COMT val158met predicts reward responsiveness in humans

A functional variant of the catechol‐O‐methyltransferase (COMT) gene [val158met (rs4680)] is frequently implicated in decision‐making and higher cognitive functions. It may achieve its effects by modulating dopamine‐related decision‐making and reward‐guided behaviour. Here we demonstrate that individuals with the met/met polymorphism have greater responsiveness to reward than carriers of the val allele and that this correlates with risk‐seeking behaviour. We assessed performance on a reward responsiveness task and the Balloon analogue risk task, which measure how participants (N = 70, western European, university and postgraduate students) respond to reward and take risks in the presence of available reward. Individuals with the met/met genotype (n = 19) showed significantly higher reward responsiveness, F_2,64 = 4.02, P = 0.02, and reward‐seeking behaviour, F(2,68) = 4.52, P = 0.01, than did either val/met (n = 25) or val/val (n = 26) carriers. These results highlight a scenario in which genotype‐dependent reward responsiveness shapes reward‐seeking, therefore suggesting a novel framework by which COMT may modulate behaviour.     

COMT Val158Met genotype is associated with reward learning: a replication study and meta‐analysis

Identifying mechanisms through which individual differences in reward learning emerge offers an opportunity to understand both a fundamental form of adaptive responding as well as etiological pathways through which aberrant reward learning may contribute to maladaptive behaviors and psychopathology. One candidate mechanism through which individual differences in reward learning may emerge is variability in dopaminergic reinforcement signaling. A common functional polymorphism within the catechol‐O‐methyl transferase gene (COMT; rs4680, Val¹⁵⁸Met) has been linked to reward learning, where homozygosity for the Met allele (linked to heightened prefrontal dopamine function and decreased dopamine synthesis in the midbrain) has been associated with relatively increased reward learning. Here, we used a probabilistic reward learning task to asses response bias, a behavioral form of reward learning, across three separate samples that were combined for analyses (age: 21.80 ± 3.95; n = 392; 268 female; European‐American: n = 208). We replicate prior reports that COMT rs4680 Met allele homozygosity is associated with increased reward learning in European‐American participants (β = 0.20, t = 2.75, P < 0.01; ΔR² = 0.04). Moreover, a meta‐analysis of 4 studies, including the current one, confirmed the association between COMT rs4680 genotype and reward learning (95% CI ?0.11 to ?0.03; z = 3.2; P < 0.01). These results suggest that variability in dopamine signaling associated with COMT rs4680 influences individual differences in reward which may potentially contribute to psychopathology characterized by reward dysfunction.     

The impact of mineralocorticoid receptor ISO/VAL genotype (rs5522) and stress on reward learning

Research suggests that stress disrupts reinforcement learning and induces anhedonia. The mineralocorticoid receptor (MR) determines the sensitivity of the stress response, and the missense iso/val polymorphism (Ile180Val, rs5522) of the MR gene (NR3C2) has been associated with enhanced physiological stress responses, elevated depressive symptoms and reduced cortisol‐induced MR gene expression. The goal of these studies was to evaluate whether rs5522 genotype and stress independently and interactively influence reward learning. In study 1, participants (n = 174) completed a probabilistic reward task under baseline (i.e. no‐stress) conditions. In study 2, participants (n = 53) completed the task during a stress (threat‐of‐shock) and no‐stress condition. Reward learning, i.e. the ability to modulate behavior as a function of reinforcement history, was the main variable of interest. In study 1, in which participants were evaluated under no‐stress conditions, reward learning was enhanced in val carriers. In study 2, participants developed a weaker response bias toward a more frequently rewarded stimulus under the stress relative to no‐stress condition. Critically, stress‐induced reward learning deficits were largest in val carriers. Although preliminary and in need of replication due to small sample size, findings indicate that psychiatrically healthy individuals carrying the MR val allele, gene, which has been recently linked to depression, showed a reduced ability to modulate behavior as a function of reward when facing an acute, uncontrollable stressor. Future studies are warranted to evaluate whether rs5522 genotype interacts with naturalistic stressors to increase the risk of depression and whether stress‐induced anhedonia might moderate such risk.     

