Mortality at 9 years in alcohol-dependence: The respective roles of alcohol, tobacco, and vulnerability genes

Mathias Wohl, Laetitia Sirolli, Lucia Romo, Philippe Batel, Claudette Boni, Philip Gorwood

AP-HP, CHU Louis Mourier, Service de Psychiatrie, Colombes, France.
CMME, Centre Hospitalier Sainte Anne, Paris, France.
INSERM U894, Centre de Psychiatrie et Neuroscience, Paris, France.

DOI: 10.4236/ojpsych.2012.23024                

Abstract

Aims: Different vulnerability genes have been proposed in alcohol dependence, but replications are sparse, probably due to 1) phenotypical heterogeneity and 2) difficulties to rely on reliable definition of the correct phenotype. Indeed, specific subgroups of patients may be more directly concerned with some vulnerability genes, the actions of these genes being more directly related to their function. We postulated that three potential vulnerability genes, that were at least twice associated with alcohol dependence, influence the extreme of the severity of alcohol dependence, i.e. mortality, through traits with which they were previously associated, namely impulsivity and antisocial personality disorder and the 5-HT1B gene, suicide attempt and the short allele of 5-HTTLPR, and addictive disorder comorbidity and the DRD2 gene. Methods: We analysed the survival status of a male alcohol-dependent sample (n = 126) recruited 9 years before, and could compare 61 surviving patients to 41 patients who died during this period (representing 81.0% of the initial sample). Results: The main clinical characteristic that was associated with an increased mortality rate was a larger cumulative tobacco use (pack-years). We also found that the C allele of the 5-HT1b was the only one in excess in the non-surviving patients. Contrary to our hypothesis, impulsivity and antisocial personality disorder were not explaining the role of this gene. Conclusions: Even if there is a significant involvement of the 5- HT1B C allele, no intermediate phenotype was detected in our sample. The relatively short delay of 9 years and the somewhat old age at baseline of our patients could have limited the influence of psychiatric comorbidity or the specificities of alcohol dependence, explaining why the only detected co-factor was tobacco consumption. Tobacco dependence is therefore the main factor to explain mortality within the first decade, and the effect of this comorbid condition is not explained by three vulnerability genes previously associated to alcohol dependence.

