Genetic variation in TNFα, PPARγ, and IRS-1 genes, and their association with breast-cancer survival in the HEAL cohort

Breast Cancer Res Treat. 2018 Apr;168(2):567-576. doi: 10.1007/s10549-017-4621-x. Epub 2017 Dec 18.


Purpose: Tumor necrosis factor-α (TNF-α), peroxisome proliferator-activated receptor-γ (PPARγ), and insulin receptor substrate-1 (IRS-1) are associated with obesity, insulin resistance, and inflammation. Few data exist on associations between polymorphisms in these genes and mortality in breast cancer survivors.

Methods: We investigated associations between TNF-α -308G > A (rs1800629); PPARγ Pro12Ala (rs1801282); and IRS-1 Gly972Arg (rs1801278) polymorphisms and anthropometric variables, circulating levels of previously measured biomarkers, and tumor characteristics in 553 women enrolled in the Health, Eating, Activity, and Lifestyle Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer between 1995 and 1999 (median follow-up 14.7 years). Using Cox proportional hazards models adjusted for possible confounders, we evaluated associations between these polymorphisms and mortality.

Results: Carriers of the PPARγ variant allele had statistically significantly lower rates of type 2 diabetes (P = 0.04), lower BMI (P = 0.01), and HOMA scores [P = 0.004; non-Hispanic White (NHWs) only]; carriers of the TNF-α variant A allele had higher serum glucose (P = 0.004, NHW only); and the IRS-1 variant was associated with higher leptin levels (P = 0.003, Hispanics only). There were no associations between any of the polymorphisms and tumor characteristics. Among 141 deaths, 62 were due to breast cancer. Carriers of the TNF-α-variant A allele had a decreased risk of breast-cancer-specific mortality [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.10-0.83] and all-cause mortality (HR 0.51; 95% CI 0.28-0.91).

Conclusions: Neither the PPARγ nor the IRS-1 polymorphism was associated with mortality outcome. The TNF-α -308 G > A polymorphism was associated with reduced breast-cancer-specific and all-cause mortality.

Keywords: All-cause mortality; PPARγ IRS-1 TNF-α breast-cancer-specific mortality.

MeSH terms

  • Aged
  • Breast Neoplasms / genetics
  • Breast Neoplasms / mortality*
  • Breast Neoplasms / pathology
  • Cancer Survivors / statistics & numerical data*
  • Female
  • Humans
  • Insulin Receptor Substrate Proteins / genetics*
  • Los Angeles / epidemiology
  • Middle Aged
  • Neoplasm Staging
  • New Mexico / epidemiology
  • PPAR gamma / genetics*
  • Polymorphism, Genetic
  • Prospective Studies
  • SEER Program / statistics & numerical data
  • Survival Analysis
  • Tumor Necrosis Factor-alpha / genetics*
  • Washington / epidemiology


  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • PPAR gamma
  • PPARG protein, human
  • TNF protein, human
  • Tumor Necrosis Factor-alpha