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Carcinogenesis Advance Access originally published online on January 18, 2007
Carcinogenesis 2007 28(6):1232-1236; doi:10.1093/carcin/bgm002
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trans-Fatty acid intake and increased risk of advanced prostate cancer: modification by RNASEL R462Q variant

Xin Liu1,4,*, Fredrick R. Schumacher2, Sarah J. Plummer3, Eric Jorgenson1, Graham Casey3 and John S. Witte1,*

1 Department of Epidemiology and Biostatistics and Institute for Human Genetics, University of California, San Francisco, CA 94143-0794, USA
2 Channing Laboratory, Brigham and Women’s Hospital and Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA
3 Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH 44195, USA
4 Present address: Mary Ann and J. Milburn Smith Child Health Research Program, Department of Pediatrics, Northwestern University Feinberg School of Medicine and Children’s Memorial Hospital and Children’s Memorial Research Center, Chicago, IL 60614, USA

* To whom correspondence should be addressed. Tel: +1 415 502 6882; Fax: +1 415 476 1356;

Email: wittej{at}humgen.ucsf.edu

Correspondence may also be addressed to Xin Liu. Tel: +1 312 573 7751; Fax: +1 312 573 7825;

Email: xnliu{at}childrensmemorial.org


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Previous studies have examined the role of higher trans-fatty acid consumption on prostate cancer risk, but the results remain unclear. Any potential association may be modified by variants in genes involved with immune and inflammatory responses. To investigate this, we undertook a case–control study (N = 1012) of the association between trans-fatty acid intake and advanced prostate cancer, and evaluated whether this effect was modified by a functional polymorphism in the RNASEL gene (R462Q). Among Caucasians (N = 834), we observed that each type of trans-fatty acid and total trans-fatty acid intake showed a statistically significant positive association with prostate cancer, but only weakly increased risk for the isomers of cis-fatty acids. Compared with the lowest quartile of total trans-fatty acid consumption, the higher quartiles gave odds ratios (ORs) equal to 1.58 [95% confidence interval (CI): 1.00, 2.48], 1.95 (95% CI: 1.20, 3.19) and 2.77 (95% CI: 1.60, 4.79) (P-trend = 0.0003); this effect was modified by the RNASEL R462Q polymorphism (Pinteraction = 0.01). Among men with the QQ/RQ genotype, the association between total trans-fatty acid intake and prostate cancer was substantially stronger [ORs of higher quartiles equal to 2.93 (95% CI: 1.62, 5.30), 3.13 (95% CI: 1.64, 5.98) and 4.80 (95% CI: 2.29, 10.08), respectively]. For men with the RR genotype, total trans-fatty acid intake was not associated with disease. This suggests that among Caucasians, positive association between higher trans-fatty acid consumption and prostate cancer may be modified by the functional RNASEL variant R462Q.

Abbreviations: CI, confidence interval; FFQ, food frequency questionnaire; OR, odds ratio


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
trans-Fatty acids are unsaturated fatty acids with at least one double bond in the trans configuration, formed via the hydrogenation of liquid vegetable fats used to produce shortening and margarine (1,2). Higher intake of trans-fatty acids is associated with increased risk of heart disease (3–5), due in part to their detrimental effects on serum lipid levels (e.g. elevating low-density lipoprotein cholesterol and lowering high-density lipoprotein cholesterol). trans-Fatty acids appear to impact markers of systemic inflammation, which may in turn affect cancer risk. For example, two crossover human feeding studies found that trans-fatty acid intake increased the production of tumor necrosis factor-{alpha}, interleukin-6 and C-reactive protein (6,7). In addition, higher consumption of trans-fatty acids was associated with inflammatory markers among healthy (8) and obese women (9), as well as patients with cardiovascular disease (10).

With regard to cancer risk, previous epidemiologic studies have found that higher consumption of trans-fatty acids increased the risk of breast and colorectal cancer (11–14). Studies investigating the potential association with prostate cancer, however, have been equivocal. One study found that serum phospholipids C18 trans-fatty acids but not C16 trans-fatty acids were associated with an increased risk of prostate cancer (15). Another study found no association between trans-fatty acids in adipose tissue and prostate cancer (11), whereas two others reported no association between dietary trans-fatty acids and this disease (16,17). These inconsistent results may reflect the evaluation of trans-fatty acid values from different sources [e.g. adipose, serum and food frequency questionnaires (FFQs)]. Another potential explanation is that the studies did not consider modification of the trans-fatty acid effects, especially by genes involved with innate immunity and inflammation.

