Intake of a-linolenic acid and other fatty acids in relation to the risk of
bladder cancer: results from the New Hampshire case–control study
Maree T. Brinkman1,2*, Margaret R. Karagas3, Michael S. Zens3, Alan R. Schned4, Raoul C. Reulen5
and Maurice P. Zeegers2,6
1Department of General Practice, Academisch Centrum voor Huisartsgeneeskunde, Katholieke Universiteit Leuven,
Kapucijnenvoer 33 Blok J, 3000 Leuven, Belgium
2Unit of Urologic and Genetic Epidemiology, Department of Public Health, Epidemiology and Biostatistics, School of
Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
3Section of Biostatistics and Epidemiology, Dartmouth Medical School and Norris-Cotton Cancer Centre, Lebanon,
New Hampshire, USA
4Department of Pathology, Dartmouth Medical School, Lebanon, New Hampshire, USA
5Centre for Childhood Cancer Survivor Studies, School of Health and Population Sciences, University of Birmingham,
6Department of Complex Genetics, Cluster of Genetics and Cell Biology, NUTRIM School for Nutrition, Toxicology
and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
(Received 24 September 2010 – Revised 6 January 2011 – Accepted 12 February 2011 – First published online 10 May 2011)
The role of dietary fat in bladder cancer aetiology is currently unclear due to few studies, equivocal findings and a lack of information on
important dietary fatty acids. The aim of the present study was to investigate the association between the intake of major dietary fats
and fatty acids and the risk of bladder cancer. A case–control study was conducted in New Hampshire, USA. Dietary data were collected
from 322 cases and 239 controls, and OR and 95% CI were calculated using unconditional logistic regression. Adjustment was made for
potential confounders: sex, age, smoking status, pack-years smoked, cholesterol and energy intake. Statistically significant reduced odds
of bladder cancer were observed for high intakes (highest quartile v. lowest quartile) of a-linolenic acid (ALA) (OR 0·26, 95% CI 0·10, 0·65;
P for trend¼0·01) and vegetable fat (OR 0·39, 95% CI 0·18, 0·86; P for trend¼0·03). Borderline statistically significant reduced odds were
detected for polyunsaturated fat (OR 0·43, 95% CI 0·19, 0·98; P for trend¼0·07) and linoleic acid (OR 0·43, 95% CI 0·19, 0·96; P for
trend¼0·06). These fats and fatty acids were highly correlated and following adjustment for each other, the only potential inverse associ-
ation to remain was for ALA. The present findings suggest that ALA may have a protective role against developing bladder cancer; however,
further investigation and replication in other epidemiological studies are required. Future research should focus on the type, source and
quantities of different dietary fatty acids consumed.
Key words: Bladder cancer: a-Linolenic acid: Essential fatty acids
Wide variation exists between countries for both the incidence
of bladder cancer(1)and the consumption of dietary fat(2).
Compared with Asian countries such as Japan, the age-
standardised incidence rate of bladder cancer is approximately
three times higher in the USA(1). Similarly, the USA, like
many Western countries, consumes a diet higher in total
fat (30–40% of total dietary intake)(3)than the traditional
Japanese diet (,30%)(4).
While a meta-analysis(5)and systematic review(6)have
reported a possible increased risk of bladder cancer associated
with a high intake of dietary fat, not all studies have observed
such an association(7–9). A possible explanation for inconsis-
tencies in the literature may be due to the fact that dietary
fat is obtained from both animal and vegetable or plant
sources and comprises more than forty different fatty acids
from nature(10). Furthermore, many other fatty acids are pro-
duced during food processing and cooking(10). Depending
on the chemical structure, there can be different metabolic,
physiological and even opposing effects between the various
fatty acids(11). It may be that the composition of dietary fat is
*Corresponding author: Dr M. T. Brinkman, fax þ32 16 33 74 80, email firstname.lastname@example.org
Abbreviations: AA, arachidonic acid; ALA, a-linolenic acid; EFA, essential fatty acid; LA, linoleic acid; NSAID, non-steroid anti-inflammatory drugs.