Keywords

Addiction; Survival; Outcome; Serotonin; Dopamine; Pack Years; Genetics

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Banks, S.M., Pandiani, J.A., Schacht, L.M. and Gauvin, LM. (2000) Age and mortality among white male problem drinkers. Addiction, 95, 1249-1254. doi:10.1046/j.1360-0443.2000.958124911.x
[2]	Smith, E.M., Cloninger, C.R. and Bradford, S. (1983) Predictors of mortality in alcoholic women: Prospective follow-up study. Alcoholism: Clinical and Experimental Research, 7, 237-243. doi:10.1111/j.1530-0277.1983.tb05449.x
[3]	Jorm, A.F., Rodgers, B., Jacomb, P.A., Christensen, H., Henderson, S. and Korten, A.E. (1999) Smoking and mental health: Results from a community survey. Medical Journal of Australia, 170, 74-77.
[4]	Regier, D.A., Farmer, M.E., Rae, D.S., Locke, B.Z., Keith, S.J., Judd, L.L. and Goodwin, F.K. (1990) Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. Journal of the American Medical Association, 264, 2511-2518. doi:10.1001/jama.1990.03450190043026
[5]	Martin, R.L., Cloninger, C.R., Guze, S.B. and Clayton, P.J. (1985) Mortality in a follow-up of 500 psychiatric outpatients. I. Total mortality. Archives of General Psychiatry, 42, 47-54. doi:10.1001/archpsyc.1985.01790240049005
[6]	Eckhardt, L., Woodruff, S.I. and Elder, J.P. (1994). A Longitudinal analysis of adolescent smoking and its correlates. Journal of School Health, 64, 67-72. doi:10.1111/j.1746-1561.1994.tb06181.x
[7]	Bien, T.H. and Burge, R. (1990) Smoking and drinking: A review of the literature. International Journal of the Addictions, 25, 1429-1454.
[8]	DiFranza, J.R. and Guerrera, M.P. (1990) Alcoholism and smoking. Journal of Studies on Alcohol, 51, 130-135.
[9]	Hartwig, W., Werner, J., Ryschich, E., Mayer, H., Schmidt, J., Gebhard, M.M., Herfarth, C. and Klar, E. (2000) Cigarette smoke enhances ethanol-induced pancreatic injury. Pancreas, 21, 272-278. doi:10.1097/00006676-200010000-00009
[10]	Powell, B.J., Landon, J.F., Cantrell, P.J., Penick, E.C., Nickel, E.J., Liskow, B.I., Coddington, T.M., Campbell, J.L., Dale, T.M., Vance, M.D. and Rice, A.S. (1998) Prediction of drinking outcomes for male alcoholics after 10 to 14 years. Alcoholism: Clinical and Experimental Research, 22, 559-566. doi:10.1111/j.1530-0277.1998.tb04293.x
[11]	Martin, R.L., Cloninger, C.R., Guze, S.B. and Clayton, P.J. (1985) Mortality in a follow-up of 500 psychiatric outpatients. II. Cause-specific mortality. Archives of General Psychiatry, 42, 58-66. doi:10.1001/archpsyc.1985.01790240060006
[12]	Fridell, M. and Hesse, M. (2006) Psychiatric severity and mortality in substance abusers: A 15-year follow-up of drug users. Addictive Behaviors, 31, 559-565. doi:10.1016/j.addbeh.2005.05.036
[13]	Berggren, U., Fahlke, C., Berglund, K.J., Wadell, K., Zetterberg, H., Blennow, K., Thelle, D. and Balldin, J. (2010) Dopamine D2 receptor genotype is associated with increased mortality at a 10-year follow-up of alcohol-dependent individuals. Alcohol and Alcoholism, 45, 1-5. doi:10.1093/alcalc/agp041
[14]	Gorwood, P., Wohl, M., Le Strat, Y. and Rouillon, F. (2007) Gene-environment interactions in addictive disorders: Epidemiological and methodological aspects. Comptes Rendus Biologies, 330, 329-338. doi:10.1016/j.crvi.2007.02.017
[15]	Garcia-Banuelos, J., Panduro, A., Gordillo-Bastidas, D., Gordillo-Bastidas, E., Munoz-Valle, J.F., Gurrola-Diaz, C.M., Sánchez-Enriquez, S., Ruiz-Madrigal, B. and Bastidas-Ramirez, B.E. (2011) Genetic polymorphisms of genes coding to alcohol-metabolizing enzymes in western Mexicans: Association of CYP2E1*c2/CYP2E1*5B allele with cirrhosis and liver function. Alcoholism: Clinical and Experimental Research, 36, 425-431.
