Clinical and genetic factors associated with post-operative nausea and vomiting after propofol anaesthesia.

BACKGROUND: The incidence of post-operative nausea and vomiting (PONV) remains at about 30% despite all therapeutic efforts to reduce it. The clinical risk factors guiding the prophylactic treatment are well established, but genetic factors associated with PONV remain poorly known. The aim of this study was to explore clinical and genetic factors impacting PONV by performing a genome-wide association study (GWAS) together with relevant clinical factors as covariates, and systematically attempt to replicate previously reported PONV associations. Relevant clinical factors are explored with logistic regression model. METHODS: This was an observational case control study in Helsinki University Hospital between 1 August 2006 and 31 December 2010. One thousand consenting women with elevated risk for PONV, undergoing breast cancer surgery with standardised propofol anaesthesia and antiemetics. After exclusions for clinical reasons and failed genotyping, 815 patients were included with 187 PONV cases and 628 controls. Emergence of PONV up to 7th post-operative day was recorded. PONV at 2-24 h after surgery was selected to be the primary outcome. The GWAS explored associations between PONV and 653 034 genetic variants. Replication attempts included 31 variants in 16 genes. RESULTS: The overall incidence of PONV up to 7th post-operative day was 35%, where 3% had PONV at 0-2 h and 23% at 2-24 h after surgery. Age, American Society of Anaesthesiologists status, the amount of oxycodone used in the post-anaesthesia care unit, smoking status, previous PONV, and history of motion sickness were statistically significant predictive factors in the logistic model. The receiver operating characteristic-area under the curve of 0.75 (95% CI 0.71-0.79) was calculated for the model. The GWAS identified six variants with suggestive association to PONV (p < 1 × 10-5 ). Of the previously reported variants, association with the DRD2 variant rs18004972 (TaqIA) was replicated (p = .028). CONCLUSIONS: Our GWAS approach did not identify any high-impact PONV susceptibility variants. The results provide some support for a role of dopamine D2 receptors in PONV.

The efficacy of 5HT3-receptor antagonists in postoperative nausea and vomiting: the role of pharmacogenetics.

INTRODUCTION: Genetic variants may affect drug efficacy on postoperative nausea and vomiting (PONV). The understanding of these mechanisms will help to identify the surgical patients who might benefit from specific prophylactic and therapeutic antiemetic treatment. The aim of the present review was to investigate gene polymorphisms that influence 5-hydroxytryptamine (serotonin) type 3 receptor antagonists (5HT3RA) efficacy in PONV. EVIDENCE AQUISITION: We included articles published from 2005 to 2022, utilizing the electronic databases PUBMED, EMBASE, COHRANE Library and ScienceDirect. To explore the relationship between genetic variations and 5HT3 receptor antagonist efficacy in PONV we focused on three different gene polymorphisms: the cytochrome P450 mono-oxygenase system gene (CYP2D6), the adenosine triphosphate (ATP)-binding cassette subfamily B gene (ABCB1) as well as the 5HT3 receptor gene (5HT3R). We also explored the relationship between the above genetic variations and their impact on 5HT3RA efficacy in the context of chemotherapy induced nausea and vomiting. EVIDENCE SYNTHESIS: Our search retrieved a total of 70 articles; 29 of them were included in the present review. Regarding polymorphisms of the CYP2D6 gene and the efficacy of serotonin antagonists in PONV, the ultra-rapid metabolizer genotype was associated with reduced efficacy of ondansetron, dolasetron and tropisetron, with the latter presenting more pronounced failure in these patients, while granisetron's efficacy remained unaffected. Regarding variations in the ABCB1 gene, three polymorphisms ("2677G>T/A" in exon 21; "3435C>T" in exon 27; "C1236T" in exon 12) were associated with a better response to ondansetron and ramosetron, while they did not affect palonosetron's efficacy. Additionally, polymporphisms of the 5-HT3B receptor gene were associated with ondancetron's postoperative efficacy; the "100_-102AAG" deletion variant was associated with reduced efficacy, while the Y129S variant did not show any effect on the drug's antiemetic effect. CONCLUSIONS: This review highlights that inefficacy of a specific drug in managing PONV could be attributed to specific genetic profiles and patients would possibly benefit from a drug switch.

