Nut consumption and risk of cancer and type 2 diabetes : a systematic review and meta-analysis

Context: The identification of foods that can decrease the risk of cancer and type 2 diabetes may be helpful in reducing the burden of these diseases. Although nut consumption has been suggested to have a disease-preventive role, current evidence remains inconsistent. Objective: The aim of this systematic review and meta-analysis was to clarify the association between nut consumption and risk of cancer or type 2 diabetes. Data Sources: Six databases were searched for relevant studies from the time of database inception to August 2014. Reference lists of relevant review articles were hand searched, and authors were contacted when data were insufficient. Study Selection: Eligible studies included epidemiological studies (case–control and cohort) or clinical trials that reported an association between nut consumption and the outcome of type 2 diabetes or specific cancers. Data Extraction: Two investigators independently extracted descriptive, quality, and risk data from included studies. Data Synthesis: Random-effects meta-analysis was used to pool relative risks from the included studies. The I statistic was used to assess heterogeneity. A total of 36 eligible observational studies, which included 30 708 patients, were identified. The studies had fair methodological quality, and length of follow-up ranged between 4.6 years and 30 years. Comparison of the highest category of nut consumption with the lowest category revealed significant associations between nut consumption and decreased risk of colorectal cancer (3 studies each with separate estimates for males and females, RR 0.76, 95% confidence interval [95%CI] 0.61–0.96), endometrial cancer (2 studies, RR 0.58, 95%CI 0.43–0.79), and pancreatic cancer (1 study, RR 0.68, 95%CI 0.48–0.96). No significant association was found with other cancers or type 2 diabetes. Overall, nut consumption was significantly associated with a reduced risk of cancer incidence (RR 0.85, 95%CI 0.76–0.95). Conclusions: Nut consumption may play a role in reducing cancer risk. Additional studies are needed to more accurately assess the relationship between nut consumption and the prevention of individual types of cancer, given the scarcity of available data.


INTRODUCTION
As the third leading cause of death worldwide, 1 cancer represents a significant health burden.With the elderly population growing, the global burden of cancer is expected to rise by 50% by 2020. 2 Cancer prevention is thus the optimal means of decreasing the cancer burden, and is particularly important given the severity of the disease.][5] The age-standardized prevalence of adult diabetes in 2008 was nearly 10% worldwide, with the majority of cases being type 2 diabetes. 6The prevalence of this disease has continued to increase in developed as wells as developing countries for the last 3 decades. 7,8Finding an appropriate way to prevent type 2 diabetes is, thus, essential to reduce the health burden with which it is associated.One strategy for preventing cancer and type 2 diabetes is to promote the consumption of appropriate foods that can decrease the risk of disease occurrence.
Nuts are widely available around the world and contain many bioactive compounds, including fiber, vegetable protein, minerals, phytosterols, and phenolic compounds. 9Since the first report of an association between nut consumption and a lower risk of coronary heart disease in 1992, 10 extensive research has been conducted to investigate the effects of nuts on health outcomes. 91][12][13] Frequent nut consumption is also associated with a lower risk of developing gallstones. 14,15dditionally, consumption of nuts has not been shown to adversely affect body weight or energy balance. 16t has been hypothesized that nut consumption may reduce the risk of cancer and type 2 diabetes.8][19] For example, vitamin E and selenium in almonds and walnuts, as well as quercetin and resveratrol in pine nuts, are antioxidants. 20,21Vitamin E in almonds and hazelnuts can regulate cell differentiation and proliferation, 17,22 and quercetin and resveratrol in almonds and pine nuts, as well as polyphenols in walnuts, can inhibit chemically induced carcinogenesis. 20Folic acid in almonds and pine nuts can reduce DNA damage, 17,19,22 and resveratrol in pine nuts can regulate inflammatory response and immunological activity as well as induce phase 2 metabolic enzymes. 18,20,23Additionally, dietary fiber is supplied by almonds and walnuts and oleic acid is provided by hazelnuts; both of these components are recognized to be cancer protective. 19,24,25However, the current evidence from human studies is inconsistent.A 2006 review summarizing epidemiological studies that evaluated the association between nut consumption and cancer risk showed inconclusive results for the effects of nuts on the risk of various kinds of neoplasms, including colorectal, prostate, stomach, pancreatic, breast, and endometrial cancers. 19Similarly, 3 epidemiological studies estimating the relationship between consumption of nuts and type 2 diabetes risk suggested inconsistent conclusions. 26Two of them, the Nurses' Health Study (n ¼ 83 818, 14-y follow-up) and the Shanghai Women's Health Study (n ¼ 64 000, 4.6-year follow-up), suggested an inverse association, while the third, the Iowa Women's Health Study (n ¼ 1800, 11-y follow-up), did not detect such an association.Thus, the present systematic review and meta-analysis was conducted to comprehensively evaluate the association between nut consumption and risk of developing cancer and type 2 diabetes.

