Genome-Wide Association Study Identifies Novel Candidate Variants Associated with Postoperative Nausea and Vomiting.

Considerable individual differences are widely observed in the incidence of postoperative nausea and vomiting (PONV). We conducted a genome-wide association study (GWAS) to identify potential candidate single-nucleotide polymorphisms (SNPs) that contribute to PONV by utilizing whole-genome genotyping arrays with more than 950,000 markers. The subjects were 806 patients who provided written informed consent and underwent elective surgery under general anesthesia with propofol or desflurane. The GWAS showed that two SNPs, rs2776262 and rs140703637, in the LOC100506403 and CNTN5 gene regions, respectively, were significantly associated with the frequency of nausea. In another GWAS conducted only on patients who received propofol, rs7212072 and rs12444143 SNPs in the SHISA6 and RBFOX1 gene regions, respectively, were significantly associated with the frequency of nausea as well as the rs2776262 SNP, and the rs45574836 and rs1752136 SNPs in the ATP8B3 and LOC105370198 gene regions, respectively, were significantly associated with vomiting. Among these SNPs, clinical and SNP data were available for the rs45574836 SNP in independent subjects who underwent laparoscopic gynecological surgery, and the association was replicated in these subjects. These results indicate that these SNPs could serve as markers that predict the vulnerability to PONV. Our findings may provide valuable information for achieving satisfactory prophylactic treatment for PONV.

Genome-Wide Association Study Identifies Genetic Polymorphisms Associated with Estimated Minimum Effective Concentration of Fentanyl in Patients Undergoing Laparoscopic-Assisted Colectomy.

Sensitivity to opioids varies widely among individuals. To identify potential candidate single-nucleotide polymorphisms (SNPs) that may significantly contribute to individual differences in the minimum effective concentration (MEC) of an opioid, fentanyl, we conducted a three-stage genome-wide association study (GWAS) using whole-genome genotyping arrays in 350 patients who underwent laparoscopic-assisted colectomy. To estimate the MEC of fentanyl, plasma and effect-site concentrations of fentanyl over the 24 h postoperative period were estimated with a pharmacokinetic simulation model based on initial bolus doses and subsequent patient-controlled analgesia doses of fentanyl. Plasma and effect-site MECs of fentanyl were indicated by fentanyl concentrations, estimated immediately before each patient-controlled analgesia dose. The GWAS revealed that an intergenic SNP, rs966775, that mapped to 5p13 had significant associations with the plasma MEC averaged over the 6 h postoperative period and the effect-site MEC averaged over the 12 h postoperative period. The minor G allele of rs966775 was associated with increases in these MECs of fentanyl. The nearest protein-coding gene around this SNP was DRD1, encoding the dopamine D1 receptor. In the gene-based analysis, the association was significant for the SERP2 gene in the dominant model. Our findings provide valuable information for personalized pain treatment after laparoscopic-assisted colectomy.

Tsc2 mutation rather than Tsc1 mutation dominantly causes a social deficit in a mouse model of tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is associated with neurological symptoms, including autism spectrum disorder. Tuberous sclerosis complex is caused by pathogenic germline mutations of either the TSC1 or TSC2 gene, but somatic mutations were identified in both genes, and the combined effects of TSC1 and TSC2 mutations have been unknown. METHODS: The present study investigated social behaviors by the social interaction test and three-chambered sociability tests, effects of rapamycin treatment, and gene expression profiles with a gene expression microarray in Tsc1 and Tsc2 double heterozygous mutant (TscD+/-) mice. RESULTS: TscD+/- mice exhibited impairments in social behaviors, and the severity of impairments was similar to Tsc2+/- mice rather than Tsc1+/- mice. Impairments in social behaviors were rescued by rapamycin treatment in all mutant mice. Gene expression profiles in the brain were greatly altered in TscD+/- mice more than in Tsc1+/- and Tsc2+/- mice. The gene expression changes compared with wild type (WT) mice were similar between TscD+/- and Tsc2+/- mice, and the overlapping genes whose expression was altered in mutant mice compared with WT mice were enriched in the neoplasm- and inflammation-related canonical pathways. The "signal transducer and activator of transcription 3, interferon regulatory factor 1, interferon regulatory factor 4, interleukin-2R α chain, and interferon-γ" signaling pathway, which is initiated from signal transducer and activator of transcription 4 and PDZ and LIM domain protein 2, was associated with impairments in social behaviors in all mutant mice. LIMITATIONS: It is unclear whether the signaling pathway also plays a critical role in autism spectrum disorders not caused by Tsc1 and Tsc2 mutations. CONCLUSIONS: These findings suggest that TSC1 and TSC2 double mutations cause autistic behaviors similarly to TSC2 mutations, although significant changes in gene expression were attributable to the double mutations. These findings contribute to the knowledge of genotype-phenotype correlations in TSC and suggest that mutations in both the TSC1 and TSC2 genes act in concert to cause neurological symptoms, including autism spectrum disorder.