Polymorphisms of 5-hydroxytryptamine receptor type 3B gene and clinical characteristics for vomiting after breast surgery in chinese han female population.

WHAT IS KNOWN AND OBJECTIVE: The 5-hydroxytryptamine type 3B receptor (HTR3B) is involved in postoperative vomiting. We aimed to investigate whether genomic variations of rs1176744 and rs1672717 in HTR3B are associated with postoperative vomiting (POV) in the Chinese Han female population after surgery. METHODS: Five hundred and sixty-eight female patients classified as ASA I-II undergoing breast surgery under standard general anaesthesia were enrolled in the study. Episodes of POV in the first 24 h after surgery were recorded. Targeted single nucleotide polymorphisms (SNPs) in the HTR3B gene were identified by genotyping using the SNPscanTM technique. Univariate and multivariate analyses were conducted to investigate the association between SNPs and POV. RESULTS: We eventually analysed 407 subjects undergoing breast surgery under general anaesthesia. Of these, 104(25.6%) patients suffered POV within 24 h after surgery. In the multivariate logistic regression analysis, we found that age≥50 years (p = 0.012) and longer duration of surgery (p = 0.019) were independent risk factors for POV. Simultaneously, in the dominant model of rs1672717, compared with the AA genotype, GG+GA carriers suffered more POV (OR=1.669, p = 0.038). However, the use of atropine reduced the incidence of POV in our study (p = 0.019). WHAT IS NEW AND CONCLUSION: Our investigation demonstrated that polymorphism of rs1672717 (HTR3B) may be a genetic risk factor for developing POV. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT03705026.

Long non-coding RNA MIR4300HG polymorphisms are associated with postoperative nausea and vomiting: a genome-wide association study.

BACKGROUND: Genetic factors such as single-nucleotide polymorphisms (SNPs) play a key role in the development of postoperative nausea and vomiting (PONV). However, previous findings are not widely applicable to different populations because of population-specific genetic variation. We developed a Japanese-specific DNA microarray for high-throughput genotyping. The aim of the current study was to identify SNPs associated with PONV on a genome-wide scale using this microarray in a sample of Japanese surgical patients. METHODS: Associations between 659,636 SNPs and the incidence of PONV 24 h after surgery in a limited sample of 24 female patients were assessed using the microarray. After imputation of genotypes at 24,330,529 SNPs, 78 SNPs were found to be associated with the incidence of PONV. We chose 4 of the 78 SNPs to focus on by in silico functional annotation. Finally, we genotyped these 4 candidate SNPs in 255 patients using real-time PCR to verify association with the incidence of PONV. RESULTS: The T > C variant of rs11232965 in the long non-coding RNA MIR4300HG was significantly associated with reduced incidence of PONV among genotypes and between alleles (p = 0.01 and 0.007). CONCLUSIONS: We identified a novel SNP (rs11232965) in the long non-coding RNA MIR4300HG that is associated with PONV. The rs11232965-SNP variant (T > C) is protective against the incidence of PONV. TRIAL REGISTRATION: This study was registered at the UMIN Clinical Trials Registry (Identifier: UMIN000022903 , date of registration: June 27, 2016, retrospectively registered.

Genetic contribution to PONV risk.

