Influence of Clinical and Genetic Factors on Propofol Dose Requirements: A Genome-wide Association Study.

BACKGROUND: Propofol is a widely used intravenous hypnotic. Dosing is based mostly on weight, with great interindividual variation in consumption. Suggested factors affecting propofol requirements include age, sex, ethnicity, anxiety, alcohol consumption, smoking, and concomitant valproate use. Genetic factors have not been widely explored. METHODS: This study considered 1,000 women undergoing breast cancer surgery under propofol and remifentanil anesthesia. Depth of anesthesia was monitored with State Entropy (GE Healthcare, Finland). Propofol requirements during surgery were recorded. DNA from blood was genotyped with a genome-wide array. A multivariable linear regression model was used to assess the relevance of clinical variables and select those to be used as covariates in a genome-wide association study. Imputed genotype data were used to explore selected loci further. In silico functional annotation was used to explore possible consequences of the discovered genetic variants. Additionally, previously reported genetic associations from candidate gene studies were tested. RESULTS: Body mass index, smoking status, alcohol use, remifentanil dose (ln[mg · kg-1 · min-1]), and average State Entropy during surgery remained statistically significant in the multivariable model. Two loci reached genome-wide significance (P < 5 × 10-8). The most significant associations were for single-nucleotide polymorphisms rs997989 (30 kb from ROBO3), likely affecting expression of another nearby gene, FEZ1, and rs9518419, close to NALCN (sodium leak channel); rs10512538 near KCNJ2 encoding the Kir2.1 potassium channel showed suggestive association (P = 4.7 × 10-7). None of these single-nucleotide polymorphisms are coding variants but possibly affect the regulation of nearby genes. None of the single-nucleotide polymorphisms previously reported as affecting propofol pharmacokinetics or pharmacodynamics showed association in the data. CONCLUSIONS: In this first genome-wide association study exploring propofol requirements, This study discovered novel genetic associations suggesting new biologically relevant pathways for propofol and general anesthesia. The roles of the gene products of ROBO3/FEZ1, NALCN, and KCNJ2 in propofol anesthesia warrant further studies.

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.

FinnGen provides genetic insights from a well-phenotyped isolated population.

Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10-11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

A Randomized, Sham-Controlled Trial of Repetitive Transcranial Magnetic Stimulation Targeting M1 and S2 in Central Poststroke Pain: A Pilot Trial.

OBJECTIVES: Central poststroke pain (CPSP), a neuropathic pain condition, is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) targeted to the primary motor cortex (M1) can alleviate the condition, but not all patients respond. We aimed to assess a promising alternative rTMS target, the secondary somatosensory cortex (S2), for CPSP treatment. MATERIALS AND METHODS: This prospective, randomized, double-blind, sham-controlled three-arm crossover trial assessed navigated rTMS (nrTMS) targeted to M1 and S2 (10 sessions, 5050 pulses per session at 10 Hz). Participants were evaluated for pain, depression, anxiety, health-related quality of life, upper limb function, and three plasticity-related gene polymorphisms including Dopamine D2 Receptor (DRD2). We monitored pain intensity and interference before and during stimulations and at one month. A conditioned pain modulation test was performed using the cold pressor test. This assessed the efficacy of the descending inhibitory system, which may transmit TMS effects in pain control. RESULTS: We prescreened 73 patients, screened 29, and included 21, of whom 17 completed the trial. NrTMS targeted to S2 resulted in long-term (from baseline to one-month follow-up) pain intensity reduction of ≥30% in 18% (3/17) of participants. All stimulations showed a short-term effect on pain (17-20% pain relief), with no difference between M1, S2, or sham stimulations, indicating a strong placebo effect. Only nrTMS targeted to S2 resulted in a significant long-term pain intensity reduction (15% pain relief). The cold pressor test reduced CPSP pain intensity significantly (p = 0.001), indicating functioning descending inhibitory controls. The homozygous DRD2 T/T genotype is associated with the M1 stimulation response. CONCLUSIONS: S2 is a promising nrTMS target in the treatment of CPSP. The DRD2 T/T genotype might be a biomarker for M1 nrTMS response, but this needs confirmation from a larger study.