On the genetic basis of face cognition and its relation to fluid cognitive abilities

The oxytocin and the dopaminergic systems have turned out to be highly relevant for social abilities and cognition. Therefore, we examined the association between two functional gene polymorphisms and face cognition (FC) in a multivariate study (N = 250) by applying structural equation modeling. The catechol‐O‐methyltransferase (COMT) val158met polymorphism influences the enzyme activity of COMT, which affects the prefrontal dopamine concentration. The rs226849 is a single‐nucleotide polymorphism located in the promoter region of the oxytocin receptor (OXTR) gene, modulating the mRNA expression. By modeling a general fluid ability factor (defined by working memory and reasoning) and nested FC factors, we tested genetic contributions to FC, after controlling for variance in FC that was also associated with fluid abilities. In line with several previous studies, we found a significant association between the COMT genotype and fluid abilities (Gf) but not with FC. The association between the oxytocin polymorphism and Gf was opposite in direction for men and women. Women with the C⁺ genotype performed better on Gf tasks than those with the C^? genotype. Conversely, men with the C^? genotype performed better than those with the C⁺ genotype. There was no significant association between OXTR and the nested FC factor. Therefore, the relationship between the oxytocin polymorphism and FC can be fully accounted for by Gf. The sex specificity of this relationship is a novel finding and warrants a mechanistic explanation.     

Catechol‐O‐methyltransferase gene methylation and substance use in adolescents: the TRAILS study

Substance use often starts in adolescence and poses a major problem for society and individual health. The dopamine system plays a role in substance use, and catechol‐O‐methyltransferase (COMT) is an important enzyme that degrades dopamine. The Val^108/158Met polymorphism modulates COMT activity and thus dopamine levels, and has been linked to substance use. COMT gene methylation, on the other hand, may affect expression and thus indirectly COMT activity. We investigated whether methylation of the COMT gene was associated with adolescents' substance use. Furthermore, we explored whether the COMT Val^108/158Met polymorphism interacts with COMT gene methylation in association with substance use. In 463 adolescents (mean age = 16, 50.8% girls), substance use (cigarette smoking, alcohol and cannabis use) was assessed with self‐report questionnaires. From blood samples, COMT Val^108/158Met genotype and methylation rates of membrane bound (MB) and soluble (S) COMT promoters were assessed. MB‐COMT promoter methylation was associated with non‐daily smoking [odds ratio (OR) = 1.82, P = 0.03], but not with daily smoking (OR = 1.20, P = 0.34), MB‐COMT promoter methylation was not associated with alcohol use. Adolescents with the Met/Met genotype and high rates of MB‐COMT promoter methylation were less likely to be high‐frequent cannabis users than adolescents with the Val/Val or Val/Met genotype. S‐COMT promoter methylation was not associated with substance use. These results indicate that there is an association between substance use and COMT gene methylation. Although this association is complex, combining genetic and epigenetic variation of the COMT gene may be helpful in further elucidating the influence of the dopamine system on substance use in adolescence.     

Does COMT genotype influence the effects of d‐amphetamine on executive functioning?

In a widely cited study, Mattay et al. reported that amphetamine (0.25 mg/kg oral, or 17 mg for a 68 kg individual) impaired behavioral and brain indices of executive functioning, measured using the Wisconsin Card Sorting Task (WCST) and N‐Back working memory task, in 6 individuals homozygous for the met allele of the val158met polymorphism in the catechol‐O‐methyltransferase (COMT) gene, whereas it improved executive functioning in 10 individuals homozygous for the more active val allele. We attempted to replicate their behavioral findings in a larger sample, using similar executive functioning tasks and a broader range of amphetamine doses. Over four sessions, n = 200 healthy normal adults received oral placebo, d‐amphetamine 5, 10, and 20 mg (average of 0.07, 0.15 and 0.29 mg/kg), under counterbalanced double‐blind conditions and completed WCST and N‐back tests of executive functioning. Amphetamine had typical effects on blood pressure and processing speed but did not affect executive functioning. COMT genotype (val158met) was not related to executive functioning under placebo or amphetamine conditions, even when we compared only the homozygous val/val and met/met genotypes at the highest dose of amphetamine (20 mg). Thus, we were not able to replicate the behavioral interaction between COMT and amphetamine seen in Mattay et al. We discuss possible differences between the studies and the implications of our findings for the use of COMT genotyping to predict clinical responses to dopaminergic drugs, and the use of intermediate phenotypes in genetic research.     