Numerous proteins are known to affect infection and inflammation, but the role of variants in their corresponding genes in prostate cancer has been little studied. Genes studied to date include RNASEL (18–26), MSR1 (24,27–30), COX-2 (31,32), TNF{alpha} (33,34) and TLRs (35–38). We focus here on the effect modification of trans-fatty acid intake by RNASEL, the putative HPC1 gene (39) that encodes 2-5A-dependent ribonuclease (RNase L), which in turn plays a critical role in the anti-viral and pro-apoptotic activities of the interferon-induced 2-5A system (40–42). The RNASEL missense variant R462Q was found to reduce RNase L enzymatic activity ~3-fold and was deficient in causing apoptosis in response to 2-5A (18,43). Some—though not all—genetic epidemiologic studies detected associations between R462Q and prostate cancer (18–22,24–26).

As with the trans-fatty acid results, these equivocal findings for RNASEL R462Q may reflect the need to look at potential effect modification. Therefore, we present here results from a genetic epidemiologic investigation of the relationship among trans-fatty acids, R462Q and prostate cancer.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Study subjects
The study population comprised 1012 men: 506 cases diagnosed with advanced prostate cancer (with any one of the following: Gleason score ≥ 7; tumor stage ≥ T2c (44) or PSA at diagnosis >10 ng/ml) and an equal number of age-, ethnicity- and institution-matched controls, as described previously (45). All subjects were recruited from the major medical institutions in Cleveland, OH (i.e. Cleveland Clinic Foundation, University Hospitals of Cleveland and their affiliates) from 2001 to 2004. The advanced cases were identified from a consecutive series of prostate cancer patients at these medical institutions, and diagnosis was verified by review of medical records. The Gleason score measures were based on pathology results from radical prostatectomy specimens when available, otherwise from biopsy specimens. Tumor stage is based on a combination of clinical and pathologic measures. The controls are men who underwent standard annual medical exams at the above institutions. To avoid the potential for bias arising from using ‘hospital-based’ controls, men who had been diagnosed with any non-skin cancer were not eligible for the study. Cases and controls were matched on age, so they should have similar risks of medical conditions that may be associated with altered dietary habits. Institutional Review Board approval was obtained from the participating medical institutions, and all study participants gave informed consent.

Dietary intake of fatty acids
We collected information on diet using a validated semi-quantitative FFQ (46,47). For cases, we asked about their intake of food and dietary supplements in the year prior to diagnosis. For controls, we asked about their food consumption and dietary supplement intake during the previous year. Since we recruited incident cases and controls at approximately the same time, the cases and controls had relatively similar periods of recall for the questionnaire information. These questionnaires were scanned at the Fred Hutchinson Cancer Research Center and converted to measures of food and nutrient intake, including measures of fatty acid consumption.

In April 2004, the food and drug administration (FDA) Food Advisory Committee recommended that trans-fatty acid intake should be reduced to <1% of energy. And on 1 January 2006, the FDA required food manufacturers to list trans fat on all nutrition labels. Therefore, we anticipate that the consumption of trans-fatty acids was stable over the study time period.

Genotyping RNASEL R462Q
The RNASEL R462Q variant (rs486907) was genotyped using a premade TaqMan SNP assay (C_935391_1, Applied Biosystems, Foster City, CA) with TaqMan Universal PCR Master Mix. Fluorescence was measured and genotypes were assigned on a 7900HT Sequence Detection System with SDS2.2 software according to the manufacturer’s instructions (Applied Biosystems). The genotyping success rate was 100%. A concordance rate of 100% was obtained using 3% replicate samples. Genotyping was performed by individuals blinded to case–control status.

