Genetics and genomics in postoperative pain and analgesia

Purpose of reviewThe 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 findingsRecent 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 -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.SummaryGenetic 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.Peer reviewe

Varhaiskasvatuksen opiskelijoiden näkemyksiä minäpystyvyydestä

Minäpystyvyydellä on todettu merkittävä rooli yksilön elämässä ja yksilö alkaa muodostaa pystyvyyteensä liittyviä käsityksiään jo lapsena. Tämän tutkielman tarkoituksena oli tarkastella varhaiskasvatuksen opiskelijoiden näkemyksiä minäpystyvyydestä, sen mahdollisista vaikutuksista varhaiskasvatusikäisiin lapsiin ja siitä, miten lasten minäpystyvyyttä voidaan vahvistaa varhaiskasvatuksessa. Varhaiskasvatuksen opiskelijoiden käsityksiä minäpystyvyydestä ei ole tutkittu aikaisemmin. Minäpystyvyyteen liittyvä tutkimus on varhaiskasvatuksen kontekstissa muutenkin melko vähäistä, kun taas koulukontekstissa sitä on tutkittu enemmän. Tutkimus oli laadullinen ja se toteutettiin neljää varhaiskasvatuksen opiskelijaa haastattelemalla. Kaikki haastateltavat olivat kolmannen vuoden opiskelijoita, joista osalla oli kokemusta varhaiskasvatuksen alalla työskentelystä. Haastattelut toteutettiin parihaastatteluina ja tutkimuksen aineiston sisällönanalyysi oli teorialähtöistä. Pääteoriana toimi Banduran (1977) sosiaalis-kognitiivinen teoria. Tutkimuksessa haluttiin päästä käsiksi erilaisiin minäpystyvyyteen liittyviin käsityksiin ja näkemyksiin, joten tutkimussuuntausta voidaan luonnehtia fenomenografisena. Tutkimuksen tutkimuskysymykset olivat seuraavat: Millaisena varhaiskasvatuksen opiskelijat käsittävät minäpystyvyyden? Millaisia vaikutuksia minäpystyvyydellä on lapselle? Miten lasten minäpystyvyyttä voidaan vahvistaa varhaiskasvatuksessa? Tutkimuksen mukaan haastateltavat eivät olleet juurikaan törmänneet minäpystyvyys-käsitteeseen, mutta osasivat kuitenkin kuvata mitä sillä tarkoitetaan. Tutkimuksessa havaittiin, että opiskelijoiden minäpystyvyyteen liittyvät näkemykset olivat hyvin positiivisia ja lasten minäpystyvyyden vahvistaminen koettiin varhaiskasvatuksen toiminnassa tärkeäksi. Minäpystyvyyden nähtiin olevan yhteydessä muun muassa periksiantamattomuuteen, yritteliäisyyteen ja oppimiseen. Sen lisäksi sillä nähtiin myös monia muita vaikutuksia liittyen lapsen toimintaan ja käyttäytymiseen varhaiskasvatuksessa. Lasten minäpystyvyyden vahvistamisessa tärkeänä pidettiin etenkin sosiaalista vakuuttelua eli lasten sanallista kannustamista ja lasten onnistumisen kokemuksia. Lasten minäpystyvyys koettiin merkityksellisenä sekä nykyhetkeä että tulevaisuutta ajatellen

PRKCDBP (CAVIN3) and CRY2 associate with major depressive disorder

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CRY1 and CRY2 genetic variants in seasonality : A longitudinal and cross-sectional study

Cryptochromes are key components of the circadian clocks that generate and maintain seasonal variations. The aim of our study was to analyze the associations of CRY1 and CRY2 genetic variants with the problematicity of seasonal variations, and whether the problematicity of seasonal variations changed during the follow-up of 11 years. Altogether 21 CRY1 and 16 CRY2 single-nucleotide polymorphisms (SNPs) were genotyped and analyzed in 5910 individuals from a Finnish nationwide population-based sample who had filled in the self-report on the seasonal variations in mood and behavior in the year 2000. In the year 2011, 3356 of these individuals filled in the same self-report on the seasonal variations in mood and behavior. Regression models were used to test whether any of the SNPs associated with the problematicity of seasonal variations or with a change in the problematicity from 2000 to 2011. In the longitudinal analysis, CRY2 SNP rs61884508 was protective from worsening of problematicity of seasonal variations. In the cross-sectional analysis, CRY2 SNP rs72902437 showed evidence of association with problematicity of seasonal variations, as did SNP rs1554338 (in the MAPK8IP1 and downstream of CRY2). (C) 2016 Elsevier Ireland Ltd. All rights reserved.Peer reviewe

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 iPLEX (TM) 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.Peer reviewe

Development of an AmpliSeq (TM) 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 AmpliSeq (TM) 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 . 10(6) 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.Peer reviewe

Genetic predisposition to acute kidney injury - a systematic review

Background: The risk of an individual to develop an acute kidney injury (AKI), or its severity, cannot be reliably predicted by common clinical risk factors. Whether genetic risk factors have an explanatory role poses an interesting question, however. Thus, we conducted a systematic literature review regarding genetic predisposition to AKI or outcome of AKI patients. Methods: We searched Ovid SP (MEDLINE) and EMBASE databases and found 4027 references to AKI. Based on titles and abstracts, we approved 37 articles for further analysis. Nine were published only as abstracts, leaving 28 original articles in the final analysis. We extracted the first author, year of publication, study design, clinical setting, number of studied patients, patients with AKI, ethnicity of patients, studied polymorphisms, endpoints, AKI definition, phenotype, significant findings, and data for quality scoring from each article. We summarized the findings and scored the quality of articles. Results: The articles were quite heterogeneous and of moderate quality (mean 6.4 of 10). Conclusions: Despite different gene polymorphisms with suggested associations with development or severity or outcome of AKI, definitive conclusions would require replication of associations in independent cohort studies and, preferably a hypothesis-free study design.Peer reviewe

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

Abstract 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 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 mu-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.Peer reviewe