BACKGROUND: Clinical risk factors for postoperative nausea and vomiting (PONV) are usually stratified using the Apfel Score. While a genetic predisposition has recently been demonstrated with the muscarinic acetylcholine receptor (CHRM3) rs2165870 single nucleotide polymorphism (SNP), we investigated whether (1) other SNPs contribute to PONV risk and (2) a genetic risk score might summarise genetic PONV risk. METHODS: We retrospectively analysed data from a study with 472 patients undergoing elective surgery. We investigated the SNPs rs3218315 (IL2RB), rs349358 (KCNB2), rs703363 (intergenic variant), rs1800497 (DRD2), rs1799971 (OPRM1), and rs1176713 (HTR3A). A genetic risk score was established and association with PONV investigated. RESULTS: Early PONV occurred in 37%. There was a significant association of the KCNB2 rs349358 SNP with nausea (P = 0.021), retching (P = 0.001), and PONV (P = 0.006). The rs349358 genotype distribution was TT in 310 and TC/CC in 155 patients. The KCNB2 SNP was associated with an Odds Ratio (OR) of 1.6 for CT/CC vs. TT (95% CI 1-2.5; P = 0.031) to develop PONV and this was independent from the Apfel Score, and the CHRM3 rs2165870 SNP. A genetic risk score based on the CHRM3 rs2165870 and the KCNB2 rs349358 SNP was created and this genetic score (OR per genetic risk score point: 1.6 (1.3-2.1), P < 0.0001) was independent from the Apfel Score (OR per Apfel score point: 1.6 (1.3-1.9), P < 0.0001) associated with PONV. CONCLUSION: The KCNB2 rs349358 SNP is also an independent PONV predictor and a genetic risk score has a similar impact on PONV susceptibility compared to the Apfel Score.

A serotonin transporter polymorphism is associated with postoperative nausea and vomiting: An observational study in two different patient cohorts.

BACKGROUND: Clinical risk factors for postoperative nausea and vomiting (PONV) are well described, whereas genetic findings are conflicting. OBJECTIVE: The aim of this study was to investigate a possible association of genetic variants and nongenetic variables with the incidence and severity of PONV. DESIGN: A prospective observational study in two independent and different patient cohorts. SETTING: Two independent patient cohorts differing in surgical procedures were enrolled in two tertiary care hospitals between 2008 and 2016. PATIENTS: Consecutive patients of European origin undergoing elective surgery in two university hospitals. Clinical data were collected up to 24 h after surgery, and blood was drawn for genotyping. Of 2773 patients enrolled, 918 (Cohort A) and 1663 (Cohort B) with complete data sets were analysed. MAIN OUTCOME MEASURE: Patients were allocated to one of three groups (No PONV, Intermediate PONV or Severe PONV) depending on the frequency of vomiting, the severity of nausea and the need for antiemetics. Clinical variables and 13 genetic variants of seven candidate genes were evaluated for association with these three phenotypes. The cohorts were analysed separately by ordinal logistic regression analysis, treating PONV as a dependent ordinal three-stage variable. Odds ratios (ORs) with 95% confidence intervals were calculated. RESULTS: In Cohort A, the main predictors for PONV were female sex [OR (95% CI): 3.6 (2.7 to 4.8), P < 0.0001], nonsmoking status 1.8 (1.3 to 2.5), P < 0.001, the SS genotype (5-HTTLPR, rs4795541) of the promoter polymorphism in the serotonin transporter 1.5 (1.1 to 2.1), P = 0.019, and patient age 0.99 (0.98 to 0.99), P = 0.013. Analysis of Cohort B was consistent with these findings [5-HTTLPR: 1.8 (1.4 to 2.3), P < 0.00001]. Sex-specific regression models confirmed this 5-HTTLPR association in women and men. CONCLUSION: In two independent cohorts, in addition to the well known clinical factors, a polymorphism of 5-HTTLPR in the serotonin transporter was independently associated with PONV. A possible evaluation of this biomarker to improve risk prediction within the scope of precision medicine should be considered. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT03490175.

Pharmacogenetics of Postoperative Nausea and Vomiting.

