title: Inflammatory pathway genes associated with inter-individual variability in the trajectories of morning and evening fatigue in patients receiving chemotherapy.
abstract: Fatigue, a highly prevalent and distressing symptom during chemotherapy (CTX), demonstrates diurnal and interindividual variability in severity. Little is known about the associations between variations in genes involved in inflammatory processes and morning and evening fatigue severity during CTX. The purposes of this study, in a sample of oncology patients (N=543) with breast, gastrointestinal (GI), gynecological (GYN), or lung cancer who received two cycles of CTX, were to determine whether variations in genes involved in inflammatory processes were associated with inter-individual variability in initial levels as well as in the trajectories of morning and evening fatigue. Patients completed the Lee Fatigue Scale to determine morning and evening fatigue severity a total of six times over two cycles of CTX. Using a whole exome array, 309 single nucleotide polymorphisms SNPs among the 64 candidate genes that passed all quality control filters were evaluated using hierarchical linear modeling (HLM). Based on the results of the HLM analyses, the final SNPs were evaluated for their potential impact on protein function using two bioinformational tools. The following inflammatory pathways were represented: chemokines (3 genes); cytokines (12 genes); inflammasome (11 genes); Janus kinase/signal transducers and activators of transcription (JAK/STAT, 10 genes); mitogen-activated protein kinase/jun amino-terminal kinases (MAPK/JNK, 3 genes); nuclear factor-kappa beta (NFkB, 18 genes); and NFkB and MAP/JNK (7 genes). After controlling for self-reported and genomic estimates of race and ethnicity, polymorphisms in six genes from the cytokine (2 genes); inflammasome (2 genes); and NFkB (2 genes) pathways were associated with both morning and evening fatigue. Polymorphisms in six genes from the inflammasome (1 gene); JAK/STAT (1 gene); and NFkB (4 genes) pathways were associated with only morning fatigue. Polymorphisms in three genes from the inflammasome (2 genes) and the NFkB (1 gene) pathways were associated with only evening fatigue. Taken together, these findings add to the growing body of evidence that suggests that morning and evening fatigue are distinct symptoms.
authors.affiliation: Yale School of Nursing, New Haven, CT, USA.
authors.forename: Fay
authors.initials: F
authors.lastname: Wright
authors.affiliation: Department of Nursing, Mount Sinai Hospital, New York, NY, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Hammer
authors.affiliation: Department of Physiologic Nursing, School of Nursing, University of California at San Francisco, San Francisco, CA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Paul
authors.affiliation: Bluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, College of Dentistry, New York University, New York, NY, USA.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Aouizerat
authors.affiliation: Department of Physiologic Nursing, School of Nursing, University of California at San Francisco, San Francisco, CA, USA.
authors.forename: Kord M
authors.initials: KM
authors.lastname: Kober
authors.affiliation: School of Nursing, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Yvette P
authors.initials: YP
authors.lastname: Conley
authors.affiliation: Department of Physiologic Nursing, School of Nursing, University of California at San Francisco, San Francisco, CA, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Cooper
authors.affiliation: Department of Psychiatry, School of Medicine, Stanford University, Palo Alto, CA, USA.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Dunn
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Dentistry, University of California at San Francisco, San Francisco, CA, USA.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Levine
authors.affiliation: Florence S. Downs PhD Program in Nursing Research and Theory Development, College of Nursing, New York University, New York, NY, USA.
authors.forename: Gail
authors.initials: G
authors.lastname: DEramo Melkus
authors.affiliation: Department of Physiologic Nursing, School of Nursing, University of California at San Francisco, San Francisco, CA, USA. Electronic address: chris.miaskowski@ucsf.edu.
authors.forename: Christine
authors.initials: C
authors.lastname: Miaskowski
mesh_terms: D016207:Cytokines / Q000235:genetics*; D005221:Fatigue / Q000139:chemically induced / Q000235:genetics; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000235:genetics*; D053612:Janus Kinases / Q000235:genetics*; D008297:Male; D016328:NF-kappa B / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D050791:STAT Transcription Factors / Q000235:genetics*
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D016328:NF-kappa B; D050791:STAT Transcription Factors; D053612:Janus Kinases
keywords: Cancer; Chemotherapy; Diurnal variability; Fatigue; Genes; Hierarchical linear modeling; Inflammation