British Journal of Nutrition (2011), 106, 1070–1077
q The Authors 2011
British Journal of Nutrition
more important in the aetiology of bladder cancer than the
actual amount of fat consumed(12). Reports from in vitro(11)
and animal studies(13)suggest that the effect of fat on bladder
cells can range from anti-carcinogenic to pro-carcinogenic
depending on the type of fat/fatty acid involved.
Although not fully understood, one of the mechanisms
by which major n-3 polyunsaturated fatty acids, EPA and
DHA, are reported to possibly inhibit carcinogenesis is
through their anti-inflammatory activity(14). While the major
n-6 PUFA, linoleic acid (LA), has previously been reported
to induce carcinogenesis through oxidative damage and pro-
inflammatory mechanisms, this is not supported by the current
evidence from recent human experimental(15)and epidemio-
To date, few epidemiological studies(7,12,17,18)have exam-
ined the relationship between bladder cancer and the major
subgroups of dietary fat. A Serbian case–control study on
bladder cancer(19), however, highlighted the importance of
considering different dietary sources when it reported a
possible inverse association with sunflower oil and positive
association with animal fat intake. Similarly, the need
to account for the different types of dietary fats in analyses
was demonstrated by a Spanish multicentre case–control
study(12). The spanish study found that the increased risk of
bladder cancer associated with higher intakes of monounsatu-
rated fat disappeared following adjustment for saturated fat.
However, quite opposite effects were observed in a Japanese
case–control study(18), which has reported inverse associ-
ations between bladder cancer risk and both saturated and
monounsaturated fat intake.
Even less evidence is available on the association between
dietary intake of specific fatty acids and bladder cancer risk.
To our knowledge, there is only one such epidemiological
study(20), and it has reported no association between bladder
cancer overall and intake of n-3 marine fatty acids, EPA
Due to the current lack of information, the aim of the
present study was to investigate major dietary fats and fatty
acids to determine whether and to what extent they may
influence the risk of bladder cancer. Given the varying phys-
iological functions, it seemed appropriate that some of the
key dietary fatty acids be analysed separately.
Subjects and methods
A population-based case–control study was conducted in
New Hampshire, USA. Details of the study have previously
been reported(21,22). Briefly, bladder cancer cases were ident-
ified from the New Hampshire State Department of Health and
Human Services Cancer Registry as histologically confirmed,
primary bladder cancer diagnosed between 1 July 1998 and
31 December 2001. To be eligible for inclusion in the study,
all cases had to be New Hampshire residents aged between
25 and 74 years, had to have a listed phone number and
had to speak English. Physician consent was obtained
before contacting potential participants. Of the 472 potentially
eligible cases who were contacted, a total of 398 (84%) were
interviewed. For efficiency, controls were shared with another
study on non-melanoma cancer covering a reference period
from 1 July 1997 to 30 March 2000(23). Controls ,65 years
of age were selected from lists obtained from the New
Hampshire Department of Transportation. Controls who
were 65 years of age and older were chosen from data files
provided by the Centers for Medicare and Medicaid Services
of New Hampshire. Controls were randomly assigned a com-
parable reference date corresponding to dates of diagnoses
of the case group(24). A total of 526 controls (76%) were
interviewed from a potential 694 confirmed eligible partici-
pants(22). The present study was conducted according to the
guidelines laid down in the Declaration of Helsinki, and all
procedures involving human subjects/patients were approved
by the Committee for the Protection of Human Subjects at
Dartmouth College. Written informed consent was obtained
from all subjects/patients.
participants, usually in the homes of the participants. Data
were collected on participants’ sociodemographic information
such as education level, residence, occupation (history), medi-
cal history, lifestyle factors (including tobacco smoking),
household water supply and family history of cancer. Inter-
viewers were blind to case/control status, and interviews
were tape recorded with subjects’ consent (,5% refused to
have the interview taped) to ensure consistent quality of the
interview and clarification of details. Cases were also asked
whether they held a driver’s licence or a Medicare enrolment
card for comparability with controls.
interviewswere conductedwith consenting
The majority of interviews that included dietary assessment
took place between 2000 and 2003 for both cases and controls
(for 95% of subjects). This left data unavailable for 150 cases
and 455 controls; a total of 322 cases and 239 controls were
included in the dietary analyses of the present study. Subjects
from whom dietary data were collected were comparable
with those who did not provide dietary data with respect to
age, sex and smoking history (data not shown).
