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| 12. |
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| 13. |
- Bien, Stephanie A., et al.
(författare)
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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
- 2019
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 138:4, s. 307-326
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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| 14. |
- Büchner, Frederike L, et al.
(författare)
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Variety in vegetable and fruit consumption and risk of bladder cancer in the European prospective investigation into cancer and nutrition
- 2011
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 128:12, s. 2971-2979
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Tidskriftsartikel (refereegranskat)abstract
- Recent research does not show an association between fruit and vegetable consumption and bladder cancer risk. None of these studies investigated variety in fruit and vegetable consumption, which may capture different aspects of consumption. We investigated whether a varied consumption of vegetables and fruits is associated with bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Detailed data on food consumption and complete follow-up for cancer incidence were available for 452,185 participants, who were recruited from ten European countries. After a mean follow-up of 8.7 years, 874 participants were diagnosed with bladder cancer. Diet diversity scores (DDSs) were used to quantify the variety in fruit and vegetable consumption. Multivariable Cox proportional hazard models were used to assess the effect of the DDSs on bladder cancer risk. There was no evidence of a statistically significant association between bladder cancer risk and any of the DDSs when these scores were considered as continuous covariates. However, the hazard ratio (HR) for the highest tertile of the DDS for combined fruit and vegetable consumption was marginally significant compared to the lowest (HR = 1.30, 95% confidence interval: 1.00-1.69, p-trend = 0.05). In EPIC, there is no clear association between a varied fruit and vegetable consumption and bladder cancer risk. This finding provides further evidence for the absence of any strong association between fruit and vegetable consumption as measured by a food frequency questionnaire and bladder cancer risk.
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| 15. |
- Buechner, Frederike L., et al.
(författare)
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Consumption of vegetables and fruit and the risk of bladder cancer in the European Prospective Investigation into Cancer and Nutrition
- 2009
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 125:11, s. 2643-2651
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Tidskriftsartikel (refereegranskat)abstract
- Previous epidemiologic studies found inconsistent associations between vegetables and fruit consumption and the risk of bladder cancer. We therefore investigated the association between vegetable and fruit consumption and the risk of bladder cancer among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Data on food consumption and complete follow-up for cancer occurrence was available for a total of 478,533 participants, who were recruited in 10 European countries. Estimates of rate ratios were obtained by Cox proportional hazard models, stratified by age at recruitment, gender and study centre, and adjusted for total energy intake, smoking status, duration of smoking and lifetime intensity of smoking. A calibration study in a subsample was used to control for dietary measurement errors. After a mean follow-up of 8.7 years, 1015 participants were newly diagnosed with bladder cancer. Increments of 100 g/day in fruit and vegetable consumption combined did not affect bladder cancer risk (i.e., calibrated HR = 0.98; 95%CI: 0.95-1.01). Borderline statistically significant lower bladder cancer risks were found among fever smokers with increased consumption of fruit and vegetables combined (HR = 0.94 95%CI: 0.87-1.00 with increments of 100 g/day; calibrate HR = 0.92 95%CI 0.79-1.06) and increased consumption of apples and pears (hard fruit; calibrated HR = 0.90 95%CI: 0.82-0.98 with increments of 25 g/day). For none of the associations a statistically significant interaction with smoking status was found. Our findings do not support an effect of fruit and vegetable consumption, combined or separately, on bladder cancer risk. (c) 2009 UICC
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| 16. |
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| 17. |
- Guo, Xingyi, et al.
(författare)
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Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects
- 2020
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Ingår i: Gastroenterology. - : Elsevier. - 0016-5085 .- 1528-0012. ; 160:4, s. 1164-1178
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.Methods: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.Results: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.Conclusions: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
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| 18. |
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| 19. |
- Luoto, Kaisa E., et al.