Postoperative nausea and vomiting (PONV) remains one of the most common adverse effects of anesthesia, affecting up to 80% of high-risk patients within 24 hours after surgery. Patient-related factors, surgical procedure, and perioperative medications such as opioids determine a patient's risk for PONV. To prevent and manage PONV, ondansetron, a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, is frequently administered. Ondansetron is metabolized predominantly by hepatic cytochrome P450 (CYP2D6) enzymes, encoded by the CYP2D6 gene, whereas most of the effects of opioids are exerted at the opioid mu-1 receptor, encoded by the OPRM1 gene. Genetic polymorphisms of the CYP2D6 and OPRM1 genes may have a role in interindividual variation in the occurrence of PONV. Specifically, the occurrence of the G-allele produced by the OPRM1 A118G appears to be protective against PONV, whereas CYP2D6 ultrarapid metabolism increases the risk for PONV. The Clinical Pharmacogenetics Implementation Consortium guidelines provide CYP2D6-guided therapeutic recommendations for ondansetron. However, further studies are needed to investigate the role of genetic polymorphism in the occurrence of PONV and response to antiemetics.

Association of anti-emetic efficacy of Ondansetron with 18792A>G polymorphism in a drug target gene 5-HT3B in Pakistani population.

OBJECTIVE: To evaluate the association of anti-emetic efficacy of ondansetron with 18792A>G polymorphism in the target gene of 5-hydroxytryptamine type 3 subtype B. METHODS: The prospective clinical study was conducted at Combined Military Hospital, Rawalpindi and the genetic analysis was carried out at Institute of Biomedical and Genetic Engineering, Islamabad from August 2012 to September 2013. The subjects enrolled were undergoing elective laparoscopic cholecystectomy under general anaesthesia. All the patients were given anti-emetic ondansetron (4mg) intravenously 30 minutes before the end of surgery. Within the first two hours after surgery the response to ondansetron was noted down. Patients with the complaints of vomiting and those who had no vomiting were analysed for 18792A>G polymorphism using polymerase chain reaction- restriction fragment length polymorphism method. RESULTS: Of the 350 patients, 183(52%) had complaints of vomiting and 167(48%) had no such complaints. Overall, 195(56%) patients had 18792AA genotype, 130(37%) had genotype AG, and 25(7%) had GG genotype. No significant association was found between the incidence of vomiting and the 18792A>G genotypes at 2 hours after surgery (p>0.05). CONCLUSIONS: No association of anti-emetic efficacy of ondansetron with 18792A>G polymorphism in the target gene of 5-hydroxytryptamine type 3 subtype B was found.

CHRM3 rs2165870 polymorphism is independently associated with postoperative nausea and vomiting, but combined prophylaxis is effective.

BACKGROUND: Clinical risk factors for postoperative nausea and vomiting (PONV) are evaluated with the Apfel score, however patients with low Apfel scores still experience PONV suggesting a genetic predisposition. PONV risk associates with specific M3 muscarinic acetylcholine receptor (CHRM3) rs 2165870 polymorphism. We investigated whether the Apfel score and this genetic variation independently contribute to PONV risk and whether prophylaxis reduces PONV in patients with low Apfel score but at high genetic risk. METHODS: In a prospective, controlled study, 454 subjects undergoing elective surgery were genotyped for rs2165870 and its association with PONV was investigated with log-binomial regression analysis. Subjects were randomised to receive acustimulation/dexamethasone, acustimulation/vehicle, sham acustimulation/dexamethasone, or sham acustimulation/vehicle to investigate their effects on PONV risk. RESULTS: Early PONV occurred in 37% of subjects. The rs2165870 genotype distribution was GG in 191, GA in 207, and AA in 56 subjects. The CHRM3 polymorphism was associated with a relative risk (RR) of 1.5 for GA vs GG [95% confidence interval (CI): 1.1-1.9; P=0.003] and 1.6 for AA vs GG (95% CI: 1.1-2.2; P=0.009) genotypes to develop PONV, and this was independent from the Apfel score (RR per Apfel point: 1.3, 95% CI: 1.2-1.5; P<0.0001). While dexamethasone and acustimulation each reduced the PONV risk by 30% in AA genotype carriers with low Apfel score, combined therapy reduced the risk by 86% (P=0.015). CONCLUSIONS: The CHRM3 polymorphism and the Apfel score independently predict PONV susceptibility. Dexamethasone/acustimulation should be considered in patients with low Apfel score but at high genetic risk. CLINICAL TRIAL REGISTRATION: DRKS00005664.