METHODS
The study protocol defined inclusion and exclusion criteria, search strategy, outcomes, and analysis methods.The PICOS (participants, interventions, comparisons, outcomes, and study design) criteria used to define the research question are presented in Table 1.The metaanalysis was performed in accordance with the MOOSE guidelines (see Appendix S1 in the Supporting Information for this article available online). 27

Data sources and search strategies
A comprehensive search of 6 databases was conducted from each database's earliest inception to December 2013, in any language, for any population.The databases included Medline In-Process & Other Non-Indexed Citations, MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus.The search strategy was designed and conducted by an experienced librarian with input from the study's principle investigator.Controlled vocabulary, supplemented with

Data extraction and quality assessment
Two investigators (L.W. and J.Z.) independently carried out the abstract screening, full-text screening, data extraction, and quality assessment.Disagreements were resolved by consensus, with input from the senior investigator (M.H.M.).Data abstracted from each study included the following: authors' names, year of publication, study region, study design, characteristics of study population (sample size, age, length of follow-up, measures and types of nut, along with consumption levels, and outcomes of interest).If multiple estimates of the association for the same outcome were reported, the estimate that adjusted for the most appropriate covariates was extracted.If no adjusted estimates were presented, the crude estimate was included.When an eligible study did not present enough data, the corresponding and first authors were contacted.
To assess study quality, the Newcastle-Ottawa Quality Assessment Scale 28 was used; population and sample methods, exposure and outcome descriptions, and statistical matching/adjustments of the data were included in the assessment.The scale was used to assign a maximum of 9 points for each study.

Statistical methods
Relative risks (RRs) and the related 95% confidence intervals (95%CIs) were extracted from or calculated for each of the included studies.Due to the rarity of cancer in the general population, RR and odds ratio were deemed equivalent for the studies that focused on cancer.With regard to type 2 diabetes, RR was used because all of the available studies used it to estimate associations.The log-transformed RR, obtained using the DerSimonian and Laird random-effects method, was then pooled with the estimate of heterogeneity from the Mantel-Haenszel model. 29A subgroup analysis based on study design (either case-control study design or cohort study design) for each outcome was also conducted.
The I 2 was used to assess heterogeneity across the included studies, where I 2 > 50% suggests high heterogeneity. 30It was not possible to evaluate potential publication bias using visual inspection of symmetry of funnel plots and the Egger regression asymmetry test because of the small number of studies included and the high heterogeneity (I 2 > 50%) in most analyses. 31ll statistical analyses were conducted using STATA version 12.1 (StataCorp LP, College Station, TX, USA).

Literature search
The detailed steps of the literature search are shown in Figure 1.A total of 36 studies met the inclusion criteria and were included in the review.The association of nut exposure was evaluated with type 2 diabetes (5 studies), breast cancer (4 studies), colorectal cancer (3 studies, including 2 of colon cancer), endometrial cancer (2 studies), leukemia (1 study), acute myeloid leukemia (2 studies), hepatocellular cancer (4 studies), ovarian cancer (3 studies), prostate cancer (5 studies), stomach cancer (2 studies), and 1 study each of gastric cancer, glioma, lymphoma, pancreatic cancer, and upperaerodigestive tract cancer.

Study characteristics
The detailed characteristics of the included studies are shown in Table 2.  In tal, 16 cohort studies and 20 case-control studies were evaluated.Overall, 10 studies were conducted in Europe, 15 in the Americas, 7 in Asia, 3 in Australia, and 1 in Africa.A total of 22 studies provided estimations of nut consumption with risk of disease, 6 provided estimations of peanut intake only, 4 provided estimations of nut and seed intake only, 2 provided estimations of pulse, nut, and seed intake only, 1 provided estimations of fruit/nut intake only, and 1 provided estimations of beans/lentil/nut/seed intake only.The studies enrolled 30 708 patients and had a median follow-up period of 10.15 years (range 4.6-30 y).
The detailed quality ratings for each study are listed in Tables 3 and 4. Overall, the studies had fair methodological quality.All cohort studies and all but 2 casecontrol studies reported the estimations after adjusting for covariates.Exposure (nut consumption) was ascertained through interview in 41.7% of the studies and through self-completed questionnaire in the remaining studies.

