Association between Val158Met polymorphism in the COMT gene with anxiety and heart rate variability in children with irritable bowel syndrome
DOI:
https://doi.org/10.14739/2310-1210.2023.5.278878Keywords:
COMT gene, trait anxiety, heart rate variability, irritable bowel syndrome, childrenAbstract
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.
References
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Sies, H. (2020). Oxidative Stress: Concept and Some Practical Aspects. Antioxidants, 9(9), 852. https://doi.org/10.3390/antiox9090852
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
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
Downloads
Published
How to Cite
Issue
Section
License
Authors who publish with this journal agree to the following terms:- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access)