Fatigue is the most common symptom reported by oncology patients undergoing radiation therapy (RT) (1
), with prevalence rates of between 25% to 99% (4
). In addition, while often not evaluated in oncology patients, prevalence rates for sleep disturbance range from 24% to 95% (8
). Both of these symptoms have negative effects on patients’ mood and quality of life (11
). However, the mechanisms that underlie the development of these symptoms remain to be elucidated.
Equally important, recent evidence suggests that fatigue and sleep disturbance occur with similar prevalence rates in family caregivers (FCs) of oncology patients (14
). While high levels of these two symptoms may be related to the physical and psychological stressors associated with caring for a patient with cancer (16
), the molecular mechanisms for these symptoms require investigation.
Most studies of fatigue and sleep disturbance in oncology evaluated patients and FCs separately. However, recent evidence suggests that patients and FCs experience similar levels of these two symptoms (19
). While the factors that contribute to the development of fatigue and sleep disturbance may be different in patients and FCs, it is plausible to hypothesize that these factors produce similar physiologic processes that are mediated through similar molecular mechanisms.
Several lines of experimental and clinical evidence suggest that pro-inflammatory cytokines may mediate the effects of a variety of physical and psychological stressors (21
). In fact, in a recent study of breast cancer survivors (24
), higher levels of ex vivo monocyte production of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were found in survivors classified with persistent fatigue compared to nonfatigued individuals. In a follow-up candidate gene study with the same sample of breast cancer survivors (25
), the presence of at least one cytosine at IL1-β c.-511 C>T (rs16944) and homozygosity for either variant of the IL6 c.-174 G>C (rs1800795) genotype (i.e., GG or CC) was associated with being in the fatigued group. While the major limitation of these two studies is the small sample size (n
=50), they provide preliminary evidence that pro-inflammatory cytokines are associated with increased levels of fatigue in breast cancer survivors.
Additional evidence for the role of pro-inflammatory cytokines in the development of fatigue and sleep disturbance in both oncology patients and their FCs comes from work by our research team that evaluated whether a functional polymorphism in TNF-α (c.-308 G>A (rs1800629) promoter polymorphism) was associated with overall ratings of fatigue and sleep disturbance as well as with the trajectories of these symptoms (26
). No differences were found in patients’ (n
=168) and FCs’ (n
=85) self-reported levels of fatigue or sleep disturbance. However, in this sample, common allele homozygotes reported significantly higher levels of morning fatigue and sleep disturbance compared to minor allele carriers. Multivariate analyses demonstrated that age and genotype were predictors of both mean symptoms scores, as well as the trajectories of these symptoms.
Based on these initial studies in oncology patients and their FCs (24
), additional candidate gene studies of pro-inflammatory cytokines are warranted to evaluate the role of genetic polymorphisms in the development of fatigue and sleep disturbance. IL6 is a pleiotrophic cytokine, produced by both lymphoid and nonlymphoid cells, that plays a key role in inflammation (27
). Within-population differences in IL6 concentrations are known to be due to both genetic and environmental influences (28
). This genetic difference is exaggerated during inflammatory events, when IL6 concentration increases in response to diverse stimuli (29
). Two single nucleotide polymorphisms (SNP) of IL6 have been studied in detail (i.e., the common -174 G>C variant (30
) and the less frequent c.-572 G>C allele (rs1800796) (31
)). The -174C allele was associated with higher IL-6 serum concentrations in several studies (32
), with no effect in one study (35
), and with lower concentrations in another study (36
). With the -572 G>C SNP, carriers of the rare C allele had higher IL-6 concentrations (37
). Recent work suggests that genetic variation in the distal IL6 promoter region (i.e., IL6 c.-6331 T>C (rs10499563)) plays an important role in IL6 gene regulation and is associated with increases in IL6 concentration in common allele homozygotes (27
Taken together, these converging lines of evidence suggest that a genetic variation in the IL6 gene might contribute to differences in the severity of fatigue and sleep disturbance experienced by oncology patients and their FCs. In this study, we sought to extend our previous work on the genetic determinants of symptoms (26
) and determine, in the same sample of participants, if a functional polymorphism in IL6 was associated with overall ratings of evening fatigue, morning fatigue, and sleep disturbance as well as with the trajectories of these symptoms. We hypothesized that differences in the severity of evening fatigue, morning fatigue, and sleep disturbance would be associated with genetic variation in IL6, as measured by the c.–6101A>T (rs4719714) functional promoter polymorphism. This polymorphism is in complete linkage disequilibrium (LD) with the IL6 -6331 T>C polymorphism, which is associated with higher serum concentrations of IL6 in common allele homozygotes (27
). Therefore, we further hypothesized that common allele homozygotes for the IL6 -6101 A>T polymorphism would report higher levels of these three symptoms.