Metabolic syndrome (MS) is a condition characterized by the coexistence of at least three metabolic risk markers, including impaired fasting blood glucose (sugar), dyslipidemia (low high-density cholesterol and high triglyceride), abdominal obesity (high waist circumference), and elevated blood pressure (1–4). MS is a public health challenge with a huge global burden: it enhances morbidity and mortality related to chronic diseases such as cancer, stroke, diabetes, asthma, and atherosclerotic and nonatherosclerotic cardiovascular disease (5–7). Metabolic risk factors such as blood pressure, fasting plasma glucose, and high total cholesterol were among the ten largest contributors to global disability-adjusted life years (DALYs) in 2015 (8). MS has multiple promoting factors including, age (9), unhealthy diet (10, 11), obesity (11), alcohol consumption (12, 13), physical inactivity (11, 13), cigarette smoking (13–23), and PM_2.5 (24–27).

Cigarette smoking is a major preventable promoter of global cardiovascular mortality and morbidity (16, 28, 29). In 2015, it was among the five top risk factors attributable to global DALYs in 109 countries (8). The influence of cigarette smoking on MS and its components is contentious (14, 30). For instance, cigarette smoking was a significant cause of MS among Chinese (14), Koreans (31–33), and Japanese (18, 23). Nonetheless, it was not significantly associated with MS among Japanese (34) and Chinese (35). Furthermore, heavy cigarette smoking among Turkish women was suggested as being protective against future MS (36).

Air pollution, especially PM_2.5 (fine PM) is an urgent global public health concern, with continuously increasing implications (4, 9, 37–46). It significantly enhances neurological and cardiovascular morbidity and mortality (47, 48). Several studies reported contrasting findings regarding the relationship between MS and PM_2.5 (14–23, 31–33, 49–51). A recent systematic review and meta-analysis found that PM_2.5 could contribute to as much as 12.28% of MS (52). In several original studies, PM_2.5 exposure significantly elevated the risk of MS among Chinese (25–27, 53, 54), Saudi (55), and Korean adults (56). On the contrary, PM_2.5 did not significantly affect the risk of MS among Germans (57) and Chinese (50).

The positive association between PM_2.5 and MS was more prominent in cigarette smokers, alcohol drinkers, and obese people (25, 26, 53). This suggests that smoking and other unhealthy habits could exacerbate the adverse effects of air pollution (25, 26, 53). Smoking could also confound the effect of air pollution on cardiovascular health (58). Hence, pinpointing the combined effect of cigarette smoking and PM_2.5 could narrow the data gap for the burden of disease attributable to both exposures (59). Moreover, determining the interaction between PM_2.5 and smoking could provide insightful knowledge regarding the susceptibility to PM_2.5-related adverse health conditions in smokers and nonsmokers (59). High exposure to PM_2.5 among Chinese was recently associated with a higher risk of hypertension caused by smoking (60). However, robust studies have not been conducted to determine the combined effect of PM_2.5 and cigarette smoking on MS. In the current study, we determined the independent association of ambient PM_2.5 and smoking with MS in Taiwanese adults. Moreover, we determined the interaction between PM_2.5 and smoking regarding MS.

Table 1 shows the demographic characteristics of the 126,366 study participants comprising 26,767 MS cases and 99,599 individuals without MS. The PM_2.5 quartiles were PM_2.5 ≤ Q1 (PM_2.5 ≤ 27.137), Q1 < PM_2.5 ≤ Q2 (27.137 < PM_2.5 ≤ 32.589 μg/m³), Q2 < PM_2.5 ≤ Q3 (32.589 < PM_2.5 ≤ 38.205 μg/m³), and PM_2.5 > Q3 (PM_2.5 > 38.205 μg/m³). Individuals with and without MS significantly differed in terms of PM_2.5 concentration (p-value = 0.0280), cigarette smoking, and other variables, including sex, age, BMI, alcohol intake, marital status, educational level, secondhand smoke exposure, and duration of residence (p-value < 0.0001). Among the 99,599 individuals without MS, 24,378 (24.48%), 27,157 (27.27%), 23,147 (23.24%), 24,917 (25.02%) were within the PM_2.5 quartiles, PM_2.5 ≤ Q1, Q1 < PM_2.5 ≤ Q2, Q2 < PM_2.5 ≤ Q3, and PM_2.5 > Q3, respectively. Among the 26,767 MS cases, 6,370 (23.80%), 7,250 (27.09%), 6,414 (23.96%), and 6,733 (25.15%) were within the PM_2.5 quartiles, PM_2.5 ≤ Q1, Q1 < PM_2.5 ≤ Q2, Q2 < PM_2.5 ≤ Q3, and PM_2.5 > Q3, respectively. The group without MS comprised 81,706 (82.03%) nonsmokers, 9,687 (9.73%) former smokers, and 8,206 (8.24%) current smokers. The MS group comprised 19,541 (73.00%) nonsmokers, 3,628 (13.55%) former smokers, and 3,598 (13.44%) nonsmokers.

