Association between Val158Met polymorphism in the COMT gene with anxiety and heart rate variability in children with irritable bowel syndrome

Authors

DOI:

https://doi.org/10.14739/2310-1210.2023.5.278878

Keywords:

COMT gene, trait anxiety, heart rate variability, irritable bowel syndrome, children

Abstract

The aim of this study was to examine the peculiarities of trait anxiety and heart rate variability parameters as well as their relationship depending on the catechol O-methyltransferase (COMT) gene Val158Met polymorphism in children with irritable bowel syndrome.

Materials and methods. A total of 26 children aged 6–12 years with a verified diagnosis of irritable bowel syndrome according to the Rome IV criteria were examined. Beforehand, all the patients underwent molecular genetic testing for the COMT Val158met single nucleotide polymorphism by using the polymerase chain reaction-restriction fragment length polymorphism method. Heart rate variability was analyzed via cardiointervalography (Neurosoft) based on short five-minute resting-state ECG recordings.

The CMAS (Children’s Manifest Anxiety Scale) test was used to measure trait anxiety levels. The Pearson’s test was used to assess correlations between heart rate variability parameters and anxiety levels. Data were processed using Microsoft Excel 2016 and analyzed with GraphPad (Prism 5.0).

Results. Depending on the functional COMT Val158met polymorphism, all the patients were allocated to 3 groups: 8 children with 472 GA (Val/Met) COMT genotype; 10 children with 472 AA (Met/Met) genotype; 8 children with 472 GG (Val/Val) genotype. Time and frequency domain parameters of heart rate variability were significantly different in each group.

The highest level of anxiety and the largest percentage of LF component (mainly sympathetic activity) in the structure of heart rate variability was noted among Met/Met carriers. Val/Val carriers had a significantly lower anxiety level and an autonomic imbalance with a higher percentage of HF component (parasympathetic activity). Positive correlations between trait anxiety and heart rate variability parameters were found only in Val/Val and Val/Met groups.

Conclusions. Our study has revealed the influence of the COMT Val158met polymorphism on the level of trait anxiety and heart rate variability parameters. It is important for a better understanding of the gut-brain axis dysregulation and impaired stress resilience in children with irritable bowel syndrome. Also, these data could be used to improve current schemes for the treatment of irritable bowel syndrome, supplementing them with activation therapy, psychotherapy, psychopharmacotherapy.

Author Biographies

M. O. Semen, Danylo Halytsky Lviv National Medical University, Ukraine

MD, PhD Student, Department of Propaedeutics of Pediatrics and Medical Genetics

O. L. Lychkovska, Danylo Halytsky Lviv National Medical University, Ukraine

MD, PhD, DSc, Professor, Head of the Department of Propaedeutics of Pediatrics and Medical Genetics

M. Ya. Tyrkus, Institute of Hereditary Pathology of the NAMS of Ukraine, Lviv

PhD, Senior Researcher

D. V. Kaminskyy, Danylo Halytsky Lviv National Medical University, Ukraine

PhD, Associate Professor, Department of Pharmaceutical, Organic and Bioorganic Chemistry

