| 1. |
- Myhrstad, Mari C. W., et al.
(författare)
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Healthy Nordic Diet Modulates the Expression of Genes Related to Mitochondrial Function and Immune Response in Peripheral Blood Mononuclear Cells from Subjects with Metabolic Syndrome-A SYSDIET Sub-Study
- 2019
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Ingår i: Molecular Nutrition & Food Research. - : John Wiley & Sons. - 1613-4125 .- 1613-4133. ; 63:13
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Tidskriftsartikel (refereegranskat)abstract
- Scope To explore the effect of a healthy Nordic diet on the global transcriptome profile in peripheral blood mononuclear cells (PBMCs) of subjects with metabolic syndrome. Methods and results Subjects with metabolic syndrome undergo a 18/24 week randomized intervention study comparing an isocaloric healthy Nordic diet with an average habitual Nordic diet served as control (SYSDIET study). Altogether, 68 participants are included. PBMCs are obtained before and after intervention and total RNA is subjected to global transcriptome analysis. 1302 probe sets are differentially expressed between the diet groups (p-value < 0.05). Twenty-five of these are significantly regulated (FDR q-value < 0.25) and are mainly involved in mitochondrial function, cell growth, and cell adhesion. The list of 1302 regulated probe sets is subjected to functional analyses. Pathways and processes involved in the mitochondrial electron transport chain, immune response, and cell cycle are downregulated in the healthy Nordic diet group. In addition, gene transcripts with common motifs for 42 transcription factors, including NFR1, NFR2, and NF-kappa B, are downregulated in the healthy Nordic diet group. Conclusion These results suggest that benefits of a healthy diet may be mediated by improved mitochondrial function and reduced inflammation.
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| 2. |
- Baselli, Guido A, et al.
(författare)
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Rare ATG7 genetic variants predispose patients to severe fatty liver disease.
- 2022
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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 77:3, s. 596-606
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci contributing to severe NAFLD by examining rare variants.We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n=301) and examined the enrichment of likely pathogenic rare variants vs. the general population, followed by validation at gene level.In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; OR 5.26, 2.1-12.6; p=0.003) of autophagy-related 7 (ATG7), which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9, 1.9-612; p=0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30, 1.1-7.5 and OR 12.30, 2.6-36, respectively; p<0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T>C) was also associated with severe NAFLD in the clinical cohort (OR=1.7, 1.2-2.5; p=0.003), predisposed to hepatocellular ballooning (p=0.007) evolving to fibrosis in a Liver biopsy cohort (n=2268), and was associated with liver injury in the UK Biobank (AST levels, p<0.001), with a larger effect in severely obese individuals where it was linked to hepatocellular carcinoma (p=0.009). ATG7 protein localized to periportal hepatocytes, more so in the presence of ballooning. In the Liver Transcriptomic cohort (n=125) ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers.We identified rare and low-frequency ATG7 loss-of-function variants as modifiers of NAFLD progression by impairing autophagy and facilitating ballooning and inflammation.•We found that rare mutations in a gene called autophagy related (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. •These mutations cause an alteration in protein function and impairment of self-renewal of cellular content, leading to liver damage and inflammation.
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| 3. |
- Dongiovanni, Paola, et al.
(författare)
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PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients.
- 2019
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Ingår i: Journal of lipid research. - 1539-7262. ; 60:June, s. 1144-1153
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Tidskriftsartikel (refereegranskat)abstract
- Dyslipidemia and altered iron metabolism are typical features of non-alcoholic fatty liver disease (NAFLD). Proprotein Convertase Subtilisin/Kexin Type 7 (PCSK7) gene variation has been associated with circulating lipids and liver damage during iron overload. Aim of this study was to examine the impact of the PCSK7 rs236918 variant on NAFLD-related traits in 1,801 individuals from the Liver Biopsy Cohort (LBC), 500,000 from the UK Biobank Cohort (UKBBC), and 4,580 from the Dallas Heart Study (DHS). The minor PCSK7 rs236918 C allele was associated with higher triglycerides, aminotransferases and hepatic inflammation in the LBC (p<0.05) and with hypercholesterolemia and liver disease in the UKBBC. In the DHS, PCSK7 missense variants were associated with circulating lipids. PCSK7 was expressed in hepatocytes and its hepatic expression correlated with that of lipogenic genes (p<0.05). The rs236918 C allele was associated with upregulation of a new 'intra-PCSK7' lnc-RNA predicted to interact with the protein, higher hepatic and circulating PCSK7 protein (p<0.01), and the latter correlated with triglycerides (p=0.04). In HepG2, PCSK7 deletion reduced lipogenesis, fat accumulation, inflammation, TGFB pathway activation and fibrogenesis. In conclusion, PCSK7 gene variation is associated with dyslipidemia and more severe liver disease in high risk individuals, likely by modulating PCSK7 expression/activity.
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| 4. |
- Dongiovanni, Paola, et al.
(författare)
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Statin use and nonalcoholic steatohepatitis in at risk individuals.
- 2015
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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 63:3, s. 705-712
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Tidskriftsartikel (refereegranskat)abstract
- Excess hepatic free cholesterol contributes to the pathogenesis of nonalcoholic steatohepatitis, and statins reduce cholesterol synthesis. Aim of this study was to assess whether statin use is associated with histological liver damage related to steatohepatitis.
