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Genetic variation of the growth hormone secretagogue receptor gene is associated with alcohol use disorders identification test scores and smoking.

ABSTRACT: The multifaceted gut-brain peptide ghrelin and its receptor (GHSR-1a) are implicated in mechanisms regulating not only the energy balance but also the reward circuitry. In our pre-clinical models, we have shown that ghrelin increases whereas GHSR-1a antagonists decrease alcohol consumption and the motivation to consume alcohol in rodents. Moreover, ghrelin signaling is required for the rewarding properties of addictive drugs including alcohol and nicotine in rodents. Given the hereditary component underlying addictive behaviors and disorders, we sought to investigate whether single nucleotide polymorphisms (SNPs) located in the pre-proghrelin gene (GHRL) and GHSR-1a gene (GHSR) are associated with alcohol use, measured by the alcohol use disorders identification test (AUDIT) and smoking. Two SNPs located in GHRL, rs4684677 (Gln90Leu) and rs696217 (Leu72Met), and one in GHSR, rs2948694, were genotyped in a subset (n = 4161) of a Finnish population-based cohort, the Genetics of Sexuality and Aggression project. The effect of these SNPs on AUDIT scores and smoking was investigated using linear and logistic regressions, respectively. We found that the minor allele of the rs2948694 SNP was nominally associated with higher AUDIT scores (P = 0.0204, recessive model) and smoking (P = 0.0002, dominant model). Furthermore, post hoc analyses showed that this risk allele was also associated with increased likelihood of having high level of alcohol problems as determined by AUDIT scores ? 16 (P = 0.0043, recessive model). These convergent findings lend further support for the hypothesized involvement of ghrelin signaling in addictive disorders.

SUBMITTER: Suchankova P

PROVIDER: S-EPMC5033010 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Genetic variation of the growth hormone secretagogue receptor gene is associated with alcohol use disorders identification test scores and smoking.

Suchankova Petra P Nilsson Staffan S von der Pahlen Bettina B Santtila Pekka P Sandnabba Kenneth K Johansson Ada A Jern Patrick P Engel Jörgen A JA Jerlhag Elisabet E

Addiction biology 20150609 2

The multifaceted gut-brain peptide ghrelin and its receptor (GHSR-1a) are implicated in mechanisms regulating not only the energy balance but also the reward circuitry. In our pre-clinical models, we have shown that ghrelin increases whereas GHSR-1a antagonists decrease alcohol consumption and the motivation to consume alcohol in rodents. Moreover, ghrelin signaling is required for the rewarding properties of addictive drugs including alcohol and nicotine in rodents. Given the hereditary compone ...[more]

PMID: 26059200

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Project description:BackgroundExisting studies on intellectual consequences of alcohol-related disorders are primarily cross-sectional and compare intelligence test scores of individuals with and without alcohol-related disorders, hence mixing the influence of alcohol-related disorders and predisposing factors such as premorbid intelligence. In this large-scale study, the primary aim was to estimate associations of alcohol-related disorders with changes in intelligence test scores from early adulthood to late midlife.MethodsData were drawn from a follow-up study on middle-aged men, which included a re-examination of the same intelligence test as completed in young adulthood at military conscription (total analytic sample = 2,499). Alcohol-related hospital diagnoses were obtained from national health registries, whereas treatment for alcohol problems was self-reported at follow-up. The analyses included adjustment for year of birth, retest interval, baseline intelligence quotient (IQ) score, education, smoking, alcohol consumption, and psychiatric and somatic comorbidity.ResultsIndividuals with alcohol-related hospital diagnoses (8%) had a significantly lower baseline IQ score (95.0 vs. 100.5, p < 0.001) and a larger decline in IQ scores from baseline to follow-up (-8.5 vs. -4.8, p < 0.001) than individuals without such diagnoses. The larger decline in IQ scores with alcohol-related hospital diagnoses remained statistically significant after adjustment for all the covariates. Similar results were revealed when IQ scores before and after self-reported treatment for alcohol problems (10%) were examined.ConclusionsIndividuals with alcohol-related disorders have a lower intelligence test score both in young adulthood and in late midlife, and these disorders, moreover, seem to be associated with more age-related decline in intelligence test scores. Thus, low mean intellectual ability observed in individuals with alcohol-related disorders is probably a result of both lower premorbid intelligence and more intellectual decline.

