Norepinephrine transporter polymorphisms T-182C and G1287A are not associated with alcohol dependence and its clinical subgroups.

Several studies have suggested that the norepinephrine transporter (NET) may play an important role in the pathogenesis of alcohol dependence. Additional studies have shown that the polymorphisms of T-182C (rs2242446) and G1287A (rs5569) in NET gene (hSLC6A2) may affect the NET function. Therefore, in this study, we examined whether these hSLC6A2 gene polymorphisms are a susceptibility factor for alcohol dependence or its clinical subgroup(s). A total of 690 Han Chinese subjects (408 alcohol dependent patients and 282 controls) in Taiwan were recruited for this study. Individuals with alcohol dependence were classified into several clinical subgroups to reduce the clinical heterogeneity. All subjects were interviewed with identical methods, and the mental disorders were diagnosed according to DSM-IV criteria. The polymorphisms of T-182C and G1287A in hSLC6A2 gene were analyzed by using a standard method. No significant differences in genotype and allele frequencies of hSLC6A2 polymorphisms were found between controls and total alcohol dependence or between more homogeneous subgroups with alcohol dependence and controls. This study suggests that the polymorphisms of T-182C and G1287A in hSLC6A2 gene are not major risk factors in increasing susceptibility to either alcohol dependence or its clinical subtypes.

[1]  Christina N. Lessov-Schlaggar,et al.  Heritability of cigarette smoking and alcohol use in Chinese male twins: the Qingdao twin registry. , 2006, International journal of epidemiology.

[2]  K. Lesch,et al.  Cloning and functional characterization of the human norepinephrine transporter gene promoter , 1998, Journal of Neural Transmission.

[3]  M. Nöthen,et al.  Norepinephrine transporter gene (NET) variants in patients with panic disorder , 2002, Neuroscience Letters.

[4]  J. Cubells,et al.  A Previously Undescribed Intron and Extensive 5′ Upstream Sequence, but Not Phox2a-mediated Transactivation, Are Necessary for High Level Cell Type-specific Expression of the Human Norepinephrine Transporter Gene* , 1999, The Journal of Biological Chemistry.

[5]  Sean O'Connor,et al.  A family study of alcohol dependence: coaggregation of multiple disorders in relatives of alcohol-dependent probands. , 2004, Archives of general psychiatry.

[6]  K. Merikangas,et al.  Clinical significance and comorbidity of subthreshold depression and anxiety in the community , 2001, Acta psychiatrica Scandinavica.

[7]  M. Smolka,et al.  Norepinephrine transporter gene polymorphism is not associated with susceptibility to alcohol dependence , 2002, Psychiatry Research.

[8]  M Knapp,et al.  Systematic search for variation in the human norepinephrine transporter gene: identification of five naturally occurring missense mutations and study of association with major psychiatric disorders. , 1996, American journal of medical genetics.

[9]  P. Hrdina,et al.  Norepinephrine transporter gene polymorphism is not associated with susceptibility to major depression , 1999, Psychiatry Research.

[10]  H. Ko,et al.  Neither antisocial personality disorder nor antisocial alcoholism is associated with the MAO-A gene in Han Chinese males. , 2003, Alcoholism, clinical and experimental research.

[11]  B. Carroll,et al.  Monoamine transporter gene polymorphisms and antidepressant response in koreans with late-life depression. , 2006, JAMA.

[12]  T. Harford Early onset of alcohol use and health problems: spurious associations and prevention. , 2003, Addiction.

[13]  L. Bierut,et al.  Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism. , 1998, Archives of general psychiatry.

[14]  E. Loh,et al.  Association of monoamine oxidase A alleles with alcoholism among male Chinese in Taiwan. , 1996, The American journal of psychiatry.

[15]  M. Nöthen,et al.  Polymorphisms in the dopamine, serotonin, and norepinephrine transporter genes and their relationships to monoamine metabolite concentrations in CSF of healthy volunteers , 1998, Psychiatry Research.

[16]  R. Kessler,et al.  The comorbidity of alcoholism with anxiety and depressive disorders in four geographic communities. , 1998, Comprehensive psychiatry.

[17]  H. Bönisch,et al.  Chrosomal mapping of the human gene for the tricyclic antidepressant-sensitive noradrenaline transporter , 1993, Human Genetics.