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder.

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.

Polygenic risk provides biological validity for the ICHD-3 criteria among Finnish migraine families.

BACKGROUND: Migraine is diagnosed using the extensively field-tested International Classification of Headache Disorders (ICHD-3) consensus criteria derived by the International Headache Society. To evaluate the criteria in respect to a measurable biomarker, we studied the relationship between the main ICHD-3 criteria and the polygenic risk score, a measure of common variant burden in migraine. METHODS: We used linear mixed models to study the correlation of ICHD-3 diagnostic criteria, underlying symptoms, and main diagnoses with the polygenic risk score of migraine in a cohort of 8602 individuals from the Finnish Migraine Genome Project. RESULTS: Main diagnostic categories and all underlying diagnostic criteria formed a consistent continuum along the increasing polygenic burden. Polygenic risk was associated with the heterogeneous clinical picture starting from the non-migraine headache (mean 0.07; 95% CI 0.02-0.12; p = 0.008 compared to the non-headache group), to probable migraine (mean 0.13; 95% CI 0.08-0.18; p < 0.001), migraine headache (mean 0.17; 95% CI 0.14-0.21; p < 0.001) and migraine with typical visual aura (mean 0.29; 95% CI 0.26-0.33; p < 0.001), all the way to the hemiplegic aura (mean 0.37; 95% CI 0.31-0.43; p < 0.001). All individual ICHD-3 symptoms and the total number of reported symptoms, a surrogate of migraine complexity, demonstrated a clear inclination with an increasing polygenic risk. CONCLUSIONS: The complex migraine phenotype progressively follows the polygenic burden from individuals with no headache to non-migrainous headache and up to patients with attacks manifesting all the features of the ICHD-3 headache and aura. Results provide further biological support for the ICHD-3 diagnostic criteria.

First genome-wide association study on rocuronium dose requirements shows association with SLCO1A2.

BACKGROUND: Rocuronium, a common neuromuscular blocking agent, is mainly excreted unchanged in urine (10-25%) and bile (>70%). Age, sex, liver blood flow, smoking, medical conditions, and ethnic background can affect its pharmacological actions. However, reasons for the wide variation in rocuronium requirements are mostly unknown. We hypothesised that pharmacogenetic factors might explain part of the variation. METHODS: One thousand women undergoing surgery for breast cancer were studied. Anaesthesia was maintained with propofol (50-100 µg kg-1 min-1) and remifentanil (0.05-0.25 µg kg-1 min-1). Neuromuscular block was maintained with rocuronium to keep the train-of-four ratio at 0-10%. DNA was extracted from peripheral blood and genotyped with a next-generation genotyping array. The genome-wide association study (GWAS) was conducted using an additive linear regression model with PLINK software. The FINEMAP tool and data from the Genotype-Tissue Expression project v8 were utilised to study the locus further. RESULTS: The final patient population comprised 918 individuals. Of the clinical variables tested, age, BMI, ASA physical status, and total dose of propofol correlated significantly (all P<0.001) with the rocuronium dose in a linear regression model. The GWAS highlighted one genome-wide significant locus in chromosome 12. The single-nucleotide polymorphisms (SNPs) with the most significant evidence of association were located in or near SLCO1A2. The two top SNPs, rs7967354 (P=5.3e-11) and rs11045995 (P=1.4e-10), and the clinical variables accounted for 41% of the variability in rocuronium dosage. CONCLUSIONS: Genetic variation in the gene SLCO1A2, encoding OATP1A2, an uptake transporter, accounted for 4% of the variability in rocuronium consumption. The underlying mechanism remains unknown.

Genetic Risk Score for Serum 25-Hydroxyvitamin D Concentration Helps to Guide Personalized Vitamin D Supplementation in Healthy Finnish Adults.

