A118G Polymorphism Research Articles

Human Expression Variation in the Mu-Opioid Receptor is Paralleled in Rhesus Macaque

The mu-opioid receptor is a key component in many neurobiological systems including those affecting perceptions of pain and pleasure. In humans and non-human primate model systems, genetic variation in the receptor has been associated with numerous behavioral and physiological traits. In humans, polymorphisms have been identified which affect not only the biochemical function of the receptor, but also expression level. Existing rhesus macaque variation parallels the functional protein changes seen in human, but it remains unknown if expression level differences or concomitant protein changes may also exist. Here we perform a comprehensive survey of naturally occurring polymorphisms in Indian-origin rhesus macaques and identify three 5' UTR haplotypes with effects on expression level. These expression level effects are in linkage disequilibrium with the previously identified rhesus coding polymorphism C77G. The C77G polymorphism in rhesus parallels the functional effects of the A118G polymorphism in humans and expression level differences occur within both species. Together, the functional variations reported here have implications for future studies seeking to model the opioid system and its associated phenotypes in rhesus macaques.

New polymorphic mtDNA restriction site in the 12S rRNA gene detected in Tunisian patients with non-syndromic hearing loss

The 12S rRNA gene was shown to be a hot spot for aminoglycoside-induced and non-syndromic hearing loss since several deafness-associated mtDNA mutations were identified in this gene. Among them, we distinguished the A1555G, the C1494T and the T1095C mutations and C-insertion or deletion at position 961. One hundred Tunisian patients with non-syndromic hearing loss and 100 hearing individuals were analysed in this study. A PCR-RFLP analysis with HaeIII restriction enzyme showed the presence of the A1555G mutation in the 12S rRNA gene in only one out of the 100 patients. In addition, PCR-RFLP and radioactive PCR revealed the presence of a new HaeIII polymorphic restriction site in the same gene of 12S rRNA site in 4 patients with non-syndromic hearing loss. UVIDOC-008-XD analyses showed the presence of this new polymorphic restriction site with a variable heteroplasmic rates at position +1517 of the human mitochondrial genome. On the other hand, direct sequencing of the entire mitochondrial 12S rRNA gene in the 100 patients and in 100 hearing individuals revealed the presence of the A750G and A1438G polymorphisms and the absence of the C1494T, T1095C and 961insC mutations in all the tested individuals. Sequencing of the whole mitochondrial genome in the 4 patients showing the new HaeIII polymorphic restriction site revealed only the presence of the A8860G transition in the MT-ATP6 gene and the A4769G polymorphism in the ND2 gene.

A Study of the Mu Opioid Receptor Gene Polymorphism A118G in Patients with Primary Biliary Cirrhosis with and without Pruritus

The increase in opioidergic tone by the central administration of morphine, which binds to the mu opioid receptor, is associated with pruritus. Pruritus is a symptom of cholestasis, which appears to result, in part, from increased opioidergic tone; a central mechanism has been proposed. The single nucleotide polymorphism Al18G in exon 1 of the opioid receptor mu 1 (OPRM1) gene, which codes for the mu opioid receptor, has been associated with alterations in functions mediated by the endogenous opioid system. In this study we found A118G in heterozygosity in 29% of the DNA samples from patients with primary biliary cirrhosis from the USA and from Italy with and without pruritus. A118G was 1.5 times more frequent in the samples from patients without pruritus from the USA than in the rest of the samples. The possibility of protection from pruritus associated with A118G supports the study of genetic polymorphisms of the OPRM1 gene in patients with cholestasis.

The influence ofABCB1andOPRM1genetic polymorphism on fentanyl requirements for postoperative pain control

