The relationship between metabolic syndrome and the incidence of colorectal cancer

Objectives This study evaluated the incidence of colorectal cancer (CRC) according to the number of metabolic syndrome (MetS) components. Methods Using health checkup and insurance claims data of 6,365,409 subjects, the occurrence of CRC according to stage of MetS by sex was determined from the date of the health checkup in 2009 until December 31, 2018. Results Cumulative incidence rates (CIR) of CRC in men and women was 3.9 and 2.8 per 1000 (p < 0.001), respectively. CIR of CRC for the normal, pre-MetS, and MetS groups in men was 2.6, 3.9, and 5.5 per 1000 (p < 0.001) and CIR in women was 2.1, 2.9, and 4.5 per 1000 (p < 0.001), respectively. Compared with the normal group, the hazard ratio (HR) of CRC for the pre-MetS group was 1.25 (95% CI 1.17–1.33) in men and 1.09 (95% CI 1.02–1.17) in women, and the HR of CRC for the MetS group was 1.54 (95% CI 1.43–1.65) in men and 1.39 (95% CI 1.26–1.53) in women after adjustment. Conclusions We found that MetS is a risk factor for CRC in this study. Therefore, the prevention and active management of MetS would contribute to the prevention of CRC.


Introduction
Colorectal cancer (CRC) is the third most common cancer worldwide and accounts for 10.2% of all cancers (approximately 1.8 million people a year) [1]. CRC is the second most common cancer after stomach cancer in Korea [1], so identifying and managing risk factors is the first step in preventing CRC. In Korea, the incidence of CRC has increased over the past decade, and the ageadjusted incidence per 100,000 men and women has increased from 26.2, 16.4 in 1999 to 40.4, 22.4 in 2016, respectively [2]. Major risk factors for CRC include genetic predisposition, Western dietary habits, lifestyle (smoking, drinking, physical activity, etc.), and metabolic diseases (obesity, insulin resistance, etc.) [3].
Metabolic syndrome (MetS) is a cluster of metabolic risk factors that includes abdominal obesity, hypertension, hyperglycemia, and dyslipidemia; several definitions have been suggested using different criteria [4,5]. More than 20% of adults are known to have MetS [6], but its prevalence worldwide varies depending on race, environmental factors, the age and gender composition of the population, genetic differences, physical activity level, eating habits, and differences in measurement standards [7,8]. The estimated total prevalence of MetS for adults in Korea is 26.9%: 30.0% in males and 24.6% in females [9].
Some studies on the correlation between metabolic syndrome and CRC have been reported recently, but many studies have been conducted in Western countries and races [10][11][12][13]. However, studies on Asian races are still limited to East Asian countries such as Taiwan and Japan [14,15]. In addition, the study population is limited to those who are screened at only university hospital screening centers, so it is not easy to generalize to the entire population [14]. Also there is a limitation that it is difficult to produce a meaningful result because of the short observation period and the lack of cancer cases [15].
In order to complement the limitations of previous research conducted on Asian races, this study evaluated the incidence of CRC according to the number of MetS components using the health checkup data and insurance claims data from the National Health Insurance Service (NHIS) in Korea.

Study design and population
This was a retrospective observational study that used health checkup and insurance claims data from the NHIS (Fig. 1). NHIS is constructing and providing health database that includes medical history, treatment, type of disease, and prescription history of all Koreans who use health checkup or medical service under national health insurance. The database has been operating continuously, and about 50 million people's medical data are monitored from 2002 to 2018. In detail, the National Health Information database is divided into Qualification database, Treatment database, and Health check-up database. The National Health Information database is significant in terms of representation because it monitors medical history of all Koreans, and it is also useful because it can be linked and analyzed with other administrative data through the social security number. The Health check-up database used in this study is very suitable for the purpose of research because it contains the actual measurement value such as blood pressure, blood sugar, triglycerides, HDL, and health habits for those who undergo health checkups every 2 years.
The source population was defined as those who had had health checkups in 2009. While this comprised 15,036,607 people, only 9,927,538 people were actually examined. Of these, 3,562,129 were excluded for the following reasons:

Dependent variable
The dependent variable was the occurrence of CRC, as identified operationally from insurance benefit claims data, with codes C18-C20 as a primary diagnosis from the International Classification of Diseases-Tenth revision and V193 as a special code. A special code is a system whereby the economic burden on patients diagnosed with cancer, severe burns, cerebrovascular and heart diseases, or intractable diseases is reduced by decreasing the copayment. If a disease is claimed with this special code, it means that the diagnosis is more accurate than a claim disease without a special code.