BACKGROUND: Genetic factors modify serum 25-hydroxyvitamin D [25(OH)D] concentration and can affect the optimal intake of vitamin D. OBJECTIVES: We aimed to personalize vitamin D supplementation by applying knowledge of genetic factors affecting serum 25(OH)D concentration. METHODS: We performed a genome-wide association study of serum 25(OH)D concentration in the Finnish Health 2011 cohort (n = 3339) using linear regression and applied the results to develop a population-matched genetic risk score (GRS) for serum 25(OH)D. This GRS was used to tailor vitamin D supplementation for 96 participants of a longitudinal Digital Health Revolution (DHR) Study. The GRS, serum 25(OH)D concentrations, and personalized supplementation and dietary advice were electronically returned to participants. Serum 25(OH)D concentrations were assessed using immunoassays and vitamin D intake using FFQs. In data analyses, cross-sectional and repeated-measures statistical tests and models were applied as described in detail elsewhere. RESULTS: GC vitamin D-binding protein and cytochrome P450 family 2 subfamily R polypeptide 1 genes showed genome-wide significant associations with serum 25(OH)D concentration. One single nucleotide polymorphism from each locus (rs4588 and rs10741657) was used to develop the GRS. After returning data to the DHR Study participants, daily vitamin D supplement users increased from 32.6% to 60.2% (P = 6.5 × 10-6) and serum 25(OH)D concentration from 64.4 ± 20.9 nmol/L to 68.5 ± 19.2 nmol/L (P = 0.006) between August and November. Notably, the difference in serum 25(OH)D concentrations between participants with no risk alleles and those with 3 or 4 risk alleles decreased from 20.7 nmol/L to 8.0 nmol/L (P = 0.0063). CONCLUSIONS: We developed and applied a population-matched GRS to identify individuals genetically predisposed to low serum 25(OH)D concentration. We show how the electronic return of individual genetic risk, serum 25(OH)D concentrations, and factors affecting vitamin D status can be used to tailor vitamin D supplementation. This model could be applied to other populations and countries.

Machine-learned analysis of global and glial/opioid intersection-related DNA methylation in patients with persistent pain after breast cancer surgery.

BACKGROUND: Glial cells in the central nervous system play a key role in neuroinflammation and subsequent central sensitization to pain. They are therefore involved in the development of persistent pain. One of the main sites of interaction of the immune system with persistent pain has been identified as neuro-immune crosstalk at the glial-opioid interface. The present study examined a potential association between the DNA methylation of two key players of glial/opioid intersection and persistent postoperative pain. METHODS: In a cohort of 140 women who had undergone breast cancer surgery, and were assigned based on a 3-year follow-up to either a persistent or non-persistent pain phenotype, the role of epigenetic regulation of key players in the glial-opioid interface was assessed. The methylation of genes coding for the Toll-like receptor 4 (TLR4) as a major mediator of glial contributions to persistent pain or for the µ-opioid receptor (OPRM1) was analyzed and its association with the pain phenotype was compared with that conferred by global genome-wide DNA methylation assessed via quantification of the methylation in the retrotransposon LINE1. RESULTS: Training of machine learning algorithms indicated that the global DNA methylation provided a similar diagnostic accuracy for persistent pain as previously established non-genetic predictors. However, the diagnosis can be based on a single DNA based marker. By contrast, the methylation of TLR4 or OPRM1 genes could not contribute further to the allocation of the patients to the pain-related phenotype groups. CONCLUSIONS: While clearly supporting a predictive utility of epigenetic testing, the present analysis cannot provide support for specific epigenetic modulation of persistent postoperative pain via methylation of two key genes of the glial-opioid interface.

Machine-learned analysis of the association of next-generation sequencing-based genotypes with persistent pain after breast cancer surgery.

Cancer and its surgical treatment are among the most important triggering events for persistent pain, but additional factors need to be present for the clinical manifestation, such as variants in pain-relevant genes. In a cohort of 140 women undergoing breast cancer surgery, assigned based on a 3-year follow-up to either a persistent or nonpersistent pain phenotype, next-generation sequencing was performed for 77 genes selected for known functional involvement in persistent pain. Applying machine-learning and item categorization techniques, 21 variants in 13 different genes were found to be relevant to the assignment of a patient to either the persistent pain or the nonpersistent pain phenotype group. In descending order of importance for correct group assignment, the relevant genes comprised DRD1, FAAH, GCH1, GPR132, OPRM1, DRD3, RELN, GABRA5, NF1, COMT, TRPA1, ABHD6, and DRD4, of which one in the DRD4 gene was a novel discovery. Particularly relevant variants were found in the DRD1 and GPR132 genes, or in a cis-eCTL position of the OPRM1 gene. Supervised machine-learning-based classifiers, trained with 2/3 of the data, identified the correct pain phenotype group in the remaining 1/3 of the patients at accuracies and areas under the receiver operator characteristic curves of 65% to 72%. When using conservative classical statistical approaches, none of the variants passed α-corrected testing. The present data analysis approach, using machine learning and training artificial intelligences, provided biologically plausible results and outperformed classical approaches to genotype-phenotype association.

