Research Article| Volume 18, ISSUE 1, P85-93, February 2014

Associations between cytokine gene variations and self-reported sleep disturbance in women following breast cancer surgery

Published:September 09, 2013DOI:


      Purpose of the research

      To attempt to replicate the associations found in our previous study of patients and family caregivers between interleukin 6 (IL6) and nuclear factor kappa beta 2 (NFKB2) and sleep disturbance and to identify additional genetic associations in a larger sample of patients with breast cancer.

      Methods and sample

      Patients with breast cancer (n = 398) were recruited prior to surgery and followed for six months. Patients completed a self-report measure of sleep disturbance and provided a blood sample for genomic analyses. Growth mixture modeling was used to identify distinct latent classes of patients with higher and lower levels of sleep disturbance.

      Key results

      Patients who were younger and who had higher comorbidity and lower functional status were more likely to be in the high sustained sleep disturbance class. Variations in three cytokine genes (i.e., IL1 receptor 2 (IL1R2), IL13, NFKB2) predicted latent class membership.


      Polymorphisms in cytokine genes may partially explain inter-individual variability in sleep disturbance. Determination of high risk phenotypes and associated molecular markers may allow for earlier identification of patients at higher risk for developing sleep disturbance and lead to the development of more targeted clinical interventions.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Oncology Nursing
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Berger A.M.
        • Wielgus K.
        • Hertzog M.
        • Fischer P.
        • Farr L.
        Patterns of circadian activity rhythms and their relationships with fatigue and anxiety/depression in women treated with breast cancer adjuvant chemotherapy.
        Support Care in Cancer. 2010; 18: 105-114
        • Brunner F.
        • Bachmann L.M.
        • Weber U.
        • Kessels A.G.
        • Perez R.S.
        • Marinus J.
        • et al.
        Complex regional pain syndrome 1 – the Swiss cohort study.
        BMC Musculoskeletal Disorders. 2008; 9: 92
        • Chang M.
        • Li Y.
        • Yan C.
        • Callis-Duffin K.P.
        • Matsunami N.
        • Garcia V.E.
        • et al.
        Variants in the 5q31 cytokine gene cluster are associated with psoriasis.
        Genes and Immunity. 2008; 9: 176-181
        • Chen F.
        • Castranova V.
        • Shi X.
        • Demers L.M.
        New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases.
        Clinical Chemistry. 1999; 45: 7-17
        • Cieza A.
        • Geyh S.
        • Chatterji S.
        • Kostanjsek N.
        • Ustun B.T.
        • Stucki G.
        Identification of candidate categories of the International Classification of Functioning Disability and Health (ICF) for a Generic ICF Core Set based on regression modelling.
        BMC Medical Research Methodology. 2006; 6: 36
        • Cirelli C.
        The genetic and molecular regulation of sleep: from fruit flies to humans.
        Nature Reviews Neuroscience. 2009; 10: 549-560
        • Clevenger L.
        • Schrepf A.
        • Christensen D.
        • DeGeest K.
        • Bender D.
        • Ahmed A.
        • et al.
        Sleep disturbance, cytokines, and fatigue in women with ovarian cancer.
        Brain Behavior and Immunity. 2012; 26: 1037-1044
        • Colotta F.
        • Re F.
        • Muzio M.
        • Bertini R.
        • Polentarutti N.
        • Sironi M.
        • et al.
        Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4.
        Science. 1993; 261: 472-475
        • Conde L.
        • Vaquerizas J.M.
        • Dopazo H.
        • Arbiza L.
        • Reumers J.
        • Rousseau F.
        • et al.
        PupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes.
        Nucleic Acids Research. 2006; 34: W621-W625
        • Davidson J.R.
        • MacLean A.W.
        • Brundage M.D.
        • Schulze K.
        Sleep disturbance in cancer patients.