Table 2 and Supplementary Figures S1, S2 present the association of MS with PM_2.5 and cigarette smoking. Higher compared to lower PM_2.5 levels (27.137 < PM_2.5 ≤ 32.589, 32.589 < PM_2.5 ≤ 38.205, and PM_2.5 > 38.205 vs. PM_2.5 ≤ 27.137 μg/m³) were significantly associated with a higher risk of MS (OR; 95% CI = 1.058; 1.014–1.104 for 27.137 < PM_2.5 ≤ 32.589 μg/m³, 1.185; 1.134–1.238 for 32.589 < PM_2.5 ≤ 38.205 μg/m³, and 1.149; 1.101–1.200 for PM_2.5 > 38.205 μg/m³). Compared to nonsmokers, former and current smokers had a higher risk of MS (OR = 1.062, 95% CI = 1.008–1.118 for former smokers and 1.531; 1.450–1.616 for current smokers). The dose–response relationship between smoking and MS was significant (p-trend <0.0001). According to the quantity of cigarettes smoked, a weekly consumption of ≥140 cigarettes per week was significantly associated with a higher risk of MS in both former and current smokers (Supplementary Table S1). The interaction between PM_2.5 and cigarette smoking was significant: p-value = 0.0157 (Table 2). The risk of MS was also significantly higher among people who were ≥ 50 years (OR = 2.277, 95% CI = 2.190–2.367), overweight (OR; 95% CI = 4.219; 4.056–4.388), obese (OR; 95% CI = 13.232; 12.707–13.778), current alcohol drinkers (OR = 1.162, 95% CI = 1.092–1.236), divorced/separated (OR; 95% CI = 1.097; 1.039–1.159), and widowed (OR; 95% CI = 1.178;1.098–1.264). However, the risk was lower among underweight individuals (OR = 0.084, 95% CI = 0.057–0.124), those who exercised regularly (OR = 0.866, 95% CI = 0.839–0.895), single people (OR; 95% CI = 0.928; 0.882–0.976), those who attained a junior and senior high school level (OR; 95% CI = 0.821; 0.769–0.876), and university education and above (OR = 0.692, 95% CI = 0.648–0.740).

Table 3 shows the association between PM_2.5 and MS in current, former, and nonsmokers. PM_2.5 was significantly associated with a higher risk of MS among nonsmokers: OR = 1.074, 95% CI = 1.022–1.128, 1.226; 1.166–1.290, and 1.187; 1.129–1.247 for 27.137 < PM_2.5 ≤ 32.589, 32.589 < PM_2.5 ≤ 38.205, and PM_2.5 > 38.205 μg/m³, respectively.

Table 4 illustrates the association between cigarette smoking and MS stratified by PM_2.5 quartiles. Compared to nonsmokers, the risk of MS was significantly higher in former smokers when the PM_2.5 concentration was ≤32.589 μg/m³: OR (95% CI) = 1.139 (1.027–1.263) for PM_2.5 ≤ 27.137 μg/m³ and 1.138 (1.032–1.254) for 27.137 < PM_2.5 ≤ 32.589 μg/m³. The risk of MS was significantly higher among current smokers, regardless of the PM_2.5 concentration. The ORs; 95% CIs were 1.605; 1.444–1.785, 1.561; 1.409–1.728, 1.359; 1.211–1.524; and 1.585; 1.418–1.772 for PM_2.5 ≤ 27.137, 27.137 < PM_2.5 ≤ 32.589, 32.589 < PM_2.5 ≤ 38.205, and PM_2.5 > 38.205 μg/m³, respectively.

