title: Impact of TNF-α (rs1800629) and IL-6 (rs1800795) Polymorphisms on Cognitive Impairment in Asian Breast Cancer Patients.
abstract: OBJECTIVE
  Expression of pro-inflammatory cytokines is influenced by single nucleotide polymorphisms (SNPs) in the promoter regions of the pro-inflammatory cytokine genes, and cytokines are associated with the occurrence of post-chemotherapy cognitive impairment. Hence, the aim of this study was to evaluate the associations between two common pro-inflammatory cytokine gene polymorphisms namely, IL6-174 (rs1800795 G>C) and TNF-308 (rs1800629 G>A), and chemotherapy-associated cognitive impairment (CACI) among Asian early-stage breast cancer patients. In addition, the differential effect of these SNPs on plasma IL-6 and TNF-α levels, and the associations of plasma IL-6 and TNF-α levels with CACI were also assessed.
  
  
  METHODS
  Asian early-stage breast cancer patients (Stage I to III) receiving chemotherapy were prospectively recruited from two cancer centers in Singapore. Patients' cognitive function was longitudinally assessed using the validated FACT-Cog (ver. 3) and an objective computerized battery, Headminder™ at three-time points. Plasma IL-6 and TNF-α levels were analyzed using the multiplex immunoassay, and genotyping was performed using Sanger sequencing. Regression analyses and generalized estimating equation were utilized for statistical analysis.
  
  
  RESULTS
  A total of 125 patients were included (mean age: 50.3; Chinese: 80.8%; post-menopausal: 48.0%; 68.0% received anthracycline-based chemotherapy). 36.8% patients experienced self-perceived cognitive impairment, detected in memory (32.8%) and attention (34.2%) domains. Patients with higher levels of anxiety (p<0.001) and insomnia (p = 0.003) also reported more self-perceived cognitive impairment. Higher plasma concentrations of IL-6 were associated with greater severity of self-perceived cognitive impairment (p = 0.001). Polymorphisms of cytokine genes were not associated with expression of plasma cytokines.
  
  
  CONCLUSIONS
  Present findings further contribute to the growing evidence that supports the role of the pro-inflammatory cytokine IL-6 in the occurrence of cognitive impairment post-chemotherapy. However, genetic polymorphism of these cytokines did not play a major role to the cytokine fluctuations as well as cognitive impairment in this cohort. With an increasing evidence to support the cytokine hypothesis, future studies should investigate the role of anti-inflammatory agents in mitigating the cognitive impairment associated with chemotherapy.
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Chae
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Terence
authors.initials: T
authors.lastname: Ng
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Hui Ling
authors.initials: HL
authors.lastname: Yeo
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Maung
authors.initials: M
authors.lastname: Shwe
authors.affiliation: Department of Pharmacy, National Cancer Centre Singapore, Singapore.
authors.forename: Yan Xiang
authors.initials: YX
authors.lastname: Gan
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Ho
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.|Department of Pharmacy, National Cancer Centre Singapore, Singapore.|Duke-NUS Graduate Medical School Singapore, Singapore.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chan
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects*; D044466:Asian People / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000523:psychology; D060825:Cognitive Dysfunction / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D016015:Logistic Models; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C508600:IL6 protein, human; D015850:Interleukin-6; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha