Circadian rhythm the subconscious mystery

What have clock genes got to do with MS?

PLoS One. 2018 Jan 11;13(1):e0190601. doi: 10.1371/journal.pone.0190601. eCollection 2018.

Association of circadian rhythm genes ARNTL/BMAL1 and CLOCK with multiple sclerosis.

Lavtar P1, Rudolf G1, Maver A1, Hodžić A1, Starčević Čizmarević N2, Živković M3, Šega Jazbec S4, Klemenc Ketiš Z5,6, Kapović M2, Dinčić E7, Raičević R7, Sepčić J8, Lovrečić L1, Stanković A3, Ristić S2, Peterlin B1.


Prevalence of multiple sclerosis varies with geographic latitude. We hypothesized that this fact might be partially associated with the influence of latitude on circadian rhythm and consequently that genetic variability of key circadian rhythm regulators, ARNTL and CLOCK genes, might contribute to the risk for multiple sclerosis. Our aim was to analyse selected polymorphisms of ARNTL and CLOCK, and their association with multiple sclerosis. A total of 900 Caucasian patients and 1024 healthy controls were compared for genetic signature at 8 SNPs, 4 for each of both genes. We found a statistically significant difference in genotype (ARNTL rs3789327, P = 7.5·10-5; CLOCK rs6811520 P = 0.02) distributions in patients and controls. The ARNTL rs3789327 CC genotype was associated with higher risk for multiple sclerosis at an OR of 1.67 (95% CI 1.35-2.07, P = 0.0001) and the CLOCK rs6811520 genotype CC at an OR of 1.40 (95% CI 1.13-1.73, P = 0.002). The results of this study suggest that genetic variability in the ARNTL and CLOCK genes might be associated with risk for multiple sclerosis.

Believe it or not, nothing comes as close to perfection as your body’s internal clock; it thrums almost effortlessly in the background like a well tuned Ferrari looking to prance again. Unbeknown to us it controls our body’s physiological and behavioral responses (the list includes hormones, behavior, memory/intelligence, seasonal cycle, cell division, function and death). Day/night dynamics, sunlight all shift the equilibrium and we’re all aware of this effect in the modern era with shift work and air travel. Serious abnormalities in the clock, however, understandably can be hazardous to health. Genetic deletions in the so-called clock genes have been linked to sleep, mood, metabolic disorders, including infertility, cancers, heart disorders and psychiatric illnesses. It also has an effect on the immune system, and regulates the activation and accumulation of immune cells, as well as their cross-talk.

Lavtar et al.  hypothesize that the latitude influence in MS may also affect our body’s internal clock (circadian rhythm) and any variability in the clock genes may contribute to the risk of MS. They studied the core regulator genes ARNTL/CLOCK in 900 PwMS vs 1024 controls. They found variations in both ARNTL and CLOCK genes increased the risk of MS by odds of  1.68 and 1.40, respectively. In their discussion, the authors mention a publication linking shift work at a young age increasing the risk of MS (Hedstrom AK, Akerstedt T, Hillert J, Olsson T, Alfredsson L. Shift work at young age is associated with increased risk for multiple sclerosis. Annals of neurology. 2011;70(5):733–41). In EAE (mouse model of MS), the usual fluctuations in CLOCK gene expressions that normally occur over a 24h period were noted to be reduced, suggesting that there may be disturbances in circadian rhythm during inflammation (Buenafe AC. Diurnal rhythms are altered in a mouse model of multiple sclerosis. Journal of neuroimmunology. 2012;243(1–2):12–7).

Whatever the case, this is a new area of research for MS, so let’s hope that there are new developments in this area.

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Neuro Doc Gnanapavan


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  • Mice with a targeted deletion of Bmal1 from myeloid cells have significantly enhanced pro-inflammatory and T cell-polarizing cytokine responses. On the other hand, the clock actively suppresses inflammatory pathways during the dark phase.

    Sutton CE, Finlay CM, Raverdeau M, et al. Loss of the molecular clock in myeloid cells exacerbates T cell-mediated CNS autoimmune disease. Nat Commun 2017;8:1923.

    Oishi Y, Hayashi S, Isagawa T, et al. Bmal1 regulates inflammatory responses in macrophages by modulating enhancer RNA transcription. Sci Rep 2017;7:7086.

    Hand LE, Hopwood TW, Dickson SH, et al. The circadian clock regulates inflammatory arthritis. FASEB J 2016;30:3759-3770.

  • Lolll

    My clock is upside down ..10h in the morning i am most a sleep …2h

    the morning i am most awake… 🙂




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