The divergent impact of COMT Val158Met on executive function in children with and without attention‐deficit/hyperactivity disorder

Children with attention‐deficit/hyperactivity disorder (ADHD) usually display deficits in executive function (EF), which are primarily mediated by prefrontal cortex (PFC). The functional polymorphism of catechol‐O‐methyltransferase (COMT), Val158Met (rs4680), leads to observed polymorphic differences in the degradation of dopamine within PFC. This study aimed to explore the effect of rs4680 on EF using case–control design. In addition, considering the dynamic development of EF, we also attempted to investigate whether this genetic influence changes during development or not. A total of 597 ADHD children and 154 unaffected controls were recruited. The EF was evaluated using Rey–Osterrieth complex figure test (RCFT), trail making test (TMT) and Stroop color and word test for working memory, shifting and inhibition. Association between genotype and EF was analyzed using analysis of covariance (ancova ). The results showed significant interaction effect of genotype and ADHD diagnosis on RCFT performance (P < 0.001). However, the associated genotypes between ADHD and controls were divergent. In ADHD, the Met carriers performed better than the Val homozygotes on detail immediate [(10.38 ± 6.90) vs. (9.33 ± 6.92), P = 0.007] and detail delay [(9.96 ± 6.86) vs. (8.86 ± 6.89), P = 0.004], while Val homozygotes showed better performance compared with Met carrier controls [for detail immediate (14.55 ± 6.18) vs. (11.10 ± 6.45), P<0.001; for detail delay (14.31 ± 5.96) vs. (11.31 ± 6.96), P = 0.001]. We did not find significant interaction between genetic variant and development. COMT Val158Met (rs4680) may have divergent effect on working memory in ADHD children compared with healthy controls.     

Variants in <Emphasis Type="Italic">COMT</Emphasis> and <Emphasis Type="Italic">DBH</Emphasis> Influence on Response Inhibition Ability in Chinese Han Females

Catechol-O-methyltransferase (COMT) and dopamine-beta hydroxylase (DBH) are key enzymes to breakdown dopamine. Some previous studies have indicated that val158met in COMT and 19 bp insertion/deletion in 5′ flank of DBH are related to the performance of executive function. To further investigate the associations of the two genes with executive function, we performed a population-based study in a Chinese Han population. The results indicated that val158met in COMT and the 19 bp insertion/deletion of DBH were associated with the average reaction time of response inhibition in female group (P = 0.01, P = 0.03), respectively. Furthermore, there was a significant interaction of the two genes on the reaction time (P = 0.006). This present study suggests that not only do COMT and DBH influence independently on response inhibition in females, but also exert a significant interaction on response inhibition.     

Association between maternal COMT gene polymorphisms and fetal neural tube defects risk in a Chinese population

Maternal tea consumption was reported to increase the risk of fetal neural tube defects (NTDs). Catechol‐O‐methyltransferase (COMT) may be involved in the metabolism of polyphenolic methylation of tea, thus influence the risk of fetal NTDs. Methods: A total of 576 fetuses or newborns with NTDs and 594 healthy newborns were included in the case–control study. Information on maternal tea consumption, sociodemographic characteristics, reproductive history, and related behavior was collected through face‐to‐face interviews. Maternal blood samples were collected to examine polymorphisms in COMT, and the possible interaction of COMT and tea consumption was analyzed. RESULTS: After controlling for potential confounders, homozygotes of rs737865 showed an elevated risk for total NTDs (odds ratio [OR] = 2.04, 95% confidence interval [CI], 1.24–3.35) and for the anencephaly subtype (OR = 1.99, 95% CI, 1.17–3.39). The CC genotype of rs4633 was positively associated with the overall risk of NTDs (OR = 3.66, 95% CI, 1.05–12.83). Heterozygotes for rs4680 were associated with a decreased risk of spina bifida (OR = 0.71, 95% CI, 0.51–0.98). The COMT rs4680 A allele was negatively related with the risk of spina bifida, with adjusted OR = 0.64 (95% CI, 0.45–0.89). An interaction between tea consumption (1 to 2 cups/day) and the rs4680AA/AG genotype was found in the spina bifida subtype (P_interaction = .08). Conclusion: Several COMT variants were associated with elevated risk of NTDs in a Chinese population. Maternal tea consumption may be associated with an increased risk for fetal NTDs in genetically susceptible subgroups. Birth Defects Research (Part A) 100:22–29, 2014. © 2013 Wiley Periodicals, Inc.     