        Social Science and Medicine. 2002; 54: 1309-1321
        • Dunn L.B.
        • Aouizerat B.E.
        • Langford D.J.
        • Cooper B.A.
        • Dhruva A.
        • Cataldo J.K.
        • et al.
        Cytokine gene variation is associated with depressive symptom trajectories in oncology patients and family caregivers.
        European Journal of Oncology Nursing. 2013; 17: 346-353
        • Fletcher B.S.
        • Paul S.M.
        • Dodd M.J.
        • Schumacher K.
        • West C.
        • Cooper B.
        • et al.
        Prevalence, severity, and impact of symptoms on female family caregivers of patients at the initiation of radiation therapy for prostate cancer.
        Journal of Clinical Oncology. 2008; 26: 599-605
        • Foley K.A.
        • Sarsour K.
        • Kalsekar A.
        • Walsh J.K.
        Subtypes of sleep disturbance: associations among symptoms, comorbidities, treatment, and medical costs.
        Behavioral Sleep Medicine. 2010; 8: 90-104
        • Gabriel S.B.
        • Schaffner S.F.
        • Nguyen H.
        • Moore J.M.
        • Roy J.
        • Blumenstiel B.
        • et al.
        The structure of haplotype blocks in the human genome.
        Science. 2002; 296: 2225-2229
        • Halder I.
        • Shriver M.
        • Thomas M.
        • Fernandez J.R.
        • Frudakis T.
        A panel of ancestry informative markers for estimating individual biogeographical ancestry and admixture from four continents: utility and applications.
        Human Mutation. 2008; 29: 648-658
        • Hoggart C.J.
        • Parra E.J.
        • Shriver M.D.
        • Bonilla C.
        • Kittles R.A.
        • Clayton D.G.
        • et al.
        Control of confounding of genetic associations in stratified populations.
        American Journal of Human Genetics. 2003; 72: 1492-1504
        • Illi J.
        • Miaskowski C.
        • Cooper B.
        • Levine J.D.
        • Dunn L.
        • West C.
        • et al.
        Association between pro- and anti-inflammatory cytokine genes and a symptom cluster of pain, fatigue, sleep disturbance, and depression.
        Cytokine. 2012; 58: 437-447
        • Jung T.
        • Wickrama K.A.S.
        An introduction to latent class growth analysis and growth mixture modeling.
        Social and Personality Psychology Compass. 2008; 2: 302-317
        • Karnofsky D.
        • Abelmann W.H.
        • Craver L.V.
        • Burchenal J.H.
        The use of nitrogen mustards in the palliative treatment of carcinoma.
        Cancer. 1948; 1: 634-656
        • Lee K.A.
        Self-reported sleep disturbances in employed women.
        Sleep. 1992; 15: 493-498
        • McCann B.
        • Miaskowski C.
        • Koetters T.
        • Baggott C.
        • West C.
        • Levine J.D.
        • et al.
        Associations between pro- and anti-inflammatory cytokine genes and breast pain in women prior to breast cancer surgery.
        Journal of Pain. 2012; 13: 425-437
        • Miaskowski C.
        • Cooper B.
        • Paul S.M.
        • West C.
        • Langford D.
        • Levine J.D.
        • et al.
        Identification of patient subgroups and risk factors for persistent breast pain following breast cancer surgery.
        Journal of Pain. 2012; 13: 1172-1187
        • Miaskowski C.
        • Cooper B.A.
        • Dhruva A.
        • Dunn L.B.
        • Langford D.J.
        • Cataldo J.K.
        • et al.
        Evidence of associations between cytokine genes and subjective reports of sleep disturbance in oncology patients and their family caregivers.
        PLoS One. 2012; 7: e40560
        • Miaskowski C.
        • Dodd M.
        • Paul S.M.
        • West C.
        • Hamolsky D.
        • Abrams G.
        • et al.
        Lymphatic and angiogenic candidate genes predict the development of secondary lymphedema following breast cancer surgery.
        PLoS One. 2013; 8: e60164
        • Nylund K.L.
        • Asparouhov T.
        • Muthen B.O.
        Deciding on the number of classes in latent class analysis and growth mixture modeling: a Monte Carlo simulation study.
        Structural Equation Modeling. 2007; 14: 535-569
