Effect of D2R, NMDAR and CB1R genetic variants associated with cannabis use and childhood trauma in first-episode psychosis in a Brazilian population [abstract only]

Introduction Gene-environment interactions increase psychosis risk (Gayer-Anderson et al. Soc Psychiatry Psychiatr Epidemiol 2020; 55(5):645-657). However, identifying the genetic variants involved and how they interact with environmental risk factors underlying psychosis remains challenging. Objectives To investigate whether there are gene-environment interactions in the relationships of childhood trauma, lifetime cannabis use, and single nucleotide variants (SNVs) of dopamine D2 receptor (D2R: DRD2), N-methyl-d-aspartate receptor (NMDAR: GRIN1, GRIN2A and GRIN2B) and cannabinoid receptor type 1 (CB1R: CNR1) with psychosis. Methods In a population-based case-control study nested in an incident study (STREAM, Brazil) (Del-Ben et al. Br J of Psychiatry 2019; 215(6):726-729), part of the EU-GEI consortium (Gayer-Anderson et al. Soc Psychiatry Psychiatr Epidemiol 2020; 55(5):645-657), 143 first-episode psychosis patients and 286 community-based controls of both sexes aged between 16 and 64 years were included over a period of 3 years. Twenty-three SNVs of D2R (rs1799978, rs7131056, rs6275), NMDAR (GRIN1: rs4880213, rs11146020; GRIN2A: rs1420040, rs11866328; GRIN2B: rs890, rs2098469, rs7298664), and CB1R genes (CNR1: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898), were genotyped from peripheral blood DNA using a custom Illumina HumanCoreExome-24 BeadChip. Environmental adversities were evaluated using the Cannabis Experience Questionnaire (Di Forti et al. The Lancet Psychiatry 2009; 6(5):427–436) and the Childhood Trauma Questionnaire (Grassi-Oliveira et al. Rev Saude Publica 2006; 40(2):249-55). Associations between SNVs and environmental risk factors were performed using the nonparametric multifactor dimensionality reduction software (version 3.0.2). Results Single locus analysis showed no association among the 23 SNVs with psychosis; however, gene-environment analysis was significant for the polymorphic loci rs12720071 and rs7766029 in CNR1. The best association models were the two-factor representing by the combination of CNR1 rs12720071 with lifetime cannabis use (p<0.001), and CNR1 rs12720071 with childhood trauma (p<0.05), both suggesting an increased risk of psychosis. Additionally, when considering the interaction of both environmental factors in the same model, we found CNR1 rs7766029 to be associated with psychosis (p<0.001). Conclusions Our study supports the hypothesis of gene-environment interactions for psychosis involving the T allele carriers of CNR1 SNVs (rs12720071 and rs7766029), childhood trauma and lifetime cannabis use in psychosis

Gene and environmental risk factors: interplay between CNR1 genetic variants cannabis use, childhood trauma and psychosis [abstract only]

Background: Cannabis use and childhood trauma have been proposed as environmental risk factors for psychosis and its known that gene-environment (G×E) interactions increase the risk of psychosis [1]. In particular, a recent finding suggests a link between genetic variants in the cannabinoid receptor type 1 (CNR1) gene, which encodes CB1 receptors and is expressed widely in the central and peripheral systems, and cannabis playing a role in the multifactorial pathogenesis of psychosis [2]. However, how the genetic variants interact with lifetime cannabis use and other environmental risk factors, such as childhood trauma, underlying psychosis remains challenging. Objective: To investigate whether there are associations of gene and environmental factors with psychosis, as well as G×E interactions in the relationship between lifetime cannabis use, childhood trauma, and single nucleotide variants (SNVs) of CNR1 and psychosis in a Brazilian sample. Methods: In a population-based case-control study nested in an incident study (STREAM, Brazil) [3], part of the WP2 EU-GEI consortium, 143 first-episode psychosis patients (FEPp) and 286 community-based controls of both sexes, aged between 16 and 64 years, were included over a period of three years. Thirteen SNVs of CNR1 gene (rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898), were genotyped from peripheral blood DNA using a custom Illumina HumanCoreExome-24 BeadChip genotyping arrays (GWAS Cardiff chip). Environmental adversities were evaluated using the Cannabis Experience and the Childhood Trauma Questionnaires. Data were analysed using a binary logistic regression model (Adj OR, 95% CI), including a binary outcome (community-based controls and FEPp), adjusted by sex, age, skin colour, years of education and tobacco smoking. Genotype frequencies were analysed under the dominant model (homozygous ancestral x heterozygous + homozygous variant). The significance level was set at α≤0.05. Results: Lifetime cannabis use and childhood trauma increased the risk for psychosis (OR=3.7; 2.6-6.195% CI, p<0.001; OR=3.0; 1.9-4.7 95% CI, p<0.001, respectively). We also showed that the presence of CNR1 rs12720071-T-allele moderated the association between lifetime cannabis use and psychosis (OR=6.0; 2.0-17.5 95% CI; p=0.001). Moreover, the combination of CNR1 rs12720071-T-allele carriers with childhood trauma also suggests a change in the risk of psychosis (OR=3.6; 1.4-9.0 95% CI; p=0.006). No significant associations between the environmental factors and other SNVs were found. Conclusions: We demonstrated a significant interaction between CNR1 rs12720071 SNV and two important environmental risk factors in their association with psychosis. T allele carriers of CNR1 rs12720071 had a higher risk of psychosis when lifetime cannabis use or childhood trauma were present. Our results suggest a G×E interaction involving the CNR1 gene, trauma and cannabis in psychosis. We will explore the associations between genetic and epigenetic markers of the CNR1 gene with environmental factors in larger and longer follow-up cohorts to better understand the mechanisms of endocannabinoid system dysfunction in the etiology of psychosis

Delay From Fracture To Hospital Admission: A New Risk Factor For Hip Fracture Mortality?