Dietary information was collected for the 12-month period
before the reference date using a detailed semi-quantitative
FFQ originally developed by Willett et al.(25)for the Nurses’
Health Study. It contained 121 food items assigned to the
following broad categories: dairy; fruit; vegetables; eggs and
meat; breads and baked goods. Within these categories,
there were specific foods that are rich sources of both
animal fats (beef, lamb, pork, poultry, fish, eggs, milk,
yogurt, cheese and butter) and vegetable fats (margarine,
nuts, salad dressing, soyabeans, vegetable oils, leafy green
vegetables and cereals). The FFQ also included a list of bev-
erages, common mineral and vitamin supplements including
n-3 fatty acids, and seven questions relating to fat consump-
tion, e.g. amount of visible fat removed from meat before
a-Linolenic acid and bladder cancer1071
British Journal of Nutrition
consumption, frequency of fried foods eaten at home and
away from home, the type of margarine used and types of
fat used for frying/saute ´ing and baking. Additionally, there
were three open-ended questions where subjects could
specify the type of fat or oil usually used in cooking, any
additional nutritional supplements and food items not already
listed in the FFQ.
Frequency options ranged from never to six or more times a
day. Nutrient intake was calculated by multiplying frequency
of each food item on the FFQ by the nutrient content for
the specific portion size(26). Food composition data were
based on data from the United States Department of Agricul-
ture(27). The composition of fatty acids (ranging from short-
chain SFA to long-chain PUFA) was available in the nutrient
database for all foods included in the FFQ except for the
few items without fat content such as alcoholic beverages.
We investigated major dietary fats and fatty acids for potential
associations with bladder cancer. These included saturated
fat (palmitic acid and stearic acid), monounsaturated fat
(palmitoleic acid and oleic acid), polyunsaturated fat, n-3
PUFA (a-linolenic acid (ALA), EPA and DHA) and n-6 PUFA
(LA and arachidonic acid (AA)).
Usual dietary intake for the previous 12 months of all of
these fats and fatty acids was estimated in g/d. The data
were analysed in quartiles based on the control group distri-
butions. OR and corresponding 95% CI were calculated
using unconditional logistic regression analysis. As cases and
controls were not matched for age and sex (as described ear-
lier, due to using a shared control group), age and sex were
included in all models as covariates. Adjustment was also
made for a number of possible confounding variables inclu-
ding cigarette smoking status (current/non-current smoker),
pack-years of cigarette smoking, cholesterol (except vegetable
fat) and total energy intake (quartiles for kJ/d). Likelihood-
ratio tests for linear trend were conducted by assigning
an integer to each quartile of the nutrient, e.g. 1–4, then fitting
the term as a continuous variable in the model and comparing
the log likelihood of this model to the log likelihood of a
nested model without the nutrient. Potential multicollinearity
was assessed by calculating variance inflation factors(28).
Interaction was investigated between the intake of ALA and
smoking status/history, lipid-soluble antioxidants (vitamin E
and total carotenoids) and non-steroid anti-inflammatory
drugs (NSAID). In this analysis, smoking status was dichoto-
mised into never/ever smoker, cigarettes/d into high and
low categories (,20/$20 cigarettes/d) and duration of smok-
ing (,27/$27years). ALA and antioxidants were dichoto-
mised into high and low categories based on median values
of the controls and NSAID or analgesics based on use
before the reference date (no/yes). Participants were classified
as having had prior use if they had taken NSAID or other pain
medicine at least four times per week for 1month or longer
before the reference date (diagnosis for cases and comparable
date randomly assigned to the controls)(22). Drug categories
for NSAID/analgesicsincluded phenacetin, paracetamol,
ibuprofen and aspirin, and any NSAID (diclofenac, aspirin
and ibuprofen)(22). We used the likelihood-ratio test to
evaluate interaction, i.e. comparing the log likelihood of
regression models with and without the interaction term.
