Dietary Inflammatory Index and risk of esophageal squamous cell cancer in a case-control study from Iran

Abstract

Background

Diet and inflammation have been suggested to be important risk factors for esophageal squamous cell carcinoma (ESCC). In this study, we examined the ability of the dietary inflammatory index (DII) to predict ESCC in a case-control study conducted in Iran.

Methods

This study included 47 ESCC cases and 96 controls hospitalized for acute non-neoplastic diseases. The DII was computed based on dietary intake assessed by a previously validated food frequency questionnaire. Logistic regression models were used to estimate odds ratios (ORs) adjusted for age, energy, sex, BMI, years of education, physical activity, smoking and gastro-esophageal reflux.

Results

Subjects with higher DII scores (i.e., with a more pro-inflammatory diet) had a higher risk of ESCC, with the DII being used as both a continuous variable (OR_continuous 3.58, 95% confidence interval, CI, 1.76–7.26; one unit increase corresponding to ≈16% of its range in the current study) and a categorical variable (OR_{dii>1.20 vs ≤ 1.20}8.24, 95%CI 2.03–33.47).

Conclusion

These results indicate that a pro-inflammatory diet is associated with increased risk of ESCC.

Introduction

Esophageal cancer (EC) is the eighth most common cancer worldwide, with an estimated 456,000 new cases in 2012 (3.2% of the total), and the sixth most common cause of death from cancer, with an estimated 400,000 deaths (4.9% of the total) (1). There are two type of esophageal cancer (EC) based on histology – squamous cell carcinoma and adenocarcinoma; both are highly lethal, with a 5-year survival rate <10% (2–4). An esophageal “cancer belt,” primarily squamous cell cancers (ESCC), extends from northeast China to the Middle East (5, 6). In this region (where there is a high incidence of esophageal cancer) esophageal squamous cell carcinoma (ESCC) contributes to more than 90% of all EC cases (7) The latest World Cancer Report indicated the highest prevalence of ESCC to be in Iran (8, 9).

Chronic inflammation – which is characterized by the continuous presence of inflammatory cytokines in circulation and in the tissues – is known to play a key role in the development of various epithelial cancers (10, 11). In particular, it has been shown that chronic inflammation is important in triggering the development of EC, especially epithelial damage involved in ESCC (12, 13).

Evidence of an association between environment (including diet) and EC comes from the profound differences in incidence observed in various parts of the world. The majority of the factors, thus far implicated in EC appear to act directly on the esophagus rather than systemically. There also is growing evidence that specific dietary components influence both inflammation (14–17) and ESCC (18–21). Diet represents a complex set of exposures that often interact, and whose cumulative effect modifies both inflammatory responses and health outcomes. A literature-derived, population-based dietary inflammatory index (DII) was developed to assess the inflammatory potential of an individual’s diet (21), and has been validated with various inflammatory markers, including C-reactive protein (17, 22), interleukin-6 (23–25), and homocysteine (23). Additionally, increasing DII has been shown to be associated with the increased glucose intolerant and dyslipidemic components of metabolic syndrome (22, 26), shift work status in a large population-based survey in the USA (27), increased risk of asthma in Australia (25), colorectal cancer in case-control studies in Spain (28) and in cohort studies in USA (29–31) and pancreatic and prostate cancers in Italy (32, 33).

Our hypothesis is that a higher DII score (indicating a pro-inflammatory diet) increases risk of incident ESCC. In the current study, we thus examined the association between DII and ESCC using a case-control study conducted in Iran (34). This provided original information on a Iranian population where dietary and life-style habits and awareness of diet-related health issues are different from those in North America and Europe, and where most ECs are ESCC.

Methods

The current study was conducted in Kurdistan Province in Iran. Cases were 40–75 years old with histologically confirmed ESCC who were identified from hospital records in the major general hospitals in the area under study (Kurdistan Province, Iran) (34, 35). Controls were selected from the same hospitals and were frequency matched to cases on age (±5 years) and sex. The control group consisted of participants admitted to the same hospital for a wide spectrum of acute non-neoplastic diseases that were unrelated to smoking, alcohol abuse, and long-term diet modification. Controls were hospitalized mainly due to the following conditions: trauma (25.9%, mostly fractures and sprains), surgical conditions (20.1%, mostly abdominal such as acute appendicitis and kidney stones), non-traumatic orthopedic conditions (4.2%, mostly disk disorders and back pain), and miscellaneous diseases (49.8%, including acute eye, nose, skin, and throat disorders). Fifty ESCC patients and 100 hospital controls were enrolled in the present study. Seven participants were excluded from the analysis because of their total energy intake being either greater than 3 or less than 3 SD from the mean (n = 2 controls), missing body mass index (BMI) values (n = 3 cases), and poor responses with regard to dietary questions (n = 2 controls), which left 47 cases and 96 controls for final analysis. The National Nutrition and Food Technology Research Institute in Iran reviewed and approved all study and ethical procedures, and informed written consent was obtained from each participant.

