Letter to the Editor |
RE: "ASSOCIATIONS BETWEEN BREAST CANCER RISK AND THE CATALASE GENOTYPE, FRUIT AND VEGETABLE CONSUMPTION, AND SUPPLEMENT USE"
1 Unité 780 (Epidemiology and Biostatistics), Institut National de la Santé et de la Recherche Médicale, 94807 Villejuif, France
2 Institut Federatif de Recherche 69, Faculté de Médicine, Université de Paris-Sud, 94807 Villejuif, France
3 Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
(e-mail: nadif{at}vjf.inserm.fr)
We read with interest the paper by Ahn et al. (1
) on breast cancer. They reported a protective role of the catalase (CAT) –262 CC genotype that was enhanced by high intake of fruit, a source of antioxidants. This result is of potentially great importance, as catalase is a primary defense against oxidative stress, which could play a role in a variety of diseases. Ahn et al. (1) observed that the CC genotype was associated with higher catalase activity in 18 subjects—a result at variance with the lower protein level observed by Forsberg et al. (2) in 29 subjects—and concluded that larger genotype-phenotype association studies are required. We recently conducted such a study in a sample of 196 coal miners in France (3). The highest red blood cell catalase activity was observed in coal miners with the CAT –262 CC genotype; miners with the TT genotype had a loss of activity of 31 percent (3). Our results extend those of Ahn et al. (1) with another method of measurement, and we also showed that persons who were heterozygous for the T allele had intermediate activity.
Regarding gene x environment interactions, the study by Ahn et al. (1) and our study (3) provide convergent results. In both studies, the effect of factors previously found to be protective was enhanced only in subjects with the CC genotype (i.e., persons with genetically high catalase activity). In the Long Island Breast Cancer Study Project (1), significantly lower risk was observed among women with high fruit and/or vegetable intake—an antioxidant-rich dietary environment—and this effect was enhanced in CAT –262 CC carriers. In our study, miners carrying the NcoI B1 allele in the lymphotoxin 
gene (i.e., persons with a low level of circulating proinflammatory cytokine (4)) were found to be at lower risk of pneumoconiosis (5), considering disease prevalence and computed tomography score, a subclinical marker of the disease. After stratifying subjects according to the CAT –262 polymorphism, we observed that this effect was enhanced in CAT –262 CC carriers (for both 4-year change in computed tomography score and pneumoconiosis prevalence at the end of follow-up, p for interaction = 0.01). Regardless of the disease, both studies showed that the effects of other factors studied seemed to be beneficial only in subjects with the CAT –262 CC genotype.
Among CAT –262 T carriers (i.e., persons with genetically low catalase activity), exposure to coal dust, the primary risk factor for pneumoconiosis and a constituent of an oxidant-rich environment, further decreased catalase activity (3). Moreover, CAT –262 T carriers were found less frequently among highly exposed miners than among others (odds ratio = 0.39, 95 percent confidence interval: 0.20, 0.78); this observation needs confirmation but is consistent with a healthy worker effect related to deleterious consequences of low catalase activity. Judging from the data presented by Ahn et al. (1), no association was observed between environment and genotype, but in that case the environment studied was a protective one.
It is possible that the CAT –262 polymorphism plays an important role in numerous oxidant-related diseases and it has not been studied in large epidemiologic surveys until now. Because it investigated associations with the genotype controlling the activity of a relevant enzyme, the study by Ahn et al. (1) presents a methodological advantage which has been described as Mendelian randomization (6), since it may control for unmeasured confounders. Indeed, considering CAT –262 genotype or classes based on catalase activity as was done previously (5) did not show the same interaction with the lymphotoxin polymorphism.
To better understand whether catalase plays a pivotal role leading to a heterogeneous etiology of oxidant-related diseases due to CAT –262 CC genotype, it is important to study simultaneously the relations of genotype and enzymatic activity with potential oxidant and antioxidant environmental factors.
ACKNOWLEDGMENTS
Conflict of interest: none declared.
NOTES
Editor's note: In accordance with Journal policy, Ahn et al. were asked if they wished to respond to this letter, but they chose not to do so.
References
- Ahn J, Gammon MD, Santella RM, et al. Associations between breast cancer risk and the catalase genotype, fruit and vegetable consumption, and supplement use. Am J Epidemiol 2005;162:943–52. (Electronic publication September 28, 2005).
[Abstract/Free Full Text] - Forsberg L, Lyrena L, De Faire U, et al. A common functional C-T substitution polymorphism in the promoter region of the human catalase gene influences transcription factor binding, reporter gene transcription and is correlated to blood catalase levels. Free Radic Biol Med 2001;30:500–5.[CrossRef][ISI][Medline]
- Nadif R, Mintz M, Jedlicka A, et al. Association of CAT polymorphisms with catalase activity and exposure to environmental oxidative stimuli. Free Radic Res 2005;39:1345–50.[CrossRef][Medline]
- Stuber F, Petersen M, Bokelmann F, et al. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med 1996;24:381–4.[CrossRef][ISI][Medline]
- Nadif R, Jedlicka A, Mintz M, et al. Role of TNF and LTA polymorphisms on biological markers of response to oxidative stimuli in coal miners: a model of gene-environment interaction. J Med Gen 2003;40:96–103.
[Abstract/Free Full Text] - Clayton D, McKeigue PM. Epidemiological methods for studying genes and environment factors in complex diseases. Lancet 2001;358:1356–60.[CrossRef][ISI][Medline]
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