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Wageningen Centre for Food Sciences, Wageningen The Netherlands and Division of Human Nutrition Wageningen University Wageningen, The Netherlands
Dear Editor:
de Lorgeril and Salen criticize our interpretations of the available evidence of the relationship between intake of 
-linolenic acid (ALA) and both heart disease risk and prostate cancer risk (1), and they underline the importance of the Lyon Diet Heart Study (2,3). We recognize the importance of this study for the relationship between ALA intake and cardiovascular disease. In our paper we only mentioned the subjects for whom dietary data were provided (192 and 219 in each group) and not all randomized subjects (n = 605). However, changes in the diet in the Lyon Diet Heart Study involved more than just ALA intake. The authors used a multivariate model to identify ALA as the unique dietary factor, but the use of a multivariate model as a post-hoc analysis in a trial confers the same problem of confounding as in observational studies. Therefore, ALA consumption might have a substantial effect on heart disease, but the evidence is not yet conclusive. A currently ongoing 3-y randomized double-blind placebo-controlled trial in The Netherlands (Alpha-Omega Trial) is investigating the effects of consumption of ALA relative to marine (n-3) fatty acid on coronary heart disease mortality in 4000 myocardial infarction patients and might provide more definitive answers by 2008.
The Lyon Diet Heart Study (4) was not designed to investigate cancer incidence, and the total of 24 cancers observed—of which at most 5 were prostatic—do not affect our estimates. Therefore, for the evaluation of the relationship between ALA intake and prostate cancer we could only rely on observational data. Heterogeneity of the studies is indeed a problem and that is one of the reasons why we carefully formulated our conclusion and clearly state that at present it is uncertain whether the effect on prostate cancer is real. However, we used a random-effects model to calculate our combined risk estimates; this model takes heterogeneity into account. Furthermore, we separately reported the risk estimate for all studies combined and for the prospective studies only, i.e., the cohort and the nested-case control studies. Both estimates point to the direction of a higher risk of prostate cancer for those subjects with a high intake of ALA. Thus, we believe that the direction of the currently available evidence is worrisome and cannot be ignored.
de Lorgeril and Salen state that we neglected to mention some negative studies. In fact, the study by Alberg et al. (5) was the only study mentioned that we did not include in our analysis. This study was only published as an abstract and never as a full paper. The abstract provided no risk estimate; it only stated there was no clear difference in fatty acid status between cases and controls (5). The recent paper by Leitzmann et al. (6)—published after our meta-analysis—does provide high quality data on the relationship between ALA intake and prostate cancer. It provides an extension to the Health Professionals Follow-up Study that was already included in our meta-analysis. Replacing the data from Giovannucci et al. (7) by those of Leitzmann et al. (6) result in a relative risk for all studies of 1.55 (1.12–2.13) instead of 1.62 (1.11–2.37) and for the prospective studies of 1.18 (0.86–1.61) instead of 1.28 (0.84–1.94). Thus, both estimates still point towards an increased risk of prostate cancer with a higher intake of ALA.
As we explained in our paper, differences in dietary sources of ALA could lead to different types of confounding. However, heterogeneity of results could not be explained by food sources in those studies that provided information on that subject. For example, the association with prostate cancer could not be explained by meat intake. Finally, we agree that the range of intake of ALA between the high and low consumers might be smaller in some studies than in other studies. However, we believe it is credible to pool the results of these studies, because this difference in range of intake can affect only the size of the risk estimate, not the direction.
We agree that the association between high intake of ALA and prostate cancer is weak and that more research is needed. Studies on levels of fatty acids in prostate tissue or on prostate-specific antigen could provide useful additional evidence. However, in the meantime, very long-chain (n-3) fatty acids from fish should remain the recommended source of (n-3) fatty acids in the prevention of heart disease, if only because the link with coronary heart disease is more robust for fish fatty acids.
Manuscript received 14 September 2004. Revision accepted 15 September 2004.
LITERATURE CITED
1. Brouwer, I. A., Katan, M. B. & Zock, P. L. (2004) Dietary -linolenic acid is associated with reduced risk of fatal coronary heart disease, but increased prostate cancer risk: a meta-analysis. J. Nutr. 134:919-922.
2. de Lorgeril, M., Renaud, S., Mamelle, N., Salen, P., Martin, J. L., Monjaud, I., Guidollet, J., Touboul, P. & Delaye, J. (1994) Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 343:1454-1459.[Medline]
3. de Lorgeril, M., Salen, P., Martin, J. L., Monjaud, I., Delaye, J. & Mamelle, N. (1999) Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction. Final report of the Lyon Diet Heart Study. Circulation 99:779-785.
4. de Lorgeril, M., Salen, P., Martin, J. L., Monjaud, I., Boucher, P. & Mamelle, N. (1998) Mediterranean dietary pattern in a randomized trial: prolonged survival and possible reduced cancer rate. Arch. Intern. Med. 158:1181-1187.
5. Alberg, A. J., Kafonek, S, Huang, H. Y., Hoffman, S. C., Cornstock, G. W. & Helzlsouer, K. (1996) Fatty acid levels and the subsequent development of prostate cancer. Proc. Am. Assoc. Cancer Res. 37:281.
6. Leitzmann, M. F., Stampfer, M. J., Michaud, D. S., Augustsson, K., Colditz, G. C., Willett, W. C. & Giovannucci, E. L. (2004) Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. Am. J. Clin. Nutr. 80:204-216.
7. Giovannucci, E., Rimm, E. B., Colditz, G. A., Stampfer, M. J., Ascherio, A., Chute, C. C. & Willett, W. C. (1993) A prospective study of dietary fat and risk of prostate cancer. J. Natl. Cancer Inst. 85:1571-1579.
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