Professionally trained dietitians interviewed the 50 cases and 100 controls using structured pretested questionnaires. They evaluated the sociodemographic characteristics (age, sex, education, monthly family income, and place of residence), eating habits (food and beverage temperature and cooking method), smoking history (status, duration, and intensity), medical history, familial cancer history, medication use, and gastroesophageal reflux disease (GERD) symptoms (heartburn and acid regurgitation). Body mass index was calculated by dividing the subjects’ weight in kilograms by the square of height in meters. Physical activity was measured using a validated questionnaire listing of different metabolic equivalent (MET) categories (36), and was then expressed as MET-hrs/day to estimate the physical activity level of participants (37).

Participants’ dietary intake during the past year was assessed using a valid and reliable semi-quantitative food frequency questionnaire (FFQ) (38). This FFQ consists of 125 food items with standard serving sizes, and participants were asked to specify their consumption frequency for each food item on a daily, weekly, monthly or yearly basis. Nutrients of foods were then calculated using the Nutrients Composition of Iranian Foods (NCIF) (39)supplemented with the USDA Food Composition Data. The consumption of alcohol was not asked to our participants due to their cultural beliefs and was not included in the analysis. The FFQ was interviewer-administered. FFQ-derived dietary data were used to calculate DII scores for all participants. The DII is based on literature published through 2010 linking diet to inflammation. Individuals’ intakes of food parameters on which the DII is based are then compared to a world standard database. A complete description of the DII is available elsewhere (21). A description of validation work, including DII derived from both dietary recalls and a structured questionnaire similar to an FFQ and related to interval values of hs-CRP, also is available (21). Briefly, to calculate DII for the participants of this study, the dietary data were first linked to the regionally representative world database that provided a robust estimate of a mean and standard deviation for each parameter (21). These then become the multipliers to express an individual’s exposure relative to the “standard global mean” as a z-score. This is achieved by subtracting the “standard global mean” from the amount reported and dividing this value by the standard deviation. To minimize the effect of “right skewing” (a common occurrence with dietary data), this value is then converted to a centered percentile score. The centered percentile score for each food parameter for each individual was then multiplied by the respective food parameter effect score, which is derived from the literature review, in order to obtain a food parameter-specific DII score for an individual. All of the food parameter-specific DII scores are then summed to create the overall DII score for every participant in the study (21). Methodology was described in figure 1. DII= b1*n1+b2*n2………..b27*n27, where b refers to the literature-derived inflammatory effects score for each of the evaluable food parameters and n refers to the food parameter-specific centered percentiles, which were derived from this case-control’s dietary data. A total of 27 food parameters were available from the FFQ and therefore could be used to calculate DII (carbohydrate, protein, total fat, fiber, cholesterol, saturated fat, mono-unsaturated fat, poly unsaturated fat, omega-3, omega-6, niacin, thiamin, riboflavin, vitamin B12, vitamin B6, iron, magnesium, selenium, zinc, vitamin A, vitamin C, vitamin D, vitamin E, folic acid, beta carotene, onion and pepper.)

Figure 1.

Sequence of steps in creating the dietary inflammatory index in the Esophageal cancer case-control study in Iran.

The DII was analyzed both as a continuous variable and as a dichotomous variable, categorized based on the median value of the DII for the entire study (1.20). DII (as dichotomous) was examined across the following characteristics: age, education, physical activity level, body mass index (BMI), smoking, gastro-esophageal reflux using Student t-test or χ² test for continuous and categorical variables, respectively. We also examined the distribution of various food groups across DII categories separately for cases and controls. Odds ratios and 95% confidence intervals (OR; 95% CI) were estimated using logistic regression models, adjusting only for age and energy, and then fitting a model with additional adjustment for sex, BMI, years of education, physical activity, smoking, and gastro-oesophageal reflux. The covariates were chosen a priori as they were shown to be risk factors for ESCC. Statistical tests were performed using SAS^® 9.3 (SAS Institute Inc., Cary, NC); all p values were based on two-sided tests.