O. P. Yelisyeyeva, Danylo Halytsky Lviv National Medical University, Ukraine

PhD, DSc, Professor of the Department of Histology, Cytology and Embryology

References

  1. Devanarayana, N. M., & Rajindrajith, S. (2018). Irritable bowel syndrome in children: Current knowledge, challenges and opportunities. World journal of gastroenterology, 24(21), 2211-2235. https://doi.org/10.3748/wjg.v24.i21.2211
  2. Ford, A. C., Sperber, A. D., Corsetti, M., & Camilleri, M. (2020). Irritable bowel syndrome. Lancet, 396(10263), 1675-1688. https://doi.org/10.1016/S0140-6736(20)31548-8
  3. Hyams, J. S., Di Lorenzo, C., Saps, M., Shulman, R. J., Staiano, A., & van Tilburg, M. (2016). Functional Disorders: Children and Adolescents. Gastroenterology, S0016-5085(16)00181-5. Advance online publication. https://doi.org/10.1053/j.gastro.2016.02.015
  4. Salvioli, B., Pellegatta, G., Malacarne, M., Pace, F., Malesci, A., Pagani, M., & Lucini, D. (2015). Autonomic nervous system dysregulation in irritable bowel syndrome. Neurogastroenterology and motility, 27(3), 423-430. https://doi.org/10.1111/nmo.12512
  5. Ali, M. K., & Chen, J. D. Z. (2023). Roles of Heart Rate Variability in Assessing Autonomic Nervous System in Functional Gastrointestinal Disorders: A Systematic Review. Diagnostics, 13(2), 293. https://doi.org/10.3390/diagnostics13020293
  6. Taralov, Z. Z., Terziyski, K. V., & Kostianev, S. S. (2015). Heart Rate Variability as a Method for Assessment of the Autonomic Nervous System and the Adaptations to Different Physiological and Pathological Conditions. Folia medica, 57(3-4), 173-180. https://doi.org/10.1515/folmed-2015-0036
  7. Verkuil, B., Brosschot, J. F., Tollenaar, M. S., Lane, R. D., & Thayer, J. F. (2016). Prolonged Non-metabolic Heart Rate Variability Reduction as a Physiological Marker of Psychological Stress in Daily Life. Annals of behavioral medicine, 50(5), 704-714. https://doi.org/10.1007/s12160-016-9795-7
  8. Yelisyeyeva, O., Semen, K., Zarkovic, N., Kaminskyy, D., Lutsyk, O., & Rybalchenko, V. (2012). Activation of aerobic metabolism by Amaranth oil improves heart rate variability both in athletes and patients with type 2 diabetes mellitus. Archives of physiology and biochemistry, 118(2), 47-57. https://doi.org/10.3109/13813455.2012.659259
  9. Jarrett, M., Heitkemper, M., Czyzewski, D., Zeltzer, L., & Shulman, R. J. (2012). Autonomic nervous system function in young children with functional abdominal pain or irritable bowel syndrome. The journal of pain, 13(5), 477-484. https://doi.org/10.1016/j.jpain.2012.02.007
  10. Chelimsky, G., Rausch, S., Bierer, D., Feng, M., Simpson, P., Awe, E., & Chelimsky, T. (2019). Cardiovagal modulation in pediatric functional gastrointestinal disorders. Neurogastroenterology and motility, 31(5), e13564. https://doi.org/10.1111/nmo.13564
  11. Semen, M. O., Lychkovska, O. L., Semen, V. D., & Yelisyeyeva, O. P. (2022). Variabelnist rytmu sertsia ta osobystisna tryvozhnist u ditei iz syndromom podraznenoho kyshkivnyka: chy ye zviazok? [Heart rate variability and trait anxiety in children with irritable bowel syndrome: is there a link?]. Zaporozhye medical journal, 24(5), 547-555. [in Ukrainian]. https://doi.org/10.14739/2310-1210.2022.5.256942
  12. Chang, L., Sundaresh, S., Elliott, J., Anton, P. A., Baldi, P., Licudine, A., Mayer, M., Vuong, T., Hirano, M., Naliboff, B. D., Ameen, V. Z., & Mayer, E. A. (2009). Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome. Neurogastroenterology and motility, 21(2), 149-159. https://doi.org/10.1111/j.1365-2982.2008.01171.x