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| 5. |
- Garcia-Calzon, Sonia, et al.
(författare)
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Epigenetic markers associated with metformin response and intolerance in drug-naive patients with type 2 diabetes
- 2020
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 12:561
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Tidskriftsartikel (refereegranskat)abstract
- Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naive patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in discovery and replication cohorts. Greater methylation at these sites associated with a higher risk of not responding to or not tolerating metformin with odds ratios between 1.43 and 3.09 per 1-SD methylation increase. Methylation risk scores (MRSs) of the 11 identified sites differed between glycemic responders and nonresponders with areas under the curve (AUCs) of 0.80 to 0.98. MRSs of the 4 sites associated with future metformin intolerance generated AUCs of 0.85 to 0.93. Some of these blood-based methylation markers mirrored the epigenetic pattern in adipose tissue, a key tissue in diabetes pathogenesis, and genes to which these markers were annotated to had biological functions in hepatocytes that altered metformin-related phenotypes. Overall, we could discriminate between glycemic responders/nonresponders and participants tolerant/intolerant to metformin at diagnosis by measuring blood-based epigenetic markers in drug-naive patients with T2D. This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy.
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| 6. |
- Jarvela-Reijonen, Elina, et al.
(författare)
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The Effects of Acceptance and Commitment Therapy (ACT) Intervention on Inflammation and Stress Biomarkers : a Randomized Controlled Trial
- 2020
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Ingår i: International Journal of Behavioral Medicine. - : Springer Science and Business Media LLC. - 1070-5503 .- 1532-7558. ; 27:5, s. 539-555
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Tidskriftsartikel (refereegranskat)abstract
- Background Psychological processes can be manifested in physiological health. We investigated whether acceptance and commitment therapy (ACT), targeted on psychological flexibility (PF), influences inflammation and stress biomarkers among working-age adults with psychological distress and overweight/obesity. Method Participants were randomized into three parallel groups: (1) ACT-based face-to-face (n = 65; six group sessions led by a psychologist), (2) ACT-based mobile (n = 73; one group session and mobile app), and (3) control (n = 66; only the measurements). Systemic inflammation and stress markers were analyzed at baseline, at 10 weeks after the baseline (post-intervention), and at 36 weeks after the baseline (follow-up). General PF and weight-related PF were measured with questionnaires (Acceptance and Action Questionnaire, Acceptance and Action Questionnaire for Weight-Related Difficulties). Results A group x time interaction (p = .012) was detected in the high-sensitivity C-reactive protein (hsCRP) level but not in other inflammation and stress biomarkers. hsCRP decreased significantly in the face-to-face group from week 0 to week 36, and at week 36, hsCRP was lower among the participants in the face-to-face group than in the mobile group (p = .035, post hoc test). Age and sex were stronger predictors of biomarker levels at follow-up than the post-intervention PF. Conclusion The results suggest that ACT delivered in group sessions may exert beneficial effects on low-grade systemic inflammation. More research is needed on how to best apply psychological interventions for the health of both mind and body among people with overweight/obesity and psychological distress.
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| 7. |
- Pyykko, Okko T., et al.
(författare)
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Incidence, Comorbidities, and Mortality in Idiopathic Normal Pressure Hydrocephalus
- 2018
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Ingår i: World Neurosurgery. - : ELSEVIER SCIENCE INC. - 1878-8750 .- 1878-8769. ; 112, s. E624-E631
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Tidskriftsartikel (refereegranskat)abstract
- OBJECT: To investigate the incidence, comorbidities, mortality, and causes of death in idiopathic normal pressure hydrocephalus (iNPH). METHODS: A cohort of 536 patients with possible NPH from a defined population with a median follow-up time of 5.1 years, (range 0.04-19.9 years) was included in the study. Patients were evaluated by brain imaging and intraventricular pressure monitoring, with a brain biopsy specimen immunostained against amyloid-beta and hyper-phosphorylated tau. Hospital records were reviewed for vascular diseases and type 2 diabetes mellitus (T2DM). Death certificates and yearly population of the catchment area were obtained from national registries. RESULTS: A total of 283 patients had a clinical diagnosis of iNPH, leading to a median annual incidence of 1.58 iNPH patients per 100,000 inhabitants (range, 0.8-4.5). Alzeimer disease-related brain biopsy findings were less frequent in iNPH patients than in non-iNPH patients (P < 0.05). An overrepresentation of hypertension (52% vs. 33%, P < 0.001) and T2DM (23% vs. 13%, P = 0.002) was noted in iNPH patients. Age (hazard ratio [HR] 1.04/year, 95% confidence interval [CI] 1.03-1.06, P< 0.001) and T2DM (HR 1.63, 95% CI 1.23-2.16, P < 0.001) increased the risk of death in the iNPH patients and in the total population. iNPH was associated with decreased risk of death (HR 0.63, 95% CI 0.50-0.78, P < 0.001). The most frequent causes of death were cardiovascular and cerebrovascular disease. Dementia as a cause of death was more common in non-iNPH patients (27% vs. 10%, P < 0.001). CONCLUSIONS: Hypertension and T2DM are common in iNPH and the latter causes excess mortality in the affected patients.
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