Is There a Link between Circadian Clock Protein PERIOD 3 (PER3) (rs57875989) Variant and the Severity of COVID-19 Infection?

Abstract

Objective

Corona Virus Disease-2019 (COVID-19) has been among the major infectious events of the century. In today’s literature where COVID-19 and host factor effects are frequently examined, we aimed to examine another factor: Circadian Clock Protein PERIOD 3 (PER3). There is a significant correlation between PER3 gene polymorphism and circadian rhythm disturbances and immune system dysregulation.

Methods

In our study, we recruited 200 patients diagnosed with COVID-19 in our hospital between April–June 2020, and 100 volunteers without known comorbidities to create a healthy control group. After comparing the initial gene polymorphisms of the patients with healthy controls, three separate clinical subgroups were formed. Gene polymorphism distribution and statistical significance were examined in the formed patient groups.

Results

No significant difference was found between the patient group and the healthy controls (P>0.05, for all). When patients were divided into two separate clinical subgroups as exitus/alive according to their last condition during their 28-day follow-up, the 4R/5R genotype was significantly more common in patients with a mortal course (P=0.007). The PER3 4R/5R genotype was found at a significantly higher rate in the group of patients with the need for intensive care (P=0.034).

Conclusion

The 4R/5R genotype may be associated with the need for intensive care and mortality in COVID-19 patients. These important results will be a guide for future studies.

Keywords

corona virus disease 2019 / circadian rhythm / PER3 / prognosis

References

[1] WHO Corona Virus Disease 2019 (COVID-19) Dashboard. 2021; https://covid19.who.int. Accessed May 14, 2021.

[2] WuC, ChenX, CaiY, et al.. Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients with Corona-virus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med, 2020, 180(7): 934-943

[3] GuanWJ, NiZY, HuY, et al.. China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med, 2020, 382(18): 1708-1720

[4] CaiQ, ChenF, WangT, et al.. Obesity and COVID-19 Severity in a Designated Hospital in Shenzhen, China. Diabetes Care, 2020, 43(7): 1392-1398

[5] Centers for Disease Control and Prevention. People Who Are at Higher Risk for Severe Illness. 2020; https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-risk.html. Accessed April 8, 2020.

[6] ScheiermannC, GibbsJ, InceL, et al.. Clocking in to immunity. Nat Rev Immunol, 2018, 18(7): 423-437

[7] LabrecqueN, CermakianN. Circadian Clocks in the Immune System. J Biol Rhythms, 2015, 30(4): 277-290

[8] GuessJ, BurchJB, OgoussanK, et al.. Circadian disruption, Per3, and human cytokine secretion. Integr Cancer Ther, 2009, 8(4): 329-336

[9] EbisawaT, UchiyamaM, KajimuraN, et al.. Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. EMBO Rep, 2001, 2(4): 342-346

[10] HelvaciN, OguzSH, KabacamS, et al.. Clock gene PERIOD3 polymorphism is associated with susceptibility to Graves’ disease but not to Hashimoto’s thyroiditis. Chronobiol Int, 2019, 36(10): 1343-1350

[11] ZhuY, BrownHN, ZhangY, et al.. Period3 structural variation: a circadian biomarker associated with breast cancer in young wom-en. Cancer Epidemiol Biomarkers Prev, 2005, 14(1): 268-270

[12] MillerSA, DykesDD, PoleskyHF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res, 1988, 16(3): 1215

[13] NursalA, Cetinay AydinP, UysalM, et al.. PER3 VNTR variant and susceptibility to smoking status/substance use disorder in a Turkish population. Arch Clin Psychiatry, 2020, 47(3): 71-74

[14] MedetalibeyogluA, BahatG, SenkalN, et al.. Mannose binding lectin gene 2 (rs1800450) missense variant may contribute to devel-opment and severity of COVID-19 infection. Infect Genet Evol, 2021, 89: 104717

[15] VgontzasAN, ChrousosGP. Sleep, the hypothalamic-pituitary-adrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders. Endocrinol Metab Clin North Am, 2002, 31(1): 15-36

[16] VgontzasAN, ZoumakisM, BixlerEO, et al.. Impaired nighttime sleep in healthy old versus young adults is associated with elevated plasma interleukin-6 and cortisol levels: physiologic and therapeutic implications. J Clin Endocrinol Metab, 2003, 88(5): 2087-2095

[17] VenneriMA, HasenmajerV, FioreD, et al.. Circadian Rhythm of Glucocorticoid Administration Entrains Clock Genes in Immune Cells: A DREAM Trial Ancillary Study. J Clin Endocrinol Metab, 2018, 103(8): 2998-3009

[18] YangMY, LinPM, HsiaoHH, et al.. Up-regulation of PER3 Expression Is Correlated with Better Clinical Outcome in Acute Leu-kemia. Anticancer Res, 2015, 35(12): 6615-6622

[19] WuY, TaoB, ZhangT, et al.. Pan-Cancer Analysis Reveals Disrupted Circadian Clock Associates With T Cell Exhaustion. Front Immunol, 2019, 10: 2451

[20] Morales-SantanaS, MorellS, LeonJ, et al.. An Overview of the Polymorphisms of Circadian Genes Associated With Endocrine Cancer. Front Endocrinol (Lausanne), 2019, 10: 104

[21] LesickaM, JabłońskaE, WieczorekE, et al.. Circadian Gene Polymorphisms Associated with Breast Cancer Susceptibility. Int J Mol Sci, 2019, 20(22): 5704

[22] YoungBE, OngSWX, NgLFP, et al.. Singapore 2019 Novel Coronavirus Outbreak Research team. Viral dynamics and immune correlates of COVID-19 disease severity. Clin Infect Dis, 2020, 28: ciaa1280Aug

[23] ChiY, GeY, WuB, et al.. Serum Cytokine and Chemokine Profile in Relation to the Severity of Coronavirus Disease 2019 in China. J Infect Dis, 2020, 222(5): 746-754

[24] KongY, HanJ, WuX, et al.. VEGF-D: a novel biomarker for detection of COVID-19 progression. Crit Care, 2020, 24(1): 373

[25] MazzoccoliG, PalmieriO, CorritoreG, et al.. Association study of a polymorphism in clock gene PERIOD3 and risk of inflammato-ry bowel disease. Chronobiol Int, 2012, 29(8): 994-1003