Background: Fentanyl, which is a potent synthetic μ-opioid receptor agonist, is one of the most widely used opioids in anes- thesia and pain control. However, the pharmacodynamics of fentanyl show wide inter-individual variability. Therefore, this study was conducted to evaluate the influence of the blood-brain barrier transporter protein, p-glycoprotein, and μ-opioid receptor genetic polymorphism on fentanyl pharmacodynamics. Methods: Seventy-nine patients who underwent posterior lumbar interbody fusion (PLIF) were included in this study. Postoperatively, the patients received fentanyl via an intravenous patient controlled analgesia device. The cumulative fentanyl doses and other pharmacodynamic data were then recorded at 2 h, 6 h, 12 h, 24 h and 48 h after the operation. In addition, genomic DNA was isolated from the patient's peripheral leukocytes and then evaluated for the presence of OPRM1 A118G and ABCB1 C3435T genetic polymorphism using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The results of this study indicated that ABCB1 C3435T genetic polymorphism may be related to the cumulative fentanyl requirement for postoperative pain control. However, these findings were not statistically significant (P = 0.09). In addition, no relationship was observed between OPRM1 A118G and the cumulative postoperative fentanyl requirement. However, the cumu- lative postoperative fentanyl requirement was lower in the TTAA group (ABCB1 3435 TT, OPRM1 118 AA) than in the CCGG group (ABCB13435 CC, OPRM1 118 GG). Conclusions: The ABCB1 C3435T polymorphism may affect fentanyl pharmacodynamics. However, further studies are required to confirm the relationship between p-glycoprotein and fentanyl. (Korean J Anesthesiol 2008; 55: 332~7)

Association between Heroin Dependence and 5-HT2A Receptor Gene Polymorphisms

Objective: To investigate the association between four polymorphisms of the 5-HT_2A receptor and 5-HT transporter genes and heroin dependence. Methods: 113 heroin- dependent patients (DSM-IV criteria) and 420 unrelated healthy controls from Asturias (Northern Spain) were genotyped using standard methods. Results: There was an apparent difference in the distribution of genotypes for A-1438G polymorphisms (p = 0.024, not significant after Bonferroni correction). The 5-HT_2A -1438A allele was significantly more common in patients than controls [0.55 and 0.45, respectively; corrected p = 0.042, OR = 1.51 (95% CI = 1.13–2.03)]. An interaction was observed between A-1438G of 5-HT_2A and 5-HTT polymorphisms. The association between the -1438AA vs. AG/GG genotypes and heroin dependence was enhanced in the presence of 12-repeat 5-HTT VNTR and short 5-HTTLPR alleles [24.8% in heroin-dependent patients vs. 12.6% in controls; corrected p = 0.045, OR = 2.28 (95% CI = 1.36–3.82)]. Conclusions: Our findings support a contribution of the 5-HT_2A gene to susceptibility to heroin dependence, as well as a possible synergistic effect of 5-HT_2A and 5-HTT genes on susceptibility to heroin dependence.

Association study between obsessive–compulsive disorder and serotonergic candidate genes

Background To date, research examining the relationship between serotonergic genes and obsessive–compulsive disorder (OCD) has yielded conflicting results. The purpose of this study is to investigate the association between four serotonergic polymorphisms (STin2 VNTR and 5-HTTLPR of the SLC6A4 gene, and A-1438G (rs6311) and T102C (rs6313) of the HTR2A gene) and OCD. Methods 99 OCD patients, 456 non-OCD psychiatric patients, and 420 healthy controls from a homogeneous Spanish Caucasian population were genotyped using standard methods. Results All groups showed Hardy–Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms were in complete linkage disequilibrium. OCD patients showed an excess of STin2.12 carriers (12/12, 12/10, and 12/9 genotypes) compared with healthy controls ( χ 2 (1) = 7.21, corrected p = 0.021; OR = 3.38, 95% CI = 1.32–8.62) and non-OCD psychiatric patients ( χ 2 (1) = 6.70, corrected p = 0.030; OR = 3.24, 95% CI = 1.27–8.26). However, no differences were found between non-OCD patients and healthy controls ( χ 2 (1) = 0.05, corrected p> 1; OR = 1.04, 95% CI = 0.72–1.51). No significant differences were found with respect to A-1438G and 5-HTTLPR polymorphisms. Conclusions Our data provide supporting evidence of an association between the STin2 VNTR polymorphism of the SLC6A4 gene and OCD.