Rs11726196 Single-Nucleotide Polymorphism of the Transient Receptor Potential Canonical 3 (TRPC3) Gene Is Associated with Chronic Pain.

Chronic pain is reportedly associated with the transient receptor potential canonical 3 (TRPC3) gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the TRPC3 gene and chronic pain. The genomic samples from 194 patients underwent linkage disequilibrium (LD) analyses of 29 SNPs within and around the vicinity of the TRPC3 gene. We examined the associations between the SNPs and the susceptibility to chronic pain by comparing the genotype distribution of 194 patients with 282 control subjects. All SNP genotype data were extracted from our previous whole-genome genotyping results. Twenty-nine SNPs were extracted, and a total of four LD blocks with 15 tag SNPs were observed within and around the TRPC3 gene. We further analyzed the associations between these tag SNPs and chronic pain. The rs11726196 SNP genotype distribution of patients was significantly different from the control subjects even after multiple-testing correction with the number of SNPs. The TT + TG genotype of rs11726196 is often carried by chronic pain patients, suggesting a causal role for the T allele. These results contribute to our understanding of the genetic risk factors for chronic pain.

Fentanyl-induced muscle rigidity in a dog during weaning from mechanical ventilation after emergency abdominal surgery: A case report.

A 22.5-kg, 8.4-year-old female mixed breed dog was presented for an emergency ovariohysterectomy for pyometra. No neurological abnormalities were observed on preoperative physical examination. Surgery was completed uneventfully under fentanyl- and sevoflurane-based anaesthesia. Cardiorespiratory indices remained stable under mechanical ventilation throughout the procedure. Approximately 23 min after the discontinuation of fentanyl infusion, the investigator noticed jaw closure and stiffness and thoraco-abdominal muscle rigidity. To rule out fentanyl-induced muscle rigidity, naloxone was administered. Following administration of naloxone, there was a return of spontaneous respiratory effort, indicated by capnogram and visible chest wall excursion. Based on the clinical signs and response to naloxone administration, the dog was diagnosed with suspected fentanyl-induced muscle rigidity. Six minutes after the return of spontaneous respiration, the dog was extubated uneventfully without additional naloxone administration. During 4 days of postoperative hospitalization, no recurrent muscle rigidity was observed, and the patient was discharged safely. The total dose of fentanyl administered was 0.61 mg (27 µg kg-1 ).

Genome-Wide Association Study Identifies Candidate Loci Associated with Opioid Analgesic Requirements in the Treatment of Cancer Pain.

Considerable individual differences have been widely observed in the sensitivity to opioids. We conducted a genome-wide association study (GWAS) in patients with cancer pain to identify potential candidate single-nucleotide polymorphisms (SNPs) that contribute to individual differences in opioid analgesic requirements in pain treatment by utilizing whole-genome genotyping arrays with more than 650,000 markers. The subjects in the GWAS were 428 patients who provided written informed consent and underwent treatment for pain with opioid analgesics in a palliative care unit at Higashi-Sapporo Hospital. The GWAS showed two intronic SNPs, rs1283671 and rs1283720, in the ANGPT1 gene that encodes a secreted glycoprotein that belongs to the angiopoietin family. These two SNPs were strongly associated with average daily opioid requirements for the treatment of pain in both the additive and recessive models (p < 5.0000 × 10−8). Several other SNPs were also significantly associated with the phenotype. In the gene-based analysis, the association was significant for the SLC2A14 gene in the additive model. These results indicate that these SNPs could serve as markers that predict the efficacy of opioid analgesics in cancer pain treatment. Our findings may provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment.

Pattern recognition with neuromorphic computing using magnetic field-induced dynamics of skyrmions.