        • Oeckinghaus A.
        • Hayden M.S.
        • Ghosh S.
        Crosstalk in NF-kappaB signaling pathways.
        Nature Immunology. 2011; 12: 695-708
        • Palesh O.G.
        • Roscoe J.A.
        • Mustian K.M.
        • Roth T.
        • Savard J.
        • Ancoli-Israel S.
        • et al.
        Prevalence, demographics, and psychological associations of sleep disruption in patients with cancer: University of Rochester Cancer Center-Community Clinical Oncology Program.
        Journal of Clinical Oncology. 2010; 28: 292-298
        • Popko K.
        • Gorska E.
        • Potapinska O.
        • Wasik M.
        • Stoklosa A.
        • Plywaczewski R.
        • et al.
        Frequency of distribution of inflammatory cytokines IL-1, IL-6 and TNF-alpha gene polymorphism in patients with obstructive sleep apnea.
        Journal of Physiology and Pharmacology. 2008; 59: 607-614
        • Price A.L.
        • Patterson N.J.
        • Plenge R.M.
        • Weinblatt M.E.
        • Shadick N.A.
        • Reich D.
        Principal components analysis corrects for stratification in genome-wide association studies.
        Nature Genetics. 2006; 38: 904-909
        • Rothman K.J.
        No adjustments are needed for multiple comparisons.
        Epidemiology. 1990; 1: 43-46
        • Sangha O.
        • Stucki G.
        • Liang M.H.
        • Fossel A.H.
        • Katz J.N.
        The Self-Administered Comorbidity Questionnaire: a new method to assess comorbidity for clinical and health services research.
        Arthritis and Rheumatism. 2003; 49: 156-163
        • Savard J.
        • Ivers H.
        • Villa J.
        • Caplette-Gingras A.
        • Morin C.M.
        Natural course of insomnia comorbid with cancer: an 18-month longitudinal study.
        Journal of Clinical Oncology. 2011; 29: 3580-3586
        • Savard J.
        • Villa J.
        • Ivers H.
        • Simard S.
        • Morin C.M.
        Prevalence, natural course, and risk factors of insomnia comorbid with cancer over a 2-month period.
        Journal of Clinical Oncology. 2009; 27: 5233-5239
        • Sehgal A.
        • Mignot E.
        Genetics of sleep and sleep disorders.
        Cell. 2011; 146: 194-207
        • Seruga B.
        • Zhang H.
        • Bernstein L.J.
        • Tannock I.F.
        Cytokines and their relationship to the symptoms and outcome of cancer.
        Nature Reviews Cancer. 2008; 8: 887-899
        • SPSS
        IBM SPSS for Windows (Version 19).
        SPSS, Inc., Chicago, Illinois2010
        • StataCorp
        Stata Statistical Software: Release 9.
        Stata Corporation, College Station, Texas2005
        • Stephens M.
        • Smith N.J.
        • Donnelly P.
        A new statistical method for haplotype reconstruction from population data.
        American Journal of Human Genetics. 2001; 68: 978-989
        • Tian C.
        • Gregersen P.K.
        • Seldin M.F.
        Accounting for ancestry: population substructure and genome-wide association studies.
        Human Molecular Genetics. 2008; 17: R143-R150
        • Tofighi D.
        • Enders C.K.
        Identifying the Correct Number of Classes in Growth Mixture Models.
        Information Age Publishing, Charlotte, NC2008
        • Van Onselen C.
        • Aouizerat B.E.
        • Dunn L.B.
        • Paul S.M.
        • West C.
        • Hamolsky D.
        • et al.
        Differences in sleep disturbance, fatigue and energy levels between women with and without breast pain prior to breast cancer surgery.
        Breast. 2013; 22: 273-276
        • Van Onselen C.
        • Cooper B.A.
        • Lee K.
        • Dunn L.
        • Aouizerat B.E.
        • West C.
        • et al.
        Identification of distinct subgroups of breast cancer patients based on self-reported changes in sleep disturbance.
        Supportive Care in Cancer. 2012; 20: 2611-2619
        • Zhu Z.
        • Zheng T.
        • Homer R.J.
        • Kim Y.K.
        • Chen N.Y.
        • Cohn L.
        • et al.
        Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation.
        Science. 2004; 304: 1678-1682