Online Exclusive Article

Disturbed Sleep in Pediatric Patients With Leukemia: The Potential Role of Interleukin-6 (-174GC) and Tumor Necrosis Factor (-308GA) Polymorphism

Kelly Vallance

Jie Yang

Jiang Li

Valerie McLaughlin Crabtree

Pamela S. Hinds

Belinda N. Mandrell

acute leukemia, leukemia, sleep, sleep disturbance, sleep-wake disturbances, children
ONF 2011, 38(5), E365-E372. DOI: 10.1188/11.ONF.E365-E372

Purpose/Objectives: To explore an association between sleep quality in children and adolescents undergoing therapy for acute lymphoblastic leukemia (ALL) and polymorphisms in two proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor (TNF).

Design: Retrospective exploratory analysis using data from a multi-institutional prospective study comparing objective sleep measures by actigraphy over 10 days with retrospective genotyping of IL-6 (-174GC) and TNF (-308GA).

Setting: Pediatric oncology centers in the southeastern and southwestern United States and in Canada.

Sample: 88 children or adolescents with ALL.

Methods: Secondary analysis of 88 patients (ages 5-18) with sleep quality measured by actigraphy over 10 days in their home environment and retrospective DNA genotyping.

Main Research Variables: Sleep variables and genotype.

Findings:IL-6 promoter (-174G>C) C allele was associated with fewer total daily sleep minutes (p = 0.028) and fewer daily nap minutes (p < 0.01). Patients with the TNF genotype AA had 28.2 more minutes of wake after sleep onset (p = 0.015), 3.4 more nocturnal wake episodes (p = 0.026), and a 5% lower sleep efficiency rate (p = 0.03) than their GA genotype counterparts.

Conclusions: Patients with the TNF (-308G>A) or IL-6 (-174G>C) polymorphisms demonstrated disturbed sleep. This study is the first to find a relationship between these two cytokines and disturbed sleep in children and adolescents with cancer.

Implications for Nursing: Disturbed sleep among pediatric patients with cancer is multifactoral and includes interactions among environment, medications, and genotype. Additional research should explore serum proinflammatory cytokine levels and the influence of mood and worry on sleep.

