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National Institute for Public Health and the Environment Department of Chronic Diseases Epidemiology PO Box 1 3720 BA Bilthoven Netherlands E-mail: ejm.feskens{at}rivm.nl
Dear Sir:
In their letter, Renaud and Lanzmann-Petithory question the validity of our conclusion concerning the available evidence on the association between -linolenic acid intakes and the risk of coronary artery disease (CAD) (1). We agree that our questionable conclusion may have been too firm, but we would like to point out that we arrived at this conclusion not only on the basis of our cohort results but also on our review of previous studies. Therefore, we believe that the issue is still open to question.
One of Renaud and Lanzmann-Petithory’s comments relates to confounding by a concomitant intake of trans fatty acids. The largest contribution to the intake of -linolenic acid in our study was provided by foods that also contained trans fatty acid (margarines and meat). We observed a nonsignificant increased CAD risk with high -linolenic acid intakes [relative risk (RR): 1.68] as well as with high -linolenic acid intake from sources with trans fatty acids (RR: 1.51) but a nonsignificant smaller RR with -linolenic acid intakes from sources without trans fatty acids (RR: 1.15). As we indicated in our discussion, modification with trans fatty acids, residual confounding, or both may have played a role in our study as well as in others; therefore, Renaud and Lanzmann-Petithory seem to agree with us.
However, the main controversy seems to be the interpretation of the results of former studies. We respectfully disagree with the author’s optimistic review. We commented on each former individual study in our article, and the findings are far less consistent than suggested. A summary of the cohort and trial results is therefore presented in Table 1. The strongest association was observed in the Nurses’ Health Study (6), because the association was not modified by other risk or dietary factors. In the other cohorts, however, the results were less clear and only in a few instances were they statistically significant. The results were strongly affected by adjustments for other dietary factors. In the Health Professionals Follow-up Study (4), the adjusted RR was strengthened after adjustment for total fat. In the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, the RR for the fifth quintile was reduced from 0.99 to 0.75 after additional adjustment for trans- and cis-monounsaturated and saturated fatty acids (5). In the Multiple Risk Factor Intervention Trial, the association may have been confounded by dietary factors other than energy and alcohol use, because such adjustments were not made (3). Second, there was no suggestion of a linear dose-response relation in data from the Health Professionals Follow-up Study because there was no reduced risk of fatal CAD in the highest quintile and a nonsignificant reduction in the risk of fatal plus nonfatal CAD. Finally, a recent cross-sectional study reported an inverse significant association between -linolenic acid intake and CAD risk (9). However, because of the cross-sectional design, subjects with CAD may have changed their dietary habits (including -linolenic acid intake) after diagnosis. Because this could have affected the RRs, the results of this study have to be interpreted with caution.
View this table:
TABLE 1 . Summary of the effect of dietary -linolenic acid (ALA) intake on fatal coronary artery disease (CAD) and fatal plus nonfatal CAD reported in prospective studies1
Concerning the intervention studies that suggest beneficial effects of -linolenic acid, we note that the analysis of plasma fatty acids in relation to endpoints in the Lyon Diet Heart Study (7) is not clearly described in terms of adjustments for other dietary changes that were introduced in the trial. In the Indian mustard-oil trial, the intervention and control groups differed in important characteristics such as smoking, which were not taken into account in the data analyses (8). Therefore, as mentioned in our discussion, we maintain our conclusion that on the basis of this trial it cannot be concluded that the protective effect was solely due to -linolenic acid.
A final issue is the difference in -linolenic acid intakes in our study compared with those in the studies described in Table 1. In our article the median intake varied from 0.40% of energy in the lowest tertile to 0.67% of energy in the highest tertile, a 1.7-fold increase. This finding agrees with an absolute difference in intakes between the extreme categories of 0.8 g -linolenic acid/d, which we think is a better indication of the range of exposure. Other studies reported -linolenic acid intakes as energy-adjusted grams per day. The lowest differences in intake were observed in the Nurses’ Health Study (6) and the Health Professional Follow-up Study (4), 0.7 g/d (a 1.9-fold increase), which is comparable with the range in intake of 0.8 g/d in the Zutphen Elderly Study. Thus, of the 3 prospective studies with a similar range in -linolenic acid intakes (1, 4, 6), only 1 study observed a significant inverse association (6). Therefore, the suggestion by Renaud and Lanzmann-Petithory that a 1.9-fold difference seems at least necessary to observe a beneficial effect is unwarranted.
In summary, we observed no beneficial effect of -linolenic acid on the risk of CAD. We conclude that the methodologic limitations of our study and of other prospective studies, including trials, and the limited evidence on the responsible mechanisms, indicate that the protective effect of -linolenic acid on CAD has not yet been proven.
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