| 1. |
- Okhuijsen-Pfeifer, C, et al.
(författare)
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Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders
- 2022
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 12:1, s. 145-
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Tidskriftsartikel (refereegranskat)abstract
- Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10−3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10−4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10−3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10−7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.
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| 2. |
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| 3. |
- Edlinger, M., et al.
(författare)
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Metabolic syndrome and risk of brain tumour in a large population-based cohort study
- 2011
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Ingår i: IEA World Congress of Epidemiology, 7–11 August 2011, Edinburgh International Conference Centre, Edinburgh, Scotland. - : BMJ.
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Konferensbidrag (refereegranskat)abstract
- Background: There are few established determinants of brain tumour. We assessed among adults the risk of brain tumour in relation to metabolic syndrome factors. Methods: 580 000 subjects from Sweden, Austria, and Norway were followed for a median of 10 years (Me-Can). Brain tumour information was obtained from national cancer registries. The factors of metabolic syndrome, body mass index, blood pressure, and blood levels of glucose, cholesterol, and triglycerides, were analysed in quintiles and for transformed z-scores (mean of 0 and SD of 1). Cox proportional hazards regression models were applied, stratified by cohort and corrected for measurement error. Results: In total 1312 primary brain tumours were diagnosed during follow-up, predominantly high-grade glioma (n=436) and meningioma (n=348). For meningioma, the HR was increased for systolic blood pressure (HR=1.27 per unit SD, 95% CI 1.03 to 1.57), for diastolic blood pressure (HR=1.29, 95% CI 1.04 to 1.58), and for the combined metabolic syndrome score (HR=1.31, 95% CI 1.11 to 1.54). For high-grade glioma the risk was increased for diastolic blood pressure (HR=1.23, 95% CI 1.01 to 1.50) and triglycerides (HR=1.35, 95% CI 1.05 to 1.72). For both meningioma and high-grade glioma, the risk was more than doubled in the fifth quintiles of diastolic blood pressure compared to the first quintile. For systolic blood pressure the meningioma risk was even larger. Conclusion: Increased blood pressure was related to risk of brain tumour, particularly of meningiomas.
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| 4. |
- Nagel, Gabriele, et al.
(författare)
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Metabolic risk factors and skin cancer in the Metabolic Syndrome and Cancer Project (Me-Can)
- 2012
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Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 0007-0963 .- 1365-2133. ; 167:1, s. 59-67
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Tidskriftsartikel (refereegranskat)abstract
- Background Little is known about the associations of metabolic aberrations with malignant melanoma (MM) and nonmelanoma skin cancer (NMSC). Objectives To assess the associations between metabolic factors (both individually and combined) and the risk of skin cancer in the large prospective Metabolic Syndrome and Cancer Project (Me-Can). Methods During a mean follow-up of 12 years of the Me-Can cohort, 1728 (41% women) incident MM, 230 (23% women) fatal MM and 1145 (33% women) NMSC were identified. Most NMSC cases (76%) were squamous cell carcinoma (SCC) (873, 33% women). Hazard ratios (HRs) were estimated by Cox proportional hazards regression for quintiles and standardized z-scores (with a mean of 0 and SD of 1) of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and for a combined metabolic syndrome score. Risk estimates were corrected for random error in the measurements. Results Blood pressure per unit increase of z-score was associated with an increased risk of incident MM cases in men and women [HR 1·17, 95% confidence interval (CI) 1·04-1·31 and HR 1·18, 95% CI 1·03-1·36, respectively] and fatal MM cases among women (HR 2·39, 95% CI 1·58-3·64). In men, all quintiles for BMI above the reference were associated with a higher risk of incident MM. In women, SCC NMSC risk increased across quintiles for glucose levels (P-trend 0·02) and there was a trend with triglyceride concentration (P-trend 0·09). Conclusion These findings suggest that mechanisms linked to blood pressure may be involved in the pathogenesis of MM. SCC NMSC in women could be related to glucose and lipid metabolism.
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