Colorectal cancer (CRC) is an important public health concern, and its incidence has been increasing worldwide.^1,2 As most CRCs develop from colorectal adenomas through the adenoma-carcinoma sequence, CRC screening can decrease CRC-related mortality through early detection and removal of colorectal adenomas.^3,4 Growing evidence supports a role of inflammation in the pathogenesis of CRC.^{5,6,7,8,9,10,11,12,13} Patients with IBD have an increased risk of CRC,⁵ and laboratory animals with continuous inflammatory conditions are predisposed to CRC development.⁶ Several studies have shown a reduced occurrence of CRC with aspirin or NSAID use.^{7,8,9,10,11,12,13}

CRP, a widely used maker of inflammation, could be used as a marker to identify individuals at risk for developing CRC.¹⁴ Although a positive correlation between serum CRP level and risk of colorectal neoplasia has been demonstrated,^{15,16,17,18,19} several subsequent studies have shown inconsistent results.^20,21,22,23 The discrepancies between previous studies might be influenced by ethnic population and sex effects. Furthermore, little is known about the association between serum CRP level and risk of colorectal adenoma, a precursor lesion of CRC. Chiu et al.¹⁷ showed a positive association between serum CRP level and risk of colorectal neoplasia in Chinese men, but not women. The association of CRP with colorectal adenoma remains undetermined, and further studies on this issue are warranted.

The aim of this study was to assess the association between serum CRP and risk of colorectal adenoma.

During the study period, 3,603 asymptomatic subjects underwent colonoscopy as part of a regular medical examination, and 147 subjects were excluded from the first-time screening colonoscopy database based on the following criteria: previous colonoscopy (n=69); history of CRC, IBD, or colorectal surgery (n=5); and age younger than 30 or older than 75 years (n=73). An additional 148 patients were excluded from analysis for either failing to complete the study (n=41) or having missing serum CRP or insufficient data (n=107). Ultimately, 3,309 patients were eligible for this study and were divided into either the HRA group (n=206, 6.2%) or the LRA group (n=3,103, 93.8%). The study population included 1,985 men (60.0%) and 1,324 women (40.0%), with a mean age of 52.4±10.0 years. The prevalence of adenoma in the study population was 24.3%.

Here, we present an association between CRP level and HRA. Compared with the lowest quartile of serum CRP level, the prevalence of HRA was 3.5 times higher in the highest quartile, and HRA was associated with an elevated CRP level in both men and women. In a logistic regression analysis, a higher quartile of CRP was found to be an independent risk factor of HRAs (OR, 1.8; 95% CI, 1.3-2.5; P=0.000). Our results support a role of chronic inflammation in the development of colorectal neoplasia. Previous studies have primarily focused on CRC; however, our study focused on HRA, which may be an intermediate lesion in the adenoma-carcinoma sequence. Although some previous studies have suggested sex differences in the association between CRP and colorectal neoplasia,^17,25 no sex differences were observed in this study.

The role of chronic inflammation in colorectal carcinogenesis has been well established in IBD patients,⁵ and a number of studies have also demonstrated an association between CRP level and CRC risk.^15,16,19 A recent meta-analysis found a positive association between CRP level and CRC risk.¹⁴ Due to the inconsistencies in previous results,^{17,20,21,22,26,27,28} little was conclusively known about the relationship between CRP and colorectal adenoma. In a Japanese case-control study, Otake et al.²⁶ reported a positive association between CRP and prevalence of large adenomas. The multivariate-adjusted ORs of large adenomas for the lowest to highest quartiles of CRP were 1.00 (reference), 1.81, 1.61, and 2.21, respectively (P=0.01). However, that study was limited due to a lack of information on the use of aspirin or NSAIDs and the nonuniversal definition of large (≥5 mm) adenomas. In a Chinese study,¹⁷ high serum CRP level was independently associated with increased risk of synchronous and advanced colorectal neoplasia in Chinese men, but not women. These data supported an association between chronic inflammation and colorectal neoplasia, and suggested an effect of sex on this association. In a small (n=242), colonoscopy-based cross-sectional study, the prevalence of colorectal adenomas was associated with a higher CRP level.²⁷ Our positive association between CRP level and HRA risk might have been due to the large sample size and use of HRA as a target, as this might indicate an advanced phenotype of colorectal adenoma toward CRC.

Positive associations between CRP and adenoma have not been consistently observed in previous studies.^20,21,22,23 In a small case-control study, serum CRP was not associated with increased risk of colorectal adenoma; however, that study was limited, as only 135 adenoma cases were analyzed.²³ In a case-control study from Korea, serum CRP was not significantly different between normal and adenoma groups.²² In that study, CRP levels were classified as <1 mg/dL, 1 to 3 mg/dL, >3 mg/dL; however, this classification was arbitrary and included very high levels, considering the relatively healthy population. In our study, the mean CRP level was 0.2±0.9 mg/dL, and only 2.4% of the study population had CRP >1 mg/dL. CRP may be associated with increased risk of adenoma at very low levels, and this positive association might be obscured by arbitrary classifications of CRP levels. Recently, a prospective colorectal adenoma chemoprevention study found no significant relationship between CRP level and recurrent adenoma or advanced neoplasm.²⁰ However, this was a chemoprevention study with calcium supplementation (1,200 mg/day), which might have influenced the levels of CRP, and recurrent adenoma was evaluated only 3 years after baseline CRP levels were measured, which could have been too short of a duration to evaluate the recurrence of adenoma. In another prospective case-control study,²¹ high CRP level was protective effect against colorectal adenoma development; however, that study was also limited by a sigmoidoscopy-based study design with small sample size. These inconsistent previous results might have arisen from different study methodologies, patient populations, and prevalence of colorectal neoplasia.

The mechanism involved in the association between CRP level and colorectal neoplasia is currently unknown. Further studies on this subject are required; however, there are several possible explanations. As patients with obesity,²⁹ smoking,³⁰ physical inactivity,³¹ and diabetes mellitus³² have high CRP levels, we infer that these factors jointly contribute to the increased risk for HRA. However, even after adjustment for these confounding factors,¹⁷ CRP remained an independent risk factor for colorectal neoplasia. Another possible explanation is that CRP level might be associated with insulin resistance,^32,33,34 which is a shared pathway for the development of colorectal neoplasia.^32,35 These results may suggest that the association between CRP and colorectal neoplasia is not a coincidence but rather the result of a common pathway.

There are several advantages to our study. First, this is the first study to explore the association between CRP and presence of HRA. As the prevalence of HRA, which must be evaluated with invasive colonoscopy and pathologic examination, has been increasing, a laboratory marker for HRA would be clinically useful. Second, we included many potential confounding factors that can influence CRP level, such as BMI, diabetes mellitus, aspirin/NSAID use, alcohol consumption, and smoking. However, we cannot exclude the possibility of residual confounding factors. Finally, the data collected in this study are of high quality, despite the retrospective design of this study, because the questionnaires were completed by trained nurses, and the adenoma detection rate (24.3%) of this study was matched to quality indicators of colonoscopy.

Despite these advantages, there are also several limitations to our study. First, our study used only a single measurement of CRP at baseline before colonoscopy. However, single measurements of baseline CRP have strongly predicted risk for diabetes mellitus,³² coronary heart disease,³⁶ and hypertension³⁷ in other studies. Furthermore, CRP level is stable over long periods,³⁸ with little or no diurnal variation.³⁹ Second, we measured CRP level before colonoscopy without a subsequent measurement after removal of the colonic neoplasia, preventing us from concluding a causal relationship. Third, our results are based on a single-center retrospective study, which limits the generalization of our findings. Finally, we cannot exclude the possibility that a high CRP level is an epiphenomenon of a systemic infectious state. However, this possibility is remote, as only asymptomatic individuals were included and individuals with a suspicious clinical infection or fever were excluded. Furthermore, the proportion of patients with CRP ≥5 mg/dL was only 0.4% and with CRP ≥10 mg/dL was only 0.2%.

In conclusion, our study showed that high CRP level is associated with HRA in both men and women. The feasibility of using CRP as a laboratory marker for identifying HRA and related mechanisms warrants further investigation.