In this community-based cohort study in the Republic of Korea, we found that an increased risk of CRC in women associated with MetS and abnormal TG level by conducting PS-based analyses. In women, both MetS and abnormal TG level were associated with an approximately 2.0-fold to 2.2-fold increased risk of CRC. However, we showed that there was no significant association between MetS and CRC in men no matter which analytic methods we performed.
To our knowledge, our study is the first cohort study using PS-based methods to examine the effect of MetS on CRC incidence for both sexes in the Asian population. It seems that previous research findings were inconsistent: A meta-analysis reported that there was the significant association between MetS and CRC in both sexes in cohort studies across populations including the United States, European, Asian, and other populations (RR for men, 1.25 [95% CI, 1.19, 1.32]; RR for women, 1.34, [95% CI, 1.09, 1.64]) [2]. In another meta-analysis, the results in cohort studies across populations showed that men with MetS had a significantly elevated risk on CRC, but women with MetS did not [4]. However, in the United States, a cohort study that examined for postmenopausal women showed a similar risk level to ours (HR, 2.15; 95% CI, 1.30, 3.53) [19]; the subsequent study recruited more participants but reported non-significant lower risks (HR, 1.16; 95% CI, 0.95-1.41) [20].
To discuss the association between MetS and CRC for the Asian population, two previous meta-analyses reported results using a couple of cohort studies for the Asian population: One showed that there was no association in cohort studies (RR for men, 1.10 [95% CI, 0.80, 1.51]; RR for women, 1.02, [95% CI, 0.76, 1.36]) [2]. Another also found that RRs for men and women from datasets across study designs were non-significant (RR for men, 1.23 [95% CI, 0.80, 1.88]; RR for women, 1.12, [95% CI, 0.86, 1.48]) [4]. In the case of the Republic of Korea, there were prior cohort studies about this association. Of these two studies using colon or colorectal adenoma risks as outcomes, one reported no association, but the other showed an association (adjusted HR, 1.28; 95% CI, 1.09-1.51) [6, 7]. The subjects of these cohort studies underwent colonoscopy for a health examination in a large hospital and could, therefore, be generally regarded as individuals who are interested in the prevention of future disease and the pursuit of a healthy lifestyle. Two studies using the National Health Insurance Service–National Sample Cohort to represent the Korean population reported somewhat conflicting results: One found only a significantly increased risk of colon cancer, not rectum cancer, for men with MetS (HR, 1.40 [95% CI, 1.14, 1.71]) , but did not find significant colon or rectum cancer risks for women [5]; the other found that MetS was associated with the development of CRC in both sexes (HR for men, 1.41 [95% CI, 1.37, 1.44]; HR for women, 1.23 [95% CI, 1.20, 1.27]) [21]. Our finding seems to be slightly different from previous studies above, as we have estimated using PS-based methods and study subjects of our study were just community residents. Thus, we expect that this study might contribute to providing additional evidence that there is the association between MetS and an elevated risk of CRC in the Asian population and future large cohort studies using PS-based methods could provide more definitive evidence.
In addition, our study showed that abnormal TG levels were associated with CRC risk in women. However, a previous review and meta-analysis reported that TG was not related to the risk of CRC [4]. Cohort studies in the United States and Japan also arrived at similar conclusions [19, 22]. In the Republic of Korea, previous cohort studies showed the HRs of colorectal adenoma to be 1.19 (95% CI, 1.03, 1.37) and 0.76 (95% CI, 0.45, 1.27) [6, 7] and the HR of CRC to be 1.15 (95% CI, 1.07, 1.23) [21]. Future studies are recommended as it remains controversial whether the risk of CRC or colorectal adenoma is elevated when individuals’ levels of TG are 150 mg/dL or higher.
As is well known, MetS is widely known as a risk factor for CRC, but the biological mechanism underlying this association remains to be clarified. Insulin resistance, systemic inflammation, and oxidative stress, and higher leptin levels have been suggested as potential mechanisms that may explain the association between MetS and CRC [3]. Insulin increases cell proliferation and reduces apoptosis, which may lead to tumor development. Insulin also induces the overstimulation of receptors of insulin-like growth factor-1 and 2 (IGF-1 and IGF-2), a key promoter of tumor development. Besides, deteriorated metabolic status influences elevated levels of inflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), and leptin hormone, which may be implicated in insulin resistance and tumor development. Further studies are required to elucidate the mechanism underlying the effect of each component of MetS on CRC.
The strengths of this study include its prospective nature (i.e., cohort design), the strong causality between MetS and CRC by using PS-based methods. The selection biases that are present in most observational studies may lead to a lack of causality in this study. To improve the causality between MetS and CRC incidence, we performed PS-based analyses in a community-based cohort. A major advantage of using PS-based methods in observational studies can minimize selection biases by balancing nonrandomized individuals’ data to reach the level of causality determined by randomized controlled trials. Recently, there have been some well-designed studies that have revealed associations between MetS and non-communicable diseases, including cancers, using PS-based analyses [23, 24].
There were several limitations to this study. We could not observe the following confounders: the history of MetS before cohort entry, individuals' stressful events, menopause, the consumption of carbohydrate and starchy foods, etc. Also, there is the possibility of information bias due to the use of a self-reported questionnaire. Also, we measured MetS only at the entry of this cohort study, so we could not estimate the risk of CRC due to changes in MetS over time. Furthermore, we used BMI as a measure of abdominal obesity of MetS due to the absence of WC data, although BMI and WC have slightly difference in the pathological meaning of MetS. Last, we could not obtain mortality data between 2014 and 2016 for non-cancer cases among the study population from Statistics Korea, so we could not calculate a time-to-event outcome of performing survival analyses.
In conclusion, this study may provide additional evidence that deteriorated metabolic profiles increase the risk of CRC in women. We highlight the importance of effective population-level interventions for deteriorated metabolic profiles at the early stages.