Results

The DII score in this study ranged from −2.33 (most anti-inflammatory score) to 3.89 (most pro-inflammatory score). Table 1 shows the distribution of 47 cases of ESCC and 96 controls according to selected variables. By design, age and sex distributions were similar in cases and controls. Cases had higher tobacco consumption and symptomatic gastro-esophageal reflux. Controls had higher BMI and years of education. The mean DII value among cases was 1.81 (SD=1.23) and among controls it was 0.76(SD=1.35) indicating a more pro-inflammatory diet for cases.

Table 1.

Characteristics of prostate cancer cases and controls, Iranian Esophageal Squamous Cell Cancer Case-Control Study.

Characteristics	Cases	Controls	P-Valuea,b
	N =47	N =96
Age, (years): mean ± sd	58.0 ± 10.1	58.0 ± 10.4	0.89
Female n (%)	29 (62)	58 (60)	0.88
Symptomatic gastro-oesophageal reflux- (%)	16 (34)	9 (9)	<0.001
BMI, kg/m2: mean ± sd	20.4 ± 3.2	25.3±4.2	<0.001
Physical activity, METs/day: mean ± sd	36.6±6.7	35.7±8.0	0.52
Education (%)			0.65
No	41 (87.2)	81 (84.4)
Yes	6 (12.8)	15 (15.6)
Smokinga (%)			0.60
Nonsmoker	30 (63.8)	67 (69.8)
Ex-smoker	10 (21.3)	14 (14.6)
Current smoker	7 (14.9)	15 (15.6)

^aStudent t-test was used for continuous variables

^bChi-square test was used for categorical variables

Control characteristics across by DII categories are provided in Table 2. There were some differences in sociodemographic factors, and lifestyle habits across DII categories. In particular, participants in DII> 1.20 category had lower BMI, physical activity, tobacco exposure and were slightly older, more likely to be men and educated. However the results were not significant except for BMI.

Table 2.

Participant characteristics by level of dietary inflammatory index (DII) among controls, Iranian Esophageal Squamous Cell Cancer case-control study.

Continuous variables (mean ± SD)	DII≤1.20 (n=72)	DII>1.20 (n=71)	P-Valuea,b
Age (years)	58.0±10.9	59.9±10.0	0.30
Body mass Index (kg/m2)	24.5±4.8	22.9±4.2	0.04
Physical activity (METs)	36.2±8.4	35.5±6.5	0.61
Sex (%):			0.36
Males	40.0	30.6
Females	60.0	69.4
Smoking (%)			0.17
Non-smoker	67.3	72.2
Ex-smoker	10.9	19.4
Current smoker	21.8	8.3
Education (%)			0.54
No	85.5	80.6
Yes	14.5	19.4

^aStudent t-test was used for continuous variables

^bChi-square test was used for categorical variables

Odds ratios (OR) and 95% confidence intervals (CI) for the risk of ESCC according to cut-point of DII are shown in Table 3. Results obtained from modeling DII as a continuous variable in relation to risk of ESCC showed a positive association after adjustment for age (OR=3.10 CI=1.83–5.24) and in the multivariate analyses (OR=3.58 CI=1.76–7.26). When analysis was carried out with DII expressed as a dichotomous variable, and adjusting for age, subjects with DII score >1.20 were at 655% times higher risk of having ESCC compared to subjects with DII ≤1.20 (OR_{DII (> 1.20/≤1.20)} =7.55 CI=2.63–21.70). After multivariate adjustment, subjects with DII >1.20 were at 724% higher risk of having ESCC compared to subjects with DII ≤1.20 (OR_{DII (>1.20/≤1.20)} =8.24; CI=2.03–33.47).

Table 3.

Odds ratios and confidence intervals for the association between DII and ESCC, Iranian Esophageal Squamous Cell Cancer case-control study.

	Dietary Inflammatory Index OR (95% CI)		P-Value	DII (Continuous)a OR (95% CI)	P-Value
DII	DII≤1.20	DII>1.20
Age-adjusted	1 (ref.)	7.55 (2.63, 21.70)	0.0002	3.10 (1.83, 5.24)	<.0001
Multivariate-adjustedb	1 (ref.)	8.24 (2.03, 33.47)	0.003	3.58 (1.76, 7.26)	0.0004

^aone unit increase corresponding to ≈16% of its range in the current study.