Heme oxygenase-1 repeat polymorphism in septic acute kidney injury.

Acute kidney injury (AKI) is a syndrome that frequently affects the critically ill. Recently, an increased number of dinucleotide repeats in the HMOX1 gene were reported to associate with development of AKI in cardiac surgery. We aimed to test the replicability of this finding in a Finnish cohort of critically ill septic patients. This multicenter study was part of the national FINNAKI study. We genotyped 300 patients with severe AKI (KDIGO 2 or 3) and 353 controls without AKI (KDIGO 0) for the guanine-thymine (GTn) repeat in the promoter region of the HMOX1 gene. The allele calling was based on the number of repeats, the cut off being 27 repeats in the S-L (short to long) classification, and 27 and 34 repeats for the S-M-L2 (short to medium to very long) classification. The plasma concentrations of heme oxygenase-1 (HO-1) enzyme were measured on admission. The allele distribution in our patients was similar to that published previously, with peaks at 23 and 30 repeats. The S-allele increases AKI risk. An adjusted OR was 1.30 for each S-allele in an additive genetic model (95% CI 1.01-1.66; p = 0.041). Alleles with a repeat number greater than 34 were significantly associated with lower HO-1 concentration (p<0.001). In septic patients, we report an association between a short repeat in HMOX1 and AKI risk.

Common Inflammation-Related Candidate Gene Variants and Acute Kidney Injury in 2647 Critically Ill Finnish Patients.

Acute kidney injury (AKI) is a syndrome with high incidence among the critically ill. Because the clinical variables and currently used biomarkers have failed to predict the individual susceptibility to AKI, candidate gene variants for the trait have been studied. Studies about genetic predisposition to AKI have been mainly underpowered and of moderate quality. We report the association study of 27 genetic variants in a cohort of Finnish critically ill patients, focusing on the replication of associations detected with variants in genes related to inflammation, cell survival, or circulation. In this prospective, observational Finnish Acute Kidney Injury (FINNAKI) study, 2647 patients without chronic kidney disease were genotyped. We defined AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We compared severe AKI (Stages 2 and 3, n = 625) to controls (Stage 0, n = 1582). For genotyping we used iPLEXTM Assay (Agena Bioscience). We performed the association analyses with PLINK software, using an additive genetic model in logistic regression. Despite the numerous, although contradictory, studies about association between polymorphisms rs1800629 in TNFA and rs1800896 in IL10 and AKI, we found no association (odds ratios 1.06 (95% CI 0.89⁻1.28, p = 0.51) and 0.92 (95% CI 0.80⁻1.05, p = 0.20), respectively). Adjusting for confounders did not change the results. To conclude, we could not confirm the associations reported in previous studies in a cohort of critically ill patients.

CACNG2 polymorphisms associate with chronic pain after mastectomy.