FTO Genotype Is Associated With Exercise Training–induced Changes in Body Composition

The fat mass (FM) and obesity‐associated (FTO) gene is the first obesity‐susceptibility gene identified by genome‐wide association scans and confirmed in several follow‐up studies. Homozygotes for the risk allele (A/A) have 1.67 times greater risk of obesity than those who do not have the allele. However, it is not known whether regular exercise‐induced changes in body composition are influenced by the FTO genotype. The purpose of our study was to test whether the FTO genotype is associated with exercise‐induced changes in adiposity. Body composition was derived from underwater weighing before and after a 20‐week endurance training program in 481 previously sedentary white subjects of the HERITAGE Family Study. FTO single‐nucleotide polymorphism (SNP) rs8050136 was genotyped using Illumina GoldenGate assay. In the sedentary state, the A/A homozygotes were significantly heavier and fatter than the heterozygotes and the C/C homozygotes in men (P = 0.004) but not in women (P = 0.331; gene‐by‐sex interaction P = 0.0053). The FTO genotype was associated with body fat responses to regular exercise (P < 0.005; adjusted for age, sex, and baseline value of response trait): carriers of the C allele showed three times greater FM and %body fat losses than the A/A homozygotes. The FTO genotype explained 2% of the variance in adiposity changes. Our data suggest that the FTO obesity‐susceptibility genotype influences the body fat responses to regular exercise. Resistance to exercise‐induced reduction in total adiposity may represent one mechanism by which the FTO A allele promotes overweight and obesity.     

A preliminary study suggests that nicotine and prefrontal dopamine affect cortico‐striatal areas in smokers with performance feedback

Nicotine and tonic dopamine (DA) levels [as inferred by catechol‐O‐methyl tranferase (COMT) Val158Met genotype] interact to affect prefrontal processing. Prefrontal cortical areas are involved in response to performance feedback, which is impaired in smokers. We investigated whether there is a nicotine × COMT genotype interaction in brain circuitry during performance feedback of a reward task. We scanned 23 healthy smokers (10 Val/Val homozygotes, 13 Met allele carriers) during two fMRI sessions while subjects were wearing a nicotine or placebo patch. A significant nicotine × COMT genotype interaction for BOLD signal during performance feedback in cortico‐striatal areas was seen. Activation in these areas during the nicotine patch condition was greater in Val/Val homozygotes and reduced in Met allele carriers. During negative performance feedback, the change in activation in error detection areas such as anterior cingulate cortex (ACC)/superior frontal gyrus on nicotine compared to placebo was greater in Val/Val homozygotes compared to Met allele carriers. With transdermal nicotine administration, Val/Val homozygotes showed greater activation with performance feedback in the dorsal striatum, area associated with habitual responding. In response to negative feedback, Val/Val homozygotes had greater activation in error detection areas, including the ACC, suggesting increased sensitivity to loss with nicotine exposure. Although these results are preliminary due to small sample size, they suggest a possible neurobiological mechanism underlying the clinical observation that Val/Val homozygotes, presumably with elevated COMT activity compared to Met allele carriers and therefore reduced prefrontal DA levels, have poorer outcomes with nicotine replacement therapy .     

