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Genetic vulnerability and susceptibility to substance dependence.

ABSTRACT: The development of substance dependence requires the initiation of substance use and the conversion from experimental use to established use before development of dependence. Numerous large twin studies have indicated a significant genetic contribution to this process. Genetic studies to date have been most successful at identifying genetic factors that influence the transition from regular use to dependence. The availability of large cohort samples for nicotine and alcohol dependence has resulted in significant progress being made in understanding at least some of the genetic contributions to these addictions. Fewer studies have replicated specific genetic contributions to illicit drug use, though it is clear that there is a strong genetic component involved here as well. Substance dependence can be thought of as a pharmacogenetic illness, and most likely hundreds and more probably thousands of genetic variants will be required to fully explain the genetic input to this disease.

SUBMITTER: Bierut LJ

PROVIDER: S-EPMC3095110 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Genetic vulnerability and susceptibility to substance dependence.

Bierut Laura Jean LJ

Neuron 20110201 4

The development of substance dependence requires the initiation of substance use and the conversion from experimental use to established use before development of dependence. Numerous large twin studies have indicated a significant genetic contribution to this process. Genetic studies to date have been most successful at identifying genetic factors that influence the transition from regular use to dependence. The availability of large cohort samples for nicotine and alcohol dependence has result ...[more]

PMID: 21338875

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Project description:ObjectiveAlthough tribes differ with regard to the use of alcohol and drugs, substance dependence is one of the primary sources of health problems facing Native Americans. General population studies have demonstrated that substance dependence has a substantially heritable component (approximately 50% of the risk resulting from genetic influences); however, fewer studies have investigated the role of genetics in the risk for substance dependence in Native Americans.MethodThe authors present a literature review of the evidence for a genetic component in the etiology of substance dependence in Native Americans, including studies of heritability, linkage analyses, and candidate genes.ResultsEvidence for the heritability of alcohol and drug dependence was found. Linkage analyses revealed that genes influencing risk for substance dependence and related phenotypes, such as body mass index (BMI), drug tolerance, EEG patterns, and externalizing traits, reside on several chromosome regions identified in other population samples. Overlap in the gene locations for substance dependence and BMI suggests that a common genetic substrate may exist for disorders of consumption. Studies of the genes that code for alcohol-metabolizing enzymes have not revealed any risk variants specific to Native American populations, although most Native Americans lack protective variants seen in other populations. Other candidate genes associated with substance dependence phenotypes in Native Americans include OPRM1, CRN1, COMT, GABRA2, MAOA, and HTR3-B.ConclusionsSubstance dependence has a substantial genetic component in Native Americans, similar in magnitude to that reported for other populations. The high rates of substance dependence seen in some tribes is likely a combination of a lack of genetic protective factors (metabolizing enzyme variants) combined with genetically mediated risk factors (externalizing traits, consumption drive, and drug sensitivity or tolerance) that combine with key environmental factors (trauma exposure, early age at onset of use, and environmental hardship) to produce an elevated risk for the disorder.

Project description:BackgroundThe quinone oxidoreductase 1 (NQO1) gene was involved in the pathophysiological process of illicit drugs abuse, and its polymorphisms might be associated with methamphetamine (METH) dependence susceptibility. The purpose of this study was to examine the NQO1 mRNA and protein levels and to analyze the 609C/T polymorphism (rs1800566) between METH-dependent patients and controls.MethodsA total of 392 METH-dependent patients (cases) and 669 healthy controls (controls) were enrolled in the study. The quantitative real-time polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the relative expressions of NQO1 mRNA in PBMCs and protein levels in plasma, respectively. PCR-restriction fragment length polymorphism (RFLP-PCR) and direct-sequencing genotyping were used to detect the alleles and genotypes of NQO1 609C/T polymorphism.ResultsThe levels of NQO1 mRNA in cases (3.2650 ± 2.2943) was significantly higher than in controls (1.0125 ± 0.7959) (p < 0.001), the plasma protein in cases (0.2368 ± 0.1486) was significantly lower than in controls (0.5844 ± 0.1742) (p < 0.001). The T allele of the 609C/T polymorphism significantly increased the risk of METH dependence (p = 0.032, OR = 1.214, 95%CI = 1.017-1.450). The TC and TC/TT genotypes of 609C/T were observed significantly more frequently in cases than in controls, respectively (TC vs CC: p = 0.012, OR = 1.457, 95% CI = 1.087-1.952; TC/TT vs CC: p = 0.008, OR = 1.460, 95% CI = 1.102-1.935). Similar results were obtained after adjusting for age and sex. We failed to find that any genotype of 609C/T polymorphism affected the mRNA or plasma protein levels in controls, respectively (p > 0.05).ConclusionThe findings suggested that NQO1 might play an important role in the pathophysiological process of METH dependence, and the 609C/T polymorphism might contribute to the susceptibility to METH dependence in a Chinese Han population.

Dataset Information

Genetic vulnerability and susceptibility to substance dependence.

Publications

Genetic vulnerability and susceptibility to substance dependence.

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