  13. Khlevner, J., Park, Y., & Margolis, K. G. (2018). Brain-Gut Axis: Clinical Implications. Gastroenterology clinics of North America, 47(4), 727-739. https://doi.org/10.1016/j.gtc.2018.07.002
  14. Qin, H. Y., Cheng, C. W., Tang, X. D., & Bian, Z. X. (2014). Impact of psychological stress on irritable bowel syndrome. World journal of gastroenterology, 20(39), 14126-14131. https://doi.org/10.3748/wjg.v20.i39.14126
  15. Stasi, C., Rosselli, M., Bellini, M., Laffi, G., & Milani, S. (2012). Altered neuro-endocrine-immune pathways in the irritable bowel syndrome: the top-down and the bottom-up model. Journal of gastroenterology, 47(11), 1177-1185. https://doi.org/10.1007/s00535-012-0627-7
  16. Kvetnansky, R., Sabban, E. L., & Palkovits, M. (2009). Catecholaminergic systems in stress: structural and molecular genetic approaches. Physiological reviews, 89(2), 535-606. https://doi.org/10.1152/physrev.00042.2006
  17. Volko, C. D., Regidor, P. A., & Rohr, U. D. (2016). Model approach for stress induced steroidal hormone cascade changes in severe mental diseases. Hormone molecular biology and clinical investigation, 25(3), 157-170. https://doi.org/10.1515/hmbci-2015-0038
  18. Eisenhofer, G., Kopin, I. J., & Goldstein, D. S. (2004). Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacological reviews, 56(3), 331–349. https://doi.org/10.1124/pr.56.3.1
  19. Bastos, P., Gomes, T., & Ribeiro, L. (2017). Catechol-O-Methyltransferase (COMT): An Update on Its Role in Cancer, Neurological and Cardiovascular Diseases. Reviews of physiology, biochemistry and pharmacology, 173, 1-39. https://doi.org/10.1007/112_2017_2
  20. Serrano, J. M., Banks, J. B., Fagan, T. J., & Tartar, J. L. (2019). The influence of Val158Met COMT on physiological stress responsivity. Stress, 22(2), 276-279. https://doi.org/10.1080/10253890.2018.1553949
  21. Chen, J., Lipska, B. K., Halim, N., Ma, Q. D., Matsumoto, M., Melhem, S., Kolachana, B. S., Hyde, T. M., Herman, M. M., Apud, J., Egan, M. F., Kleinman, J. E., & Weinberger, D. R. (2004). Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. American journal of human genetics, 75(5), 807-821. https://doi.org/10.1086/425589
  22. Semen, M. O., Lychkovska, O. L., Shymanska, I. E., Semen, V. D., & Makukh, H. V. (2022). Vysoka chastota homozyhotnoho henotypu 472AA COMT (Val158) hena katekhol-O-metyltransferazy (COMT) u ditei iz syndromom podraznenoho kyshkivnyka [High frequency of the 472AA COMT (Val158) homozygous genotype of the catechol-O-methyltransferase (COMT) gene in children with irritable bowel syndrome]. Modern Pediatrics. Ukraine, 6(126), 23-29. [in Ukrainian]. https://doi.org/10.15574/SP.2022.126.23
  23. Mueller, A., Strahler, J., Armbruster, D., Lesch, K. P., Brocke, B., & Kirschbaum, C. (2012). Genetic contributions to acute autonomic stress responsiveness in children. International journal of psychophysiology, 83(3), 302-308. https://doi.org/10.1016/j.ijpsycho.2011.11.007
  24. Karling, P., Danielsson, Å., Wikgren, M., Söderström, I., Del-Favero, J., Adolfsson, R., & Norrback, K. F. (2011). The relationship between the val158met catechol-O-methyltransferase (COMT) polymorphism and irritable bowel syndrome. PloS one, 6(3), e18035. https://doi.org/10.1371/journal.pone.0018035
  25. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. (1996). Circulation, 93(5), 1043-1065. https://doi.org/10.1161/01.cir.93.5.1043