Genetic Factors Associated with Postoperative Nausea and Vomiting: a Systematic Review.

BACKGROUND: In previous studies, there seems to be a relationship between different genetic polymorphisms and postoperative nausea and vomiting (PONV). We perform a systematic review of the current literature about the relationship between genetic polymorphisms and the presence of PONV. METHODS: Two bibliographic searches were carried out in three databases (PubMed, Web of Science, and Scopus) of studies, preferably prospective, about PONV following abdominal surgery. It was completed with a backward citation searching. A total of 73 articles were found of which 6 were selected after their critical lecture using CASPe network criteria. Relative frequency and relative risk were taken in each study according to the polymorphism. RESULTS: Studies about 5-HT3B gene receptor polymorphisms, ABCB1 transporter, and dopamine D2 receptor showed a significant association with the presence of PONV (p = 0.02, 0.01, and 0.034 respectively). In relation to cytochrome P-450 2D6 (CYP2D6) polymorphisms, two of the three analysed articles showed a significant association with postoperative vomiting (p = 0.007). CONCLUSION: Genetic polymorphisms could play an important role in PONV. The AAG deletion in both alleles of the 5-HT3B receptor gene, the Taq IA polymorphism of the dopamine D2 receptor, and the presence of three or more functional alleles of CYP2D6 seem to be related with a higher incidence of PONV, especially in the first 24 h after surgery. The 2677TT and 3435TT genotypes of the ABCB1 transporter could reduce the PONV due to their association with a greater effectiveness of ondansetron. However, new quality studies are needed to consider this relationship.

Prospective observational pharmacogenetic study of side effects induced by intravenous morphine for postoperative analgesia.

Nausea and vomiting are probably the most unpleasant side effects that occur when morphine used. A number of studies have investigated the effect on pain relief of single nucleotide polymorphisms (SNPs) in genes involved in morphine's metabolism, distribution, binding, and cellular action. The mechanism through which morphine causes nausea and vomiting has not been elucidated clearly. We examined all the reported SNPs which are associated with the complications of morphine, including SNPs in genes for phase I and phase II metabolic enzymes, ABC binding cassette drug transporters, κ and δ opioid receptors, and ion channels implicated in the postreceptor action of morphine.A prospective, observational study in 129 female patients was conducted to investigate the effect of 14 SNPs on nausea or vomiting induced by intravenous patient-controlled analgesia (IVPCA) with morphine after gynecology surgery. Clinical phenotype, subjective complaints, and objective observations were recorded. DNA from blood samples was used to record the SNPs. Eleven SNPs were then analyzed further.No significant association with the presence of phenotype (nausea or vomiting) versus genotype was observed (all P > .05). No significant association with severity of phenotype versus genotype of the 11 SNPs was observed except for unadjusted data for rs2737703.There was no significant difference between severity or incidence of IVPCA morphine-induced nausea and vomiting and genotype (11 SNPs). Further study should perhaps be focused on mRNA and proteinomics rather than SNPs.

Pharmacogenomics in Anesthesia.

A significant number of commonly administered medications in anesthesia show wide clinical interpatient variability. Some of these include neuromuscular blockers, opioids, local anesthetics, and inhalation anesthetics. Individual genetic makeup may account for and predict cardiovascular outcomes after cardiac surgery. These interactions can manifest at any point in the perioperative period and may also only affect a specific system. A better understanding of pharmacogenomics will allow for more individually tailored anesthetics and may ultimately lead to better outcomes, decreased hospital stays, and improved patient satisfaction.

Exploring the multifactorial nature of postoperative nausea and vomiting in women following surgery for breast cancer.