A118G POLYMORPHISM IN MU OPIOID RECEPTOR GENE (OPRM1): ASSOCIATION WITH OPIATE ADDICTION IN SUBJECTS OF INDIAN ORIGIN

The opioidergic hypothesis suggests an association between genetic variations at the opioid receptor mu 1 (OPRM1) gene locus and opiate addiction. The OPRM1 gene, which encodes for mu opioid receptor, contains several single nucleotide polymorphisms (SNPs) in exon I. Two of these, C17T and A118G, have been reported to be associated with substance abuse. The present study aims to delineate the frequency of these variants in the subjects of Indian origin and study their association with the phenotype of opioid dependence. A118G (rs 1799971) and C17T (rs 1799972) were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. For 118G allele, the control subjects (n = 156) showed a frequency of 0.12 while the opioid dependents (n = 126) had an approximately 2.5-fold higher frequency of 0.31 (Odds Ratio 3.501; CI(95%) 2.212-5.555; p < 0.0001). For C17T polymorphism, the controls (n = 57) showed a frequency of 0.89 for C allele versus 0.83 seen in dependents (n = 123; odds ratio of 0.555; CI(95%) 0.264-1.147; p = 0.121). A significant association was observed between the 118G allele and no association was seen with C17T polymorphism and opioid dependence.

Population-specific effects of the Asn40Asp polymorphism at the μ-opioid receptor gene (OPRM1) on HPA-axis activation

Studies in European Americans (EAs) have shown that the hypothalamic-pituitary-adrenal (HPA)-axis activation by the opioid blockade is moderated by the single nucleotide polymorphism (SNP) A118G (Asn40Asp) at the mu-opioid receptor locus (OPRM1). We examined the effect of this, and of five intronic OPRM1 SNPs, on adrenocorticotropic hormone and cortisol concentrations, following the placebo-controlled administration of naloxone to healthy individuals who were of EA or Asian ancestry. We used a balanced, within-participant design with two test sessions to examine the hormonal responses to intravenous naloxone (an opioid antagonist) (125 microg/kg) or placebo in 29 healthy participants (62% men, 59% of Asian ancestry). DNA isolated from whole blood was PCR amplified and genotyped using a fluorogenic 5 nuclease assay (TaqMan) method. Consistent with earlier reports, participants with one or two Asp40 alleles (n=16) had a significantly greater cortisol response to naloxone than Asn40 homozygotes, but the effect was limited to EAs. Asians with the Asp40 allele did not show a greater increase in cortisol response compared with Asn40 homozygotes. None of the intronic SNPs was associated with cortisol response either directly or via an interaction effect with Asn40Asp. Effects of the Asn40Asp polymorphism at OPRM1 on HPA-axis activation seem to be population-specific. The association between the Asn40Asp and the HPA-axis response to naloxone cannot, therefore, be explained with reference only to the amino acid substitution encoded by that polymorphism. Further research to understand the basis for the observed association is warranted.

P.6.a.010 Study of alcohol consumption in ambulatory psychiatric patients

Provoked vestibulodynia (PVD) is the most common cause of dyspareunia among young women. The aetiology is largely unknown and treatment is often extensive and longstanding with varying outcomes. Patients display general pain hypersensitivity and there are correlations with other chronic pain syndromes such as fibromyalgia later in life. The A118G polymorphism in the μ-opioid receptor (OPRM1) gene influences endogenous pain regulation and pain sensitivity, but has not been studied in this patient group before. We aimed to investigate a possible association between A118G polymorphism and PVD, with correlation to plasma levels of β-endorphin, and to explore relationships between this polymorphism and pain sensitivity among women with PVD and healthy controls.This case–control study included 98 women with PVD and 103 controls. Participants filled out study-specific questionnaires and underwent quantitative sensory testing of pressure pain thresholds on the arm, leg and in the vestibular area. Levels of β-endorphin were analyzed by radioimmunoassay using the EURIA-beta-endorphin kit, and the A118G single-nucleotide polymorphism (SNP; rs1799971) in the OPRM1 gene was analyzed using the TaqMan SNP genotyping assay.The 118G allele was more common in controls (44%) than in patients (30%) (p = 0.042). The odds ratio of having PVD was 1.8 in participants carrying the 118A allele compared to participants hetero- or homozygous for the 118G allele (OR = 1.846, CI: 1.03–3.31, p = 0.039). Pressure pain thresholds on the leg were higher for participants carrying the 118G allele (mean 480 kPa, SD 167.5) than for those carrying the 118A allele (mean 419, SD 150.4, p = 0.008). Levels of β-endorphin were higher in patients (mean 17.9 fmol/ml, SD 4.71) than in controls (mean 15.8 fmol/ml, SD 4.03) (p < 0.001).We found an association between the A118G polymorphism in the OPRM1 gene and an increased risk of PVD and increased pain sensitivity among participants carrying the 118A allele. PVD patients were more sensitive to pressure pain and had higher levels of plasma β-endorphin than controls. The results indicate that differences in endogenous pain modulation involving the opioid system could contribute to the pathophysiology of PVD and the general pain hypersensitivity seen in these women.The data support the conceptualization of PVD as part of a general pain disorder with a possible genetic predisposition. The age of onset of PVD is usually between 18 and 25 years and already at this age general pain hypersensitivity is present but rarely causing disability. We believe that early recognition and treatment, with the risk of further development of chronic pain taken into consideration, might prevent future aggravated pain problems in this patient group.