All reported P values were two-sided, and values less than
or equal to 0·05 were considered to be statistically significant.
All statistical analyses were performed using the statistical
software package Stata/IC 10.1(29)(StataCorp, College Station,
Table 1 presents the frequency distributions of selected study
characteristics for cases and controls. Approximately three
times more men (74%) than women were bladder cancer
cases. A majority of both cases and controls were in the
older age category (60 years and over). Compared with
controls, there was a higher prevalence of current smokers,
a greater number of both cigarettes smoked per day and
years smoked among the cases. Cases and controls were com-
parable for the intake of the major dietary characteristics listed
in the table: kJ, total fat, saturated fat, monounsaturated
fat, polyunsaturated fat, animal fat and vegetable fat.
The OR and 95% CI for bladder cancer and intake of major
categories of dietary fats and fatty acids are presented in
Tables 2 and 3, respectively.
Table 1. Distribution of bladder cancer cases and controls by demo-
graphic characteristics, environmental and dietary exposures
(Mean values, standard deviations, number of subjects and percentages)
Total dietary fat (g/d)
Saturated fat (g/d)
Monounsaturated fat (g/d)
Polyunsaturated fat (g/d)
Animal fat (g/d)
Vegetable fat (g/d)
62·0 9·260·7 10·6
* Mean values were significantly different between cases and controls (P,0·05).
M. T. Brinkman et al.1072
British Journal of Nutrition
Statistically significant reduced odds of bladder cancer were
observed for the highest quartile compared with the lowest
quartile of intake for ALA (OR 0·26, 95% CI 0·10, 0·65; P for
trend¼0·01) and vegetable fat (OR 0·39, 95% CI 0·18, 0·86;
P for trend¼0·03). Borderline statistically significant inverse
associations were also observed for LA (OR 0·43, 95% CI
0·19, 0·96; P for trend¼0·06) and polyunsaturated fat (OR
0·43, 95% CI 0·19, 0·98; P for trend¼0·07). An inverse associ-
ation and trend of borderline statistical significance was
observed for high intake of polyunsaturated fats according
to the n-6:n-3 ratio (OR 0·59, 95% CI 0·34, 1·04; P for
trend¼0·06). No statistically significant associations or trends
were observed for the extent of disease (non-invasive v. inva-
sive disease) for these fats/fatty acids or any of the other
dietary fats or fatty acids including total intake of n-3 or n-6
fatty acids (data not shown).
There was a high correlation between intake of vegetable
fat, polyunsaturated fat and LA (vegetable fat and poly-
unsaturated fat, r 0·88; vegetable fat and LA, r 0·88; LA and
polyunsaturated fat, r 0·97). Similarly, intake of ALA was
highly correlated with vegetable fat (r 0·76) and polyunsatu-
rated fat (r 0·88). Of these dietary fats and fatty acids, only
LA and polyunsaturated fat had a high variance inflation
factor value (.10), indicating the presence of multicollinearity
(data not shown).
We performed additional adjustment for the correlated
fats and fatty acids. The only potential inverse association
remaining after these adjustments, although it was borderline
statistically significant, was between bladder cancer and intake
of ALA (highest v. lowest quartile for the intake of ALA:
adjusted for vegetable fat (OR 0·32, 95% CI 0·11, 0·91; P for
trend¼0·08); adjusted for polyunsaturated fat (OR 0·30,
95% CI 0·09, 1·01; P for trend¼0·07); adjusted for LA (OR
0·30, 95% CI 0·09, 1·01; P for trend¼0·08)). All other previous
associations with bladder cancer disappeared, including the
ratio for the intake of n-6:n-3 fatty acids (data not shown).
We did not detect any significant interaction between smok-
ing status (ever/never), number of cigarettes smoked per day,
duration of smoking (years), intake of vitamin E or total
carotenoids and ALA. Additionally, there was no evidence of
a modifying effect for the use of aspirin, ibuprofen, paraceta-
mol or NSAID or analgesics as a group. However, there were
borderline statistically significant lower odds of bladder cancer
for high ALA intake among phenacetin users compared with
non-users (P for interaction¼0·11; data not shown).