Association study of catechol-O-methyltransferase gene polymorphisms with schizophrenia and psychopathological symptoms in Han Chinese

Although dysfunction of catechol‐O‐methyltransferase (COMT)‐mediated dopamine transmission is implicated in the etiology of schizophrenia, the human COMT gene has not been associated consistently with schizophrenia. The purpose of this study was to investigate whether the COMT gene is associated with the development of schizophrenia and whether the polymorphisms of this gene influence the psychopathological symptoms in patients with schizophrenia. Fourteen polymorphisms of the COMT gene were analyzed in a case–control study of 876 Han Chinese individuals (434 patients and 442 controls). All participants were screened using a Chinese version of the modified Schedule for Affective Disorders and Schizophrenia‐Lifetime Version (SADS‐L) and all patients met the criteria for schizophrenia. Furthermore, pretreatment of psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) in a subset of 224 hospitalized schizophrenia patients, who were drug‐naÏve or drug‐free, to examine the association between clinical symptomatology and COMT polymorphisms. No significant differences in allele or genotype frequencies were observed between schizophrenia patients and controls, for all variants investigated. Haplotype analysis showed that three haplotype blocks of the COMT gene were not associated with the development of schizophrenia. Moreover, these COMT polymorphisms did not influence the PANSS scores of schizophrenia patients. This study suggests that the COMT gene may not contribute to the risk of schizophrenia and to the psychopathological symptoms of schizophrenia among Han Chinese.     

Association between genes,stressful childhood events and processing bias in depression vulnerable individuals

The brain‐derived neurotrophic factor (BDNF) and catechol‐O‐methyltransferase (COMT) genes are relevant candidates for depression. Variation in these genes is associated with stress sensitivity and depressotypic cognitive biases. The interaction between genes and stressful events is considered as an important mechanism in the development of depression. This study examined the effects of the BDNF and COMT genes on biased processing and the interaction with childhood stress in vulnerable individuals. A total of 198 remitted depressed individuals performed an n‐back task with emotional facial stimuli (happy and sad). Childhood events were measured with a questionnaire. Genotype by childhood events interactions were analyzed for happy and sad expressions for BDNF (Val66Met; rs6265) and COMT (Val158Met; rs4680), individually and combined. BDNF and COMT both interacted significantly (P = 0.006 and P = 0.014, respectively) with childhood trauma on reaction time for happy faces. For both genes, Met‐carriers with childhood trauma showed less positive bias for happy faces than those without childhood trauma. Val‐carriers did not show a differential bias. Individuals with childhood trauma and 3 or 4 risk alleles (BDNF and COMT combined) showed less positive bias than those without childhood trauma (P = 0.011). The BDNF × COMT × childhood trauma interaction yielded a P = 0.055, but had limited power. A potential weakness is the measurement method of the childhood events, as negative bias might have affected participants' recall. Our findings endorse the association of BDNF and COMT with stress and depression and provide a possible intermediate, i.e. biased processing of positive information. Tailoring treatment to specific risk profiles based on genetic susceptibility and childhood stress could be promising.     

Polymorphisms of CYP1B1 and COMT in Breast and Endometrial Cancer

CYP1B1 and COMT code for the key enzymes of catecholestrogen biosynthesis and metabolism, and their polymorphisms determine the variation of enzyme activities. RFLP analysis was used to study the allele and genotype frequency distributions of CYP1B1 polymorphisms Arg48Gly, Ala119Ser, and Val432Leu, and COMT polymorphism Val158Met among 210 breast cancer patients, 138 endometrial cancer patients, and 152 healthy women. The COMT polymorphism showed no significant association with breast or endometrial cancer. For the first time, such association was observed for the CYP1B1 polymorphisms. CYP1B1 allele C (Arg48), which codes for the enzyme more active in estradiol 4-hydroxylation, was associated with higher risk of breast (OR = 3.22, CI 2.34–4.43, P = 0.000) and endometrial (OR = 2.43, CI 1.72–3.44, P = 0.000) cancer. Similar data were obtained for CYP1B1 allele G (Ala119): OR = 2.18, CI 1.58–3.01, P = 0.000 in breast cancer and OR = 2.52, CI 1.78–3.56, P = 0.000 in endometrial cancer. Risk of endometrial but not breast cancer was significantly higher in carriers of CYP1B1 genotype Val432/Val. This was explained by stronger estrogen dependence and, consequently, higher estrogen responsiveness of the endometrium as compared with the mammary gland.     