Association Between Migraine and the G1246A Polymorphism in the Hypocretin Receptor 2 Gene

The hypocretin receptor 2 (HCRTR2) G1246A polymorphism has been associated with the risk for cluster headache. Since the hypothalamic hypocretin/orexin system projects throughout the nervous system and affects multiple vegetative functions including generation of rhythmicity, vasomotion, autonomic symptoms as well as modulation of nociception, it may also be linked with migraine. We thus sought to evaluate whether the HCRTR2 G1246A polymorphism is associated with the risk for migraine. We prospectively established a cohort of 146 unrelated patients with migraine. The control group consisted of 279 healthy volunteers. We genotyped patients and controls for the HCRTR2 G1246A polymorphism and examined an association with presence or absence of migraine. Genotype and allele frequencies were not significantly different between migraine patients and controls (genotype distribution: chi(2)= 4.13, 2 df, P= .13; allele distribution: chi(2)= 0.9, 1 df, P= .34). Our study does not support a major contribution of the HCRTR2 G1246A polymorphism to the pathogenesis of migraine in contrast to its effects in cluster headache.

The single nucleotide polymorphism A118G alters functional properties of the human mu opioid receptor

The most common single nucleotide polymorphism in the coding region of the human mu opioid receptor gene is the A118G variant, an adenine to guanine transition at nucleotide position 118 of the coding sequence of the gene. This polymorphism codes for an asparagine to aspartic acid substitution at amino acid 40 in the amino-terminus, thereby removing a potential extracellular glycosylation site. Using in vitro cellular expression assays, this variant has been reported to change binding of the endogenous agonist beta-endorphin and signaling of the receptor following binding of beta-endorphin. Three clinical studies report that A118G genotype affects opioid antagonist-mediated increases in cortisol levels. These studies demonstrate a functional role of this variant in responses to endogenous and exogenous opioids. To further characterize function, we expressed the prototype and variant receptors in two types of cells (human 293 embryonic kidney cells and Syrian hamster adenovirus-12-induced tumor cells). Stable expression of variant and prototype receptors was characterized by differences in levels of cell surface binding capacity (B(max)), forskolin-induced cAMP accumulation, as well as agonist-induced accumulation of cAMP (EC(50)) for several agonists, but not for beta-endorphin. In contrast, transiently expressed variant receptors showed only a minor difference in cell surface binding capacity compared to the prototype, and no differences in cAMP EC(50) values.

Mu-opioid receptor and binding affinity to fentanyl is affected by sex but not by A118G polymorphism

Mu-opioid receptor and binding affinity to fentanyl is affected by sex but not by A118G polymorphism

Association between the G1246A polymorphism of the hypocretin receptor 2 gene and cluster headache: a meta-analysis

The objective of this study was to investigate the association between polymorphisms of the hypocretin receptor 2 gene (HCRTR2) and the risk of cluster headache (CH). The study is a meta-analysis of published case-control studies investigating the association between polymorphisms of the HCRTR2 gene and CH. Pooled odds ratios (OR) were estimated using both random (RE) and fixed effects (FE) models. Three studies, performed in five different European countries, with 593 cases and 599 controls, were included in the study. Allele G of the G1246A HCRTR2 polymorphism was significantly associated with CH (FE OR 1.58, CI 95% 1.27–1.95; RE OR 1.55 (1.14–2.12)). Carriers of the GG genotype showed a higher disease risk compared to the remaining genotypes (FE OR 1.75, CI 95% 1.37–2.25; RE OR 1.69, CI 95% 1.11–2.58). Our data confirm that the G1246A polymorphism of the HCRTR2 gene may modulate the genetic risk for CH.