Project description:BackgroundCluster of differentiation 4 (CD4+) T cells plays a prominent role in eliminating cancer cells. The balance between T helper (Th)17 and regulatory T (Treg) cells is crucial for optimal immune response and protection against cancer. Growth hormone secretagogue receptor 1a (GHSR1a), a member of the G protein-coupled protein receptor superfamily, plays a critical role in immune cell function. The aim of our study is to investigate the role of GHSR1a in CD4+ T cell differentiation and lung cancer progression.MethodsA subcutaneous lung cancer model was used to examine the role of GHSR1a in controlling tumor growth. Lewis lung carcinoma (LLC) cells were subcutaneously implanted into Ghsr1a -/- mice and wild-type (WT) mice. The ratio of Th17 and Treg in the draining lymph node of Ghsr1a -/- mice and WT tumor-bearing mice was detected by fluorescence-activated cell sorting (FACS). The effect of GHSR1a deficiency on Th17 and Treg cell differentiation was examined using an in vitro differentiation assay. The phosphorylation of mammalian target of rapamycin (mTOR), signal transducer, and activator of transcription (STAT)3 and STAT5 signaling was detected with Western blot.ResultsWe found that the ablation of GHSR1a resulted in impaired anti-tumor immunity to control lung cancer growth in vivo. We also demonstrated that the deficiency of GHSR1a promoted a shift in the Th17/Treg balance toward enhanced Treg differentiation and inhibited Th17 differentiation both in vivo and in vitro, which suggests that GHSR1a regulates T cell lineage choices between Th17 and Treg cell commitment in the tumor microenvironment. Mechanistically, the deficiency of GHSR1a resulted in reduced phosphorylation in mTOR and STAT3, and increased phosphorylation in STAT5.ConclusionsOur findings showed the important role of GHSR1a in CD4+ T cell differentiation in the context of the lung cancer microenvironment. This research provides a novel molecular target and insights into interventions for the prevention and treatment of lung cancer.

Project description:The gut hormone ghrelin is involved in numerous metabolic functions, such as the stimulation of growth hormone secretion, gastric motility, and food intake. Ghrelin is modified by ghrelin O-acyltransferase (GOAT) or membrane-bound O-acyltransferase domain-containing 4 (MBOAT4) enabling action through the growth hormone secretagogue receptors (GHS-R). During the course of evolution, initially strong ligand/receptor specificities can be disrupted by genomic changes, potentially modifying physiological roles of the ligand/receptor system. Here, we investigated the coevolution of ghrelin, GOAT, and GHS-R in vertebrates. We combined similarity search, conserved synteny analyses, phylogenetic reconstructions, and protein structure comparisons to reconstruct the evolutionary history of the ghrelin system. Ghrelin remained a single-gene locus in all vertebrate species, and accordingly, a single GHS-R isoform was identified in all tetrapods. Similar patterns of the nonsynonymous (dN) and synonymous (dS) ratio (dN/dS) in the vertebrate lineage strongly suggest coevolution of the ghrelin and GHS-R genes, supporting specific functional interactions and common physiological pathways. The selection profiles do not allow confirmation as to whether ghrelin binds specifically to GOAT, but the ghrelin dN/dS patterns are more similar to those of GOAT compared to MBOAT1 and MBOAT2 isoforms. Four GHS-R isoforms were identified in teleost genomes. This diversification of GHS-R resulted from successive rounds of duplications, some of which remained specific to the teleost lineage. Coevolution signals are lost in teleosts, presumably due to the diversification of GHS-R but not the ghrelin gene. The identification of the GHS-R diversity in teleosts provides a molecular basis for comparative studies on ghrelin's physiological roles and regulation, while the comparative sequence and structure analyses will assist translational medicine to determine structure-function relationships of the ghrelin/GHS-R system.

Dataset Information

Genetic variation of the growth hormone secretagogue receptor gene is associated with alcohol use disorders identification test scores and smoking.

Publications

Genetic variation of the growth hormone secretagogue receptor gene is associated with alcohol use disorders identification test scores and smoking.

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