Statistical analysis
Within each ethnic group, we evaluated the association between fatty acids, RNASEL R462Q and advanced prostate cancer using unconditional logistic regression that adjusted for the matching factors (age and medical institutions). We first examined the effects of the three main cis- and trans-fatty acids (C16:1, C18:1 and C18:2), as well as total trans-fatty acids. We did this to determine if the trans isomer has a different effect on prostate cancer from that observed for the cis isomer. Fatty acid values were categorized into quartiles based on their distributions in controls, and a corresponding ordinal variable (ranging from 1 to 4) was generated to test for a linear trend across quartiles. We then examined RNASEL R462Q, comparing men with RQ or QQ genotypes to those with the RR genotype, since this reflects the expected functional activity of the RNASEL R462Q polymorphism (18). To investigate potential effect modification, we stratified the fatty acid analyses by RNASEL R462Q genotypes, and tested for multiplicative interaction by including main effects and cross-product terms in a logistic regression model. Statistical significance was assessed via both Wald test and likelihood ratio test comparing full and reduced models (i.e. with and without the cross-product terms). All P-values are from two-sided tests, and all analyses were undertaken with SAS (version 9.1, SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Eighty-two percent of the subjects were Caucasian and 18% were African American. Consistent with the recruitment criteria, cases and controls were matched by age, ethnicity or institution. Cases were more likely than controls to have a family history of prostate cancer (two or more first-degree relatives in a family or one first-degree and two or more second-degree relatives) (P < 0.001). The majority of cases (84%) have Gleason score ≥ 7 and 10% have tumor stage ≥ T2c. As expected, cases had higher PSA levels compared with controls (mean PSA: 14.2 versus 1.7 ng/ml). Cases and controls had a similar history of benign prostatic hyperplasia, PSA screening and digital rectal examination, though controls were more likely to be highly educated and have a higher income than cases (Table I).


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  		Table I. Descriptive characteristics for cases and controls (Cleveland, OH, 2001–2004)

 
The mean intake of total energy, cis- and trans-fatty acids was higher in cases than in controls (Table II). In addition, fatty acid intake was different among Caucasian and African American controls, especially for trans-fatty acids. When looking at quartiles, total energy intake was associated with an increased risk of prostate cancer among men who are in the highest quartile: odds ratio (OR) = 1.86 [95% confidence interval (CI) = 1.26, 2.74] for Caucasians and OR = 1.84 (0.79–4.31) for African Americans (Table III). Hence, all the following results have been adjusted for quartiles of total energy intake, as well as age and medical institution.


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  		Table II. Mean energy and fatty acid intake in prostate cancer cases and age- and institution-matched controls

 


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  		Table III. Association between fatty acids and advanced prostate cancer in a case–control study

 
We observed that each type of trans-fatty acid as well as total trans-fatty acid intake had a statistically significant association with prostate cancer among Caucasians (Table III). Specifically, in comparison with lowest quartile of total trans-fatty acid consumption, the second, third and fourth quartiles had ORs equal to 1.58 (95% CI: 1.00, 2.48), 1.95 (95% CI: 1.20, 3.19) and 2.77 (95% CI: 1.60, 4.79) (P-trend = 0.0003). When looking at particular trans-fatty acids, the C18 isomers showed more significant effects on prostate cancer than C16 (Table III). The associations between isomers of cis-fatty acids and disease were much weaker (Table III). In contrast with Caucasians, higher fatty acid consumption showed protective effects on prostate cancer risk among African Americans (Table III). We consider the results from African Americans as exploratory because of the small sample size and we only present the results of interaction effects in Caucasians.

When looking at RNASEL, the R462Q genotypes were in Hardy–Weinberg equilibrium in both Caucasian [frequency (Q) = 37%] and African American [frequency (Q) = 14%] controls. The corresponding frequencies of allele Q among cases are 36% and 12%, respectively. There was no apparent association between RNASEL R462Q and prostate cancer: comparing men with the QQ/RQ genotype versus those with the RR genotype gave ORs of 0.90 (95% CI: 0.68, 1.18) in Caucasians and 1.06 (95% CI: 0.54, 2.12) in African Americans (adjusted for age and medical institution).