From our investigations into potential associations between
major dietary fats and fatty acids and bladder cancer, we ident-
ified 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
Table 2. Major categories of fat and bladder cancer*
(Adjusted odds ratios and 95% confidence intervals)
Daily intakeQ1Q2Q3 Q4P for trend
Total fat (g/d)
Animal fat (g/d)
Vegetable fat (g/d)†
Total saturated fat (g/d)
Total monounsaturated fat (g/d)
Polyunsaturated fat (g/d)
* Adjusted for age, sex, smoking status (current v. non-current smoker; pack-years smoked (categories: 0–10, 10–20, 20–30, 30–40, 40–50
and 50 þ)), cholesterol intake and total energy intake (Q, kJ/d).
† Not adjusted for cholesterol.
a-Linolenic acid and bladder cancer1073
British Journal of Nutrition
acids. However, these fats and fatty acids were all highly
correlated with each other, and initial associations dis-
appeared following mutual adjustment with the exception of
ALA. We did not observe any other potential associations,
trends or interactions.
Most oftheepidemiological evidence availableon theassoci-
ation between dietary fatty acids and the risk of cancer has
focused on cancer at other body sites, e.g. colorectal(30),
breast(31)and prostate(32). 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/vasodila-
tion(3). It has also been reported that EFA deficiency may be
‘pro-tumorigenic’ in rats(34). As EFA make up a large per-
centage 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).
Table 3. Major dietary fatty acids and bladder cancer*
(Adjusted odds ratios and 95% confidence intervals)
Major dietary fatty acids†Q1 Q2Q3 Q4P
Palmitic acid (g/d), 16:0
Stearic acid (g/d), 18:0
Palmitoleic acid (g/d), 16:1
Oleic acid (g/d), 18:1
n-3 fatty acids
a-Linolenic Acid (ALA), 18:3
EPA (g/d), 20:5
DHA (g/d), 22:6
n-6 fatty acids (g/d)
Linoleic acid (g/d), 18:2
Arachidonic acid (g/d), 20:4
* Adjusted for age, sex, smoking status (current v. non-current smoker; pack-years smoked (categories: 0–10, 10–20, 20–30,
30–40, 40–50 and 50 þ)), cholesterol intake and total energy intake (Q, kJ/d).
† Nomenclature of fatty acids, e.g. 4:0, length of the carbon chain (short chain, four carbons) and number of double bonds
(0); 18:1 (long chain, eighteen carbons) and one double bond(10).
M. T. Brinkman et al.1074
British Journal of Nutrition
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 pre-
vious studies, we found no association between bladder
cancer risk and intake of EPA and DHA(20)or n-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 adjust-
ment 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-6: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-6: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 associ-
ations 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 satu-
rated 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 perform-
ance 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 investi-
gation and a comprehensive nutrient composition database
(containing the fatty acid content of several thousand different
food items), we do, however, recognise that the present find-
ing 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 com-
prises 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 adjust-
ment 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 dis-
ease 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 with-
out 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, how-
ever, 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.
a-Linolenic acid and bladder cancer1075
British Journal of Nutrition
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 high-
lighted 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.
None of the authors has any conflict of interest to declare. The
present study was funded in part by grant no. 5 P42 ES007373
from the National Institute of Environmental Health Sciences
(NIEHS), National Institutes of Health and CA57494 from
the National Cancer Institute, National Institutes of Health.
Its contents are solely the responsibility of the authors and
do not necessarily represent the official views of the NIEHS,
National Institutes of Health. M. P. Z. was partly funded by
Cancer Research, UK. M. T. B., M. R. K. and M. P. Z. parti-
cipated in the conception and design of the study. A. R. S.
carried out histopathological reviews. M. S. Z. was involved
with the data management. M. T. B. carried out the statistical
analysis and drafted the manuscript. M. T. B., R. C. R.,
M. R. K., M. S. Z., A. R. S. and M. P. Z. participated in the
interpretation of results and critical review of several drafts
of the manuscript. All authors read and approved the final
manuscript. The authors would like to thank the physicians,
pathology laboratories, staff members and many participants
of the New Hampshire Health Study for making the present
1. Parkin DM, Bray F, Ferlay J, et al. (2005) Global cancer
statistics, 2002. CA Cancer J Clin 55, 74–108.
