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      Genetic Research on Nicotine Dependence Will Facilitate Public Health

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          Abstract

          W. D. Hall's cogent Research in Translation article [1] on the folly of attempting to use predictive genetic testing in public-health measures to prevent nicotine dependence is a valuable contribution. Indeed, his arguments against predictive testing can easily be applied to virtually any complex genetic disorder. It is certainly important that we in the medical research community continue to offer such articulate education to clinicians, the press, and society in general. There is a danger, however, that his arguments will be seized by those who oppose supporting research on the genetics of nicotine dependence and other addictions, to the detriment of public health. For example, Merikangas and Risch [2] have already proposed that addictions and several other complex diseases should be deprived of federal research support in favor of other complex disorders, arguing, “The expensive and laborious tools of molecular genetics [should] be prioritized to those diseases ... that cannot now be treated or prevented with environmental changes [such as] type 1 diabetes, multiple sclerosis, autism and schizophrenia. In contrast, gene hunting for disorders that appear to be highly amenable to environmental modification, such as type 2 diabetes, AIDS, alcohol dependence and nicotine dependence, would have lower priority [for federal research support], even though genes may be involved in their etiology.” Those arguments were picked up by right-wing commentators and trumpeted in high-profile lay outlets such as the New York Times. For example, Humphreys and Satel [3] (the latter a resident scholar at the American Enterprise Institute) cite Merikangas and Risch when they conclude, “Some gene research just isn't worth the money ... [because] major cuts in drug- and alcohol-related harm depend not on genes but on choices by policy makers and individual citizens.” Thus, the myth that addictive behavior is simply a matter of “choice” is made to appear as if it has solid science behind it, when in my view, the only real rationale for opposing genetic research on disorders related to smoking, drinking, overeating, homosexual sex, and other “sinful” behavior derives from the same strain of religious moralism underlying creationism and intelligent design. Such arguments miss the most important rationale for genetic research on addictions and other environmentally influenced complex disorders. These conditions deserve continued vigorous support from the National Institutes of Health and other sources because genetic research is a powerful tool for pointing us toward new treatments based on improved understanding of the biology of the disorders. Nicotine dependence is an important case in point because current treatments, which consist of psychosocial interventions, and medication therapies such as nicotine replacement and buproprion are, in a word, ineffective: relapse rates following smoking cessation with those strategies, while slightly better than no intervention, usually exceed 80% at one-year follow-up [4]. Genetic research, by providing suggestive evidence for associations to the genes encoding the gamma-amino butyric acid (GABA) B receptor subunit 2 [5], or the cannabinoid-1 receptor [6,7], has already helped light the way toward potentially more effective interventions for millions who struggle to quit smoking, but repeatedly fail. While predictive testing of risk for nicotine dependence based on those genetic findings is quite useless, it remains to be ascertained whether pharmacogenetic profiling will be useful for identifying those most likely to benefit from specific medications (or for that matter, psychosocial interventions), or who would be at risk for harmful side-effects from an otherwise effective drug. While the potential for such profiling has been hyped up in the popular press just as predictive testing has been, we have only to recall the lives saved by understanding the genetic basis of variation in thiopurine methyltransferase activity, in the context of thiopurine chemotherapy for acute lymphoblastic leukemia [8], to convince ourselves of the importance of studying the genetic basis of all common complex diseases, whether partially amenable to environmental prevention or not.

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          Most cited references8

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          Human cannabinoid receptor 1: 5' exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse.

          A number of lines of evidence make the gene that encodes the G-protein-coupled CB1/Cnr1 receptor a strong candidate to harbor variants that might contribute to individual differences in human addiction vulnerability. The CB1/Cnr1 receptor is the major brain site at which cannabinoid marijuana constituents are psychoactive as well as the principal brain receptor for endogenous anandamide ligands. It is densely expressed in brain circuits likely to be important for both the reward and mnemonic processes important for addiction. Altered drug effects in CB1/Cnr1 knockout mice and initial association studies also make variants at the CB1/Cnr1 locus candidates for roles in human vulnerabilities to addictions. However, many features of this gene's structure, regulation and variation remain poorly defined. This poor definition has limited the ability of previous association studies to adequately sample variation at this locus. We now report improved definition of the human CB1/Cnr1 locus and its variants. Novel exons 1-3, splice variant and candidate promoter region sequences add to the richness of the CB1/Cnr1 locus. Candidate promoter region sequences confer reporter gene expression in cells that express CB1/Cnr1. Common polymorphisms reveal patterns of linkage disequilibrium in European- and in African-American individuals. A 5' CB1/Cnr1 "TAG" haplotype displays significant allelic frequency differences between substance abusers and controls in European-American, African-American and Japanese samples. Post-mortem brain samples of heterozygous individuals contain less mRNA transcribed from the TAG alleles than from other CB1/Cnr1 haplotypes. CB1/ Cnr1 genomic variation thus appears to play roles in human addiction vulnerability.
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            Pharmacogenomics: bench to bedside.

            Pharmacogenetics is the study of the role of inheritance in inter-individual variation in drug response. Since its origins in the mid-twentieth century, a major driving force in pharmacogenetics research has been the promise of individualized drug therapy to maximize drug efficacy and minimize drug toxicity. In recent years, the convergence of advances in pharmacogenetics with rapid developments in human genomics has resulted in the evolution of pharmacogenetics into pharmacogenomics, and led to increasing enthusiasm for the 'translation' of this evolving discipline into clinical practice. Here, we briefly summarize the development of pharmacogenetics and pharmacogenomics, and then discuss the key factors that have had an influence on - and will continue to affect - the translation of pharmacogenomics from the research bench to the bedside, highlighting the challenges that need to be addressed to achieve this goal.
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              Polysubstance abuse-vulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms.

              Strong genetic contributions to drug abuse vulnerability are well documented, but few chromosomal locations for human drug-abuse vulnerability alleles have been confirmed. We now identify chromosomal markers whose alleles distinguish drug abusers from control individuals in each of two samples, on the basis of pooled-sample microarray and association analyses. Reproducibly positive chromosomal regions defined by these markers in conjunction with previous results were especially unlikely to have been identified by chance. Positive markers identify the alcohol dehydrogenase (ADH) locus, flank the brain-derived neurotropic factor (BDNF) locus, and mark seven other regions previously linked to vulnerability to nicotine or alcohol abuse. These data support polygenic contributions of common allelic variants to polysubstance abuse vulnerability.
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                Author and article information

                Journal
                PLoS Med
                pmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                November 2005
                29 November 2005
                : 2
                : 11
                : e396
                Affiliations
                [1] 1Emory University School of Medicine Atlanta, GeorgiaUnited States of America
                Author notes

                Competing Interests: JC is currently supported by a career development award from the National Institute on Drug Abuse, and collaborates in several ongoing basic research projects in addiction genetics. The opinions expressed here are solely the author's.

                Article
                10.1371/journal.pmed.0020396
                1297553
                16288563
                5b6d0127-410b-4d4c-83de-3b28c800eb1c
                Copyright: © 2005 Joe Cubells. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Categories
                Correspondence and Other Communications
                Genetics/Genomics/Gene Therapy
                Immunology
                Other
                Pharmacology/Drug Discovery
                Health Policy
                Respiratory Medicine
                Psychiatry
                Public Health
                Respiratory Medicine
                Smoking
                Substance Use (Including Alcohol)

                Medicine
                Medicine

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