BACKGROUND: Postoperative nausea and vomiting (PONV) are two of the most frequent and distressing complications following surgical procedures, with as many as 80% of patients considered to be at risk. Despite recognition of well-established risk factors and the subsequent use of clinical guidelines, 20-30% of women do not respond to antiemetic protocols, indicating that there may be a genetic risk. OBJECTIVE: The purpose of this pilot study was to describe the incidence and explore the risk factors associated with PONV after surgery in women diagnosed with early stage breast cancer. METHODS: A prospective cohort design was employed to measure PONV in women recruited prior to surgery. DNA was extracted from saliva samples collected prior to discharge. Polymorphisms for seven candidate genes with a known role in one of the neural pathways associated with PONV were included in this study; serotonin receptor (HTR3A), serotonin transport (SLC6A4), tryptophan (TPH), dopamine receptors (DRD2/ANKK and DRD3), catechol-O-methyltransferase (COMT) and histamine (H1). RESULTS: Twenty-nine (29.8%) women experienced nausea and 10 (11%) experienced nausea and vomiting while in the PACU despite administration of multiple antiemetic medications. Women who experienced PONV had higher levels of pain and received more opioids than those women who did not experienced PONV. Odds ratios demonstrated that alleles for the COMT, DRD3, and TPH genes were associated with decreased PONV. CONCLUSION: The understanding of the multifactorial nature of PONV and the recognition of genetic risk will ultimately lead to the development of personalized interventions to manage these frequent and often debilitating symptoms.

Comparison of Ramosetron and Palonosetron for Preventing Nausea and Vomiting after Spinal Surgery: Association With ABCB1 Polymorphisms.

BACKGROUND: Adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) polymorphisms may influence 5-hydroxytryptamine receptor antagonist efficacy by altering their efflux transportation. We evaluated the influence of ABCB1 polymorphisms on the efficacy of ramosetron compared with palonosetron in managing postoperative nausea and vomiting (PONV) in patients who received intravenous patient-controlled analgesia after spinal surgery. METHODS: Patients were randomly allocated to receive 2 boluses (20 min before the end of surgery and 24 h after surgery) of either ramosetron 0.3 mg (n=150) or palonosetron 0.075 mg (n=146). The incidence and severity of PONV, fentanyl consumption, and pain intensity were serially assessed for postoperative 48 hours. ABCB1 3435C>T and 2677G>T/A polymorphisms were assessed. RESULTS: The incidences of nausea were similar between the 2 groups in patients with the 3435TT (50% vs. 56%, ramosetron and palonosetron group, respectively, P>0.999) or 2677TT (50% vs. 56%, ramosetron and palonosetron group, respectively, P>0.999). Mild PONV were more frequent in the ramosetron group than in the palonosetron group among patients with 3435TT (91% vs. 33%, P=0.034) and 2677TT (92% vs. 20%, P=0.002) genotypes. The intensity of nausea experienced by ramosetron-group TT genotype patients (1 [1 to 2], 3435TT; 1 [1 to 2.5], 2677TT) was lower than that experienced by ramosetron-group non-TT genotype patients (3 [1 to 6], 3435 non-TT, P=0.030; 3 [1 to 6], 2677 non-TT, P=0.038) and palonosetron-group TT genotype patients (6 [2 to 7], 3435TT, P=0.010; 6 [4 to 7], 2677TT, P=0.002). CONCLUSIONS: Compared with palonosetron, ramosetron may be superior for reducing PONV severity, especially in patients with ABCB1 3435TT or 2677TT genotype.

Postoperative nausea and vomiting: The role of the dopamine D2 receptor TaqIA polymorphism.

