Associations Between Neurotransmitter Genes and Fatigue and Energy Levels in Women After Breast Cancer Surgery

Abstract

Context: Fatigue is a common problem in oncology patients. Less is known about decrements in energy levels and the mechanisms that underlie both fatigue and energy.

Objectives: In patients with breast cancer, variations in neurotransmitter genes between lower and higher fatigue latent classes and between the higher and lower energy latent classes were evaluated.

Methods: Patients completed assessments before and monthly for six months after surgery. Growth mixture modeling was used to identify distinct latent classes for fatigue severity and energy levels. Thirty candidate genes involved in various aspects of neurotransmission were evaluated.

Results: Eleven single-nucleotide polymorphisms or haplotypes (i.e., ADRB2 rs1042718, BDNF rs6265, COMT rs9332377, CYP3A4 rs4646437, GALR1 rs949060, GCH1 rs3783642, NOS1 rs9658498, NOS1 rs2293052, NPY1R Haplotype A04, SLC6A2 rs17841327, and 5HTTLPR + rs25531 in SLC6A4) were associated with latent class membership for fatigue. Seven single-nucleotide polymorphisms or haplotypes (i.e., NOS1 rs471871, SLC6A1 rs2675163, SLC6A1 Haplotype D01, SLC6A2 rs36027, SLC6A3 rs37022, SLC6A4 rs2020942, and TAC1 rs2072100) were associated with latent class membership for energy. Three of 13 genes (i.e., NOS1, SLC6A2, and SLC6A4) were associated with latent class membership for both fatigue and energy.

Conclusions: Molecular findings support the hypothesis that fatigue and energy are distinct, yet related symptoms. Results suggest that a large number of neurotransmitters play a role in the development and maintenance of fatigue and energy levels in breast cancer patients.

Keywords: Fatigue; breast cancer; candidate genes; energy; growth mixture modeling; neurotransmitter genes.

Figure 1

A–F – Differences between the fatigue latent classes in the percentages of patients who were homozygous for the common allele or heterozygous or homozygous for the rare allele in for each of the polymorphism identified. Values are plotted as unadjusted proportions with corresponding p-value.

Figure 2

A–D – Differences between the fatigue latent classes in the percentages of patients who were homozygous for the common allele or heterozygous or homozygous for the rare allele in for each of the polymorphism identified. Values are plotted as unadjusted proportions with corresponding p-value.

Figure 3

NPYR1 linkage disequibrium (LD)-based heatmap and haplotype analysis. The top white bar represents the physical distance along the human chromosome. Reference sequence identifiers (rsIDs) for each single-nucleotide polymorphism (SNP) are plotted on the white bar and equidistantly to render the pairwise LD estimates. The correlation statistics (r² and D′) are provided in the heatmap. The haplotype is indicated in a bolded triangle and its component SNPs are rendered in bold font. Pairwise D′ value (range: 0–1, inclusive) was rendered in color, with the darker red diamond representing D′ value approaching 1.0. When the r² (range 0–100 inclusive) is not equal to 0 or 100, it is provided in a given diamond. The 2-SNP haplotype associated with fatigue is composed of rs9764 and rs7687423.

Figure 4

A–F – Differences between the energy latent classes in the percentages of patients who were homozygous for the common allele or heterozygous or homozygous for the rare allele in for each of the polymorphism identified. Values are plotted as unadjusted proportions with corresponding p-value.

Figure 5

SLC6A1 linkage disequibrium (LD)-based heatmap and haplotype analysis. The top white bar represents the physical distance along the human chromosome. Reference sequence identifiers (rsIDs) for each single-nucleotide polymorphism (SNP) are plotted on the white bar and equidistantly to render the pairwise LD estimates. The correlation statistics (r² and D′) are provided in the heatmap. The haplotype is indicated in a bolded triangle and its component SNPs are rendered in bold font. Pairwise D′ value (range: 0–1, inclusive) was rendered in color, with the darker red diamond representing D′ value approaching 1.0. When the r² (range 0–100 inclusive) is not equal to 0 or 100, it is provided in a given diamond. The 3-SNP haplotype associated with energy is composed rs10514669, rs2697138, and rs1062246.