The results of this study support a direct association of inflammatory cytokines with adiposity-related risk factors for colorectal cancer. Our findings indicate that associations of risk factors for colorectal neoplasms with inflammation may be more strongly reflected by the use of a combined inflammation z score than by any single cytokine that reflects only a small aspect of inflammation/immunomodulation.
Previous studies suggested that there is a direct association between colorectal cancer risk and the inflammatory cytokines assessed in this study. Several CRC case-control studies found blood levels of CRP, TNF-α, IL-6, and IL-8 to be higher in cases.8,11,17
Expression-enhancing polymorphisms in the genes for IL-6, TNF-α, IL-1β, and IL-8 were associated with increased adenoma risk in two case-control studies.18,19
IL-1β is involved in COX-2 activation and activates the Wnt cell cycle pathway, the primary pathway of colon cell proliferation.20
While these inflammatory cytokines are increasingly supported as risk factors for CRC, more research is needed to examine their usefulness as biomarkers of risk for colorectal adenomas.
Obesity was previously linked to inflammation and is proposed to be an inflammatory condition.21
CRP was associated with BMI in obese or overweight young adults in a large cross-sectional study (NHANES III).22
IL-6, which stimulates CRP release from the liver, is positively correlated with CRP levels in the adipose tissue of obese individuals.21
Obesity, insulin resistance, and atherosclerosis are associated with higher levels of TNF-α, a strong mediator of inflammation and reactive oxygen/nitrogen species.21
We found statistically significantly higher levels of CRP, IL-6, and the inflammation z
score in our obese participants, as well as in those with a higher WHR, further supporting that higher levels of inflammatory cytokines are associated with general and central adiposity in patients at risk for colorectal cancer.
We found a consistent pattern of lower inflammatory cytokine levels with moderate alcohol consumption, with statistically significant lower mean IL-8 levels and inflammation z
scores. This is consistent with the finding of Pai et al who observed that in those who consume a moderate amount of alcohol, CRP, IL-6, and TNF-α receptor levels were significantly lower than in non-drinkers.23
In our study, the average alcohol consumption was quite moderate: in women, it was less than one drink per day, and in men, it was around 1.5 drinks per day. In addition, the ORs for the associations of alcohol consumption with the inflammatory markers were not statistically significant after adjusting for BMI.
We found no statistically significant associations of sex, age, serum 25-OH-vitamin D levels, NSAID use, or total energy or calcium intakes with inflammatory cytokines or the inflammation z score. This may have been due to our small sample size and the relatively homogenous population. We found that CRP was statistically significantly higher in women and TNF-α was statistically significantly higher in NSAID users; however, the ORs for the associations were not statistically significant, possibly due to the small number of women and NSAID users. Larger studies are needed to more adequately assess these possible associations.
CRP stimulates the release of IL-1β, IL-6, IL-8, and TNF-α from mononuclear phagocytes, which supports a collective analysis of these cytokines, such as by using a combined z
Previously, we reported the effects of vitamin D3
supplementation on a combined inflammation z
score (including CRP, IL-6, TNF-α, IL-1β, and IL-8) in a randomized placebo- controlled clinical trial of colorectal adenoma patients. We found that, although vitamin D3
did not significantly reduce each individual cytokine, it statistically significantly reduced the inflammation z
score in this study population by 77% (P
= 0.003) relative to placebo. In our current study, we found that the combined inflammation score was more strongly associated with measures of adiposity than were any of the individual cytokines. In light of these data, we propose further investigation of an inflammation z
score as a biomarker of risk for colorectal adenomas or cancer.
Our small cross-sectional study has several limitations. First, the small sample size, especially the small sample size of important subpopulations (ie, smokers and NSAID users), limited our analyses and conclusions. Also, the cross-sectional study design does not address temporality, and our results may not be generalizable beyond a limited colorectal adenoma patient population. Finally, about half of the study population was obese, with greater representation of overweight individuals than normal weight individuals. While this limits the comparison of obese to normal weight individuals, the high number of obese and overweight individuals allowed for an important comparison between these groups.
Strengths of this study included that it used standardized methods of collecting blood and patient information from questionnaires as well as standardized methods of assessing vitamin D and cytokine levels. All of the participants had a colorectal adenoma removed in the previous 36 months and, therefore, were unlikely to have current colorectal cancer, which could alter cytokine levels. Other strengths of this study included the array of cytokines investigated, which are well supported and linked to colorectal cancer, and the use of a summary z score to analyze the cytokines collectively.
In summary, our findings in this small cross-sectional study support direct associations of CRP, IL-6, and a combined z score of inflammatory cytokines with adiposity in colorectal adenoma patients. This study shows that the use of a combined inflammation z score may have promise in revealing stronger associations of inflammation with colorectal cancer risk than can be discerned by measuring and analyzing only individual aspects of inflammation, a large, complex system. Larger case-control and prospective studies are needed, however, to further assess the validity and usefulness of these cytokines and the combined inflammation z score in relation to risk for colorectal neoplasms or other chronic diseases.