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

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Abstract

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.

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Funding

The National Cancer Institute (N01-CN-75036-20, N01-CN-05228, N01-PC-67010, U54-CA116847, U54CA116848, R25-CA94880); The National Institutes of Health (M01-RR-00037); The University of New Mexico (NCRR M01-RR-0997); The National Institute of Child Health and Human Development (N01-HD-3-3175); The California Department of Health Services (050Q-8709-S1528); and grants from the Breast Cancer Research Foundation (BCRF-16-106, BCRF-17-105)

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Authors and Affiliations

  1. Epidemiology Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Catherine Duggan, Marian L. Neuhouser & Anne McTiernan

  2. Department of Epidemiology & Population Health, University of Louisville, Louisville, KY, USA

    Richard N. Baumgartner & Kathy B. Baumgartner

  3. Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA

    Leslie Bernstein

  4. Office of Disease Prevention, National Institutes of Health, Rockville, MD, USA

    Stephanie George & Rachel Ballard

  5. Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA

    Anne McTiernan

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  1. Catherine Duggan
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  2. Richard N. Baumgartner
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  3. Kathy B. Baumgartner
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  4. Leslie Bernstein
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  5. Stephanie George
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  6. Rachel Ballard
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  7. Marian L. Neuhouser
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  8. Anne McTiernan
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Correspondence to Catherine Duggan.

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The authors declare that they have no conflict of interest.

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All research described in this manuscript complies with laws governing Protection of Human Subjects of Biomedical and Behavioral Research. The research was performed with the approval of Institutional Review Boards of participating centers, in accordance with assurances filed with and approved by the U.S. Department of Health and Human Services.

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Duggan, C., Baumgartner, R.N., Baumgartner, K.B. et al. Genetic variation in TNFα, PPARγ, and IRS-1 genes, and their association with breast-cancer survival in the HEAL cohort. Breast Cancer Res Treat 168, 567–576 (2018). https://doi.org/10.1007/s10549-017-4621-x

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