Nonlinear phenomena in physical systems can be used for brain-inspired computing with low energy consumption. Response from the dynamics of a topological spin structure called skyrmion is one of the candidates for such a neuromorphic computing. However, its ability has not been well explored experimentally. Here, we experimentally demonstrate neuromorphic computing using nonlinear response originating from magnetic field-induced dynamics of skyrmions. We designed a simple-structured skyrmion-based neuromorphic device and succeeded in handwritten digit recognition with the accuracy as large as 94.7% and waveform recognition. Notably, there exists a positive correlation between the recognition accuracy and the number of skyrmions in the devices. The large degrees of freedom of skyrmion systems, such as the position and the size, originate from the more complex nonlinear mapping, the larger output dimension, and, thus, high accuracy. Our results provide a guideline for developing energy-saving and high-performance skyrmion neuromorphic computing devices.

Short Tandem Repeat Variation in the CNR1 Gene Associated With Analgesic Requirements of Opioids in Postoperative Pain Management.

Short tandem repeats (STRs) and variable number of tandem repeats (VNTRs) that have been identified at approximately 0.7 and 0.5 million loci in the human genome, respectively, are highly multi-allelic variations rather than single-nucleotide polymorphisms. The number of repeats of more than a few thousand STRs was associated with the expression of nearby genes, indicating that STRs are influential genetic variations in human traits. Analgesics act on the central nervous system via their intrinsic receptors to produce analgesic effects. In the present study, we focused on STRs and VNTRs in the CNR1, GRIN2A, PENK, and PDYN genes and analyzed two peripheral pain sensation-related traits and seven analgesia-related traits in postoperative pain management. A total of 192 volunteers who underwent the peripheral pain sensation tests and 139 and 252 patients who underwent open abdominal and orthognathic cosmetic surgeries, respectively, were included in the study. None of the four STRs or VNTRs were associated with peripheral pain sensation. Short tandem repeats in the CNR1, GRIN2A, and PENK genes were associated with the frequency of fentanyl use, fentanyl dose, and visual analog scale pain scores 3 h after orthognathic cosmetic surgery (Spearman's rank correlation coefficient ρ = 0.199, p = 0.002, ρ = 0.174, p = 0.006, and ρ = 0.135, p = 0.033, respectively), analgesic dose, including epidural analgesics after open abdominal surgery (ρ = -0.200, p = 0.018), and visual analog scale pain scores 24 h after orthognathic cosmetic surgery (ρ = 0.143, p = 0.023), respectively. The associations between STRs in the CNR1 gene and the frequency of fentanyl use and fentanyl dose after orthognathic cosmetic surgery were confirmed by Holm's multiple-testing correction. These findings indicate that STRs in the CNR1 gene influence analgesia in the orofacial region.

Associations between the C3orf20 rs12496846 Polymorphism and Both Postoperative Analgesia after Orthognathic and Abdominal Surgeries and C3orf20 Gene Expression in the Brain.

Considerable individual differences are widely observed in the sensitivity to opioid analgesics. We focused on rs12496846, rs698705, and rs10052295 single-nucleotide polymorphisms (SNPs) in the C3orf20, SLC8A2, and CTNND2 gene regions that we previously identified as possibly associated with postoperative analgesia after orthognathic surgery. We investigated associations between these SNPs and postoperative analgesia in 112 patients who underwent major open abdominal surgery in hospitals and were treated with analgesics, including opioids, after surgery. Total genomic DNA was extracted from peripheral blood or oral mucosa samples for genotyping each SNP. Effects of these potent SNPs on gene expression in the brain were also investigated in samples that were provided by the Stanley Foundation Brain Bank. In the association studies, carriers of the G allele of the rs12496846 SNP in the C3orf20 gene region were significantly associated with greater 24 h postoperative analgesic requirements among the three SNPs that were investigated (p = 0.0015), which corroborated a previous study of orthognathic patients (p < 0.0001). In the gene expression analysis, carriers of the G allele of the rs12496846 SNP were significantly associated with lower mRNA expression of the C3orf20 gene (p < 0.0001). These results indicate that this SNP could serve as a marker that predicts analgesic requirements.

Magnetization Precession at Sub-Terahertz Frequencies in Polycrystalline Cu2 Sb-Type (Mn-Cr)AlGe Ultrathin Films.

