ABSTRACT
Aim: Identify variants in RYR1, CACNA1S and STAC3, and predict malignant hyperthermia (MH) pathogenicity using Bayesian statistics in individuals clinically treated as MH susceptible (MHS). Materials & methods: Whole exome sequencing including RYR1, CACNA1S and STAC3 performed on 64 subjects with: MHS; suspected MH event or first-degree relative; and MH negative. Variant pathogenicity was estimated using in silico analysis, allele frequency and prior data to calculate Bayesian posterior probabilities. Results: Bayesian statistics predicted CACNA1S variant p.Thr1009Lys and RYR1 variants p.Ser1728Phe and p.Leu4824Pro are likely pathogenic, and novel STAC3 variant p.Met187Thr has uncertain significance. Nearly a third of MHS subjects had only benign variants. Conclusion: Bayesian method provides new approach to predict MH pathogenicity of genetic variants.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Calcium Channels, L-Type/genetics , Malignant Hyperthermia/genetics , Ryanodine Receptor Calcium Release Channel/genetics , Bayes Theorem , Disease Susceptibility , Exons/genetics , Female , Genetic Variation/genetics , Genotype , Humans , Male , Malignant Hyperthermia/pathology , Mutation/genetics , Exome SequencingABSTRACT
Previous studies have associated mu-opioid receptor (OPRM1) genotype with pain and analgesia responses in postoperative and patient populations. This study investigates the role of catechol-O-methyltransferase (COMT) and OPRM1 genotypes in acute postoperative pain scores, opioid use, and opioid-induced sedation after surgical procedures for orthopedic trauma in an otherwise healthy patient population. Verbal pain/sedation scores, opioid use, and physiologic responses in the immediate postoperative period were examined for association with genetic variants in Caucasians genotyped for OPRM1 single nucleotide polymorphisms (SNPs) A118G and C17T and COMT SNPs. The OPRM1 A118G genotype was associated with patients' postoperative Numerical Pain scale (NPS) ratings at 15 min in the postanesthesia care unit (PACU) (p = .01) and patients' sedation scores at 15 min in the PACU (p = .02). COMT genotype (rs4818) was associated with opioid consumption in the first 45 min in the PACU (p = .04). NPS ratings at 45 min were also higher in the group of patients with A/A genotype of rs4680 than in patients with the other two genotypes at this SNP (p = .03). Our haplotype trend analysis identified a COMT haplotype "GCGG" significantly associated with NPS at 15 min (p = .0013), amount of opioids consumed in the first 45 min (p = .0024), and heart rate at 45 min in the PACU (p = .017). The results indicate that genetic variations in COMT contribute to the acute postoperative pain and analgesia responses and physiologic responses in this group of otherwise healthy postoperative orthopedic trauma patients.
Subject(s)
Analgesics, Opioid/therapeutic use , Catechol O-Methyltransferase/genetics , Hypnotics and Sedatives/therapeutic use , Pain, Postoperative/genetics , Receptors, Opioid, mu/genetics , Genotype , Humans , Pain Measurement , Pain, Postoperative/drug therapy , Polymorphism, Single NucleotideABSTRACT
The CYP2D6 gene encodes for an enzyme that is involved in the metabolism of more than 25% of all medications, including many opioids and antiemetics. It may contribute to the risk of postoperative nausea and vomiting (PONV), a common surgical complication. However, little research has been conducted in this area. The purpose of this study was to explore the association of CYP2D6 genotypes with PONV in adult surgical trauma patients. Data from 112 patients (28% female) with single extremity fractures, aged 18-70 years, were analyzed. PONV was defined as present if patients reported nausea, were observed vomiting, or received medication for PONV. Saliva samples collected for DNA extraction and Taqman(®) allele discrimination and quantitative real time polymerase chain reaction (qRT-PCR) were used to collect genotype data that were then used to assign CYP2D6 phenotype classification. The incidence of PONV was 38% in the postanesthesia care unit and increased to 50% when assessed at 48 hr. CYP2D6 classification results were 7 (6%) poor metabolizers, 34 (30%) intermediate metabolizers, and 71 (63%) extensive metabolizers. No ultrarapid metabolizers were identified. Patients who were classified as poor metabolizers had less PONV and higher pain scores. Gender and history of PONV, but not smoking, were also significant risk factors. Findings suggest variability in CYP2D6 impacts susceptibility to PONV.