Chronic postmastectomy pain (PMP) imposes a major burden on the quality of life of the ever-increasing number of long-term survivors of breast cancer. An earlier report by Nissenbaum et al. claimed that particular polymorphisms in the gene CACNG2 are associated with the risk of developing chronic PMP after breast surgery (Nissenbaum J, Devor M, Seltzer Z, Gebauer M, Michaelis M, Tal M, Dorfman R, Abitbul-Yarkoni M, Lu Y, Elahipanah T, delCanho S, Minert A, Fried K, Persson AK, Shpigler H, Shabo E, Yakir B, Pisante A, Darvasi A. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. Genome Res 2010;20:1180-90). This information is important because in principle, it can inform the surgical, radiological, and chemotherapeutic decision-making process in ways that could mitigate the increased risk of chronic pain. In this study, we revisited this claim by independently evaluating the proposed marker haplotype using 2 different patient cohorts recruited in different research settings. Meta-analysis of these new postmastectomy cohorts and the original cohort confirmed significant association of the CACNG2 haplotype with PMP. In addition, we tested whether the same markers would predict chronic postsurgical pain in men who underwent surgery for inguinal hernia repair, and whether there is significant genetic association with cutaneous thermal sensitivity in postmastectomy and postherniotomy patients. We found that the biomarker is selective because it did not predict pain after laparoscopic hernia repair and was not associated with pain sensitivity to experimentally applied noxious thermal stimuli. We conclude that the A-C-C haplotype at the 3 single-nucleotide polymorphisms (rs4820242, rs2284015, and rs2284017) in the CACNG2 gene is associated with increased risk of developing PMP. This information may advance current knowledge on pathophysiology of PMP and serve as a step forward in the prediction of clinical outcomes and personalized pain management.

Development of an AmpliSeqTM Panel for Next-Generation Sequencing of a Set of Genetic Predictors of Persisting Pain.

Background: Many gene variants modulate the individual perception of pain and possibly also its persistence. The limited selection of single functional variants is increasingly being replaced by analyses of the full coding and regulatory sequences of pain-relevant genes accessible by means of next generation sequencing (NGS). Methods: An NGS panel was created for a set of 77 human genes selected following different lines of evidence supporting their role in persisting pain. To address the role of these candidate genes, we established a sequencing assay based on a custom AmpliSeqTM panel to assess the exomic sequences in 72 subjects of Caucasian ethnicity. To identify the systems biology of the genes, the biological functions associated with these genes were assessed by means of a computational over-representation analysis. Results: Sequencing generated a median of 2.85 ⋅ 106 reads per run with a mean depth close to 200 reads, mean read length of 205 called bases and an average chip loading of 71%. A total of 3,185 genetic variants were called. A computational functional genomics analysis indicated that the proposed NGS gene panel covers biological processes identified previously as characterizing the functional genomics of persisting pain. Conclusion: Results of the NGS assay suggested that the produced nucleotide sequences are comparable to those earned with the classical Sanger sequencing technique. The assay is applicable for small to large-scale experimental setups to target the accessing of information about any nucleotide within the addressed genes in a study cohort.

Genetics and genomics in postoperative pain and analgesia.

PURPOSE OF REVIEW: The review describes recent advances in genetics and genomics of postoperative pain, the association between genetic variants and the efficacy of analgesics, and the role of pharmacogenomics in the selection of appropriate analgesic treatments for postoperative pain. RECENT FINDINGS: Recent genetic studies have reported associations of genetic variants in catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), voltage-gated channel alpha subunit 11 (SCN11A) and µ-opioid receptor (OPRM1) genes with postoperative pain. The recent pharmacogenetics studies revealed an association of the organic cation transporter 1 (OCT1) and ATP-binding cassette C3 (ABCC3) polymorphisms with morphine-related adverse effects, an effect of polymorphisms in cytochrome P450 gene CYP2D6 on the analgesic efficacy of tramadol and no effect of CYP2C8 and CYP2C9 variants on efficacy of piroxicam. SUMMARY: Genetic variants associate with inter-individual variability in drug responses and they can affect pain sensitivity and intensity of postoperative pain. Despite the recent progress in genetics and genomics of postoperative pain, it is still not possible to precisely predict the patients who are genetically predisposed to have severe postoperative pain or who develop chronic postoperative pain.

Genetic variation in P2RX7 and pain tolerance.