BACKGROUND: The risk of developing postoperative nausea and vomiting (PONV), apart from conventional risk factors, probably includes a genetic background. OBJECTIVES: We examined the association of the DRD2 TaqIA polymorphism with PONV in a high-risk cohort of patients. DESIGN: A prospective, double-blind observational trial. SETTING: Single-centre primary care in Western Germany. PATIENTS: A total of 306 patients undergoing elective strabismus surgery under anaesthesia with etomidate/alfentanil/mivacurium (induction) and sevoflurane in air (maintenance). MAIN OUTCOME MEASURES: Nausea as well as retching/vomiting was recorded for 24 h postoperatively. The DRD2 TaqIA polymorphism (rs1800497) was genotyped using a Taqman assay and the relationship between DRD2 TaqIA polymorphism and PONV was examined by univariate and multivariate analysis. RESULTS: Regarding known risk factors for developing PONV, no patient with the A1A1 genotype (n = 15) had a history of PONV, while A1A2 carriers (n = 115) and A2A2 carriers (n = 176) had a history of PONV in 22.6 and 10.8% of patients, respectively (P = 0.005). Overall, the incidence of nausea was 40.1% and the incidence of vomiting/retching was 32.7%. Univariate analysis showed that postoperative nausea was not associated with TaqIA genotypes, but the incidence of retching/vomiting in A1A2 and A2A2 genotypes was more than 34% compared with zero in A1A1 genotypes (P = 0.022). Age, sex, smoking status and a history of PONV were independent predictors for nausea as well as for retching/vomiting, as expected, while DRD2 TaqIA polymorphism showed no independent significant impact. CONCLUSION: In a white cohort, the TaqIA A2 allele is significantly associated with a history of PONV, which may explain the increased incidence of PONV but has no further independent influence. TRIAL REGISTRATION: German registry of clinical trials identifier: DRKS00005681.

Association of Anti-Emetic Efficacy of Ondansetron with G2677T Polymorphism in a Drug Transporter Gene ABCB1 in Pakistani Population.

OBJECTIVE: To determine the association of ABCB1 polymorphism G2677T with anti-emetic efficacy in patients treated with ondansetron for preventing postoperative nausea and vomiting. STUDY DESIGN: A clinical trial. PLACE AND DURATION OF STUDY: Combined Military Hospital, Rawalpindi and Institute of Biomedical and Genetic Engineering, Islamabad, from 2012 to 2013. METHODOLOGY: Four mg ondansetron was administered intravenously 30 minutes before the end of surgery. A total of 246 patients with the complaints of nausea and vomiting and 244 patients without nausea and vomiting were analyzed for G2677T polymorphism using PCR-RFLP method. Results were described as frequency percentages and chi-square test with significance at p < 0.05. RESULTS: The patients with TT genotype had significantly lower incidence of postoperative nausea and vomiting during the first 2 hours (p < 0.001) and between 2 - 24 hours after surgery as compared to other genotypes (p < 0.001). The patients with GG genotypes had significantly higher incidence of this complaint (p=0.014). CONCLUSION: Polymorphism of ABCB1 has an association with responsiveness for ondansetron. There is a role for genetics in the management of PONV.

TACR1 gene polymorphism and sex differences in postoperative nausea and vomiting.

We hypothesised that the genetic effect of single nucleotide polymorphisms in the TACR1 gene, which encodes NK1 receptors, could influence the sex difference in postoperative nausea and vomiting. Thirty-two selected single nucleotide polymorphisms were genotyped by the Sanger sequencing method in 200 patients who underwent lower abdominal surgery. The incidence and severity of postoperative nausea and vomiting were evaluated after surgery. The rs3755468-SNP showed significant association with the incidence and severity of postoperative nausea and vomiting (p = 0.016). The TT haplotype defined by two single nucleotide polymorphisms, including the rs3755468-SNP, was associated with reduced incidence and severity of postoperative nausea and vomiting in female patients (p = 0.03). The rs3755468-SNP is located within the predicted oestrogen response element and a DNase I hypersensitive site. The single nucleotide polymorphisms in the TACR1 gene are associated with sex differences in postoperative nausea and vomiting and may help to elucidate the mechanisms underlying these differences.

Sequence variants of the HTR3A gene contribute to the genetic prediction of postoperative nausea in Taiwan.