(författare)
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Impact of Comorbid Alcohol Use Disorder on Health-Related Quality of Life Among Patients With Depressive Symptoms
- 2021
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Ingår i: Frontiers in Psychiatry. - : Frontiers Media S.A.. - 1664-0640. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aim: In psychiatric clinical practice, comorbidity of depression and alcohol use disorder (AUD) is common. Both disorders have a negative impact on health-related quality of life (HRQoL) in general population. However, research on the impact of comorbid AUD on HRQoL among clinically depressed patients is limited. The purpose of this study was to explore the impact of a psychosocial treatment intervention on HRQoL for depressive patients in specialized psychiatric care with a special focus on the impact of AUD on HRQoL.Material and Methods: Subjects were 242 patients of the Ostrobothnia Depression Study (ClinicalTrials.gov Identifier NCT02520271). Patients referred to specialized psychiatric care who scored at least 17 points on the Beck Depression Inventory at baseline and who had no psychotic disorders were included in the ODS. The treatment intervention in ODS comprised behavioral activation for all but began with motivational interviewing for those with AUD. HRQoL was assessed regularly during 24-month follow-up by the 15D instrument. In the present study, HRQoL of ODS patients with or without AUD was compared and the factors explaining 15D score analyzed with a linear mixed model. In order to specify the impact of clinical depression on HRQoL during the early phase of treatment intervention, a general population sample of the Finnish Health 2011 Survey was used as an additional reference group.Results: HRQoL improved among all ODS study sample patients regardless of comorbid AUD during the first year of follow-up. During 12–24 months of follow-up the difference between groups was seen as HRQoL continued to improve only among the non-AUD patients. A combination of male gender, anxiety disorder, and AUD was associated with the poorest HRQoL in this sample. In combined sample analyses with the reference group, clinical depression had an impact on HRQoL in short-term follow-up regardless of the treatment intervention.Conclusions: This study suggests that, in terms of improvement in HRQoL, the heterogenous group of depressive patients in specialized psychiatric care can be successfully treated with behavioral activation in combination with motivational interviewing for those with AUD.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02520271. Ostrobothnia Depression Study (ODS). A Naturalistic Follow-up Study on Depression and Related Substance Use Disorders. (2015). Available online at: https://clinicaltrials.gov/ct2/show/NCT02520271.
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| 20. |
- Luoto, Kaisa E., et al.
(författare)
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Predictors of short-term response and the role of heavy alcohol use in treatment of depression
- 2023
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Ingår i: BMC Psychiatry. - : BioMed Central (BMC). - 1471-244X. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Depression and alcohol use disorders frequently co-occur. However, research on psychosocial interventions for treating this dual pathology is limited. The Ostrobothnian Depression Study (ODS) aimed to increase the systematic use of evidence-based methods, particularly among patients with comorbid depression and substance use in a naturalistic setting. This is a secondary analysis of the ODS study. The aim of the present study was to explore the predictors of a response to treatment during the first six months of the ODS intervention with a specific focus on the role of comorbid heavy alcohol use.Methods: The study sample (n = 242) comprised psychiatric specialist care patients with depression (Beck Depression Inventory score ≥ 17) at baseline. Patients with a baseline Alcohol Use Disorders Identification Test (AUDIT) score > 10 (n = 99) were assigned to the AUD (Alcohol Use Disorder) group in this study. The ODS intervention comprised behavioral activation (BA) for all and additional motivational interviewing (MI) for those in AUD group. The predictors of response to treatment (minimum of 50% reduction in depressive symptoms) during the first six months were analyzed with logistic regression models.Results: In the total sample at six months (n = 150), predictors of response to treatment were more severe depression (OR 1.10, CI 1.02–1.18), larger amounts of alcohol consumed (OR = 1.16, CI 1.03–1.31) and antipsychotic medication "not in use" (OR = 0.17, CI 0.07–0.44). In the non-AUD group (n = 100), more severe depression (OR 1.12, CI 1.01–1.25) and antipsychotics "not in use" (OR 0.20, CI 0.06–0.67) also predicted a positive response. Among AUD group patients (n = 50), larger amounts of alcohol consumed (OR 1.54, CI 1.04–2.27) and antipsychotic medication "not in use" (OR 0.12, CI 0.02–0.60) predicted a response to the treatment intervention.Conclusions: The severity of symptoms and comorbid disorders were found to predict better treatment response, suggesting that the intervention was more effective in patients with severe symptoms. Patients with depression should be treated effectively regardless of having concomitant AUD. The results of this study suggest that BA combined with MI should be one of the treatment options for this dual pathology.Trial registration: ClinicalTrials.gov Identifier NCT02520271 (11/08/2015).
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