[16]	Grove, J., Brown, A.S., Daly, A.K., Bassendine, M.F., James, O.F. and Day, C.P. (1998) The RsaI polymerphism of CYP2E1 and susceptibility to alcoholic liver disease in Caucasians: Effect on age of presentation and dependence on alcohol dehydrogenase genotype. Pharmacogenetics, 8, 335-342. doi:10.1097/00008571-199808000-00007
[17]	Chen, J., Giovannucci, E.L. and Hunter, D.J. (1999) MTHFR polymorphism, methyl-replete diets and the risk of colorectal carcinoma and adenoma among U.S. men and women: An example of gene-environment interactions in colorectal tumorigenesis. Journal of Nutrition, 129, 560S-564S.
[18]	Lussier-Cacan, S., Bolduc, A., Xhignesse, M., Niyonsenga, T. and Sing, C.F. (2002) Impact of alcohol intake on measures of lipid metabolism depends on context defined by gender, body mass index, cigarette smoking, and apolipoprotein Egenotype. Arteriosclerosis, Thrombosis, and Vascular Biology, 22, 824-831. doi:10.1161/01.ATV.0000014589.22121.6C
[19]	Koopmans, J.R., Slutske, W.S., Heath, A.C., Neale, M.C. and Boomsma, D.I. (1999) The genetics of smoking initiation and quantity smoked in Dutch adolescent and young adult twins. Behavior Genetics, 29, 383-393. doi:10.1023/A:1021618719735
[20]	Gorwood, P., Schumann, G., Treutlein, J. and Ades, J. (2006) Pharmacogenetics of alcohol dependence. In: Gorwood, P. and Hamon, M. Eds., Psychopharmacogenetics, Springer Inc., 177-202. doi:10.1007/0-387-34577-2_7
[21]	Hinckers, A.S., Laucht, M., Schmidt, M.H., Mann, K.F., Schumann, G., Schuckit, M.A. and Heinz, A. (2006) Low level of response to alcohol as associated with serotonin transporter genotype and high alcohol intake in adolescents. Biological Psychiatry, 60, 282-287. doi:10.1016/j.biopsych.2005.12.009
[22]	Pianezza, M.L., Sellers, E.M. and Tyndale, R.F. (1998) Nicotine metabolism defect reduces smoking, Nature, 393, 750. doi:10.1038/31623
[23]	Young, S.E., Friedman, N.P., Miyake, A., Willcutt, E.G., Corley, R.P., Haberstick, B.C. and Hewitt, J.K. (2009) Behavioral disinhibition: Liability for externalizing spectrum disorders and its genetic and environmental relation to response inhibition across adolescence. Journal of Abnormal Psychology, 118, 117-130. doi:10.1037/a0014657
[24]	Gorwood, P., Batel, P., Gouya, L., Courtois, F. and Feingold, J. (2000) Reappraisal of the association between the DRD2 gene, alcoholism and addiction. European Psychiatry, 15, 90-96. doi:10.1016/S0924-9338(00)00207-8
[25]	Blum, K., Braverman, E.R., Holder, J.M., Lubar, J.F., Monastra, V.J., Miller, D., Lubar, J.O., Chen, T.J. and Comings, D.E. (2000) Reward deficiency syndrome: A biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. Journal of Psychoactive Drugs, 32, 1-112.
[26]	Blum, K., Chen, A.L., Braverman, E.R., Comings, D.E., Chen, T.J., Arcuri, V., Blum, S.H., Downs, B.W., Waite, R.L., Notaro, A., Lubar, J., Williams, L., Prihoda, T.J., Palomo, T. and Oscar-Berman, M. (2008) Attention-deficit-hyperactivity disorder and reward deficiency syndrome. Neuropsychiatric Disease and Treatment, 4, 893-918.
[27]	Gorwood, P., Aissi, F., Batel, P., Ades, J., Cohen-Salmon, C., Hamon, M., Boni, C. and Lanfumey, L. (2002) Reappraisal of the serotonin 5-HT(1B) receptor gene in alcoholism: Of mice and men. Brain Research Bulletin, 57, 103-107. doi:10.1016/S0361-9230(01)00641-4
[28]	Gorwood, P., Batel P, Ades J, Hamon M. and Boni C. (2000) Serotonin transporter gene polymorphisms, alcoholism, and suicidal behavior. Biological Psychiatry, 48, 259-264. doi:10.1016/S0006-3223(00)00840-4
