Adherence to the Western, Prudent, and Mediterranean dietary patterns and chronic lymphocytic leukemia in the MCC-Spain study

Discussion

This study provides, for the first time, evidence of an association between adherence to a Western dietary pattern and CLL. By contrast, no associations were found for a Prudent or Mediterranean pattern.

There is limited evidence linking extrinsic-risk factors, and particularly diet, with non-Hodgkin lymphoma (NHL). In the 2007 report by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR),³ the Panel decided not to make any judgements regarding the causality of associations between specific dietary factors and NHL, but pointed out a suggestive inverse association with vegetables, fruit, and alcoholic beverages, and a positive association with meat, total fat, body fatness, and dairy. Recent meta-analyses further support these associations,^36,37 but there is still not sufficient evidence to establish a causal role. Similarly, data on the association of diet and CLL are inconclusive and mainly arise from studies on nutrients or single food items. To our knowledge, 9 prospective studies^4–12 and 13 case-control studies^13–25 have been published on this topic. With the exception of a few studies that found positive associations with consumption of processed meat and poultry,⁴ total carbohydrate⁸ or fat (in women)¹¹ intake, and inverse associations with isoflavones consumption,¹⁰ generally large prospective studies found no associations between a wide range of dietary factors and CLL. By contrast, case-control studies have yielded contradictory results for meat,^{13,14,16,24,25} dairy products,^13–17 fish^15,18 or vegetables and fruit^{14,16,19,22,23,25} intake.

Inconsistencies in previous epidemiological nutritional studies in part reflect the difficulty in disentangling the influence of single food items that, when consumed in combination, may be highly correlated and exert synergistic or antagonistic effects on CLL risk. The examination of dietary patterns, which better reflect the complexity of dietary intake, has been used to address such limitations.²⁶ So far, only a few studies have examined associations of dietary patterns and risk of CLL,^25,27,28 reporting inconclusive findings, mainly due to small sample size. Ollberding et al.²⁸ pointed out that a high adherence to a ‘Meat, Fat and Sweets’ dietary pattern, characterized by a high intake of French fries, red meat, processed meat, pizza, salty snacks, sweets and desserts, was associated with an increased risk of overall NHL (ORQ4 vs. Q1=3.6; 95%CI: 1.9, 6.8) in a Nebraska case-control study. This association was maintained when stratifying according to lymphoma subtypes but sub-analyses did not include CLL cases due to sample size (n=25). By contrast, a large prospective cohort in the US did not find associations with ‘Fat and Meat’ pattern and CLL etiology.²⁷ However, this pattern did not include sweets and deserts, sweetened beverages, or convenience foods, which may be important contributing factors of these associations. Thus, not only differences in the study design and setting, but also in food groups loaded in these data-driven analyses, should be carefully considered when comparing results. In line with our findings, no associations with overall NHL^25,27,28 or CLL^25,27 were detected for a ‘healthy’ dietary pattern characterized by high intake of fruit and vegetables.

We observed opposite trends in relation to a Mediterranean diet pattern and Rai stages, with stronger adherence among cases with higher disease severity (P-het=0.04). We hypothesize that reverse causality could partly explain these results. While Rai 0 patients are usually diagnosed in a routine blood test and present an indolent course, Rai I-IV are more prone to be symptomatic (e.g. night sweat, fatigue, weight loss or fever) and to receive active treatment. Thus, those patients with a more severe disease (and probably more concerned about their illness) would be more prone to shift towards a healthier dietary pattern. However, these results have to be taken with caution since none of the trends showed statistically significant associations.

Chronic lymphocytic leukemia is the most common leukemia in Western countries while its incidence is much lower in Eastern countries, where it accounts for only 1–3% of NHL in most series.³⁸ While genetic backgrounds may be responsible for some of the differences in the CLL incidence, some studies have suggested that environmental factors also play an important role. A dramatic increase in CLL incidence in Taiwan in recent years was associated with a strong birth-cohort effect, that corresponded to the Westernization of lifestyle in Taiwan since 1960.³⁹ In addition, a higher incidence of CLL has been reported among US-born Asians compared to foreign-born Asians, pointing out the influence of environmental factors that change with immigration and acculturation to a Westernized lifestyle.⁴⁰ Our results further support the view that adopting a Western diet could partly explain these incidence patterns.