[18]  R. Lu,et al.  Lack of association between the norepinephrine transporter gene and major depression in a Han Chinese population. , 2007, Journal of psychiatry & neuroscience : JPN.

[19]  C. Nemeroff,et al.  Prediction of Antidepressant Response to Milnacipran by Norepinephrine Transporter Gene Polymorphisms , 2004 .

[20]  Nicole C. Rust,et al.  Ethanol-Associated Behaviors of Mice Lacking Norepinephrine , 2000, The Journal of Neuroscience.

[21]  M. Linnoila,et al.  Cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol and norepinephrine levels in alcohol withdrawal. Correlations with clinical signs. , 1985, Archives of general psychiatry.

[22]  P. Sham,et al.  Faster Haplotype Frequency Estimation Using Unrelated Subjects , 2002, Human Heredity.

[23]  Seung-Hwan Lee,et al.  Association between Norepinephrine Transporter Gene Polymorphism and Major Depression , 2004, Neuropsychobiology.

[24]  M. Province,et al.  Genetic dissection of complex traits , 2001 .

[25]  J. Sikela,et al.  Norepinephrine transporter: a candidate gene for initial ethanol sensitivity in inbred long-sleep and short-sleep mice. , 2005, Alcoholism, clinical and experimental research.

[26]  Martin H. Teicher,et al.  A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder , 2006, Proceedings of the National Academy of Sciences.

[27]  K. Kidd,et al.  Associations of disease with genetic markers: déjà vu all over again. , 1993, American journal of medical genetics.

[28]  H. Bönisch,et al.  Molecular cloning and organization of the coding region of the human norepinephrine transporter gene. , 1995, Biochemical and biophysical research communications.

[29]  P. Buckland Genetic association studies of alcoholism--problems with the candidate gene approach. , 2001, Alcohol and alcoholism.

[30]  J. Endicott,et al.  A diagnostic interview: the schedule for affective disorders and schizophrenia. , 1978, Archives of general psychiatry.

[31]  M. Fava,et al.  Factors that differentiate early vs. later onset of major depression disorder , 2004, Psychiatry Research.

[32]  G. Kraemer,et al.  Effects of alcohol on cerebrospinal fluid norepinephrine in rhesus monkeys , 2004, Psychopharmacology.

[33]  P. Sham,et al.  Model-Free Analysis and Permutation Tests for Allelic Associations , 1999, Human Heredity.

[34]  D. Wong,et al.  Norepinephrine uptake sites in the locus coeruleus of rat lines selectively bred for high and low alcohol preference: a quantitative autoradiographic binding study using [3H]-tomoxetine. , 2000, Alcoholism, clinical and experimental research.

[35]  H. Möller,et al.  Identification of a Naturally Occurring Polymorphism in the Promoter Region of the Norepinephrine Transporter and Analysis in Major Depression , 2002, Neuropsychopharmacology.

[36]  C. Robert Cloninger,et al.  Inheritance of alcohol abuse. Cross-fostering analysis of adopted men. , 1981, Archives of general psychiatry.

[37]  N. Risch,et al.  Comorbidity and co-transmission of alcoholism, anxiety and depression , 1994, Psychological Medicine.

[38]  H. Ko,et al.  Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence. , 2004, Alcoholism, clinical and experimental research.

[39]  K. Itoh,et al.  Positive Association between T-182C Polymorphism in the Norepinephrine Transporter Gene and Susceptibility to Major Depressive Disorder in a Japanese Population , 2004, Neuropsychobiology.

[40]  N. Risch,et al.  Co-morbidity and familial aggregation of alcoholism and anxiety disorders , 1998, Psychological Medicine.

[41]  J. Oehler,et al.  Influence of Reboxetine on Salivary MHPG Concentration and Cognitive Symptoms Among Patients with Alcohol-Related Korsakoff's Syndrome , 2003, Neuropsychopharmacology.

[42]  R. Palmiter,et al.  Regulation of norepinephrine transporter abundance by catecholamines and desipramine in vivo , 2002, Brain Research.

[43]  G. Uhl,et al.  Neurotransmitter transporters: three important gene families for neuronal function. , 1994, The Journal of experimental biology.

[44]  J. Markowitz,et al.  Age of onset in chronic major depression: relation to demographic and clinical variables, family history, and treatment response. , 1999, Journal of affective disorders.