The RNASEL R462Q variant substantially modified the effect of total trans-fatty acid intake on disease (Pinteraction = 0.01) in Caucasians: among men with QQ/RQ genotypes, ORs comparing higher quartiles of total trans-fatty acid intake with the lowest quartile were 2.93 (95% CI: 1.62, 5.30), 3.13 (95% CI: 1.64, 5.98) and 4.80 (95% CI: 2.29, 10.08), respectively. In contrast, among men with RR genotypes, the influence of total trans-fatty acid intake is largely attenuated with corresponding ORs of 0.59 (95% CI: 0.28, 1.24), 0.96 (95% CI: 0.44, 2.11) and 1.27 (95% CI: 0.54, 2.98) (Table IV). Interaction effects for each specific type of trans-fatty acid were similar to those for the total amount of each of trans-fatty acid (Table IV). We observed no statistically significant interaction between cis-fatty acids and prostate cancer (data not shown). The results did not materially change when we restricted our analyses to cases with Gleason score ≥ 7 or tumor stage ≥ T2c, when we adjusted for or stratified by body mass index (<25, 25–30 and ≥30 kg/m2) or when we used the residual energy adjustment methods (48) (data not shown).


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  		Table IV. Association between trans-fatty acid intake and advanced prostate cancer in a case–control study, stratified by RNASEL R462Q genotypes (Caucasians only)

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
We observed that a higher intake of trans-fatty acids is strongly associated with prostate cancer among Caucasians. Moreover, this association was substantially modified by the functional variant RNASEL R462Q, although this variant alone was not associated with disease.

Our findings confirm a previously reported association between serum trans-fatty acids and prostate cancer (15), but do not agree with studies that also used FFQ to assess trans-fatty acids (16,17). This discrepancy may reflect the actual FFQ used, which varied across the different studies. The current study used an FFQ designed specifically to assess nutrients in studies of prostate cancer. Another possible explanation is that different populations may have different primary sources of trans-fatty acids, which may in turn have distinct effects on risk of disease. For example, the risk of coronary heart disease is increased by higher intake of trans-fatty acids from partially hydrogenated vegetable oils, but not those occurring in milk and ruminant fat (5). The variation in these sources across the prostate cancer studies using FFQs might explain the contrasting results. For example, >80% of trans-fatty acids in the American diet derive from partially hydrogenated fat (49,50). This appears higher than that in the Dutch diet (51), and might explain the inconsistent results between our study and the Netherlands cohort study (16). Potential changes in trans-fatty acid consumption are unlikely to explain the equivocal findings since the aforementioned studies all assessed intake before changes in trans-fatty acid labeling or use in foods. Finally, the effects of trans-fatty acids may be detected only among certain groups, such as men carrying at least one RNASEL Q462 allele.

The biological mechanism underlying the potential interaction between trans-fatty acids intake and RNASEL R462Q remains unclear. Experimental studies indicate that trans-fatty acids can alter immune response by increasing levels of markers of systemic inflammation (e.g. tumor necrosis factor-{alpha}, interleukin-6 and C-reactive protein) as well as increasing vulnerability of the cell membrane to the effects of prostaglandins (e.g. PGE2) (6,7,52). Therefore, long-term high trans-fatty acid consumption might affect chronic inflammation and subsequently accelerate cancer development among men who carry a RNASEL Q allele—which has lower enzymatic activity (18), deficient apoptotic response (43) and may have reduced ability to clear viral infection in the prostate (53).

To our knowledge, this is the first study evaluating the interaction between trans-fatty acid consumption and a functional polymorphism in an innate immunity gene on prostate cancer risk. The positive results merit careful interpretation. A limitation of the current study is the potential for biased recall of trans-fatty acid intake. The recruitment period for this study was 2001–2004, primarily before the public was made aware of the potential ill-health effects of trans-fatty acids. The lack of general knowledge about how this nutrient might impact prostate cancer should make any recall bias non-differential among cases and controls, and should in turn only lead to an underestimation of the effect estimates. Moreover, cases were recruited shortly after diagnosis (median time between diagnosis and recruitment = 4.7 months), so the recall period was similar among cases and controls.

In summary, we found that higher trans-fatty acid consumption increases the risk of advanced prostate cancer among Caucasians, and RNASEL R462Q substantially modifies this effect. If this result is ultimately deemed causal, it would clarify a risk factor for prostate cancer that could be avoided among genetically susceptible men.


   Acknowledgments
 
We thank the participants in this study; their efforts have helped further our understanding of the causes of prostate cancer. This work was supported by National Institutes of Health grants (CA88164, CA94211 and CA98683).

Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received September 18, 2006; revised January 5, 2007; accepted January 5, 2007.


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