A ferromagnetic metal nanolayer with a large perpendicular magnetic anisotropy, small saturation magnetization, and small magnetic damping constant is a crucial requirement for high-speed spintronic devices. Fabrication of these devices on Si/SiO2 amorphous substrates with polycrystalline structure is also strongly desired for the mass production industry. This study involves the investigation of sub-terahertz (THz) magnetization precessional motion in a newly developed material system consisting of Cu2 Sb-type MnAlGe and (Mn-Cr)AlGe films by means of an all-optical pump-probe method. These materials exhibit large perpendicular magnetic anisotropy in regions of a few nanometers in size. The pseudo-2D crystal structures are clearly observed in the high-resolution transmission electron microscopy (TEM) images for the film samples grown on thermally oxidized silicon substrates. The TEM images also show a partial substitution of Cr atoms for the Mn sites in MnAlGe. A magnetization precession frequency of 0.164 THz with a relatively small effective magnetic damping constant of 0.012 is obtained for (Mn-Cr)AlGe. Theoretical calculation infers that the modification of the total density of states by Cr substitution decreases the intrinsic magnetic damping constant of (Mn-Cr)AlGe.

Heparan sulfate 3-O-sulfotransferase 4 is genetically associated with herpes zoster and enhances varicella-zoster virus-mediated fusogenic activity.

Acute pain that is associated with herpes zoster (HZ) can become long-lasting neuropathic pain, known as chronic post-herpetic neuralgia (PHN), especially in the elderly. HZ is caused by the reactivation of latent varicella-zoster virus (VZV), whereas PHN is not attributed to ongoing viral replication. Although VZV infection reportedly induces neuronal cell fusion in humans, the pathogenesis of PHN is not fully understood. A genome-wide association study (GWAS) revealed significant associations between PHN and the rs12596324 single-nucleotide polymorphism (SNP) of the heparan sulfate 3-O-sulfotransferase 4 (HS3ST4) gene in a previous study. To further examine whether this SNP is associated with both PHN and VZV reactivation, associations between rs12596324 and a history of HZ were statistically analyzed using GWAS data. HZ was significantly associated with the rs12596324 SNP of HS3ST4, indicating that HS3ST4 is related to viral replication. We investigated the influence of HS3ST4 expression on VZV infection in cultured cells. Fusogenic activity after VZV infection was enhanced in cells with HS3ST4 expression by microscopy. To quantitatively evaluate the fusogenic activity, we applied cytotoxicity assay and revealed that HS3ST4 expression enhanced cytotoxicity after VZV infection. Expression of the VZV glycoproteins gB, gH, and gL significantly increased cytotoxicity in cells with HS3ST4 expression by cytotoxicity assay, consistent with the fusogenic activity as visualized by fluorescence microscopy. HS3ST4 had little influence on viral genome replication, revealed by quantitative real-time polymerase chain reaction. These results suggest that HS3ST4 enhances cytotoxicity including fusogenic activity in the presence of VZV glycoproteins without enhancing viral genome replication.

Antinociceptive effects of the combined use of butorphanol and buprenorphine in mice.

Butorphanol and buprenorphine are mixed opioid receptor agonist-antagonist drugs widely used as analgesics in people and animals. There are few reports concerning the interaction of multiple opioids, and their antinociceptive effects, when combined with other opioids, remain unclear. Therefore, we report the preliminary findings of the antinociceptive effects of the combined use of butorphanol and buprenorphine in C57BL/6JJcl mice. Both drugs were administered either simultaneously or in different orders. Compared with the baseline values, the tail-flick and hot-plate test latencies increased regardless of the order of administration. Furthermore, enhanced latencies were observed on administration of butorphanol followed by buprenorphine. Combined use of these drugs may not attenuate analgesic efficacy. Besides, enhancement of these effects can be obtained by changing the order of the administration of these drugs. It is necessary to further investigate the molecular basis of the underlying mechanism in future definitive studies.

Genome-wide association study identifies candidate loci associated with chronic pain and postherpetic neuralgia.

