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

Abstract

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.

Conclusions: 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.

Keywords: Breast cancer; Cytokine genes; Growth mixture modeling; Insomnia; Sleep disturbance; Symptom trajectories.

Figure 1

Observed and estimated General Sleep Disturbance Scale (GSDS) trajectories for patients in each of the latent classes, as well as the mean GSDS scores for the total sample (Adapted from Van Onselen et al., 2012).

Figure 2

IL1R2 linkage disequilibrium-based heatmap and haplotype analysis. In the figure embedded in the top row of the table, an ideogram of interleukin 1 receptor 2 (IL1R2) is presented above the white bar that represents the physical distance along human chromosome 2 (position 31, 96,370,336 to 96,380,807; genome build 36.3, contig NT_022171.14). Exons are represented as tick marks. Gray lines connecting the exons represent introns. The black chevron indicates the direction of gene transcription. Reference sequence identifiers (rsID) for each single nucleotide polymorphism (SNP) are plotted both in terms of their physical distance (i.e., the white bar at the top of the figure) and also equidistantly to render the pairwise linkage disequilibrium (LD) estimates that were calculated and visualized with Haploview 4.2. The gene structure for IL1R2 (i.e., reference sequence NM_004633) was rendered with FancyGene 1.4. The correlation statistics (r² and D’) are provided in the heatmap. LD-based haplotype block definition was based on the D’ confidence interval method. The haploblock is indicated in a bolded triangle and its component SNPs are rendered in bold font. Pairwise D’ values (range: 0–1, inclusive) were rendered in color, with darker red diamonds representing D’ values approaching 1.0. When the r² values (range of 0–100, inclusive) are not equal to 0 or 100, they are provided in a given diamond. The haplotypes observed in the haploblock are listed in each row, starting with the nucleotide composition across the two SNPs that compose the haplotype (i.e., rs11674595, rs7570441) and both the count (n) and frequency (%) of each haplotype observed in the two GMM Sleep Disturbance groups. The T-A haplotype identified in the bivariate analyses (Table 1) that remained significant after controlling for relevant confounders is rendered in bold and italicized.

Figure 3

Figure 3A. Differences between the latent classes in the percentages of patients who were homozygous for the common allele (CC) or heterozygous or homozygous for the minor allele (CT+TT) for rs1800925 in interleukin 13 (IL13). Values are plotted as unadjusted proportions with corresponding p-value. Figure 3B - Differences between the latent classes in the percentages of patients who were homozygous for the common allele (CC) or heterozygous or homozygous for the minor allele (CT+TT) for rs1056890 in nuclear factor kappa beta 2 (NFKB2). Values are plotted as unadjusted proportions with corresponding p-value.