Table 5 and Supplementary Figure S3 show the risk of MS according to cigarette smoking and PM_2.5 exposure. Compared to nonsmokers with low PM_2.5 exposure (PM_2.5 ≤ 27.137 μg/m³), the risk of MS was significantly higher in all the categories. Of note, the category comprising current smokers and PM_2.5 > 38.205 μg/m³ had the highest risk of MS (OR = 1.801, 95% CI = 1.625–1.995).

Cigarette smoking and PM_2.5 have significant adverse effects on individual and public health. A systematic analysis of the global burden of disease ranked PM_2.5 and cigarette smoking among the ten leading causes of death and disability in 2015 (8). We evaluated the independent and joint association of both factors with MS in Taiwan Biobank volunteers. Smoking and PM_2.5 were independently associated with higher odds of MS. Moreover, both exposures were interactively associated with MS in a significant manner.

Cigarette smoking has been associated with CVD risk factors such as elevated heart rate, dyslipidemia, hyperinsulinemia, and glucose intolerance (15–17). In line with our study, several original studies and meta-analyses reported cigarette smoking as a metabolic syndrome-promoting factor (14–23, 31–33, 51). For instance, in a meta-analysis including 13 prospective studies, active smoking was positively associated with MS (51). In an original study, life-course cigarette smoking was associated with a higher risk of MS among Chinese, particularly those under 70 years (14). Moreover, a cross-sectional study among Koreans below 40 years found a higher likelihood of MS in smokers than nonsmokers (33). Furthermore, a community-based study involving Taiwanese aged 40 years and above revealed a dose-dependent positive relationship of current smoking with MS and some of its components, including high TG and low HDL (22). In addition, a study among Japanese aged 35–65 also showed a higher incidence of MS among both current and former smokers (23). Another study among Japanese between 20 and 93 years found that the risk of MS in individuals who smoked over 40 cigarettes per day persisted even after 20 years of quitting (18). A cross-sectional study among male Korean former smokers aged at least 19 years showed a higher risk of MS, hypertriglyceridemia, and hyperglycemia among those who had smoked for over 20 years (32). Another cross-sectional among male Koreans aged over 20 years also showed a higher risk of MS among former and current smokers who smoked more than ten packs of cigarettes annually (31). In a cross-sectional study involving individuals of Western European ancestry, cigarette smoking was significantly linked to a higher prevalence of MS, regardless of BMI and sex (65). In the DESIR (Données Epidémiologiques sur le Syndrome d’Insulino-Résistance) study (a longitudinal study involving French), male smokers had a significantly higher risk of MS (66). In another longitudinal study in Norway, heavy smoking increased the incidence of MS in both men and women (13). Using the Third National Health and Nutrition Examination Survey (NHANES) data, a study in the US found a lower risk of MS among normal weight and overweight men and women with no history of smoking (67).

The positive association of PM_2.5 and MS in the current study is comparable to findings from previous studies (14–23, 31–33, 51). For example, exposure to PM_2.5 exacerbated the risk of MS among Saudi adults (55) and Korean adults without CVDs (56). Moreover, several original studies found a positive relationship between long-term exposure to PM_2.5 and MS in adult Chinese (25–27, 53, 54). A meta-analysis of observational studies revealed a borderline positive association between PM_2.5 and MS (49). Exposure to PM_2.5 has also been associated with an elevated risk of MS components, including high abdominal obesity (56), FBG (54–56, 68–70), high BP (55, 56, 71), and dyslipidemia (54, 56, 70). Analyses of data from the Heinz Nixdorf Recall (HNR) cohort study in Germany revealed a borderline positive association between PM_2.5 and MS (57). A study in the US using data from the Normative Aging study found a significantly increased risk of MS due to increasing PM_2.5 concentrations (70). Nonetheless, data from the Adolescent to Adult Health (Add Health) study (a longitudinal study in the US) showed no significant association between long-term PM_2.5 exposure and MS (72).

