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Glutamate and synaptic plasticity systems and smoking behavior: results from a genetic association study.

ABSTRACT: Smoking behavior is a multifactorial phenotype with significant heritability. Identifying the specific loci that influence smoking behavior could provide important etiological insights and facilitate the development of treatments to further reduce smoking related mortality. Although several studies pointed to different candidate genes for smoking, there is still a need for replication especially in samples from different countries. In the present study, we investigated whether 21 positive signals for smoking behavior from these studies are replicated in a sample of 531 blood donors from the Brazilian population. The polymorphisms were chosen based on their representativeness of different candidate biologic systems, strength of previous evidence, location and allele frequencies. By genotyping with the Sequenom MassARRAY iPLEX platform and subsequent statistical analysis using Plink software, we show that two of the SNPs studied, in the SLC1A2 (rs1083658) and ACTN1 (rs2268983) genes, were associated with smoking behavior in our study population. These genes are involved in crucial aspects of nicotine dependence, glutamate system and synaptic plasticity, and as such, are biologically plausible candidates that merit further molecular analyses so as to clarify their potential role in smoking behavior.

SUBMITTER: dos Santos VA

PROVIDER: S-EPMC3377718 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Glutamate and synaptic plasticity systems and smoking behavior: results from a genetic association study.

dos Santos Vanessa Argondizo VA Chatkin Jose Miguel JM Bau Claiton Henrique Dotto CH Paixão-Côrtes Vanessa Rodrigues VR Sun Ye Y Zamel Noe N Siminovitch Katherine K

PloS one 20120618 6

Smoking behavior is a multifactorial phenotype with significant heritability. Identifying the specific loci that influence smoking behavior could provide important etiological insights and facilitate the development of treatments to further reduce smoking related mortality. Although several studies pointed to different candidate genes for smoking, there is still a need for replication especially in samples from different countries. In the present study, we investigated whether 21 positive signal ...[more]

PMID: 22719919

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Project description:Some controversy exists on the specific genetic variants that are associated with nicotine dependence and smoking-related phenotypes. The purpose of this study was to analyse the association of smoking status and smoking-related phenotypes (included nicotine dependence) with 17 candidate genetic variants: CYP2A6*1×2, CYP2A6*2 (1799T>A) [rs1801272], CYP2A6*9 (-48T>G) [rs28399433], CYP2A6*12, CYP2A13*2 (3375C>T) [rs8192789], CYP2A13*3 (7520C>G), CYP2A13*4 (579G>A), CYP2A13*7 (578C>T) [rs72552266], CYP2B6*4 (785A>G), CYP2B6*9 (516G>T), CHRNA3 546C>T [rs578776], CHRNA5 1192G>A [rs16969968], CNR1 3764C>G [rs6928499], DRD2-ANKK1 2137G>A (Taq1A) [rs1800497], 5HTT LPR, HTR2A -1438A>G [rs6311] and OPRM1 118A>G [rs1799971]. We studied the genotypes of the aforementioned polymorphisms in a cohort of Spanish smokers (cases, N = 126) and ethnically matched never smokers (controls, N = 80). The results showed significant between-group differences for CYP2A6*2 and CYP2A6*12 (both P<0.001). Compared with carriers of variant alleles, the odds ratio (OR) for being a non-smoker in individuals with the wild-type genotype of CYP2A6*12 and DRD2-ANKK1 2137G>A (Taq1A) polymorphisms was 3.60 (95%CI: 1.75, 7.44) and 2.63 (95%CI: 1.41, 4.89) respectively. Compared with the wild-type genotype, the OR for being a non-smoker in carriers of the minor CYP2A6*2 allele was 1.80 (95%CI: 1.24, 2.65). We found a significant genotype effect (all P≤0.017) for the following smoking-related phenotypes: (i) cigarettes smoked per day and CYP2A13*3; (ii) pack years smoked and CYP2A6*2, CYP2A6*1×2, CYP2A13*7, CYP2B6*4 and DRD2-ANKK1 2137G>A (Taq1A); (iii) nicotine dependence (assessed with the Fagestrom test) and CYP2A6*9. Overall, our results suggest that genetic variants potentially involved in nicotine metabolization (mainly, CYP2A6 polymorphisms) are those showing the strongest association with smoking-related phenotypes, as opposed to genetic variants influencing the brain effects of nicotine, e.g., through nicotinic acetylcholine (CHRNA5), serotoninergic (HTR2A), opioid (OPRM1) or cannabinoid receptors (CNR1).

Project description:Adenosine kinase (ADK) deficiency in human patients (OMIM:614300) disrupts the methionine cycle and triggers hypermethioninemia, hepatic encephalopathy, cognitive impairment, and seizures. To identify whether this neurological phenotype is intrinsically based on ADK deficiency in the brain or if it is secondary to liver dysfunction, we generated a mouse model with a brain-wide deletion of ADK by introducing a Nestin-Cre transgene into a line of conditional ADK deficient Adkfl/fl mice. These Adk?brain mice developed a progressive stress-induced seizure phenotype associated with spontaneous convulsive seizures and profound deficits in hippocampus-dependent learning and memory. Pharmacological, biochemical, and electrophysiological studies suggest enhanced adenosine levels around synapses resulting in an enhanced adenosine A1 receptor (A1R)-dependent protective tone despite lower expression levels of the receptor. Theta-burst-induced LTP was enhanced in the mutants and this was dependent on adenosine A2A receptor (A2AR) and tropomyosin-related kinase B signaling, suggesting increased activation of these receptors in synaptic plasticity phenomena. Accordingly, reducing adenosine A2A receptor activity in Adk?brain mice restored normal associative learning and contextual memory and attenuated seizure risk. We conclude that ADK deficiency in the brain triggers neuronal adaptation processes that lead to dysregulated synaptic plasticity, cognitive deficits, and increased seizure risk. Therefore, ADK mutations have an intrinsic effect on brain physiology and may present a genetic risk factor for the development of seizures and learning impairments. Furthermore, our data show that blocking A2AR activity therapeutically can attenuate neurological symptoms in ADK deficiency.A novel human genetic condition (OMIM #614300) that is based on mutations in the adenosine kinase (Adk) gene has been discovered recently. Affected patients develop hepatic encephalopathy, seizures, and severe cognitive impairment. To model and understand the neurological phenotype of the human mutation, we generated a new conditional knock-out mouse with a brain-specific deletion of Adk (Adk?brain). Similar to ADK-deficient patients, Adk?brain mice develop seizures and cognitive deficits. We identified increased basal synaptic transmission and enhanced adenosine A2A receptor (A2AR)-dependent synaptic plasticity as the underlying mechanisms that govern these phenotypes. Our data show that neurological phenotypes in ADK-deficient patients are intrinsic to ADK deficiency in the brain and that blocking A2AR activity therapeutically can attenuate neurological symptoms in ADK deficiency.

Dataset Information

Glutamate and synaptic plasticity systems and smoking behavior: results from a genetic association study.

Publications

Glutamate and synaptic plasticity systems and smoking behavior: results from a genetic association study.

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