From our investigations into potential associations between major dietary fats and fatty acids and bladder cancer, we identified a consistent inverse association with the intake of ALA. Our initial analyses detected reduced odds of bladder cancer associated with high intakes of vegetable fat, polyunsaturated fat, LA and possibly the ratio for the intake of n-6:n-3 fatty acids. However, these fats and fatty acids were all highly correlated with each other, and initial associations disappeared following mutual adjustment with the exception of ALA. We did not observe any other potential associations, trends or interactions.
Most of the epidemiological evidence available on the association between dietary fatty acids and the risk of cancer has focused on cancer at other body sites, e.g. colorectal(30)
. To our knowledge, this is one of the first epidemiological studies to investigate the association between dietary fat intake and bladder cancer that examined the effect of different fatty acids. An earlier study(33)
compared the plasma levels of essential fatty acids (EFA) of ninety-eight histologically confirmed bladder cancer patients with 477 healthy controls. It was found that levels for most of the EFA, including LA, AA and metabolites of ALA, were significantly lower for bladder cancer patients compared with the controls.
EFA are PUFA that cannot be synthesised within the body and thus must be obtained from the diet(34)
. They have a number of key physiological roles, including the regulation of inflammation, blood clotting and vasoconstriction/vasodilation(3)
. It has also been reported that EFA deficiency may be ‘pro-tumorigenic’ in rats(34)
. As EFA make up a large percentage of the phospholipid fatty acid content of the normal rat urothelial membrane, deficiency in these may increase the susceptibility of the urothelium to carcinogenic agents(34)
We investigated the effect of three of the major n
-3 fatty acids: ALA (18:3); EPA (20:5); DHA (22:6). There were no existing epidemiological studies from which to compare the inverse association that we observed between intake of ALA and bladder cancer risk. However, consistent with a few previous studies, we found no association between bladder cancer risk and intake of EPA and DHA(20)
-3 fatty acids generally(35)
. Although EPA and DHA are obtained from fatty cold water fish, they can also be synthesised to a lesser extent from their precursor, ALA(14)
Despite reports that major n
-6 fatty acids, LA and AA, may induce bladder carcinogenesis in cell culture(11)
, we detected a possible inverse relationship for intake of LA before adjustment for vegetable oil and no association with AA. LA is reportedly the major polyunsaturated fat consumed by American adults, comprising 84–89% of total energy from polyunsaturated fat compared with 9–11% for ALA(36)
. We initially observed reduced odds of bladder cancer with the higher ratio for the intake of n
-3 fatty acids; however, any potential association disappeared after adjusting for vegetable fat (data not shown). A recent expert report by the FAO/WHO(37)
concluded that absolute values of these fatty acids are more relevant than the n
-3 ratio in terms of optimal physiological function and health.
Contrary to previous studies(5,6,38)
we found no evidence that intake of total fat was associated with increased risk of bladder cancer. Similarly, we did not observe inverse associations between bladder cancer risk and intake of saturated and monounsaturated fat reported in a Japanese case–control study(18)
consisting of 297 bladder cancer cases and 295 controls. These major subgroups of fats are available from both vegetable and animal sources, and may have been derived predominantly from vegetable sources in the Japanese study population(10)
. Interestingly, we did observe a low-point estimate that was of borderline statistical significance for saturated fat, which was highly correlated with palmitic acid (r
0·96), a saturated fat also obtained from plant sources, e.g. palm oil(10)
. Similarly, our lack of association between the intake of animal fat and bladder cancer risk disagreed with reports of a positive association from a Serbian case–control study(19)
of 130 cases and controls. Population differences in the type, composition and quantity of animal fat consumed and even cooking methods may account for the lack of agreement between the Serbian and our American study.
Accurate estimation of dietary intake of specific fats/fatty acids is difficult, particularly for PUFA, like ALA, which are typically consumed in small quantities(16,39)
. In the absence of biological markers, it is important that dietary assessment instruments and nutrient composition databases can provide adequate estimates of usual dietary intake of these fatty acids(39)
. Some earlier studies(40,41)
have assessed the performance of dietary measures in estimating fatty acid exposure using biological samples. A cross-sectional study(40)
of 276 men and 257 women has reported weak, but significant, correlations between plasma measures of several EFA (LA, AA, EPA and DHA), although not ALA, and dietary intake. Arab(41)
also compared dietary measures of specific fatty acids with the fatty acid content of adipose tissue (as a long-term measure of exposure), and found that there were moderate-to-strong correlations between the two measures for PUFA, including n
-3 long-chain fatty acids. While we used a validated FFQ that contained a wide range of common food sources for the fats/fatty acids under investigation and a comprehensive nutrient composition database (containing the fatty acid content of several thousand different food items), we do, however, recognise that the present finding may be biased towards the null due to measurement error.
Estimating dietary intake of specific fatty acids is further complicated by the fact that many fatty acids share common foods(10)
. For example, while olive oil predominantly comprises the MUFA, oleic acid (approximately 70%), ALA and LA are also present in small quantities(27)
. We attempted to disentangle the effect of individual fatty acids by adjusting for highly correlated fats/fatty acids. Although this reduced the number of potential inverse associations to just ALA, there is the possibility that this may have led to over adjustment and failure to detect true effects as a consequence. While it is also possible that other dietary components common to a plant-based diet, e.g. carotenoids and vitamin E, may be responsible for the inverse associations that we observed for ALA, we detected no modifying effect by these micronutrients from our analyses.
Another limitation of dietary assessment is the potential for recall bias with a retrospective study design. However, as dietary factors are not widely associated with the risk of bladder cancer(42)
and recall of dietary intake is likely to be non-differential between cases and controls, recall bias should minimally affect the present results if at all. Although we cannot totally discount the possibility that there may have been dietary changes due to diagnosis of bladder cancer, it has previously been suggested that pre-clinical disease is unlikely to have a major effect on dietary intake(43)
. Consistent with this, we observed similar consumption levels of major dietary components, energy and total dietary fat intake for cases and controls and for cases both with and without invasive disease. Additionally, there was no association between intake of potentially protective fats/fatty acids and extent of disease (non-invasive v.
invasive bladder cancer).
While controls drawn from two sources, the Department of Transportation (for those under 65 years) and Medicare (for those 65 years and older), could be an issue, it is minimised by the fact that these are considered nearly complete sources of records in our population. Among cases, over 95 % report having a driver’s licence (for those under 65 years) as do over 95 % (for those 65 years and older) report being enrolled in Medicare (data not shown). Furthermore, we examined the characteristics of controls younger than 65 years and those over 65 years, and found them to be comparable with respect to sex, smoking and medical access variables (i.e. visit to a doctor in the past 2 years); however, older subjects had less than a college education (40% of those under 65 years and 50% of those 65 years and older). Level of education, however, is not a strong risk factor for bladder cancer (including in our own data) and thus was not considered a potential confounder in our analysis.
Dietary fat is a heterogeneous macronutrient, and in order to understand its role in bladder cancer aetiology, the effects of individual fatty acids need to be examined separately. While our observations suggest that ALA may have a protective role against developing bladder cancer, further replication in other studies is required. The present study additionally highlighted the difficulty in measuring dietary fat intake due to the wide range of fatty acids available from both different and shared food sources(10)
. Overall, the present results indicate that the possible effect of dietary fat on the risk of developing bladder cancer may depend on the type and source of fat as well as on the quantity consumed.