title: Calcium-dependent intracellular signal pathways in primary cultured adipocytes and ANK3 gene variation in patients with bipolar disorder and healthy controls.
abstract: Bipolar disorder (BD) is a chronic psychiatric disorder of public health importance affecting >1% of the Swedish population. Despite progress, patients still suffer from chronic mood switches with potential severe consequences. Thus, early detection, diagnosis and initiation of correct treatment are critical. Cultured adipocytes from 35 patients with BD and 38 healthy controls were analysed using signal pathway reporter assays, that is, protein kinase C (PKC), protein kinase A (PKA), mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK)), Myc, Wnt and p53. The levels of activated target transcriptional factors were measured in adipocytes before and after stimulation with lithium and escitalopram. Variations were analysed in the loci of 25 different single-nucleotide polymorphisms (SNPs). Activation of intracellular signals in several pathways analysed were significantly higher in patients than in healthy controls upon drug stimulation, especially with escitalopram stimulation of PKC, JNK and Myc, as well as lithium-stimulated PKC, whereas no meaningful difference was observed before stimulation. Univariate analyses of contingency tables for 80 categorical SNP results versus diagnoses showed a significant link with the ANK3 gene (rs10761482; likelihood ratio χ(2)=4.63; P=0.031). In a multivariate ordinal logistic fit for diagnosis, a backward stepwise procedure selected ANK3 as the remaining significant predictor. Comparison of the escitalopram-stimulated PKC activity and the ANK3 genotype showed them to add their share of the diagnostic variance, with no interaction (15% of variance explained, P<0.002). The study is cross-sectional with no longitudinal follow-up. Cohorts are relatively small with no medication-free patients, and there are no 'ill patient' controls. It takes 3 to 4 weeks of culture to expand adipocytes that may change epigenetic profiles but remove the possibility of medication effects. Abnormalities in the reactivity of intracellular signal pathways to stimulation and the ANK3 genotype may be associated with pathogenesis of BD. Algorithms using biological patterns such as pathway reactivity together with structural genetic SNP data may provide opportunities for earlier detection and effective treatment of BD.
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Le Gal
authors.affiliation: Sahlgrenska Academy, Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Södersten
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Vizlin-Hodzic
authors.affiliation: Sahlgrenska Academy, Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Ågren
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Funa
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D017487:Ankyrins / Q000235:genetics*; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D018692:Antimanic Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D015283:Citalopram / Q000627:therapeutic use; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D018020:Lithium Compounds / Q000627:therapeutic use; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D044465:White People / Q000235:genetics
chemical_list: C490613:ANK3 protein, human; D017487:Ankyrins; D018687:Antidepressive Agents, Second-Generation; D018692:Antimanic Agents; D018020:Lithium Compounds; D015283:Citalopram; D011493:Protein Kinase C; D002118:Calcium