Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Bengesser, S.
Shared Pathways between Obesity and Bipolar Disorder:
Endoplasmic Reticulum Stress, Oxidative Stress and
the Circadian Clock -
Genetic and Epigenetic Analysis
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp.
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Bengesser Susanne
- Betreuer*innen:
- Holasek Sandra Johanna
- Kapfhammer Hans-Peter
- Reininghaus Eva
- Altmetrics:
- Abstract:
- Background Individuals with Bipolar Disorder (BD) suffer disproportionately frequently (about 70%) from overweight and obesity. Literature postulates a relationship between Endoplasmic Reticulum (ER) stress, oxidative stress and circadian rhythms and obesity. Therefore, the triad was studied molecular biologically in synopsis with BD and obesity. Methods I. group differences between BD and controls using ANCOVAs and II. correlations with body mass index (BMI) or differences between weight groups (normal weight, overweight, obese) were investigated using ANCOVAs. The following methods were used in peripheral blood: (1) ER stress quantification by gene expression analysis with quantitative PCR of the genes BiP and CHOP, as well as semiquantitative analysis of XBP1 splicing. Hypothesis-driven gene association tests of PERK rs867529, ATF6 rs2271013, LMAN2L rs9834970 and LMAN2L s6746896 in BD and controls. (2) Oxidative stress was determined by detection of the lipid peroxidation markers malondialdehyde (MDA) and Thiobarbituric Acid Reactive Substances (TBARS), as well as the antioxidant parameters glutathione S-transferase (GST), Cu / Zn superoxide dismutase (SOD) and total antioxidant capacity (TAC). (3) The molecular circadian clock was analyzed with hypothesis-driven gene association tests of the CLOCK and PER3 genes with PLINK in BD and controls. Methylation analysis of the clock gene ARNTL (g05733463 and PS2 POS1-7) was performed with the Epitect Kit, PCR and pyrosequencing. Results: Individuals with BD had a significantly higher BiP gene expression compared to controls F(1/100) = 4.449, p < 0.05, partial Eta2 = 0.043). The total sum of the XBP1 mRNA was significantly lower in BD than in the controls (F(1/100) = 5.265, p < 0.05, Partial Eta2 = 0.050). Similarly, patients with BD had significantly less unspliced ¿¿XBP1 than controls (F(1/100) = 5.634, p < 0.05, Partial Eta2 = 0.053). The LMAN2L rs6746896 SNP showed a significant association with BD in the "basic gene association test" (X2 = 3.881, p < 0.05, OR = 0.65). ER stress markers did not differ significantly between the weight groups and there was no significant correlation between BMI and ER stress parameters. BMI did not differ between the different investigated genotype groups. The oxidative stress marker MDA was significantly lower in BD compared to controls (F(1/204) = 8.485, p < 0.05, Partial Eta2 = 0.040). The total antioxidant capacity TAC was significantly lower in patients with BD compared to controls (F(1/189) = 8.406, p < 0.05, Partial Eta2 = 0.043). Antioxidative markers correlated with BMI in the total sample independently of BD - TAC correlated negatively with BMI (r = -0.143, p < 0.05) and GST correlated positively with BMI (r = 0.151, p < 0.05). Individuals with BD showed a significantly higher methylation of ARNTL at cg05733463 compared to controls (F(1/209) = 44,500, p < 0.001, Partial Eta2 = 0.176). In contrast, the second CpG Island PS2 of ARNTL had significantly lower methylation ¿¿in individuals with BD compared to controls at PS2 POS1 (F(1/28) = 5.787, p < 0.05, Partial Eta2 = 0.043). The methylation of ARNTL did not differ between the different weight classes. Furthermore, there were no significant associations of PER3 and CLOCK with BD in the gene association test. BMI did not differ between the investigated clock gene genotype groups. Discussion The results of this dissertation underline the enormous importance of ER homeostasis, oxidative stress and disturbed circadian rhythms in the pathogenesis of BD. The ER stress gene expression markers BiP and XBP1, the oxidative stress marker MDA, the TAC, as well as the methylation of the ARNTL clock gene could represent bio-markers or new "drug targets" in BD after further intensive research.