoid CB(1) receptor in the neural substrate controlling alcohol intake, alcohol reinforcement, and the motivational properties of alcohol and (b) that rimonabant may constitute a new and potentially effective medication for the treatment of alcohol dependence.
Mol Neurobiol 2007 Aug
PMID:The cannabinoid CB1 receptor antagonist, rimonabant, as a promising pharmacotherapy for alcohol dependence: preclinical evidence. 1795 55

Cancer cells, characterized by local invasion and distant metastasis, are very much dependent on the extracellular matrix. The expression of matrix metalloproteinases (MMPs) has been implicated in the invasion and metastasis of cancer cells. In this study, we reported the effects of disulfiram, a clinically used anti-alcoholism drug, on tumor invasion suppression, as well as its effects on the activity of MMP-2 and MMP-9 in human osteosarcoma cells (U2OS). Disulfiram has been used for alcohol aversion therapy. However, recent reports have shown that disulfiram may have potential in the treatment of human cancers. Herewith, we showed that the anti-tumor effects of disulfiram, in an invasion assay using U2OS cells and that disulfiram has a type IV collagenase inhibitory activity that inhibits expression of genes and proteins responsible for both cell and non-cell mediated invasion on pathways. In conclusion, disulfiram inhibited expression of MMP-2 and MMP-9 and it regulated the invasion of human osteosarcoma cells. These observations raise the possibility of disulfiram being used clinical for the inhibition of cancer invasion.
J Biochem Mol Biol 2007 Nov 30
PMID:Disulfiram suppresses invasive ability of osteosarcoma cells via the inhibition of MMP-2 and MMP-9 expression. 1804 5

Alcohol metabolism is one of the biological determinants that could significantly be influenced by genetic polymorphisms in alcohol-metabolism genes. Alcohol dehydrogenase (ADH) converts alcohol to acetaldehyde, and aldehyde dehydrogenase (ALDH) converts acetaldehyde to acetate. The well-known genetic polymorphisms in ADH1B(His47Arg) and ALDH2(Glu487Lys) have dramatic effects on the rate of metabolizing alcohol and acetaldehyde, respectively. The protective allele of ADH1B (ADH1B*47His) encodes for a rapid ethanol-metabolizing enzyme, and the susceptible allele of the ALDH2 (ALDH2*487Lys) is strongly associated with decreased rate of metabolizing acetaldehyde. However, the combined genetic effects of both functional polymorphisms have not been clarified. The combined analysis of two polymorphisms among a Korean population (n = 1,032) revealed dramatic genetic effects on the risk of alcoholism. Individuals bearing susceptible alleles at both loci have 91 times greater risk for alcoholism [odds ratio (OR) = 91.43, P = 1.4 x 10(-32)] and individuals bearing one susceptible and one protective allele at either loci have 11 times greater risk (OR = 11.40, P = 3.5 x 10(-15)) compared with subjects who have both protective alleles. The attributable fraction of those genetic factors, calculated based on population controls, indicates that alcoholism in 86.5% of alcoholic patients can be attributed to the detrimental effect of ADH1B*47Arg and/or ALDH2*487Glu in Korean population.
Hum Mol Genet 2008 Mar 15
PMID:Major genetic components underlying alcoholism in Korean population. 1805 58

A broad region on chromosome 4q has been linked to alcohol dependence (alcoholism). We hypothesized that such broad linkage regions represent the combined action of multiple genes. Seeking to identify genes within that region that are associated with alcoholism, we have tested the association of NFKB1, located at 4q24, with alcoholism. NFKB1 encodes a 105 kDa transcription inhibitor that is cleaved to the 50 kDa DNA-binding subunit of the ubiquitous transcription factor NF-kappaB. NF-kappaB regulates many genes relevant to brain function, and its actions can be potentiated by ethanol; thus, NFKB1 is an excellent candidate gene for alcoholism. Nineteen SNPs in and near NFKB1 were analyzed in a sample of 219 multiplex alcoholic families of European American descent. Family-based association analyses detected significant evidence of association with eight SNPs and marginal evidence for five more. The association was driven by the affected individuals with earlier onset of alcoholism (55% of the sample with onset < or =21 years). Further analysis of the age of onset as a quantitative variable provided evidence for the association of 12 SNPs in this gene. Thus, variations in NFKB1 appear to affect the risk for alcoholism, particularly contributing to an earlier onset of the disease.
Hum Mol Genet 2008 Apr 01
PMID:Association of NFKB1, which encodes a subunit of the transcription factor NF-kappaB, with alcohol dependence. 1807 8


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