Jump to a section

    References

    Aouizerat, B., Dodd, M., Lee, K., West, C., Paul, S., Cooper, B., … Miaskowski, C. (2009). Preliminary evidence of a genetic association between tumor necrosis factor alpha and the severity of sleep disturbance and morning fatigue. Biological Research for Nursing, 11, 27-41. http://dx.doi.org/10.1177/1099800409333871
    Au, W. Y., Fung, A., Wong, K. F., Chan, C. H., & Liang, R. (2006). Tumor necrosis factor alpha promoter polymorphism and the risk of chronic lymphocytic leukemia and myeloma in the Chinese population. Leukemia and Lymphoma, 47, 2189-2193 http://dx.doi.org/10.1080/10428190600758645
    Bel Hadj Jrad, B., Chatti, A., Laatiri, A., Ahmed, S. B., Romdhane, A., Ajimi, S., & Chouchane, L. (2007). Tumor necrosis factor promoter gene polymorphism associated with increased susceptibility to non-Hodgkin's lymphomas. European Journal of Haematology, 78, 117-122. http://dx.doi.org/10.1111/j.1600-0609.2006.00784.x
    Belluco, C., Olivieri, F., Bonafe, M., Giovagnetti, S., Mammano, E., Scalerta, R., … Lise, M. (2003). 174 G>C polymorphism of interleukin 6 gene promoter affects interleukin 6 serum level in patients with colorectal cancer. Clinical Cancer Research, 9, 2173-2176.
    Bower, J. E., Ganz, P. A., Aziz, N., & Fahey, J. L. (2002). Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosomatic Medicine, 64, 604-611.
    Cerhan, J. R., Liu-Mares, W., Fredericksen, Z. S., Novak, A. J., Cunningham, J. M., Kay, N. E., … Slager, S. L. (2008). Genetic variation in tumor necrosis factor and the nuclear factor-kappaB canonical pathway and risk of non-Hodgkin lymphoma. Cancer Epidemiology, Biomarkers and Prevention, 17, 3161-3169. http://dx.doi.org/10.1158/1055-9965.EPI-08-0536
    Cleeland, C. S., Bennett, G. J., Dantzer, R., Dougherty, P. M., Dunn, A. J., Meyers, C. A., … Lee, B. N. (2003). Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer, 97, 2919-2925. http://dx.doi.org/10.1002/cncr.11382
    Cox, E. D., Hoffmann, S. C., DiMercurio, B. S., Wesley, R. A., Harlan, D. M., Kirk, A. D., & Blair, P. J. (2001). Cytokine polymorphic analyses indicate ethnic differences in the allelic distribution of interleukin-2 and interleukin-6. Transplantation, 72, 720-726.
    Duarte, I., Santos, A., Sousa, H., Catarino, R., Pinto, D., & Matos, A. (2005). G-308A TNF-alpha polymorphism is associated with an increased risk of invasive cervical cancer. Biochemical Biophysical Research Communications, 334, 588-592. http://dx.doi.org/10.1016/j.bbrc.2005.06.137
    Fayad, L., Cabanillas, F., Talpaz, M., McLaughlin, P., & Kurzrock, R. (1998). High serum interleukin-6 levels correlate with a shorter failure-free survival in indolent lymphoma. Leukemia and Lymphoma, 30, 563-571.
    Fishman, D., Faulds, G., Jeffery, R., Mohamed-Ali, V., Yudkin, J. S., Humphries, S., & Woo, P. (1998). The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. Journal of Clinical Investigation, 102, 1369-1376. http://dx.doi.org/10.1172/JCI2629
    Glaze, D. G. (2004). Childhood insomnia: Why Chris can't sleep. Pediatric Clinics of North America, 51, 33-50. http://dx.doi.org/10.1016/S0031-3955%2803%2900176-7
    Guo, W., Wang, N., Li, Y., & Zhang, J. H. (2005). Polymorphisms in tumor necrosis factor genes and susceptibility to esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma in a population of high incidence region of North China. Chinese Medical Journal (English), 118, 1870-1878.
    Hegedus, C. M., Skibola, C. F., Bracci, P., Holly, E. A., & Smith, M. T. (2007). Screening the human serum proteome for genotype-phenotype associations: An analysis of the IL6 -174G>C polymorphism. Proteomics, 7, 548-557. http://dx.doi.org/10.1002/pmic.200600366
    Heitkemper, M., Levy, R., Jarrett, M., & Bond, E. F. (1995). Interventions for irritable bowel syndrome: A nursing model. Gastroenterology Nursing, 18, 224-230.
    Heitkemper, M., & Shaver, J. (1989). Nursing research opportunities in enteral nutrition. Nursing Clinics of North America, 24, 415-426.
    Hinds, P. S., Hockenberry, M., Rai, S. N., Zhang, L., Razzouk, B. I., Cremer, L., … Rodriguez-Galindo, C. (2007). Clinical field testing of an enhanced-activity intervention in hospitalized children with cancer. Journal of Pain and Symptom Management, 33, 686-697.
    Hinds, P. S., Hockenberry, M., Rai, S. N., Zhang, L., Razzouk, B. I., McCarthy, K., … Rodriguez-Galindo, C. (2007). Nocturnal awakenings, sleep environment interruptions, and fatigue in hospitalized children with cancer. Oncology Nursing Forum, 34, 393-402. http://dx.doi.org/10.1188/07.ONF.393-402
    Hinds, P. S., Hockenberry, M. J., Gattuso, J. S., Srivastava, D. K., Tong, X., Jones, H., … Pui, C. H. (2007). Dexamethasone alters sleep and fatigue in pediatric patients with acute lymphoblastic leukemia. Cancer, 110, 2321-2330. http://dx.doi.org/10.1002/cncr.23039
    Hinds, P. S., Hockenberry-Eaton, M., Gilger, E., Kline, N., Burleson, C., Bottomley, S., & Quargnenti, A. (1999). Comparing patient, parent, and staff descriptions of fatigue in pediatric oncology patients. Cancer Nursing, 22, 277-288.