[29]	Nurnberger, J.I., Blehar, M.C., Kaufmann, C.A., York- Cooler, C., Simpson, S.G., Harkavy-Friedman, J., et al. (1994) Diagnostic interview for genetic studies: Rational, unique features, and training. Archives of General Psychiatry, 51, 849-862. doi:10.1001/archpsyc.1994.03950110009002
[30]	Grandy, D.K., Zhang, Y. and Civelli, O. (1993) PCR detection of the TaqA RFLP at the DRD2 locus. Human Molecular Genetics, 2, 2197. doi:10.1093/hmg/2.12.2197-a
[31]	Heils, A., Teufel, A., Petri, S., Stober, G., Riederer, P., Bengel, D. and Lesch, K.P. (1996) Allelic variation of human serotonin transporter gene expression. Journal of Neurochemistry, 66, 2621-2624. doi:10.1046/j.1471-4159.1996.66062621.x
[32]	Lappalainen, J., Dean, M., Charbonneau, L., Virkkunen, M., Linnoila, M. and Goldman, D. (1995) Mapping of the serotonin 5-HT1D autoreceptor gene on chromosome 6 and direct analysis for sequence variants. American Journal of Medical Genetics, 60, 157-161. doi:10.1002/ajmg.1320600214
[33]	Hosmer, D. Wo and Lemeshow, S. (1980) A goodness-of-for test for the multiple logistic regression. Communications in Statistics, A10, 1043-1069. doi:10.1080/03610928008827941
[34]	Kozlowski, L.T. and Ferrence, R.G. (1990) Statistical control in research on alcohol and tobacco: An example from research on alcohol and mortality. British Journal of Addiction, 85, 271-278. doi:10.1111/j.1360-0443.1990.tb03083.x
[35]	Lappalainen, J., Long, J.C., Eggert, M., Ozaki, N., Robin, R.W., Brown, G.L., Naukkarinen, H., Virkkunen, M., Linnoila, M. and Goldman, D. (1998) Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Archives of General Psychiatry, 55, 989-994. doi:10.1001/archpsyc.55.11.989
[36]	Cigler, T., LaForge, K.S., McHugh, P.F., Kapadia, S.U., Leal, S.M. and Kreek, M.J. (2001) Novel and previously reported single-nucleotide polymorphisms in the human 5-HT(1B) receptor gene: No association with cocaine or alcohol abuse or dependence. American Journal of Medical Genetics, 5, 489-497. doi:10.1002/ajmg.1473
[37]	Proudnikov, D., LaForge, K.S., Hofflich, H., Levenstien, M., Gordon, D., Barral, S., Ott, J. and Kreek, M.J. (2006) Association analysis of polymorphisms in serotonin 1B receptor (HTR1B) gene with heroin addiction: A comparison of molecular and statistically estimated haplotypes. Pharmacogenetics and Genomics, 16, 25-36. doi:10.1097/01.fpc.0000182782.87932.d6
[38]	Sinha, R., Cloninger, C.R. and Parsian, A. (2003) Linkage disequilibrium and haplotype analysis between serotonin receptor 1B gene variations and subtypes of alcoholism. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 121, 83-88. doi:10.1002/ajmg.b.20064
[39]	Cao, J.X., Hu, J., Ye, X.M., Xia, Y., Haile, C.A., Kosten, T.R. and Zhang, X.Y. (2011) Association between the 5-HTR1B gene polymorphisms and alcohol dependence in a Han Chinese population. Brain Research, 1376, 1-9. doi:10.1016/j.brainres.2010.12.039
[40]	Fehr, C., Grintschuk, N., Szegedi, A., Anghelescu, I., Klawe, C., Singer, P., Hiemke, C. and Dahmen, N. (2000) The HTR1B 861G>C receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy. Psychiatry Research, 97, 1-10. doi:10.1016/S0165-1781(00)00215-8
[41]	Soyka, M., Preuss, U.W., Koller, G., Zill, P. and Bondy, B. (2004) Association of 5-HT1B receptor gene and antisocial behavior in alcoholism. Journal of Neural Transmission, 111, 101-109. doi:10.1007/s00702-003-0064-0
[42]	Black, D.W., Baumgard, C.H., Bell, S.E. and Kao, C. (1996) Death rates in 71 men with antisocial personality disorder. A comparison with general population mortality. Psychosomatics, 37, 131-136.