Catechol-O-methyltransferase: Effects of the val108met polymorphism on protein turnover in human cells

A single nucleotide polymorphism in the human COMT (catechol-O-methyltransferase) gene has been associated with increased risk for breast cancer and several CNS diseases and disorders. The G to A polymorphism causes a valine (val) to methionine (met) substitution at codon 108 soluble - (S)/158 membrane - (MB)-COMT, generating alleles encoding high and low-activity forms of the enzyme, COMT^H and COMT^L, respectively. Tissues and cells with a COMT^LL genotype have decreased COMT activity compared to COMT^HH cells. Previously, we reported that the decreased activity was due to decreased amounts of S-COMT^L protein in human hepatocytes. In this study, we investigated the role of S-COMT protein synthesis and turnover as determinates of reduced COMT protein in COMT^LL compared to COMT^HH cells. No association between S-COMT protein synthesis and COMT genotype was detected. Using a pulse-chase protocol, the half-life of S-COMT^H was determined to be 4.7 days, which was considerably longer than expected from the half-lives of other phase 2 enzyme proteins. The half-life of S-COMT^L compared to S-COMT^H protein was significantly shorter at 3.0 days, but the difference was affected by the medium used during the chase period. These results suggest that increased turnover may contribute to reduced COMT activity in cells and tissues from COMT^LL individuals. Subtle differences appear to be able to affect the stability of the S-COMT^L protein, and this may contribute to the differences observed in epidemiological studies on the association of this polymorphism with breast cancer risk.     

The interaction of early life experiences with COMT val158met affects anxiety sensitivity

The pathogenesis of anxiety disorders is considered to be multifactorial with a complex interaction of genetic factors and individual environmental factors. Therefore, the aim of this study was to examine gene‐by‐environment interactions of the genes coding for catechol‐O‐methyltransferase (COMT) and monoamine oxidase A (MAOA) with life events on measures related to anxiety. A sample of healthy subjects (N = 782; thereof 531 women; mean age M = 24.79, SD = 6.02) was genotyped for COMT rs4680 and MAOA‐uVNTR (upstream variable number of tandem repeats), and was assessed for childhood adversities [Childhood Trauma Questionnaire (CTQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] and anxious apprehension [Penn State Worry Questionnaire (PSWQ)]. Main and interaction effects of genotype, environment and gender on measures related to anxiety were assessed by means of regression analyses. Association analysis showed no main gene effect on either questionnaire score. A significant interactive effect of childhood adversities and COMT genotype was observed: Homozygosity for the low‐active met allele and high CTQ scores was associated with a significant increment of explained ASI variance [R² = 0.040, false discovery rate (FDR) corrected P = 0.04]. A borderline interactive effect with respect to MAOA‐uVNTR was restricted to the male subgroup. Carriers of the low‐active MAOA allele who reported more aversive experiences in childhood exhibited a trend for enhanced anxious apprehension (R² = 0.077, FDR corrected P = 0.10). Early aversive life experiences therefore might increase the vulnerability to anxiety disorders in the presence of homozygosity for the COMT 158met allele or low‐active MAOA‐uVNTR alleles .     

Reward‐related ventral striatum reactivity mediates gender‐specific effects of a galanin remote enhancer haplotype on problem drinking

