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Genetic Variation of the Ghrelin Signaling System in Females With Severe Alcohol Dependence

Authors

  • Sara Landgren,

    1. From the Department of Pharmacology (SL, EJ, JAE), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Neuroscience (JH, LO), Section for Pharmacology, Uppsala University, Uppsala, Sweden; School of Public Health and Community Medicine (LL, ES), The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Biostatistics (DST), Institute of Basic Medical Science, University of Oslo, Oslo, Norway; and Institute of Neuroscience and Physiology (HZ, KB), Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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  • Elisabet Jerlhag,

    1. From the Department of Pharmacology (SL, EJ, JAE), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Neuroscience (JH, LO), Section for Pharmacology, Uppsala University, Uppsala, Sweden; School of Public Health and Community Medicine (LL, ES), The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Biostatistics (DST), Institute of Basic Medical Science, University of Oslo, Oslo, Norway; and Institute of Neuroscience and Physiology (HZ, KB), Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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  • Jarmila Hallman,

    1. From the Department of Pharmacology (SL, EJ, JAE), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Neuroscience (JH, LO), Section for Pharmacology, Uppsala University, Uppsala, Sweden; School of Public Health and Community Medicine (LL, ES), The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Biostatistics (DST), Institute of Basic Medical Science, University of Oslo, Oslo, Norway; and Institute of Neuroscience and Physiology (HZ, KB), Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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  • Lars Oreland,

    1. From the Department of Pharmacology (SL, EJ, JAE), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Neuroscience (JH, LO), Section for Pharmacology, Uppsala University, Uppsala, Sweden; School of Public Health and Community Medicine (LL, ES), The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Biostatistics (DST), Institute of Basic Medical Science, University of Oslo, Oslo, Norway; and Institute of Neuroscience and Physiology (HZ, KB), Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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  • Lauren Lissner,

    1. From the Department of Pharmacology (SL, EJ, JAE), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Neuroscience (JH, LO), Section for Pharmacology, Uppsala University, Uppsala, Sweden; School of Public Health and Community Medicine (LL, ES), The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Biostatistics (DST), Institute of Basic Medical Science, University of Oslo, Oslo, Norway; and Institute of Neuroscience and Physiology (HZ, KB), Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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  • Elisabeth Strandhagen,

    1. From the Department of Pharmacology (SL, EJ, JAE), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Neuroscience (JH, LO), Section for Pharmacology, Uppsala University, Uppsala, Sweden; School of Public Health and Community Medicine (LL, ES), The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Biostatistics (DST), Institute of Basic Medical Science, University of Oslo, Oslo, Norway; and Institute of Neuroscience and Physiology (HZ, KB), Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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  • Dag S. Thelle,

    1. From the Department of Pharmacology (SL, EJ, JAE), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Neuroscience (JH, LO), Section for Pharmacology, Uppsala University, Uppsala, Sweden; School of Public Health and Community Medicine (LL, ES), The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Biostatistics (DST), Institute of Basic Medical Science, University of Oslo, Oslo, Norway; and Institute of Neuroscience and Physiology (HZ, KB), Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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  • Henrik Zetterberg,

    1. From the Department of Pharmacology (SL, EJ, JAE), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Neuroscience (JH, LO), Section for Pharmacology, Uppsala University, Uppsala, Sweden; School of Public Health and Community Medicine (LL, ES), The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Biostatistics (DST), Institute of Basic Medical Science, University of Oslo, Oslo, Norway; and Institute of Neuroscience and Physiology (HZ, KB), Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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  • Kaj Blennow,

    1. From the Department of Pharmacology (SL, EJ, JAE), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Neuroscience (JH, LO), Section for Pharmacology, Uppsala University, Uppsala, Sweden; School of Public Health and Community Medicine (LL, ES), The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Biostatistics (DST), Institute of Basic Medical Science, University of Oslo, Oslo, Norway; and Institute of Neuroscience and Physiology (HZ, KB), Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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  • Jörgen A. Engel

    1. From the Department of Pharmacology (SL, EJ, JAE), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Neuroscience (JH, LO), Section for Pharmacology, Uppsala University, Uppsala, Sweden; School of Public Health and Community Medicine (LL, ES), The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Department of Biostatistics (DST), Institute of Basic Medical Science, University of Oslo, Oslo, Norway; and Institute of Neuroscience and Physiology (HZ, KB), Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
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Reprint requests: Sara Landgren, Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Medicinaregatan 13A, SE-405 30 Gothenburg, Sweden; Tel.: +46 31 342 7924 and +46 31 786 3418; Fax: +46 31 786 3164; E-mail: sara.landgren@pharm.gu.se

Abstract

Introduction:  Central ghrelin signaling is required for the rewarding effects of alcohol in mice. Because ghrelin is implied in other addictive behaviors such as eating disorders and smoking, and because there is co-morbidity between these disorders and alcohol dependence, the ghrelin signaling system could be involved in mediating reward in general. Furthermore, in humans, single nucleotide polymorphisms (SNPs) and haplotypes of the pro-ghrelin gene (GHRL) and the ghrelin receptor gene (GHSR) have previously been associated with increased alcohol consumption and increased body weight. Known gender differences in plasma ghrelin levels prompted us to investigate genetic variation of the ghrelin signaling system in females with severe alcohol dependence (n = 113) and in a selected control sample of female low-consumers of alcohol from a large cohort study in southwest Sweden (n = 212).

Methods:  Six tag SNPs in the GHRL (rs696217, rs3491141, rs4684677, rs35680, rs42451, and rs26802) and four tag SNPs in the GHSR (rs495225, rs2232165, rs572169, and rs2948694) were genotyped in all individuals.

Results:  We found that one GHRL haplotype was associated with reports of paternal alcohol dependence as well as with reports of withdrawal symptoms in the female alcohol-dependent group. Associations with 2 GHSR haplotypes and smoking were also shown. One of these haplotypes was also negatively associated with BMI in controls, while another haplotype was associated with having the early-onset, more heredity-driven, type 2 form of alcohol dependence in the patient group.

Conclusion:  Taken together, the genes encoding the ghrelin signaling system cannot be regarded as major susceptibility genes for female alcohol dependence, but is, however, involved in paternal heritability and may affect other reward- and energy-related factors such as smoking and BMI.

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