Summary: The relationship between surgical timing and hip fracture mortality is unknown in the context of developing countries where large delays to surgery are common. We observed that delay from fracture to hospital admission is associated with decreased survival after a hip fracture. Introduction: To examine the relationship between the time interval from fracture to surgery as well as its subcomponents (time from fracture to hospital admission and time from admission to surgery) and hip fracture survival. Methods: The medical records of all patients aged 60 years and older admitted to a public university hospital in the city of Rio de Janeiro with a primary diagnosis of hip fracture between 1995 and 2000 were reviewed. Survival to hospital discharge and at 1 year were examined. Results: Among 343 patients included in the study, there were 18 (5.3%) in-hospital deaths, and 297 (86.6%) patients remained alive 1 year after surgery. Very long delays from the time of fracture to hospital admission (mean 3 days) and from hospital admission to surgery (mean 13 days) were identified. Increased time from fracture to hospital admission was associated with reduced survival to hospital discharge (hazard ratio [HR] 1.09, 95% CI 1.03-1.15, p00.005) and reduced survival at 1 year after surgery (HR 1.07, 95% CI 1.03-1.10, p< 0.001). The interval of time from hospital admission to surgery was not associated with reduced survival to hospital discharge (HR 1.03, 95% CI 0.96-1.10, p00.379) or at 1 year after surgery (HR 1.03, 95% CI 0.99-1.07, p00.185). Conclusions: If the association estimated in our study is causal, our results provide evidence that some hip fracturerelated deaths could be prevented by improved patient access to appropriate and timely hospital care in the context of a developing country. © International Osteoporosis Foundation and National Osteoporosis Foundation 2012.231228472853Johnell, O., Kanis, J., Epidemiology of osteoporotic fractures (2005) Osteoporosis International, 16 (SUPPL. 2), pp. S3-S7. , DOI 10.1007/s00198-004-1702-6Cummings, S.R., Melton, L.J., Epidemiology and outcomes of osteoporotic fractures (2002) Lancet, 359 (9319), pp. 1761-1767Hiligsmann, M., Bruyere, O., Ethgen, O., Gathon, H.J., Reginster, J.Y., Lifetime absolute risk of hip and other osteoporotic fracture in Belgian women (2008) Bone, 43 (6), pp. 991-994Haentjens, P., Magaziner, J., Colon-Emeric, C.S., Vanderschueren, D., Milisen, K., Velkeniers, B., Boonen, S., Meta-analysis: Excess mortality after hip fracture among older women and men (2010) Ann Intern Med, 152 (6), pp. 380-390Vidan, M.T., Sanchez, E., Gracia, Y., Maranon, E., Vaquero, J., Serra, J.A., Causes and effects of surgical delay in patients with hip fracture: A cohort study (2011) Ann Intern Med, 155 (4), pp. 226-233Majumdar, S.R., Beaupre, L.A., Johnston, D.W.C., Dick, D.A., Cinats, J.G., Jiang, H.X., Lack of association between mortality and timing of surgical fixation in elderly patients with hip fracture: Results of a retrospective population-based cohort study (2006) Medical Care, 44 (6), pp. 552-559. , DOI 10.1097/01.mlr.0000215812.13720.2e, PII 0000565020060600000010Novack, V., Jotkowitz, A., Etzion, O., Porath, A., Does delay in surgery after hip fracture lead to worse outcomes? A multicenter survey (2007) International Journal for Quality in Health Care, 19 (3), pp. 170-176. , DOI 10.1093/intqhc/mzm003Shiga, T., Wajima, Z., Ohe, Y., Is operative delay associated with increased mortality of hip fracture patients? Systematic review, meta-analysis, and meta-regression (2008) Canadian Journal of Anesthesia, 55 (3), pp. 146-154Kahn, S.K., Kalra, S., Khanna, A., Thiruvengada, M.M., Parker, M.J., Timing of surgery for hip fractures: A systematic review of 52 published studies involving 291, 413 patients (2009) Injury, 40 (7), pp. 692-697Leung, F., Lau, T.W., Kwan, K., Chow, S.P., Kung, A.W.C., Does timing of surgery matter in fragility hip fractures? (2010) Osteoporos Int, 21 (SUPPL. 4), pp. S529-S534Vidal, E.I., Moreira-Filho, D.C., Coeli, C.M., Camargo, K.R., Fukushima, F.B., Blais, R., Hip fracture in the elderly: Does counting time from fracture to surgery or from hospital admission to surgery matter when studying in-hospital mortality? 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