Nicotine is the major psychoactive ingredient in tobacco, and is responsible for dependence through the nicotine-stimulated reward pathway mediated by the central dopaminergic system. Consequently, genetic polymorphisms in both nicotine metabolism and dopamine catabolism genes may influence smoking behavior, and interact with each other resulting in risk modulation. In this study, we investigated the association and multilocus gene-gene interactions of cytochrome P450 2A6 (CYP2A6), dopamine beta-hydroxylase (DBH), catechol O-methyl transferase (COMT), and monoamine oxidase A (MAOA) polymorphisms with smoking behavior in a community-based Chinese male population.
The polymorphisms were genotyped in 203 current smokers, 66 former smokers, and 102 never smokers. Multivariate logistic regression models and the multifactor dimensionality reduction method were used to analyze the association and multilocus gene-gene interactions.
Statistically significant trends were shown for increased risk of smoking initiation in participants with CYP2A6*1B/CYP2A6*1B genotypes compared with those with CYP2A6*1A/CYP2A6*1A genotypes [odds ratio (OR)=3.5, 95% confidence interval (CI)= 1.5-8.1], and participants with CYP2A6*1/CYP2A6*1 genotypes were at higher risk of smoking initiation (OR=2.4, 95% CI=1.2-4.5) and smoking persistence (OR=4.0, 95% CI=1.5-10.3) than those who have CYP2A6*4C genotypes. Moreover, the best model involved a gene-gene interaction between MAOA and CYP2A6 was characterized by the multifactor dimensionality reduction method (64.11% accuracy, P<0.001), and indicated that carriers of the combined 1460 T/O genotype for MAOA EcoRV and CYP2A6*1/CYP2A6*1 genotypes were at higher risk of smoking (OR=15.4, 95% CI=4.5-52.5).
These findings suggested a substantial influence of CYP2A6 polymorphism as well as the interaction with MAOA resulting in risk modulation on smoking behavior in Chinese male population.
"Liu and colleagues found reduced metabolic function of CYP2A6 in Chinese smokers that was associated with fewer cigarettes smoked, a later initiation of smoking regularly, a shorter duration of smoking, and a lower likelihood of smoking cessation. Tang and colleagues reported on the interaction between CYP2A6 polymorphism and MAOA in risk modulation of smoking behavior (i.e., smoking initiation and smoking persistence) in a Chinese male population. Chinese scientists have also identified important associations between genetic polymorphism of the CYP450 enzyme gene with the concomitant diseases of substance abuse disorders and with the dosage and side effects of pharmacological treatments for substance abuse disorders.,, "
[Show abstract][Hide abstract] ABSTRACT: The importance of genetic factors in substance addiction has long been established. The rationale for this work is that understanding of the function of addiction genes and delineation of the key molecular pathways of these genes would enhance the development of novel therapeutic targets and biomarkers that could be used in the prevention and management of substance abuse. Over the past few years, there has been a substantial increase in the number of genetic studies conducted on addiction in China; these studies have primarily focused on heroin, alcohol, and nicotine dependence. Most studies of candidate genes have concentrated on the dopamine, opioid, and serotonin systems. A number of genes associated with substance abuse in Caucasians are also risk factors in Chinese, but several novel genes and genetic risk factors associated with substance abuse in Chinese subjects have also been identified. This paper reviews the genetic studies of substance abuse performed by Chinese researchers. Genotypes and alleles related to addictive behavior in Chinese individuals are discussed and the contributions of Chinese researchers to the international corpus of knowledge about the genetic understanding of substance abuse are described.