Meta-analysis
The combined effect sizes are shown in Table 5.The estimations were based on the comparison of the highest category of nut consumption with the lowest category.Cancers for which only 1 study was available (gastric cancer, glioma, lymphoma, pancreatic cancer, and upper-aerodigestive tract cancer) were not metaanalyzed individually but were included in the overall meta-analysis for cancer.Significant associations were found between nut consumption and decreased risk of developing colorectal cancer ( Overall, nut consumption was significantly associated with a reduced risk of developing cancer (RR 0.85, 95%CI 0.76-0.95;I 2 66.5%).No significant association with risk of type 2 diabetes was detected (RR 0.98; 95%CI 0.84-1.14;I 2 74.2%).In subgroup analysis (Table 6), no significant difference between the prospective cohort studies and the case-control studies was found for colorectal cancer, ovarian cancer, prostate cancer, or overall cancer; however, for acute myeloid leukemia, the case-control study showed a significantly lower RR (RR 0.35, 95%CI 0.19-0.65,P ¼ 0.001) than       the prospective cohort study (RR 1.

DISCUSSION
The present comprehensive systematic review and meta-analysis assessed the associations between nut consumption and risk of developing cancer and type 2 diabetes.
After summarizing all of the available evidence, nut intake was found to be associated with a decreased risk of developing colorectal cancer, endometrial cancer, and pancreatic cancer.There was no significant association with upper-aerodigestive tract cancer, breast cancer, gastric cancer, glioma, hepatocellular carcinoma, leukemia (including acute myeloid leukemia), lymphoma, ovarian cancer, prostate cancer, stomach cancer, or type 2 diabetes.As far as can be determined, this is the first systematic review and meta-analysis to summarize the available evidence for determining the associations between nut intake and cancer.][70] The finding of a null association with type 2 diabetes in the present review is largely consistent with the findings of those studies.
The present systematic review and meta-analysis has several strengths.First, the search strategy is exhaustive and reproducible.Second, two reviewers independently performed selection, review, and extraction of data, thus decreasing potential biases and errors.
Several limitations affect inferences from this systematic review.It was not possible to test for publication bias, which is likely to exist when evidence consists of observational studies that do not require trial registration.It is plausible that studies with negative findings were conducted but not published.In addition, since the included studies were observational it is possible that patients who consumed more nuts were healthier or had other characteristics that reduced their risk of disease, and these factors could not be fully adjusted for in the analysis.In some of the cohort studies, investigators did not update the nut consumption information during the follow-up period, which could potentially cause measurement error to further affect the associations.In case-control studies, recall bias may result in deviations of estimates from actual nut consumption.Other common challenges encountered in nutrition research, such as the accuracy of dietary records and the effect of cointerventions (other nutrients consumed with nuts), also apply to this study.Scoring: 2 means the subjects were fully matched and/or the analysis was fully adjusted.1 means the study adequately fulfilled a quality criterion, 0 means it did not.Quality scale does not imply that items are of equally relevant importance.
Nuts contain nutrients that are widely thought to be beneficial for human health.As stated above, numerous mechanisms have been proposed to explain the potential effect of nuts on the risk of cancer.More investigations on the role of nuts in each of the cancers examined in the present review (colorectal, endometrial, and pancreatic) are warranted.
Although the results of several studies suggested nuts may play a protective role in type 2 diabetes, a significant association between nut consumption and risk of type 2 diabetes was not found in this review.Interestingly, one randomized clinical trial published in 2008 found that patients assigned to a Mediterranean diet that included nuts had a lower risk of developing type 2 diabetes when compared with the control group assigned to a low-fat diet (hazard ratio 0.48; 95%CI 0.24-0.96). 71This study was not included in the present analysis, however, because it was a study of the Mediterranean diet including nuts, rather than a study of nuts alone.