A Western diet has been associated with obesity phenotypes,⁴¹ including a higher waist-to-hip ratio, which has in turn been recently linked to higher OR of CLL, particularly in women, in the MCC-Spain study.⁴² Despite the fact that CLL cases showed a higher waist-to-hip ratio than controls in our study, waist-to-hip ratio and BMI were not included as covariates in the final multiple-adjusted model since they did not change risk estimates. Hence, an independent effect of the Western dietary pattern may be contributing to CLL lymphomagenesis, which seems plausible from a mechanistic point of view. On one hand, it has been well-established that dietary changes, and particularly switching from a low-fat, plant polysaccharide-rich diet to a high-fat, high-sugar Western diet, can induce alterations in microbiota composition.⁴³ Beyond its role in the biosynthesis of key components (e.g. vitamins, essential amino acids or short chain fatty acid byproducts), several studies using germ-free mice suggest that microbiota also plays a fundamental role on the induction, training, and function of the host immune system.⁴⁴ Exposure to a Western diet may have selected for a microbiota that lack the resilience and diversity required to establish balanced immune responses, and this phenomenon is proposed to account for some of the dramatic rise in autoimmune and chronic inflammatory disorders found in high-income countries. On the other hand, a diet high in fat, refined grains, red and processed meats, and sweets has been largely associated with higher levels of inflammatory markers⁴⁵ and with inflammation-related chronic diseases.⁴⁶ In particular in CLL, the strong production of inflammatory cytokines and chemokines accompanied by activation of intra-cellular pro-inflammatory pathways, and the presence of somatic mutations that activate pro-inflammatory signaling pathways, suggest that chronic inflammation plays a pathophysiological role in this disease.⁴⁷ Thus, an inflammation-related mechanism may in part underlie the observed associations with CLL, although no research on the inflammatory potential of diet and CLL risk has yet been conducted.

The dietary patterns used in this study were identified using the control population of a multicentric case-control study on female breast cancer in Spain.³⁰ By contrast, the MCC-Spain study included male participants, who may have different dietary habits. However, this difference does not preclude the application of the original scoring system over the current sample. Scores of adherence to dietary patterns can be calculated following the exact same rules over different populations, resulting in different levels of adherence while still being valid, as has been recently proved.³⁵ As a matter of fact, the current dietary patterns had previously been constructed in the MCC-study and a Western dietary pattern was positively associated with gastric,⁴⁸ breast⁴⁹ and colorectal⁵⁰ cancers.

One of the main limitations is the study design since case-control studies are prone to selection and recall biases. Measurement errors in the estimation of food intake due to the use of self-reported FFQ are also of some concern. However, the FFQ was validated in the Spanish population and included regional products.³² Moreover, some questions about general dietary habits were included in the questionnaire and were used to adjust the responses to the FFQ following the methodology described in Calvert et al.³³ The inclusion of prevalent cases might be another cause for concern since patients who survived might have a very different etiology than those who died soon after diagnosis. In addition, diet can be influenced by many external factors and patients who survive longer might have substantially modified their diet. However, results of the sensitivity analysis suggested that the use of prevalent cases might not have introduced selective survival bias or reverse causation. We may have been limited by the small sample size and lack of statistical power to detect significant associations when evaluating certain subgroups. Finally, although we adjusted for a range of potential con-founders, residual confounding factors cannot be totally ruled out.

The strengths of the study include the substantial sample size of CLL cases, with specific information on clinical presentation. We were able to collect detailed information on demographics and disease stage, and statistically adjust for a number of potential confounding factors. This allowed the evaluation of potential interactions of diet with numerous covariates and the exploration of the associations by stage. Finally, the multi-centric nature of the study, including both rural and urban areas, provided a wide geographic variability of dietary intake data.

In conclusion, in this Spanish population-based case-control study, greater adherence to a Western dietary pattern was associated with CLL. These novel results suggest that a proportion of CLL cases could be prevented by modifying dietary patterns. Further research, especially with a prospective design, is warranted to confirm these findings.