Independent variable
The independent variable was the stage of MetS, which was classified into three groups according to the criteria of modified National Cholesterol Education Program-Adult Treatment Panel III (NECP-ATP III, which are the most agreed-upon criteria [16]. MetS refers to subjects with at least three of the following five factors: (1) abdominal obesity (waist circumference ≥ 90 cm for men, ≥ 85 cm for women); (2) elevated blood pressure (systolic BP ≥ 130 mmHg or diastolic BP ≥ 85 mmHg or treatment of previously diagnosed hypertension); (3) elevated fasting glucose (≥ 100 mg/dL or treatment of previously diagnosed diabetes mellitus); (4) high TG (≥ 150 mg/dL or drug treatment for high TG); and (5) low HDL-C (< 40 mg/dL for men, < 50 mg/dL for women or drug treatment for low HDL-C). The subjects were placed in the pre-MetS group with one or two MetS factors and the Normal group with no MetS factors.

Adjusted variables
The study population was divided into two subsets by gender. Next, age, health behaviors, family history, and laboratory data from the health checkup were used as adjustment variables. Age was divided into 10-year intervals, and health behaviors were selected from smoking, drinking, and physical activities in the questionnaire.
Smoking was categorized into three groups: never smoked, smoked in the past but no longer, and currently smoking. Alcohol consumption was categorized into four groups based on the drinking frequency: nondrinker, 2-3 times per month, 1-4 times per week, and almost every day. Physical activity group was categorized into three groups based on frequency: never, 1-4 times per week, and almost every day. Family history of cancer was divided into two groups of yes or no. Height, weight, body mass index (BMI), hemoglobin, serum creatinine, total cholesterol, and alanine aminotransferase (ALT), which were health checkup items, were used as laboratory findings, and as continuous variables. BMI (kg/m 2 ), hemoglobin (g/dL), and serum creatinine (mg/dL) are categorized according to the criteria of Korean health screening [17]. Total cholesterol (mg/dL) and ALT (IU/ L) were used in the model as continuous variables, and the original data values were increased by ten times to improve the readability of the hazard ratio.

Statistical analysis
We summarized the frequency of study population for related variables according to the number of MetS components, and calculated the cumulative incidence rate (CIR) and incidence density (ID) of CRC. CIR is the incidence per 1000 person and ID is the incidence per 10, 000 person-years (PY). PY was calculated as the time from the baseline examination to the date of CRC diagnosis, the date of death, or December 31, 2018 when who survives without diagnosis of CRC.
Next, we compared the frequency between variables using the chi-square test. To analyze the risk of developing CRC due to MetS, Cox proportional hazard regression was applied. All variables affecting the incidence of CRC were considered stepwise and five Cox proportional hazard models were fitted, including one unadjusted model for comparison. Model 1 was adjusted for age. Model 2 was adjusted for health behavior (smoking, exercise). Model 3 was adjusted for family history cancer. Model 4 was adjusted for the laboratory findings (height, weight, hemoglobin, and other relevant values). Model 5 was adjusted for the laboratory findings (body mass index, creatinine, hemoglobin, and other relevant values). The results are summarized as the hazard ratio (HR) and 95% confidence interval (95% CI).
A level of α = 0.05 was used to determine the significance of the models and variables. All statistical analyses were performed using SAS ver. 9.1 (SAS Institute, Cary, NC, USA).

Ethics considerations
The study was approved by the institutional review board of Konkuk University (7001355-201909-E-100).

CIR and ID of CRC according to the number of Mets components in men
The number of study population and the CIR of CRC in men were 3,695,923 and 3.9 ( Table 1). The CIR of CRC by MetS stage was 2.6, 3.9, and 5.5 for the normal, pre-MetS, and MetS groups, respectively (p < 0.001).
The ID of CRC in men was 4.2 ( Table 1). The ID of CRC by MetS stage was 2.8, 4.2, and 6.0 for the normal, pre-MetS, and MetS groups, respectively (p < 0.001).
The number of study population and the CIR and the ID of CRC for the other variables in men were summarized in Table 1.

CIR and ID of CRC according to the number of Mets components in women
The number of study population and the CIR of CRC in women were 2,669,486 and 2.8 ( Table 2). The CIR of CRC by MetS stage was 2.1, 2.9, and 4.5 for the normal, pre-MetS, and MetS groups, respectively (p < 0.001).
The ID of CRC in women was 3.0 ( Table 2). The ID of CRC by MetS stage was 2.2, 3.1, and 4.8 for the normal, pre-MetS, and MetS groups, respectively (p < 0.001).
The number of study population and the CIR and the ID of CRC for the other variables in women were summarized in Table 2.

Risk of the number of Mets components on CRC in men and women
In men, the HR of CRC for the pre-MetS group compared with the normal group before adjustment (unadjusted model) was 1.50 (95% CI 1.43-1.57), and the HR for the MetS group was 2.16 (95% CI 2.06-2.28) ( Table 3). After full adjustment (model 5), the HR for the pre-MetS group and MetS group was 1.25 (95% CI 1.17-1.33) and 1.54 (95% CI 1.43-1.65).