  26. Castaneda, A., McCandless, B. R., & Palermo, D. S. (1956). The children's form of the manifest anxiety scale. Child development, 27(3), 317. https://doi.org/10.2307/1126201
  27. Chang, H. A., Fang, W. H., Wan, F. J., Tzeng, N. S., Liu, Y. P., Shyu, J. F., Huang, S. Y., Chang, T. C., & Chang, C. C. (2019). Age-specific associations among functional COMT Val158Met polymorphism, resting parasympathetic nervous control and generalized anxiety disorder. Psychoneuroendocrinology, 106, 57-64. https://doi.org/10.1016/j.psyneuen.2019.03.020
  28. Niarchou, M., Zammit, S., Escott-Price, V., Owen, M. J., & van den Bree, M. B. (2014). Exploring the indirect effects of catechol-O-methyltransferase (COMT) genotype on psychotic experiences through cognitive function and anxiety disorders in a large birth cohort of children. American journal of medical genetics. Part B, Neuropsychiatric genetics, 165B(5), 410-420. https://doi.org/10.1002/ajmg.b.32245
  29. McGrath, M., Kawachi, I., Ascherio, A., Colditz, G. A., Hunter, D. J., & De Vivo, I. (2004). Association between catechol-O-methyltransferase and phobic anxiety. The American journal of psychiatry, 161(9), 1703-1705. https://doi.org/10.1176/appi.ajp.161.9.1703
  30. Fernández-de-Las-Peñas, C., Ambite-Quesada, S., Florencio, L. L., Palacios-Ceña, M., Ordás-Bandera, C., & Arendt-Nielsen, L. (2019). Catechol-O-Methyltransferase Val158Met Polymorphism Is Associated with Anxiety, Depression, and Widespread Pressure Pain Sensitivity in Women with Chronic, but Not Episodic, Migraine. Pain medicine, 20(7), 1409-1417. https://doi.org/10.1093/pm/pny237
  31. Hajj, A., Hachem, R., Khoury, R., Hallit, S., Eljebbawi, B., Nasr, F., El Karak, F., Chahine, G., Kattan, J., & Rabbaa Khabbaz, L. (2021). Clinical and genetic factors associated with anxiety and depression in breast cancer patients: a cross-sectional study. BMC cancer, 21(1), 872. https://doi.org/10.1186/s12885-021-08615-9
  32. Ren, X., Zhang, L., Xiao, Q., Huang, D., Liu, Q., & Zhang, Y. (2019). Association between COMT polymorphism, labor anxiety, and analgesia in pregnant women. Journal of pain research, 12, 779-785. https://doi.org/10.2147/JPR.S192719
  33. Sies, H. (2020). Oxidative Stress: Concept and Some Practical Aspects. Antioxidants, 9(9), 852. https://doi.org/10.3390/antiox9090852
  34. Costa, V. M., Silva, R., Ferreira, L. M., Branco, P. S., Carvalho, F., Bastos, M. L., Carvalho, R. A., Carvalho, M., & Remião, F. (2007). Oxidation process of adrenaline in freshly isolated rat cardiomyocytes: formation of adrenochrome, quinoproteins, and GSH adduct. Chemical research in toxicology, 20(8), 1183-1191. https://doi.org/10.1021/tx7000916
  35. Berman, S., Suyenobu, B., Naliboff, B. D., Bueller, J., Stains, J., Wong, H., Mandelkern, M., Fitzgerald, L., Ohning, G., Gupta, A., Labus, J. S., Tillisch, K., & Mayer, E. A. (2012). Evidence for alterations in central noradrenergic signaling in irritable bowel syndrome. NeuroImage, 63(4), 1854-1863. https://doi.org/10.1016/j.neuroimage.2012.08.028

Published

2023-09-28

How to Cite

1.
Semen MO, Lychkovska OL, Tyrkus MY, Kaminskyy DV, Yelisyeyeva OP. Association between Val158Met polymorphism in the COMT gene with anxiety and heart rate variability in children with irritable bowel syndrome. Zaporozhye Medical Journal [Internet]. 2023Sep.28 [cited 2026May21];25(5):439-46. Available from: https://zmj.zsmu.edu.ua/article/view/278878

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Section

Original research