By Y. Zakosh. The Mayo Foundation. 2019.
Several QTLs for alcohol-associated behaviors have been identified in mice by using recombinant inbred strains that differ widely with respect to many alcohol-related traits cheap 600mg ethambutol with amex, and DETERMINING THE GENETIC BASIS OF by follow-up studies using interstrain crosses and congenics proven 800 mg ethambutol. VULNERABILITY TO ALCOHOLISM The behaviors for which QTLs have been mapped include acute and chronic alcohol withdrawal sensitivity, alcohol Genetic analysis of complex disorders is complicated by the consumption, and alcohol-associated hypothermia. Buck et fact that any single gene is likely to account for only a small al. To detect subtle genetic effects, large genes influencing alcohol withdrawal severity can be as- samples are needed. The four methods (59) most widely signed to QTLs on mouse chromosomes 1, 4, and 11. The used are (a) linkage analysis: the inheritance pattern of phe- locus on chromosome 11 accounted for 12% of the genetic notypes and genotypes are elucidated in pedigrees; (b) allele variability in withdrawal liability and was near the genes for sharing methods: affected relatives are compared to detect the 2, 1, and 6 subunits of GABAA receptors. Further- excess genotype sharing; (c) association (case-control) stud- more, a 2 subunit polymorphism has now been found to ies: unrelated affected and unaffected individuals are com- be genetically correlated with alcohol withdrawal severity in pared; (d) analysis of inbred, transgenic, and gene-knockout mice (65). QTLs for alcohol-induced hypothermia, alcohol animals (principally mice and rats). An alternative approach is to employ an endopheno- ships between different phenotypes indicate that the same type as a trait specific marker, e. On Serotonin is involved in behavioral inhibition and is a target chronic exposure to alcohol they show less evidence of toler- for the pharmacologic treatment of alcoholism. These mice also work harder to self-administer cocaine serotonin reuptake inhibitors play a limited role in modify- and show an increased locomotor response, behaving as if ing craving for alcohol and also modify other comorbid already sensitized to the drug (69). The dopamine-related genes that have been knocked out Pathologically low levels of serotonin may contribute to in mice are the DRD4 dopamine receptor, which is located impulsivity and ASPD; for example, a group of criminal, at the site of one of the alcohol QTLs, the D1 and D2 alcoholic Finns was shown to have low cerebrospinal fluid dopamine receptors, the dopamine transporter, and (CSF) 5-hydroxyindolacetic acid (5-HIAA), the lowest lev- VMAT2 (the vesicular transporter). The DRD4 knockout els being found in those who had committed impulsive mice appear to be supersensitive to ethanol, cocaine, and crimes (75). These are the alcoholics who would be most amphetamine (70). Mice lacking the D2 receptor consume likely to have a serotonin gene variant affecting function. VMAT2 knockout mice have a pronounced supersensitivity to cocaine, amphet- Serotonin Transporter amine, and ethanol (72). The availability of brainstem serotonin transporter, mea- For morphine preference, three loci identified on murine sured by (I-123) -CIT and single photon emission com- chromosomes 1, 6, and 10 are apparently responsible for puted tomography, has been found to be significantly re- nearly 85% of the genetic variance in this trait (73). The duced in alcoholics, and correlated with ratings of opioid receptor gene is located at the site of the largest depression and anxiety during withdrawal (76). A functional QTL, and this QTL also affects consumption of alcohol polymorphism, 5-HTTLPR, in the serotonin transporter and cocaine (73). Several association analyses result is a large genomic region of interest rather than a have shown that the s-allele, which reduces transcriptional gene. There may be functional compensation in knockout efficiency, is increased in French alcoholics (79), severely mice during development. Mice and humans may not share affected German alcoholics (80), and early-onset, violent the same functional variants at the same allele; for example, Finnish alcoholics with ASPD (81). However, neither link- the ALDH2-2 allele is not even present in all human popu- age nor association for the s-allele was found in a family- lations and is not found in mice. However, QTL analyses in mice are useful ciation study of alcoholics with withdrawal seizures was also for the identification of candidate genes and gene regions. Population stratification may be a problem GENETICS OF REWARD NEUROCIRCUITS, with these association studies as allele frequencies have been AND NEUROCIRCUITS REGULATING shown to vary in European-American, African-American, IMPULSE CONTROL and Japanese populations (85). Candidate Gene Approach: Case-Control Serotonin-Metabolizing Enzymes Association Studies A tryptophan hydroxylase (TPH) intron variant that affects A logical approach to understanding vulnerability to alcohol splicing is associated with reduced 5-HIAA and suicidality addiction is to look directly for variants in genes involved in impulsive alcoholics (86,87). Of particular interest is the reward pathway, incorporating sero- Serotonin Receptors toninergic, GABAergic, dopaminergic, opioid, and gluta- Several serotonin receptors are known to be abundant in matergic neurotransmission, and the largely serotoninergic the NAC: 5-HT1B, 5-HT2C, 5-HT3, 5-HT4, and 5-HT6. Genes for neurotransmitter me- There are as yet few published studies in which these seroto- tabolizing enzymes, transporters, and receptors are good nin receptors have been genotyped in humans. Because of the complexity of causation of alco- Studies in rats suggest that activation of 5-HT1B recep- Chapter 99: Molecular and Cellular Genetics of Alcohol Addiction 1419 tors in the NAC may be inhibitory on the behavioral effects transcriptionally significant promoter polymorphisms offer of elevated mesolimbic dopamine transmission (88) by promising tools for understanding the roles of DRD2 (101) primarily modulating the activity of glutamatergic hip- and DAT (102) in alcoholism. In a large sib-pair linkage analysis Opioid Receptors of Finnish alcoholic criminal offenders, significant evidence of linkage and association of antisocial alcoholism to Three endogenous opioid receptors ( , , and ) are the HTR1B G861C was found, and this was also observed in targets of the major opioid peptides ( -endorphin, enke- a Southwest American Indian tribe, suggesting that a locus phalins, and dynorphins, respectively). The rewarding prop- predisposing to antisocial alcoholism may be linked to erties of - and -receptor ligands are brought about by HTR1B at 6q13-15 (90). Activation Activation of 5-HT receptors inhibits DA release in of receptors is dysphoric. However, the functional Cys23Ser polymor- plicate the opioid system, particularly the opioid receptor, phism does not appear to be associated with alcohol depen- in both initial sensitivity or response to alcohol, and in the dence (92). Subjects at high 5-HT receptors may be involved in several facets of risk for alcoholism have been shown to have lower basal 3 alcohol-seeking behavior, alcohol intoxication, and addic- plasma -endorphin levels but a more pronounced release tion (93); however, at the present time there are no pub- after exposure to ethanol (103). Some studies have found lished studies on the role of 5-HT variants in alcoholics.