Discussion
To investigate the effect of MetS on the incidence of CRC, we analyzed about 6 million medical claim and check-up data that had the high external validity with large sample size and average follow-up period of 9.3 years per person from NHIS in Korea.
The results of the study revealed there is a positive association between MetS and the incidence of CRC. This supports previous findings that MetS is the main factor expediting tumor growth [18][19][20].
Although the mechanism of MetS in the development of CRC is not clear, it is thought to be related to hyperinsulinism and insulin resistance [23,24], which increases insulin-like growth factor-1 levels. In addition, adipocyte-secreted hormones such as adiponectin, leptin, and resistin [25]; the greater proportion of Firmicutes and lower proportion of Bacteroidetes within the large intestine [26,27]; and a high-fat, low-fiber diet [28] are all related to the occurrence of CRC. Since it is important to understand the pathological mechanism of CRC related to MetS [29], additional studies need to examine how to prevent CRC as MetS progresses [30].     Ref. Ref.
Ex-smoker   In this study, pre-MetS group had a 25% higher risk of CRC and MetS group had a 54% higher risk of CRC than Normal group in men based on the full adjustment model, and pre-MetS group had a 9% higher risk of CRC and MetS group had a 39% higher risk of CRC than Normal group in women. The risk of Mets on incidence of CRC was slightly higher in men than in women, and all were significant.
However, some previous studies showed different risk ratios by gender [10,12,31,32]. The reason for this is difference in the number of study subjects, study design, and fundamental biological differences between males and females. Although this study showed the positive association between MetS and the incidence of CRC, further investigation is needed as to the question of how men and women may be affected by metabolic abnormalities in terms of CRC risk [13].
Lifestyle has been known to be a major factor associated with CRC, and it is known that the risk of cancer gradually decreases if healthy lifestyles are practiced in stages [33]. This study found that drinking alcohol and smoking were related to the risk of CRC. Other studies also shown that smoking [34] and drinking alcohol have carcinogenic effects and promote cancer, especially in the case of drinking alcohol, moderate amounts of drinking alcohol can lead to an increase in CRC [35]. Education programs for lifestyle improvements should be conducted to reduce the incidence of colorectal cancer [36]. It has been suggested as an effective way to raise awareness, knowledge, and screening rate for colorectal cancer screening [37,38].
There are some studies [39][40][41] that consider height in the analysis as risk factors for colorectal cancer, and the results of the analysis are also reported to be significant. Based on these similar previous studies, this study considered the relationship between height and colorectal cancer but found no significant correlation. There was also no significant association between weight and colorectal cancer.
Previous studies of Asian races have limits, such as a lack of representativeness or only a few variables were examined. Our study identified MetS as a risk factor for CRC after adjusting for various variables and determined the magnitude of the risk using national health checkup and insurance claims data in Korea. Because there are ethnic differences in the relationship between MetS and cancer [13,25,42], the presentation of risk ratios for Asians using large data and long follow-up period sets is a significant research achievement. Study on the relationship between metabolic and disease occurrence for Asian races [43] should be conducted and other approaches to mitigate health risks need to be reviewed [44]. In addition, this study has some newly informative knowledge as follows. First, this study is meaningful in that it attempts to represent the entire Korean population using the National Health Insurance Corporation's claim data. Second, this study is the most recent longterm data taken from the initial establishment of the data source to the latest data. Third, unlike other studies, this study considered the incubation period sufficiently to closely observe the association of colorectal cancer risk due to metabolic syndrome. The incubation period was set to 3 years, and the analysis was performed except for patients with colorectal cancer who developed within 3 years of the observation. Fourth, this study was able to understand the risk of colorectal cancer in more detail by classifying subjects according to the number of factors of metabolic syndrome rather than whether they were metabolic syndrome.
This study has some limitations. First, we did not consider changes in the risk of the number of metabolic components on CRC in men and women in the study population after it was diagnosed, since we used only the health check-up data for 2009. This should be examined in a future study. Second, we did not adjust for some variables, such as the consumption of meat, which is a known risk factor for CRC, because we used secondary data. Lastly, health screening programs are being provided to all Koreans regardless of income, and the participation rate is also increasing from 72.9% in 2012 to 78.5% in 2017 [17]. However, it is mandatory for industrial workers to be screened, and the rate of participation of industrial workers is relatively higher than that of self-employees [45]. Therefore, this study cannot exclude the possibility of health workers effect.

Conclusions
This study investigated the relationship between MetS and CRC using national health check-up and insurance claims data for Korea. It showed that MetS was a risk factor for the occurrence of CRC.
From a clinical and public health perspective, Mets has emerged as an important disease that requires early management and more thorough management and prevention of Mets are needed to prevent CRC based on the results of this study with long-term follow-up and large-scale of Asian subjects.