In our study, the interaction of PM_2.5 and cigarette smoking on MS was significant. It is worth noting that the joint role of both exposures in MS pathogenesis has not received considerable attention. However, some studies investigated the joint role of PM and cigarette smoking on cardiovascular and pulmonary morbidity and mortality (59, 73–75). For instance, Turner and colleagues (59) reported an increased risk of cardiovascular mortality (i.e., about 32 extra deaths per 100,000 person-years) due to smoking-PM_2.5 interaction. Even though a study on cardiovascular mortality found no interaction between PM_2.5 and smoking, current smokers with higher exposure to PM_2.5 had a high relative risk for mortality (76). Exposure to both smoking and PM_2.5 was associated with a relative excess risk of lung cancer mortality (74). Exposure to particulate matter, especially PM_2.5, was also significantly associated with a higher risk of cardio-cerebrovascular disease among nonsmokers (73).

The potential mechanisms underpinning the role of smoking and PM_2.5 on MS are unclear. Nonetheless, the available evidence points toward insulin resistance, induced oxidative stress, inflammation, and endothelial dysfunction. That is, smoking is believed to promote MS by inducing insulin resistance, reducing insulin sensitivity, and causing hyperglycemia, high blood pressure, hyperinsulinemia, oxidative stress, endothelial dysfunction, and systemic inflammation (15, 16, 77, 78). Air pollution, especially PM_2.5, enhances MS susceptibility by disrupting insulin signaling, inducing inflammation and oxidative stress (73, 79–82). Sung Kyun Park and colleagues (83) found that in MS patients, PM could particularly affect CVDs by causing cardiac autonomic dysfunction.

The current study has some limitations. First, we included only Taiwanese adults aged 30 and 70 who were enrolled in the TWB project. The restriction of enrolment to only Taiwanese within a specific age cohort is a possible source of selection bias. As such, our conclusions may not be generalizable to non-Taiwanese and Taiwanese outside the 30–70 age group. Second, we could not ascertain PM_2.5 exposure at individual levels since data were obtained from fixed monitoring stations. The non-definitive ascertainment of smoking and PM_2.5 exposures could have resulted in measurement error or information bias and consequently, wrong classification. Nonetheless, we believe that the misclassification could be nondifferential as it involved both cases and controls from a community-based cohort. The nondifferential misclassification could have resulted in the underestimation of MS risk. We recommend that the findings from this study should be replicated in other populations. Moreover, studies in Taiwan should consider including adults outside the 30–70 years age group. Furthermore, to get the actual effect of cigarette smoking on MS, future studies should consider the number of cigarettes smoked and determine the levels of cotinine (a biomarker of tobacco consumption).

Summarily, PM_2.5 and smoking were independently and interactively associated with a higher risk of MS. Stratified analyses revealed that cigarette smoking might have a much higher effect on MS than PM_2.5. After integrating smoking and PM_2.5 exposure in the same model, the risk of MS was highest among current cigarette smokers exposed to the highest level of PM_2.5. Quitting smoking could reduce the incidence of MS in individuals exposed to PM_2.5. As PM_2.5 could affect nonsmokers, targeting it could also be very beneficial in reducing the risk of MS in these individuals. To curb smoking, PM_2.5, and their adverse effects, the government could enforce stronger and more sustainable policies such as funding mass media campaigns on the dangers of environmental factors. The government could also provide incentives for smoking cessation treatments.

The data analyzed in this study is subject to the following licenses/restrictions: the data that support the findings of this study are available from Taiwan Biobank but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are, however available from the corresponding author, Y-PL upon reasonable request and with permission of Taiwan Biobank. Requests to access these datasets should be directed to Y-PL, Liawyp@csmu.edu.tw.

The studies involving humans were approved by the Institutional Review Board (IRB) of the Chung Shan Medical University Hospital granted ethical approval for this study (IRB: CS1-20009). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

H-HT, DT, WL, C-YC, and Y-PL did the literature search, conceived, and designed the study. WL and Y-PL analyzed the data. H-HT, DT, and C-YC drafted the manuscript. DT edited the paper. All authors contributed to the article and approved the submitted version.