The G1246A Polymorphism in the Hypocretin Receptor 2 Gene is not Associated with Treatment Response in Cluster Headache

The risk of cluster headache (CH) is associated with the G-allele of the G1246A polymorphism in the hypocretin receptor 2 (HCRTR2) gene. First-line medication is effective in only about 70-80% of CH patients. We hypothesized that the HCRTR2 G1246A polymorphism is also of pharmacogenetic relevance in CH and may affect treatment response. We performed a prospective cohort study among 184 unrelated White CH patients. While the HCRTR2 1246G allele was significantly associated with CH in this group, treatment outcomes with triptans, oxygen, verapamil and corticosteroids remained unaffected. Our results do not support a role of the HCRTR2 G1246A polymorphism in drug responses in CH.

Association study of serotonin 2A receptor (5-HT2A) and serotonin transporter (5-HTT) gene polymorphisms with schizophrenia

Objective To investigate (i) the association between four serotonergic polymorphisms (A-1438G and T102C of the 5-HT2A receptor gene, and 5-HTT VNTR and 5-HTTLPR of the 5-HT transporter gene) and schizophrenia and (ii) the potential interaction of those polymorphisms in the development of schizophrenia. Subjects and methods 227 outpatients with schizophrenia (DSM-IV criteria) and 420 unrelated healthy controls from Asturias (Northern Spain) were genotyped using standard methods. Results Both groups showed Hardy–Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms are in complete linkage disequilibrium in our population. There was an apparent difference in the distribution of genotypes for the A-1438G (or T102C) polymorphisms ( p = 0.018, not significant after a Bonferroni correction). The 5-HT2A − 1438A (or 102T) allele was significantly more frequent in patients than controls (0.53 and 0.45, respectively; corrected p = 0.028, OR = 1.39 (95% CI = 1.11–1.75)). Genotype and allele distributions for 5-HTT polymorphisms were similar in both groups. However, assessment of the combined influence of 5-HT2A A-1438G and 5-HTTLPR polymorphisms demonstrated a significant effect ( χ 2 (3) = 11.51, p = 0.009), whereby the combination of − 1438A and 5-HTTLPR S alleles was associated with schizophrenia. Conclusions Our findings support a possible synergistic effect of genetic factors influencing serotonergic neurotransmission on susceptibility to schizophrenia.

No Association of the G1287A Polymorphism in the Norepinephrine Transporter Gene and Susceptibility to Major Depressive Disorder in a Japanese Population

Norepinephrinergic neurotransmission in the central nervous system have a major impact on the symptomatology in major depressive disorder (MDD), and genetic polymorphisms of norepinephrine transporter (NET) have a possibility to be involved in susceptibility to MDD. We investigated the association of the G1287A (rs5569) polymorphism of the NET gene and susceptibility to MDD by comparing 145 major depressive patients with 164 healthy individuals first in a Japanese population. The genotype frequencies in depressed patients and health volunteers of the NET G1287A polymorphism were 52.4% (G/G), 39.3% (G/A) and 8.3% (A/A) in depressed patients, 61.6% (G/G), 29.9% (G/A allele) and 8.5% (A/A) in healthy volunteers, respectively. The allele frequencies in depressed patients and health volunteers of the NET G1287A polymorphism were 72.1% (G allele) and 27.9% (A allele) in depressed patients, 76.5% (G allele) and 23.5% (A allele) in healthy volunteers, respectively. The genotype distribution and allele frequencies were not significantly different between major depressive patients and healthy volunteers. NET G1287A polymorphism appears not to be an important factor in susceptibility to MDD in a Japanese population.