Wolmarans P (2009) Background paper on global trends in
food production, intake and composition. Ann Nutr Metab
World Cancer Research Fund/American Institute for Cancer
Research (2007) Fats and oils. In Food, Nutrition, Physical
Activity and the Prevention of Cancer: A Global Perspective,
pp. 135–140. Washington DC: AICR.
Yoneyama S, Miura K, Sasaki S, et al. (2007) Dietary intake
of fatty acids and serum C-reactive protein in Japanese.
J Epidemiol 17, 86–92.
Steinmaus CM, Nunez S & Smith AH (2000) Diet and
bladder cancer: a meta-analysis of six dietary variables.
Am J Epidemiol 151, 693–702.
Brinkman M & Zeegers MP (2008) Nutrition, total fluid and
bladder cancer. Scand J Urol Nephrol Suppl 218, 25–36.
Michaud DS, Spiegelman D, Clinton SK, et al. (2000)
Prospective study of dietary supplements, macronutrients,
micronutrients, and risk of bladder cancer in US men. Am J
Epidemiol 152, 1145–1153.
8. Chyou PH, Nomura AM & Stemmermann GN (1993)
A prospective study of diet, smoking, and lower urinary
tract cancer. Ann Epidemiol 3, 211–216.
La Vecchia C, Negri E, Decarli A, et al. (1989) Dietary factors
in the risk of bladder cancer. Nutr Cancer 12, 93–101.
Jones G (1997) Fats. In Food and Nutrition Australasia, Asia
and the Pacific, 3rd ed., pp. 205–214 [ML Wahlqvist, editor].
East Melbourne, VIC: Allen & Unwin.
Maggiora M, Bologna M, Ceru MP, et al. (2004) An overview
of the effect of linoleic and conjugated-linoleic acids on
the growth of several human tumor cell lines. Int J Cancer
Riboli E, Gonzalez CA, Lopez-Abente G, et al. (1991) Diet
and bladder cancer in Spain: a multi-centre case–control
study. Int J Cancer 49, 214–219.
Cremonezzi DC, Diaz MP, Valentich MA, et al. (2004)
Neoplastic and preneoplastic lesions induced by melamine
in rat urothelium are modulated by dietary polyunsaturated
fatty acids. Food Chem Toxicol 42, 1999–2007.
Larsson SC, Kumlin M, Ingelman-Sundberg M, et al. (2004)
Dietary long-chain n-3 fatty acids for the prevention of
cancer: a review of potential mechanisms. Am J Clin Nutr
Adam O, Tesche A & Wolfram G (2008) Impact of linoleic
acid intake on arachidonic acid formation and eicosanoid
biosynthesis in humans. Prostaglandins Leukot Essent Fatty
Acids 79, 177–181.
Gerber M (2009) Background review paper on total
fat, fatty acid intake and cancers. Ann Nutr Metab 55,
Bruemmer B, White E, Vaughan TL, et al. (1996) Nutrient
intake in relation to bladder cancer among middle-aged
men and women. Am J Epidemiol 144, 485–495.
Wakai K, Takashi M, Okamura K, et al. (2000) Foods and
nutrients in relation to bladder cancer risk: a case–control
study in Aichi Prefecture, Central Japan. Nutr Cancer 38,
Radosavljevic V, Jankovic S, Marinkovic J, et al. (2005) Diet
and bladder cancer: a case–control study. Int Urol Nephrol
Holick CN, Giovannucci EL, Stampfer MJ, et al. (2006)
A prospective study of fish, marine fatty acids, and bladder
cancer risk among men and women (United States).
Cancer Causes Control 17, 1163–1173.
Karagas MR, Tosteson TD, Blum J, et al. (1998) Design of
an epidemiologic study of drinking water arsenic exposure
and skin and bladder cancer risk in a U.S. population.
Environ Health Perspect 106, 1047–1050.