It should also be acknowledged that there was significant heterogeneity among the studies of type 2 diabetes in this analysis.Research has demonstrated that nuts are associated with beneficial glycemic responses in healthy individuals.For example, almonds are shown to reduce the glycemic impact of carbohydrate foods 72 ; pistachio nuts can attenuate the relative glycemic response when taken with a carbohydrate meal 73 ; and nuts were demonstrated to have a dose-dependent effect on the glycemic response. 74Nuts have also been shown to contain a high proportion of unsaturated fatty acids, 9 and nut consumption is inversely associated with circulating inflammatory cytokines and positively associated with plasma adiponectin. 75Since all of these factors are linked to diabetes, 76,77 the exact relationship between nut consumption and type 2 diabetes, as well as between nut consumption and glycemic control, warrants further exploration.Additional well controlled, well designed studies are needed to clarify this question.
In this review, the role of nut intake in reducing the risk of developing cancer and type 2 diabetes was estimated.Several other studies have evaluated the role of nut consumption in attenuating mortality due to specific diseases. 78,79A large cohort study using data from the Nurses' Health Study and the Health Professionals Follow-up Study found that nut consumption could decrease total mortality in a dose-response manner.Moreover, nut consumption was associated with decreased mortality from cancer and heart disease, but not from type 2 diabetes.A combined evaluation of the relationships between 1) intake of nuts and disease incidence and 2) intake of nuts and mortality may provide a more comprehensive picture of the benefits of nut consumption in decreasing the burden of diseases.
In addition to the plausible benefits of nut consumption on the risk of some cancers, other benefits have been suggested.An inverse association between nut consumption and the risk of coronary heart disease was demonstrated in 5 large prospective cohort studies. 80The 2013 American College of Cardiology/ American Heart Association Guideline on Lifestyle Management to Reduce Cardiovascular Risk recommends that a heart-healthy eating pattern, when based on a diet containing 2000 calories per day, should include 4-5 servings of nuts, legumes, and seeds per week. 81Nevertheless, while nuts have health benefits, it is important to remember they are a calorie-dense food.Nuts can contain 160-200 calories per ounce.Therefore, weight gain is a concern.The recommendation from the American Heart Association (5 servings per week, with an average recommended serving size of 28 g) is consistent with the highest category of intake in most of the studies summarized in this systematic review.This level of intake is associated with a net increase of 800-1000 calories per week.Weight gain may not occur, however, if nuts are incorporated into a healthy diet in which they are substituted for other foods, as opposed to being added to an existing diet.Indeed, diets enriched with nuts did not increase body weight, body mass index, or waist circumference. 82everal mechanisms have been proposed to explain a less pronounced effect of nut intake on weight, including increased satiety with nut consumption and a possible decrease in desire to consume carbohydrates. 83n addition, the caloric and fat contents of nuts vary across the different types of nuts, and consumers can make choices to ensure the greatest personal benefit.The US Food and Drug Administration reviewed 11 interventional and observational human studies and approved a qualified health claim about nut consumption and heart Table 6 Subgroup analyses for the association between nut consumption and risk of cancers or type 2 diabetes disease and recognized that walnuts were the more commonly studied nut type. 84Nuts with the lowest saturated fatty acid content (as a percentage of total fats) are pecans, walnuts, hazelnuts, almonds, pine nuts, and pistachios.Conversely, peanuts, macadamia nuts, cashews, and Brazil nuts have the highest saturated fatty acid content. 83In conclusion, a practical recommendation for individuals interested in making better food choices to reduce the risk of cancer and heart disease is to consume nuts 4-5 times per week, to aim for a serving size of 1-1.5 ounces, to use nuts as a substitution for other foods high in saturated fat and carbohydrates and to choose healthier nut options.

CONCLUSION
Based on an analysis of evidence from 36 cohort and case-control studies, nut consumption was inversely associated with risk of colorectal cancer, endometrial cancer, and pancreatic cancer, but not other types of cancer or type 2 diabetes.Overall, nut intake was associated with a decreased risk of cancer.Given the scarcity of currently available data, however, evidence from additional studies is required to more precisely determine the relationship between nut consumption and risk of individual cancer types.

Figure 1
Figure 1 Flow diagram of selection of eligible studies the study adequately fulfilled a quality criterion (2 for case-control, fully matched and adjusted), 0 means it did not.Quality scale does not imply that items are of equally relevant importance.

Table 1
PICOS criteria used to define the research question

Table 3
Quality assessment of reviewed case-control studies

Table 4
Quality assessment of reviewed cohort studies

Table 5
Summary risk estimates for the association between nut consumption and risk of cancer or type 2 diabetes NA, not applicable; RR, relative risk.