BACKGROUND: Human twin studies and other studies have indicated that chronic pain has heritability that ranges from 30% to 70%. We aimed to identify potential genetic variants that contribute to the susceptibility to chronic pain and efficacy of administered drugs. We conducted genome-wide association studies (GWASs) using whole-genome genotyping arrays with more than 700,000 markers in 191 chronic pain patients and a subgroup of 89 patients with postherpetic neuralgia (PHN) in addition to 282 healthy control subjects in several genetic models, followed by additional gene-based and gene-set analyses of the same phenotypes. We also performed a GWAS for the efficacy of drugs for the treatment of pain. RESULTS: Although none of the single-nucleotide polymorphisms (SNPs) were found to be genome-wide significantly associated with chronic pain (p ≥ 1.858 × 10-7), the GWAS of PHN patients revealed that the rs4773840 SNP within the ABCC4 gene region was significantly associated with PHN in the trend model (nominal p = 1.638 × 10-7). In the additional gene-based analysis, one gene, PRKCQ, was significantly associated with chronic pain in the trend model (adjusted p = 0.03722). In the gene-set analysis, several gene sets were significantly associated with chronic pain and PHN. No SNPs were significantly associated with the efficacy of any of types of drugs in any of the genetic models. CONCLUSIONS: These results suggest that the PRKCQ gene and rs4773840 SNP within the ABCC4 gene region may be related to the susceptibility to chronic pain conditions and PHN, respectively.

Creation of magnetic skyrmions by surface acoustic waves.

Non-collinear and non-coplanar spin textures, such as chiral domain walls1 and helical or triangular spin structures2,3, bring about diverse functionalities. Among them, magnetic skyrmions, particle-like non-coplanar topological spin structures characterized by a non-zero integer topological charge called the skyrmion number (Nsk), have great potential for various spintronic applications, such as energy-saving, non-volatile memory and non-von Neumann devices4-7. Current pulses can initiate skyrmion creation in thin-film samples8-10 but require relatively large current densities, which probably causes Joule heating. Moreover, skyrmion creation is localized at a specific position in the film depending on the sample design. Here, we experimentally demonstrate an approach to skyrmion creation employing surface acoustic waves (SAWs); in asymmetric multilayers of Pt/Co/Ir, propagating SAWs induce skyrmions in a wide area of the magnetic film. Micromagnetic simulations reveal that inhomogeneous torque arising from both SAWs and thermal fluctuations creates magnetic textures, with pair structures consisting of a Néel skyrmion-like and an antiskyrmion-like structure. Subsequently, such pairs transform to a Néel skyrmion due to the instability of the antiskyrmion-like structure in a system with interfacial Dzyaloshinskii-Moriya interaction. Our findings provide a tool for efficient manipulation of topological spin objects without heat dissipation and over large areas, given that the propagation length of SAWs is of the order of millimetres.

Nonlocal accumulation, chemical potential, and Hall effect of skyrmions in Pt/Co/Ir heterostructure.

Magnetic skyrmion is a swirling topological spin texture behaving as an individual particle. It shows a gyro-motion similarly to that of a charged particle under a magnetic field, being led to the transverse shift to the electric current, i.e., skyrmion Hall effect. With the open boundaries of a sample, this results in an accumulation of skyrmions on one side and their depletion on the other side. Here we demonstrate experimentally that this effect propagates non-locally over tens of micrometers even where the electric current is absent, when the narrow wires bridge bar-shaped Pt/Co/Ir heterostructure thin film systems. This nonlocality can be understood in terms of the "chemical potential" gradient for the skyrmion bubble induced by the skyrmion Hall effect in the nonequilibrium steady state under the electric current. The present result shows that the skyrmion Hall effect acts as the skyrmion pump and the thermodynamic concepts can be applied to the aggregate of skyrmion bubbles.

Thermoelectric microscopy of magnetic skyrmions.

The magnetic skyrmion is a nanoscale topological object characterized by the winding of magnetic moments, appearing in magnetic materials with broken inversion symmetry. Because of its low current threshold for driving the skyrmion motion, they have been intensely studied toward novel storage applications by using electron-beam, X-ray, and visible light microscopies. Here, we demonstrate another imaging method for skyrmions by using spin-caloritronic phenomena, that is, the spin Seebeck and anomalous Nernst effects, as a probe of magnetic texture. We scanned a focused heating spot on a Hall-cross shaped MgO/CoFeB/Ta/W multilayer film and mapped the magnitude as well as the direction of the resultant thermoelectric current due to the spin-caloritronic phenomena. Our experimental and calculation reveal that the characteristic patterns in the thermoelectric signal distribution reflect the skyrmions' magnetic texture. The thermoelectric microscopy will be a complementary and useful imaging technique for the development of skyrmion devices owing to the unique symmetry of the spin-caloritronic phenomena.

Erratum: Realizing Room-Temperature Resonant Tunnel Magnetoresistance in Cr/Fe/MgAl2O4 Quasi-Quantum Well Structures.