Fortuny J, Kogevinas M, Zens MS, et al. (2007) Anal-
gesic and anti-inflammatory drug use and risk of bladder
cancer: a population based case control study. BMC Urol,
10 August, 7–13.
Applebaum KM, Karagas MR, Hunter DJ, et al. (2007)
Polymorphisms in nucleotide excision repair genes, arsenic
exposure, and non-melanoma skin cancer in New Hampshire.
Environ Health Perspect 115, 1231–1236.
Karagas MR, Park S, Warren A, et al. (2005) Gender, smo-
king, glutathione-S-transferase variants and bladder cancer
incidence: a population-based study. Cancer Lett 219,
Willett WC, Sampson L, Stampfer MJ, et al. (1985) Reprodu-
cibility and validity of a semiquantitative food frequency
questionnaire. Am J Epidemiol 122, 51–65.
Michaud DS, Spiegelman D, Clinton SK, et al. (1999) Fruit
and vegetable intake and incidence of bladder cancer in a
male prospective cohort. J Natl Cancer Inst 91, 605–613.
M. T. Brinkman et al. 1076
British Journal of Nutrition
27. US Department of Agriculture, Agricultural Research Service Download full-text
(2004) USDA Nutrient Database for Standard Release 16.
Washington, DC: US Department of Agriculture.
Slinker BK & Glantz SA (1985) Multiple regression for
physiological data analysis: the problem of multicollinearity.
Am J Physiol 249, R1–R12.
StataCorp (2009) Stata/IC 10.1. College Station TX: StataCorp.
Theodoratou E, McNeill G, Cetnarskyj R, et al. (2007) Dietary
fatty acids and colorectal cancer: a case–control study. Am J
Epidemiol 166, 181–195.
Thie ´baut AC, Chaje `s V, Gerber M, et al. (2009) Dietary
intakes of omega-6 and omega-3 polyunsaturated fatty acids
and the risk of breast cancer. Int J Cancer 124, 924–931.
Simon JA, Chen Y-H & Bent S (2009) The relation of alpha-
linolenic acid to the risk of prostate cancer: a systematic
review and meta-analysis. Am J Clin Nutr 89, 1558S–1564S.
McClinton S, Moffat LE, Horrobin DF, et al. (1991)
Abnormalities of essential fatty acid distribution in the
plasma phospholipids of patients with bladder cancer. Br J
Cancer 63, 314–316.
Eynard AR (1998) Is the risk of urinary tract tumorigenesis
enhanced by a marginal chronic essential fatty acid
deficiency (EFAD)? Nutrition 14, 211–216.
MacLean CH, Newberry SJ, Mojica WA, et al. (2006) Effects of
omega-3 fatty acids on cancer risk: a systematic review.
JAMA 295, 403–415.
36. Kris-Etherton P, Taylor DS, Yu-Poth S, et al. (2000) Poly-
unsaturated fatty acids in the food chain in the United
States. Am J Clin Nutr 71, 179S–188S.
Smit LA, Mozaffarian D & Willett W (2009) Review of fat
and fatty acid requirements and criteria for developing
dietary guidelines. Ann Nutr Metab 55, 44–55.
Vena JE, Graham S, Freudenheim J, et al. (1992) Diet in
the epidemiology of bladder cancer in western New York.
Nutr Cancer 18, 255–264.
Carayol M, Grosclaude P & Delpierre C (2010) Prospective
studies of dietary alpha-linolenic acid intake and prostate
Astorg P, Bertrais S, Laporte F, et al. (2008) Plasma n-6 and
n-3 polyunsaturated fatty acids as biomarkers of their
dietary intakes: a cross-sectional study within a cohort of
middle-aged French men and women. Eur J Clin Nutr 62,
Arab L (2003) Biomarkers of fat and fatty acid intake. J Nutr
World Cancer Research Fund/American Institute for Cancer
Research (2007) Cancers. In Food, Nutrition, Physical
Activity, and the Prevention of Cancer: a Global Perspective,
pp. 312–314. Washington DC: AICR.
Garcia-Closas R, Garcia-Closas M, Kogevinas M, et al. (2007)
Food, nutrient and heterocyclic amine intake and the risk of
bladder cancer. Eur J Cancer 43, 1731–1740.
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