The neuropeptide galanin has been implicated in the regulation of appetitive and consummatory behaviors. Prior studies have shown that direct injection of galanin into the hypothalamus results in increased release of dopamine (DA) in the nucleus accumbens (NAcc), and parallel increases in food and alcohol consumption. These studies are consistent with a role of hypothalamic galanin in regulating reward system reactivity. In humans, a common functional haplotype (GAL5.1) within a remote enhancer region upstream of the galanin gene (GAL) affects promoter activity and galanin expression in hypothalamic neurons in vitro. Given the effects of hypothalamic galanin on NAcc DA release and the effects of the GAL5.1 haplotype on GAL expression, we examined the impact of this functional genetic variation on human reward‐related ventral striatum (VS) reactivity. Using an imaging genetics strategy in Caucasian individuals (N = 138, 72 women) participating in the ongoing Duke Neurogenetics Study, we report a significant gender‐by‐genotype interaction (right hemisphere: F_1,134 = 8.08, P = 0.005; left hemisphere: F_1,134 = 5.39, P = 0.022), such that homozygosity for the GG haplotype, which predicts greater GAL expression, is associated with relatively increased VS reactivity in women (n = 50, right hemisphere: P = 0.015; left hemisphere: P = 0.060), but not in men (N = 49, P‐values > 0.10). Furthermore, these differences in VS reactivity correlated positively with differences in alcohol use, such that VS reactivity mediated a gender‐specific association between GAL5.1 haplotype and problem drinking. Our current results support those in animal models implicating galanin signaling in neural pathways associated with appetitive and consummatory behaviors of relevance for understanding risk for substance use and abuse.     

Catechol-O-Methyltransferase val158met Polymorphism Predicts Placebo Effect in Irritable Bowel Syndrome

Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment (“waitlist”), placebo treatment alone (“limited”) and, placebo treatment “augmented” with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response.     

Association of BDNF gene polymorphism with bipolar disorders in Han Chinese population

Recent data suggest that brain‐derived neurotrophic factor (BDNF) plays an essential role in neuronal plasticity and etiology of bipolar disorders (BPD). However, results from different studies have been inconsistent. In present study, 342 patients who met DSM‐IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) criteria for bipolar disorders type I (BPD‐I) or type II (BPD‐II) and 386 matched health controls were enrolled, and TaqMan® SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) were applied to detect the functional polymorphism rs6265 (Val66Met) of BDNF gene. Treatment response to lithium and valproate was retrospectively determined. The association between Val66Met polymorphism and BPD, treatment response to mood stabilizers, was estimated. The genotype and allele distribution of Val66Met polymorphism between BPD patients and control subjects showed significant difference (genotype: χ² = 6.18, df = 2, P = 0.046; allele: χ² = 5.01, df = 1, P = 0.025) with Met allele as risk factor for disease susceptibility (OR = 0.79, 95%CI as 0.64–0.97). The post hoc analysis interestingly showed that Met allele had opposite effect on the treatment response for BPD‐I and BPD‐II separately. For BPD‐I patients, the response score in Val/Val group was significantly lower than that in Met allele carriers (t = ?2.27, df = 144, P = 0.025); for BPD‐II patients, the response score in Val/Val group was significantly higher than that in Met allele carriers (t = 2.33, df = 26, P = 0.028). Although these results should be interpreted with caution because of the limited sample for Val/Val genotype in BPD‐II patients (N = 5), these findings strengthen the hypothesis that BDNF pathway gets involved in the etiology and pharmacology of BPD and suggest the differences between BPD‐I and BPD‐II.     

A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study

This study aimed to evaluate whether functional variants in the ankyrin repeat and kinase domain‐containing 1 (ANKK1) gene and/or the dopamine receptor D2 (DRD2) gene modulate the subjective effects (reward or non‐reward response to a stimulus) produced by cocaine administration. Cocaine‐dependent participants (N = 47) were administered 40 mg of cocaine or placebo at time 0, and a subjective effects questionnaire (visual analog scale) was administered 15 min prior to cocaine administration, and at 5, 10, 15 and 20 min following administration. The influence of polymorphisms in the ANKK1 and DRD2 genes on subjective experience of cocaine in the laboratory was tested. Participants with a T allele of ANKK1 rs1800497 experienced greater subjective ‘high’ (P = 0.00006), ‘any drug effect’ (P = 0.0003) and ‘like’ (P = 0.0004) relative to the CC genotype group. Although the variant in the DRD2 gene was shown to be associated with subjective effects, linkage disequilibrium analysis revealed that this association was driven by the ANKK1 rs1800497 variant. A participant's ANKK1 genotype may identify individuals who are likely to experience greater positive subjective effects following cocaine exposure, including greater ‘high’ and ‘like’, and these individuals may have increased vulnerability to continue using cocaine or they may be at greater risk to relapse during periods of abstinence. However, these results are preliminary and replication is necessary to confirm these findings.