Shanghai Archives of Psychiatry 08/2013; 25(4):199-211. DOI:10.3969/j.issn.1002-0829.2013.04.002
"One of them is the CHRNA5-CHRNA3-CHRNB4 gene cluster located on chromosome 15q24-25 –. The contribution of several other candidate genes to the vulnerability to cigarette-smoking has been reported, such as catechol O-methyltransferase , dopamine receptor 2 –, opioid receptor  as well as genes related to nicotine metabolism, such as cytochrome P450 CYP 2A6 , . The effects of these genes are often dependent on the ethnicity of the population , , . "
[Show abstract][Hide abstract] ABSTRACT: Adult cigarette smokers usually become dependent on cigarettes during adolescence. Despite recent advances in addiction genetics, little data delineates the genetic factors that account for the vulnerability of humans to smoke tobacco. We studied the operant nicotine self-administration (SA) behavior of six inbred strains of adolescent male rats (Fisher 344, Brown Norway, Dark Agouti, Spontaneous Hypertensive Rat, Wistar Kyoto and Lewis) and six selected F1 hybrids. All rats were trained to press a lever to obtain food starting on postnatal day (PN) 32, and then nicotine (0.03 mg/kg/infusion, i.v.) reinforcement was made available on PN41-42 (10 consecutive daily 2 h sessions). Of the 12 isogenic strains, Fisher rats self-administered the fewest nicotine infusions (1.45 ± 0.36/d) during the last 3 d, while Lewis rats took the most nicotine (13.0 ± 1.4/d). These strains sorted into high, intermediate and low self-administration groups in 2, 2, and 8 strains, respectively. The influence of heredity on nicotine SA (0.64) is similar to that reported for humans. Therefore, this panel of isogenic rat strains effectively models the overall impact of genetics on the vulnerability to acquire nicotine-reinforced behavior during adolescence. Separate groups of rats responded for food starting on PN41. The correlation between nicotine and food reward was not significant. Hence, the genetic control of the motivation to obtain nicotine is distinctly different from food reward, indicating the specificity of the underlying genetic mechanisms. Lastly, the behavior of F1 hybrids was not predicted from the additive behavior of the parental strains, indicating the impact of significant gene-gene interactions on the susceptibility to nicotine reward. Taken together, the behavioral characteristics of this model indicate its strong potential to identify specific genes mediating the human vulnerability to smoke cigarettes.
PLoS ONE 08/2012; 7(8):e44234. DOI:10.1371/journal.pone.0044234 · 3.23 Impact Factor
"In addition to the CGASP result mentioned above, several other studies have reported interesting results from the joint analysis of multiple loci chr15q25 in samples of European descent (Li et al. 2010a; Liu et al. 2010; Thorgeirsson et al. 2010; Tobacco and Genetics Consortium 2010), African Americans (Li et al. 2010a), and Koreans (Li et al. 2010b). Additional joint genetic effects related to smoking have been reported in other candidate regions, including interactions among variants in GABBR1 and GABBR2 related to nicotine dependence in African and European Americans (Li et al. 2009) and an interaction between CYP2A6 and MAOA affecting smoking in Chinese (Tang et al. 2009). "
[Show abstract][Hide abstract] ABSTRACT: Results from genome-wide association studies of complex traits account for only a modest proportion of the trait variance predicted to be due to genetics. We hypothesize that joint analysis of polymorphisms may account for more variance. We evaluated this hypothesis on a case-control smoking phenotype by examining pairs of nicotinic receptor single-nucleotide polymorphisms (SNPs) using the Restricted Partition Method (RPM) on data from the Collaborative Genetic Study of Nicotine Dependence (COGEND). We found evidence of joint effects that increase explained variance. Four signals identified in COGEND were testable in independent American Cancer Society (ACS) data, and three of the four signals replicated. Our results highlight two important lessons: joint effects that increase the explained variance are not limited to loci displaying substantial main effects, and joint effects need not display a significant interaction term in a logistic regression model. These results suggest that the joint analyses of variants may indeed account for part of the genetic variance left unexplained by single SNP analyses. Methodologies that limit analyses of joint effects to variants that demonstrate association in single SNP analyses, or require a significant interaction term, will likely miss important joint effects.
Human Genetics 11/2010; 129(2):177-88. DOI:10.1007/s00439-010-0911-7 · 4.82 Impact Factor
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