    Hoffmann, S. C., Stanley, E. M., Cox, E. D., Craighead, N., DiMercurio, B. S., Koziol, D. E., … Blair, P. J. (2001). Association of cytokine polymorphic inheritance and in vitro cytokine production in anti-CD3/CD28-stimulated peripheral blood lymphocytes. Transplantation, 72, 1444-1450.
    Hoffmann, S. C., Stanley, E. M., Cox, E. D., DiMercurio, B. S., Koziol, D. E., Harlan, D. M., … Blair, P. J. (2002). Ethnicity greatly influences cytokine gene polymorphism distribution. American Journal of Transplantation, 2, 560-567. http://dx.doi.org/10.1034/j.1600-6143.2002.20611.x
    Hong, S., Mills, P. J., Loredo, J. S., Adler, K. A., & Dimsdale, J. E. (2005). The association between interleukin-6, sleep, and demographic characteristics. Brain, Behavior, and Immunity, 19, 165-172. http://dx.doi.org/10.1016/j.bbi.2004.07.008
    Jeanmonod, P., von Kanel, R., Maly, F. E., & Fischer, J. E. (2004). Elevated Plasma C-reactive protein in chronically distressed subjects who carry the A allele of the TNF-alpha -308 G/A polymorphism. Psychosomatic Medicine, 66, 501-506.
    Kurzrock, R. (1997). Cytokine deregulation in hematological malignancies: Clinical and biological implications. Clinical Cancer Research, 3(12, Pt. 2), 2581-2584.
    Kurzrock, R. (2001). The role of cytokines in cancer-related fatigue. Cancer, 92(6, Suppl.), 1684-1688. http://dx.doi.org/10.1002/1097-0142(20010915)
    Lee, B. N., Dantzer, R., Langley, K. E., Bennett, G. J., Dougherty, P. M., Dunn, A. J., … Cleeland, C. S. (2004). A cytokine-based neuroimmunologic mechanism of cancer-related symptoms. Neuroimmunomodulation, 11, 279-292. http://dx.doi.org/10.1159/000079408
    Littell, R. (2006). SAS for mixed models. Cary, NC: SAS Institute, Inc.
    Meeske, K. A., Siegel, S. E., Globe, D. R., Mack, W. J., & Bernstein, L. (2005). Prevalence and correlates of fatigue in long-term survivors of childhood leukemia. Journal of Clinical Oncology, 23, 5501-5510. http://dx.doi.org/10.1159/000079408
    Pelayo, R. P., Thorpy, M. J., & Glovinsky, P. (1988). Prevalence of delayed sleep phase syndrome among adolescents. Sleep Research, 17, 391.
    Rich, T., Innominato, P. F., Boerner, J., Mormont, M. C., Iacobelli, S., Baron, B., & Levi, F. (2005). Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer. Clinical Cancer Research, 11, 1757-1764. http://dx.doi.org/10.1158/1078-0432.CCR-04-2000
    Riha, R. L., Brander, P., Vennelle, M., McArdle, N., Kerr, S. M., Anderson, N. H., & Douglas, N. J. (2005). Tumour necrosis factor-alpha (-308) gene polymorphism in obstructive sleep apnea-hypopnoea syndrome. European Respiratory Journal, 26, 673-678. http://dx.doi.org/10.1183/09031936.05.00130804
    Rosen, G. M., Shor, A. C., & Geller, T. J. (2008). Sleep in children with cancer. Current Opinion in Pediatrics, 20, 676-681. http://dx.doi.org/10.1097/MOP.0b013e328312c7ad
    Sadeh, A., Sharkey, K. M., & Carskadon, M. A. (1994). Activity-based sleep-wake identification: An empirical test of methodological issues. Sleep, 17, 201-207.
    Schiller, J. H., Storer, B. E., Witt, P. L., Alberti, D., Tombes, M. B., Arzoomanian, R., … Voss, S. D. (1991). Biological and clinical effects of intravenous tumor necrosis factor-alpha administered three times weekly. Cancer Research, 51, 1651-1658.
    Schubert, C., Hong, S., Natarajan, L., Mills, P. J., & Dimsdale, J. E. (2007). The association between fatigue and inflammatory marker levels in cancer patients: A quantitative review. Brain, Behavior and Immunity, 21, 413-427. http://dx.doi.org/10.1016/j.bbi.2006.11.004
    Vgontzas, A. N., Bixler, E. O., Lin, H. M., Prolo, P., Trakada, G., & Chrousos, G. P. (2005). IL-6 and its circadian secretion in humans. Neuroimmunomodulation, 12, 131-140. http://dx.doi.org/10.1159/000084844
    Vgontzas, A. N., Papanicolaou, D. A., Bixler, E. O., Lotsikas, A., Zachman, K., Kales, A., … Chrousos, G. P. (1999). Circadian interleukin-6 secretion and quantity and depth of sleep. Journal of Clinical Endocrinology and Metabolism, 84, 2603-2607.
    Vgontzas, A. N., Zoumakis, E., Bixler, E. O., Lin, H. M., Follett, H., Kales, A., & Chrousos, G. P. (2004). Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. Journal of Clinical Endocrinology and Metabolism, 89, 2119-2126.
    Vgontzas, A. N., Zoumakis, E., Lin, H. M., Bixler, E. O., Trakada, G., & Chrousos, G. P. (2004). Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor-alpha antagonist. Journal of Clinical Endocrinology and Metabolism, 89, 4409-4413.
    Wang, S. S., Cerhan, J. R., Hartge, P., Davis, S., Cozen, W., Severson, R. K., … Rothman, N. (2006). Common genetic variants in proinflammatory and other immunoregulatory genes and risk for non-Hodgkin lymphoma. Cancer Research, 66, 9771-9780. http://dx.doi.org/10.1158/0008-5472.CAN-06-0324
    Wilson, A. G., Symons, J. A., McDowell, T. L., McDevitt, H. O., & Duff, G. W. (1997). Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proceedings of the National Academy of Sciences of the United States of America, 94, 3195-3199.
    Wood, L. J., Nail, L. M., Gilster, A., Winters, K. A., & Elsea, C. R. (2006). Cancer chemotherapy-related symptoms: Evidence to suggest a role for proinflammatory cytokines. Oncology Nursing Forum, 33, 535-542. http://dx.doi.org/10.1188/06.ONF.535-542