Association between T102C and A–1438G polymorphisms in the serotonin receptor 2A (5-HT2A) gene and schizophrenia: relevance for treatment with antipsychotic drugs

An involvement of serotonin receptor 2A (5-HT2A) in the aetiology of schizophrenia has been hypothesised. The 5-HT2A receptor also appears to be an important site of action of atypical antipsychotic drugs. Indeed, association between schizophrenia and the T102C silent polymorphism of the 5-HTR2A gene has been reported. Another polymorphism in the promoter region of 5-HTR2A (A-1438G) in linkage disequilibrium with the T102C polymorphism has also been reported. It has been suggested that the A-1438G polymorphism alters promoter activity and expression of 5-HT2A receptors and might be responsible for the associations with schizophrenia and the efficacy of atypical antipsychotics such as risperidone. We analysed the 5-HTR2A T102C and A-1438G polymorphisms in clinically stable schizophrenia patients (SPs) and healthy volunteers (HVs). We developed an allele-specific PCR-based restriction fragment length polymorphism (PCR-RFLP) method. In SPs, we also described differences across both diagnosis subtypes (paranoid vs. non-paranoid) and antipsychotic drug treatment (risperidone vs. other classical antipsychotic drugs). Two groups of 114 SPs and 142 HVs were studied. The frequency of the 5-HTR2A -1438A allele was higher in SPs than in HVs (0.54 vs. 0.44; p<0.05). The frequency of the 102T allele was also higher among SPs than HVs (0.56 vs. 0.46; p<0.05). These two polymorphisms were in linkage disequilibrium. The percentage of carriers of the 1438A/A and 102T/T alleles was 26% and 15% for SPs and HVs, respectively (p<0.05; odds ratio 1.9). No differences in genotype or allele frequencies were found between paranoid and non-paranoid SPs or between SPs on risperidone and those on classical antipsychotic treatment. The present study demonstrates a higher frequency of 5-HTR2A -1438A and 102T alleles in SPs compared to HVs.

Genetic variability and opioid efficacy

Summary A number of clinical observations suggest that patients' genetic disposition influences their response to opioids. This position is strengthened because data from basic research agree with data obtained in human studies. However, a clinical relevance for genetic variability was only established for the CYP2D6 gene polymorphisms and the mu-opioid receptor gene A118G polymorphism. For other opioids or other candidate genes, clinical data are either not available or the data are yet too limited to reach a definitive conclusion. Still, the results obtained so far strongly indicate that opioid efficacy is related to inborn properties caused by genetic variability related to opioid metabolism, opioid receptors, opioid signaling, and opioid transporters. In addition, clinical effects are influenced by variations in other biological systems that modify the effects induced by opioid agonists. Clinical data are lacking for most opioids and little is known about the exact mechanisms by which genetic variability interacts with opioid signaling. Further research should combine basic and clinical research with the end goal of obtaining improved and individualized pain treatment.

Human Opioid Receptor A118G Polymorphism Affects Intravenous Patient-controlled Analgesia Morphine Consumption after Total Abdominal Hysterectomy

Human Opioid Receptor A118G Polymorphism Affects Intravenous Patient-controlled Analgesia Morphine Consumption after Total Abdominal Hysterectomy

A Functional Polymorphism of the μ‐Opioid Receptor Gene (OPRM1) Influences Cue‐Induced Craving for Alcohol in Male Heavy Drinkers

The mu-opioid receptor gene (OPRM1) codes for the mu-opioid receptor, which binds beta-endorphin. The A118G polymorphism in this gene affects beta-endorphin binding such that the Asp40 variant (G allele) binds beta-endorphin 3 times more tightly than the more common Asn40 variant (A allele). This study investigated the influence of the A118G polymorphism on cue reactivity after exposure to an alcoholic beverage in male heavy drinkers. Participants were either homozygous for the A allele (n=84) or carrying at least 1 copy of the G allele (n=24). All participants took part in a cue-reactivity paradigm where they were exposed to water and beer in 3-minute trials. The dependent variables of main interest were subjective craving for alcohol, subjective arousal, and saliva production. G allele carriers reported significantly more craving for alcohol than the A allele participants (as indicated by the within-subject difference in craving after beer vs after water exposure). No differences were found for subjective arousal and saliva. Both groups did not differ in family history of alcoholism. Participants with the G allele reported a significantly higher lifetime prevalence of drug use than participants homozygous for the A allele. A stronger urge to drink alcohol after exposure to an alcoholic beverage might contribute to a heightened risk for developing alcohol-related problems in individuals with a copy of the G allele. The G allele might also predispose to drug use in general.