Altered Exression of Circadian Clock Genes in Polyglandular Autoimmune Syndrome Type III

Presentation Number: MON 384
Date of Presentation: April 3rd, 2017

Anna Angelousi1, Narjes Nasiri Ansari2, Eliana Spilioti3, Vasiliki Kalotyxou4, George P. Chrousos5, Gregory A Kaltsas6 and Eva Kassi*7
1Department of Pathophysiology, Unit of Endocrinology, National and Kapodistrian University of, 2National and Kapodistrian University of Athens, Athens, Greece, Athens, Greece, 3Department of Biological Chemistry,National and Kapodistrian University of, 4Department of Internal Medicine, University of Athens, School of Medicine, Laikon General Hospital, 5University of Athens Medical School, Athens, Greece, 6University of Athens School of Medicine, 7Department of Biological Chemistry,National and Kapodistrian University of Athens, ATHENS, Greece

Abstract

Introduction:CLOCK system is a highly conserved, ubiquitous molecular ‘‘Clock’’ which creates internal circadian rhythmicity. Dysfunction of this circadian Clock gene is associated with immune dysregulation and cancer development. In the present study we investigated the circadian pattern of Clock-related genes in patients with polyglandular autoimmune syndrome type III (PASIII)

Methods: Nineteen patients diagnosed with PASIII (5 males) and 12 healthy controls (4 males) were enrolled. Peripheral blood transcript levels of 6 Clock related genes (CLOCK, BMAL1,ROR and PER1,2,3), GR-α and GILZwere determined by real-time quantitative PCR. Mesurements were performed in two time point at 8 am and at 8 pm. Protein expression of GR-α genes was also analysed by Western Blot. Serum cortisol and TSH as well as plasma ACTH were measured by chemiluminescence.

 Results No statistical differences were found in cortisol (normal range:5-20 μg/dl), ACTH(normal range:9-52 pg/ml) and TSH (normal range: 0.4-4.0 μU/ml) levels between patients and healthy controls. Patients with PAS III expressed signifficanlty higher transcript levels of CLOCK, BMAL1 and PER1 in the evening compared to the morning (p=0.03, p=0.04 and p=0.013 respectively). Circadian pattern (ΔΔCt pm/am) of GR, CLOCK, BMAL1 and PER3 genes was significantly different in patients compared to healthy controls ( P=0.05, P=0.0184, P=0.03, P=0.05 respectively). Cortisol circadian variation (ΔFpm/am) was positively correlated with GILZ circadian pattern (ΔΔCt pm/am) in the patient group and the GRcircadian pattern in controls. More over, western blot analysis revealed a significant greater slope of the GR-α protein level in the evening in control group compared to patient group ( P=0.05).

Conclucions: These findings suggest that there is an aberrant circadian rhythm of Clock-related genes in patients with PASIII compared to healthy controls. Daily pattern expression of the 4 circadian Clock genes was disrupted in patients with PAS III indicating a possible association with the pathogenesis of the disease.

 

Nothing to Disclose: AA, NN, ES, VK, GPC, GAK, EK