Carcinogenesis Advance Access published online on June 26, 2008
Carcinogenesis, doi:10.1093/carcin/bgn154
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Peroxisome proliferator-activated receptor-alpha (PPARA) genetic polymorphisms and breast cancer risk: a Long Island ancillary study
1 Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC 27599, USA
2 Pharmacoepidemiology, Risk Management and Health Outcomes, PPD, Morrisville, NC 27560, USA
3 Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
4 Department of Epidemiology, Columbia University, New York, NY 10032, USA
5 Department of Medicine, Columbia University, New York, NY 10032, USA
6 Department of Environmental Health Sciences, Columbia University, New York, NY 10032, USA
* To whom correspondence should be addressed: Amanda Golembesky, Pharmacoepidemiology, Risk Management and Health Outcomes, 3900 North Building, Suite 225, Morrisville, NC 27560. 919-456-5056 (phone); 919-654-0668 (fax); Amanda.Golembesky{at}rtp.ppdi.com.
Peroxisome proliferator-activated receptor-alpha (PPARA) has been shown to increase fatty acid oxidation and decrease cytokine levels, and has been implicated in insulin production. Genetic variants of PPARA have been associated with cardiovascular disease, obesity and type II diabetes mellitus. Although no research to date has investigated the possible link between PPARA and breast cancer, the function of this gene suggests that it could play a role in breast cancer development. Six PPARA polymorphisms were evaluated in association with incident breast cancer in a population-based case-control study (n = 1073 cases, n = 1112 controls), using unconditional logistic and multilevel regression, and haplotype-based analyses. The odds of breast cancer were doubled among women with PPARA polymorphism rs4253760 (OR = 1.97 for rare vs. common homozygote alleles; 95% CI: 1.14, 3.43). This association remained constant with the inclusion of all interrogated polymorphisms studied in hierarchical models. No additive interactions with body mass index or weight gain were present, but there was some evidence of interaction between PPARA variants and aspirin use, defined as use at least once per week for six months or longer. Fourteen haplotypes were imputed with frequencies greater than 1% among post-menopausal women, but no statistically significant differences in haplotype frequencies between cases and controls were evident. Our results are the first to evaluate the relationship between PPARA and breast cancer incidence and suggest that replication in an independent cohort is warranted.
Key Words: PPARA • obesity • NSAIDs • breast cancer
Received January 6, 2008; revised May 25, 2008; accepted June 8, 2008.