P2X7 is a nonselective cation channel activated by extracellular ATP. P2X7 activation contributes to the proinflammatory response to injury or bacterial invasion and mediates apoptosis. Recently, P2X7 function has been linked to chronic inflammatory and neuropathic pain. P2X7 may contribute to pain modulation both by effects on peripheral tissue injury underlying clinical pain states, and through alterations in central nervous system processing, as suggested by animal models. To further test its role in pain sensitivity, we examined whether variation within the P2RX7 gene, which encodes the P2X7 receptor, was associated with experimentally induced pain in human patients. Experimental pain was assessed in Tromsø 6, a longitudinal and cross-sectional population-based study (N = 3016), and the BrePainGen cohort, consisting of patients who underwent breast cancer surgery (N = 831). For both cohorts, experimental pain intensity and tolerance were assessed with the cold-pressor test. In addition, multisite chronic pain was assessed in Tromsø 6 and pain intensity 1 week after surgery was assessed in BrePainGen. We tested whether the single-nucleotide polymorphism rs7958311, previously implicated in clinical pain, was associated with experimental and clinical pain phenotypes. In addition, we examined effects of single-nucleotide polymorphisms rs208294 and rs208296, for which previous results have been equivocal. Rs7958311 was associated with experimental pain intensity in the meta-analysis of both cohorts. Significant associations were also found for multisite pain and postoperative pain. Our results strengthen the existing evidence and suggest that P2X7 and genetic variation in the P2RX7-gene may be involved in the modulation of human pain sensitivity.

Analgesic Plasma Concentrations of Oxycodone After Surgery for Breast Cancer-Which Factors Matter?

We investigated factors affecting analgesic oxycodone concentrations after breast cancer surgery in 1,000 women. Preoperatively, we studied heat and cold pain sensitivities and anxiety scores. Postoperatively, rest and motion pain intensities were measured and intravenous oxycodone was administered until satisfactory analgesia. At this point, the mean oxycodone concentration (variation coefficient) was 33.3 ng/mL (66%) and it was 21.7 ng/mL (69%) when the patient requested oxycodone again. At both time points, the concentrations varied >100-fold between individuals. The analgesic oxycodone concentration was increased by 21.3% per motion pain intensity score on a 0-10 scale and by 22.3% if axillary clearance was performed instead of sentinel node biopsy (P < 0.001). Forty-seven women who were older and less anxious than others (P < 0.01) required no oxycodone. Anxiety, age, chronic pain, or preoperative pain sensitivity were not independently associated with the analgesic oxycodone concentration. CYP2D6 and CYP3A genotypes did not affect analgesic concentration or duration of analgesia.

Genetic variants in SERPINA4 and SERPINA5, but not BCL2 and SIK3 are associated with acute kidney injury in critically ill patients with septic shock.

BACKGROUND: Acute kidney injury (AKI) is a multifactorial syndrome, but knowledge about its pathophysiology and possible genetic background is limited. Recently the first hypothesis-free genetic association studies have been published to explore individual susceptibility to AKI. We aimed to replicate the previously identified associations between five candidate single nucleotide polymorphisms (SNP) in apoptosis-related genes BCL2, SERPINA4, SERPINA5, and SIK3 and the development of AKI, using a prospective cohort of critically ill patients with sepsis/septic shock, in Finland. METHODS: This is a prospective, observational multicenter study. Of 2567 patients without chronic kidney disease and with genetic samples included in the Finnish Acute Kidney Injury (FINNAKI) study, 837 patients had sepsis and 627 patients had septic shock. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, considering stages 2 and 3 affected (severe AKI), stage 0 unaffected, and stage 1 indecisive. Genotyping was done using iPLEXTM Assay (Agena Bioscience). The genotyped SNPs were rs8094315 and rs12457893 in the intron of the BCL2 gene, rs2093266 in the SERPINA4 gene, rs1955656 in the SERPINA5 gene and rs625145 in the SIK3 gene. Association analyses were performed using logistic regression with PLINK software. RESULTS: We found no significant associations between the SNPs and severe AKI in patients with sepsis/septic shock, even after adjustment for confounders. Among patients with septic shock (252 with severe AKI and 226 without AKI (149 with KDIGO stage 1 excluded)), the SNPs rs2093266 and rs1955656 were significantly (odds ratio 0.63, p = 0.04276) associated with stage 2-3 AKI after adjusting for clinical and demographic variables. CONCLUSIONS: The SNPs rs2093266 in the SERPINA4 and rs1955656 in the SERPINA5 were associated with the development of severe AKI (KDIGO stage 2-3) in critically ill patients with septic shock. For the other SNPs, we did not confirm the previously reported associations.