[This corrects the article DOI: 10.1002/advs.201901438.].

Realizing Room-Temperature Resonant Tunnel Magnetoresistance in Cr/Fe/MgAl2O4 Quasi-Quantum Well Structures.

The quantum well (QW) realizes new functionalities due to the discrete electronic energy levels formed in the well-shaped potential. Magnetic tunnel junctions (MTJs) combined with a quasi-QW structure of Cr/ultrathin-Fe/MgAl2O4(001)/Fe, in which the Cr quasi-barrier layer confines Δ 1 up-spin electrons to the Fe well, are prepared with perfectly lattice-matched interfaces and atomic layer number control. Resonant peaks are clearly observed in the differential conductance of the MTJs due to the formation of QWs. Furthermore, enhanced tunnel magnetoresistance (TMR) peaks at the resonant bias voltages are realized for the MTJs at room temperature, i.e., it is observed that TMR ratios at specific and even high bias-voltages (V bias) are larger than zero-bias TMR ratios for the MTJs with odd Fe atomic layers, in contrast to the earlier experimental studies. In addition, a new finding in this study is unique sign changes in the temperature coefficient of resistance (TCR) depending on the Fe thickness and V bias, which is interpreted as a signature of the QW formation of Δ1 symmetry electronic states. The present study suggests that the spin-dependent resonant tunneling via the QWs formed in Cr/ultrathin-Fe/MgAl2O4/Fe structures should open a new pathway to achieve a large TMR at practically high V bias.

Brain hyperserotonemia causes autism-relevant social deficits in mice.

Background: Hyperserotonemia in the brain is suspected to be an endophenotype of autism spectrum disorder (ASD). Reducing serotonin levels in the brain through modulation of serotonin transporter function may improve ASD symptoms. Methods: We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter (Sert) knockout mice. Results: Social deficits were observed in both heterozygous knockout mice (HZ) and homozygous knockout mice (KO), but increases in general anxiety were only observed in KO mice. Two weeks of dietary restriction of the serotonin precursor tryptophan ameliorated both brain hyperserotonemia and ASD-relevant social deficits in Sert HZ and KO mice. The expression of rather distinct sets of genes was altered in Sert HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in Sert HZ and KO mice was associated with alterations in the expression of genes involved in signal transduction pathways initiated by changes in extracellular serotonin or melatonin, a derivative of serotonin. Only expression of the AU015836 gene was altered in both Sert HZ and KO mice. AU015836 expression and ASD-relevant social deficits normalized after dietary tryptophan restriction. Conclusions: These findings reveal a Sert gene dose-dependent effect on brain hyperserotonemia and related behavioral sequelae in ASD and a possible therapeutic target to normalize brain hyperserotonemia and ASD-relevant social deficits.

Association between the rs7583431 single nucleotide polymorphism close to the activating transcription factor 2 gene and the analgesic effect of fentanyl in the cold pain test.

BACKGROUND: Activating transcription factor 2 (ATF2) is a member of the leucine zipper family of DNA binding proteins and is widely distributed in tissues. Several recent studies have demonstrated that this protein is involved in mechanisms that are related to pain and inflammation. However, unclear is whether polymorphisms of the ATF2 gene, which encodes the human ATF2 protein, influence pain or analgesic sensitivity. This study examined associations between the analgesic effect of fentanyl in the cold pressor-induced pain test and polymorphisms in the ATF2 gene in 355 Japanese subjects. RESULTS: In this study, 33 single nucleotide polymorphisms (SNPs) were selected, and a total of 2 linkage disequilibrium blocks with 6 Tag SNPs (rs1153702, rs7583431, rs2302663, rs3845744, rs268214, and rs1982235) were observed in the region within and around the ATF2 gene. We further analyzed associations between these Tag SNPs and clinical data. Even after multiple testing with Bonferroni adjustments, an increase in the analgesic effect of fentanyl in the cold pressor-induced pain test was significantly associated with a greater number of the A allele of the rs7583431 SNP (linear regression, P = .001). CONCLUSIONS: The present findings may contribute to adequate pain relief in individual patients. Although more research on the genetic factors that influence opioid sensitivity is needed, analgesic requirements may be predicted by analyzing ATF2SNPs, together with other polymorphisms of genes that are reportedly associated with opioid sensitivity, such as CREB1, OPRM1, and GIRK2.