Applications for commercial reproduction should be addressed to: NIHR Journals Library cheap ethambutol 800 mg without a prescription, National Institute for Health Research ethambutol 400 mg with amex, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. RESULTS The meta-analyses showed no significant effects on hospital admissions, ED visits or total costs. Meaningful interpretation of total cost data was limited by a small number of comparisons (n = 8) and high variation across trials. Owing to a lack of data, permutation plots were not calculated for total costs. Fourteen comparisons were eligible for inclusion in a permutation plot charting the effects of self-care support on QoL and hospital admissions for mental health (Figure 17); 10 of these comparisons originated from RCTs with adequate allocation concealment. When hospital admissions were plotted against patient outcomes, the majority of comparisons were located in the lower left-hand quadrant, suggesting that self-care support can reduce utilisation for children and young people with mental health conditions without compromising QoL. A minority of studies were located in the lower right-hand quadrant, suggesting reduced hospital admissions but a marginally compromised QoL. As stated previously, data were limited and findings must be treated with caution. Nine comparisons were eligible for inclusion in a permutation plot charting ED visits against patient outcomes (Figure 18); seven were from RCTs with adequate allocation concealment. Limited data mean that these results must be treated with caution. Behavioural difficulties Five studies evaluated self-care support for children and young people with behavioural difficulties. The flow of studies through the review is depicted in Figure 19. Owing to the small number of data available for meta-analysis, meaningful interpretation of the evidence base for non-asthma physical health conditions is limited. Pooled ESs are presented in Table 6 for completeness. Table 7 summarises the results of all meta-analyses, presented according to LTC type. Studies recruiting CYP with behavioural difficulties reported both QoL and 1+ health-care utilisation data (n=5) Not suitable for meta-analysis (n=0) Studies contributing to one or more meta-analyses (n=5) • QoL: 3 studies, 4 comparisons • Admissions: 3 studies, 4 comparisons • Emergency visits: 2 studies, 2 comparisons • Total costs: 0 studies, 0 comparisons QoL and total costs QoL and admissions QoL and emergency visits n=0 comparisons n=4 comparisons n=2 comparisons FIGURE 19 Analyses of studies for patients with behavioural difficulties. TABLE 6 Results of meta-analysis (behavioural difficulties) Outcome ES 95% CI I2 statistic (%) Number of comparisons QoL –0. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that 29 suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. RESULTS TABLE 7 Summary of meta-analyses presented by LTC type LTC type Outcome Asthma Other physical health Mental health Behavioural disorders QoL Pooled ES –0. Studies were categorised according to whether the self-care intervention targeted children (aged 0–12 years), adolescents (aged 13–18 years) or both (Table 8). Across all three age groups, self-care support had statistically significant but minimal effects (ES of < 0. Self-care support was associated with a statistically significant but minimal reduction in ED use for children. Irrespective of the target age group, self-care support had no statistically significant effects on hospital admissions or total costs. Variation in the magnitude of ESs observed across the three subgroups will in part reflect differences in the number of studies available and the precision of the pooled estimates. Analyses of different types of self-care support When different intensities of self-care support were compared, intensive facilitation conferred limited benefit over and above other forms of self-care support (Table 9). Intensively facilitated or case-managed self-care support interventions produced statistically significant but minimal benefits in QoL (ES –0. Intensively facilitated or case-managed self-care support interventions were associated with statistically 30 NIHR Journals Library www. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that 31 suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. RESULTS TABLE 9 Subgroup analyses for study outcomes (continued) Outcome Subgroup QoL Hospital admission Emergency visits Total costs Intervention target CYP Pooled ES –0. Note Significant pooled effects from two or more comparisons are in bold. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that 33 suitable acknowledgement is made and the reproduction is not associated with any form of advertising.
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