Postoperative nausea (PON) is a common complication, and therefore, it is important to identify the associated genetic factors and the candidate predictive markers. Current clinical and basic research suggests that the 5-hydroxytryptamine type 3A receptor (HTR3A) may be important in the occurrence of PON. The association between three single nucleotide polymorphisms (SNPs) of the HTR3A gene and PON was examined to determine whether this can be used to predict the incidence of PON in a unique Taiwanese population without any reported postoperative nausea and vomiting (PONV) risk factors associated with PON occurrence. One thousand adult surgical patients who received general anesthesia were included in this analysis. A total of 369 patients were finally selected for a two-stage association study. Significant single-locus associations for all three HTR3A SNPs and PON were identified in both stages. In addition, two of the most common haplotypes, CTT and TAG, showed both a significant risk for and a protective effect against PON, respectively. Our findings support the notion that different haplotypes of HTR3A have reciprocal effects in the etiology of PON. Therefore specific haplotypes of HTR3A may be useful as predictors of PON for 24 h immediately after surgery in our population.

Association of µ-opioid receptor gene (OPRM1) haplotypes with postoperative nausea and vomiting.

Genetic variants, such as single-nucleotide polymorphisms (SNPs), of the µ-opioid receptor gene (OPRM1) might be associated with individual differences in opioid sensitivity, as well as with the incidence and severity of postoperative nausea and vomiting (PONV). The goal of the present study was to determine, in a cohort of Japanese surgical patients, genotypes and haplotypes of several SNPs in the OPRM1 gene, and their association with PONV during the early (first 24 h) postoperative period. We examined the incidence and severity of PONV, during the first 24 h after surgery, in 85 Japanese patients receiving intravenous patient-controlled analgesia fentanyl analgesia for postoperative pain control. Eight tag SNPs of the OPRM1 gene (rs1799971, A/G; rs510769, G/A; rs4870266, G/A; rs3798683, G/A; rs1323042, A/C; rs609623, C/T; rs9397685, A/G; and rs644261, C/G) were selected based on their minor allele frequency (>10%) and linkage disequilibrium strength (<80%), and genotyped for haplotype analysis and determination of associations with PONV. Only one out of eight investigated SNPs, rs9397685, in the intronic part of the OPRM1 gene was associated with differences in the occurrence and severity of PONV. We also found four common haplotypes with a frequency of >10% in the investigated patients, including GGGAACAC (33%), AGGGACAC (19%), GGGAACGC (12%), and AGAGACAC (10%). The severity of PONV in carriers of the GGGAACGC haplotype was significantly lower than in the carriers of the other haplotypes (P < 0.05). One intronic SNP, rs9397685, and haplotypes constructed from eight SNPs within the OPRM1 gene locus might be involved in the severity of PONV associated with general anesthesia and opioid administration. This novel finding, if validated and verified in larger and additional ethnic cohorts, might contribute to better knowledge of the contribution of the OPRM1 gene to PONV.

Genetic factors associated with pharmacotherapy and background sensitivity to postoperative and chemotherapy-induced nausea and vomiting.

Postoperative nausea and vomiting (PONV) continues to be a most common complication of surgery and anesthesia. It has been suggested that the inherited factors may play a significant role in the background sensitivity to both PONV and also chemotherapy-induced nausea and vomiting (CINV), including resistance to antiemetic prophylaxis and/or therapy. This notion could be best exemplified by occurrence of PONV in several generations of families and concordance of PONV in monozygotic twins. The most frequently addressed issue in the research on genomic background of PONV/CINV relates to the inherited resistance to the antiemetic treatment (pharmacogenomics), and in lesser degree to their genomic background. The most common group of antiemetics consists of 5HT3 receptor antagonists, and this group was an initial target of pharmacogenomic research. Most research approaches have been based on the investigation of polymorphic variations in the target for the antiemetic 5HT3 receptor antagonists, i.e., serotonin receptor subunits A and B (HTR3A and HTR3B). The other area of pharmacogenomic investigations includes metabolic pathways of 5HT3 antagonists, in particular polymorphic variants of the CYP450 2D6 isoform (CYP2D6) because most of them are metabolized in various degrees by the CYP2D6 system. The results of targeted genomic association studies indicate that other genes are also associated with PONV and CINV, including OPRM1, and ABCB1. In addition, genes such as DRD2 and CHRM3 genes have recently been associated with PONV. The new genome-wide association studies seem also to indicate that the background genomic sensitivity to PONV and CINV might be multifactorial and include several genomic pathways.