^bAdjusted for age, energy, sex, BMI, years of education, physical activity, smoking and gastro-oesophageal reflux

Discussion

In this case-control study, we observed that subjects with the higher DII (i.e., those who had the most pro-inflammatory diets) were at increased risk of developing ESCC, a result supporting our hypothesis that consuming a more pro-inflammatory diet, is associated with an increased risk of ESCC.

Consumption of food items such as vegetables and fruits have been shown to reduce inflammation (40), while others, such as red and processed meat, increase inflammation (41). Indeed, in this case-control study a healthy dietary pattern characterized by high consumption of fruits, raw vegetables and fish showed protective effects on ESCC (34), whereas an unfavorable effect of a westernized dietary pattern rich in animal products, sugar, sweet and fried potatoes has been observed (34). Consuming a diet in concordance with the principles of the Mediterranean dietary pattern was found to be protective against ESCC in this study (35).

Similarly, previous studies that have examined the effect of specific food items on ESCC have reported inverse associations for olive oil, fish and other seafood, whole grains and fruits (35, 42) and increased risks for high consumption of red and processed meat(20, 43–45).

A limitation of this approach is that these foods or nutrients are usually consumed in combination; thus, dietary correlations may attenuate or accentuate the real effects of each food or nutrient under study. In formulating the DII, a different approach was taken by focusing on the functional effects of foods and nutrients. As such, it relies on reviewing and scoring of the peer-reviewed literature on the subject of diet and inflammation. Moreover, it standardizes individuals’ dietary intakes of pro- and anti-inflammatory food constituents to world referent values, which results in values that are not dependent on the units of consumption and can be used for comparison across studies.

One of the possible mechanisms for the observed direct association of the DII with ESCC is through the effect of pro-inflammatory diet on the levels of various inflammatory cytokines such as Ki-67, vascular endothelial growth factor and interleukin-8, all of which forms an important component of the esophageal tumor micro-environment. These cytokines may have an important role in cancer development, growth and progression (46) by promoting proliferation, angiogenesis, and carcinogenesis and by recruiting immune cells to the tumor site (47).

Inflammation also alters the extracellular matrix and provides structural support to developing tumors (47). Hypoxia is a common state in inflamed tissues which causes DNA damage and induces tumorigenic factors which result in further progression of cancer (47).

An important strength of this study is that it is one of the first studies in Iran, which has a high incidence of ESCC, to explore the association between the inflammatory property of diet and ESCC. Controls were selected carefully by ensuring that none of them had any condition related to diet or other major risk factors of ESCC. However, in addition to the strengths there are certain weaknesses that need to be considered. First, dietary measurement error may lead to underestimation of results. In addition, the measurement error in confounders will lead to residual confounding (48). Although we cannot entirely rule out residual confounding due to imprecise measurement of important covariates, it is unlikely that errors in measuring the covariates would be so extreme because the crude and multivariable results were essentially the same. Secondly, because of the small number of participants, associations with wide confidence intervals for the DII were found when models were fit using DII as both continuous and as a dichotomous variable (however, the results were significant, despite this constraint). Thirdly, as with other case-control studies, recall bias and selection bias were inevitable. In case-control studies, there is the possibility that cases may recall their diets differently after a cancer diagnosis. However, our participants were generally of low literacy and socioeconomic status with little knowledge about the role of diet and nutrients in the cancer risk, which should have reduced the possibility of recall bias. Moreover, using hospital controls and administering validated FFQs by trained interviewers in a hospital setting might have further reduced the recall bias and improved comparability of information of cases and controls. With regard to the selection bias, high participation rates (94% among cases and 91% among controls) in this study minimized the potential for selective participation according to the lifestyle practices (such as diet). Fourthly, absence of data on alcohol consumption is another limitation; study participants refrained from reporting alcohol intake as consuming alcohol is legally prohibited in Iran (38).

In conclusion, subjects who consumed a more pro-inflammatory diet were at increased risk of ESCC compared to those who consumed a more anti-inflammatory diet. Thus, encouraging intake of more anti-inflammatory dietary factors, such as plant-based foods rich in fiber and phytochemicals, and reducing intake of pro-inflammatory factors, such as fried foods or processed foods rich in saturated fat or trans fatty acids, may be a strategy for reducing risk of ESCC.