Cigarette smoking and PM2.5 might jointly exacerbate the risk of metabolic syndrome

Background Cigarette smoking and particulate matter (PM) with aerodynamic diameter < 2.5 μm (PM2.5) are major preventable cardiovascular mortality and morbidity promoters. Their joint role in metabolic syndrome (MS) pathogenesis is unknown. We determined the risk of MS based on PM2.5 and cigarette smoking in Taiwanese adults. Methods The study included 126,366 Taiwanese between 30 and 70 years old with no personal history of cancer. The Taiwan Biobank (TWB) contained information on MS, cigarette smoking, and covariates, while the Environmental Protection Administration (EPA), Taiwan, contained the PM2.5 information. Individuals were categorized as current, former, and nonsmokers. PM2.5 levels were categorized into quartiles: PM2.5 ≤ Q1, Q1 < PM2.5 ≤ Q2, Q2 < PM2.5 ≤ Q3, and PM2.5 > Q3, corresponding to PM2.5 ≤ 27.137, 27.137 < PM2.5 ≤ 32.589, 32.589 < PM2.5 ≤ 38.205, and PM2.5 > 38.205 μg/m3. Results The prevalence of MS was significantly different according to PM2.5 exposure (p-value = 0.0280) and cigarette smoking (p-value < 0.0001). Higher PM2.5 levels were significantly associated with a higher risk of MS: odds ratio (OR); 95% confidence interval (CI) = 1.058; 1.014–1.104, 1.185; 1.134–1.238, and 1.149; 1.101–1.200 for 27.137 < PM2.5 ≤ 32.589, 32.589 < PM2.5 ≤ 38.205, and PM2.5 > 38.205 μg/m3, respectively. The risk of MS was significantly higher among former and current smokers with OR; 95% CI = 1.062; 1.008–1.118 and 1.531; 1.450–1.616, respectively, and a dose-dependent p-value < 0.0001. The interaction between both exposures regarding MS was significant (p-value = 0.0157). Stratification by cigarette smoking revealed a significant risk of MS due to PM2.5 exposure among nonsmokers: OR (95% CI) = 1.074 (1.022–1.128), 1.226 (1.166–1.290), and 1.187 (1.129–1.247) for 27.137 < PM2.5 ≤ 32.589, 32.589 < PM2.5 ≤ 38.205, and PM2.5 > 38.205 μg/m3, respectively. According to PM2.5 quartiles, current smokers had a higher risk of MS, regardless of PM2.5 levels (OR); 95% CI = 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 PM2.5 ≤ 27.137, 27.137 < PM2.5 ≤ 32.589, 32.589 < PM2.5 ≤ 38.205, and PM2.5 > 38.205 μg/m3, respectively. After combining both exposures, the group, current smokers; PM2.5 > 38.205 μg/m3 had the highest odds (1.801; 95% CI =1.625–1.995). Conclusion PM2.5 and cigarette smoking were independently and jointly associated with a higher risk of MS. Stratified analyses revealed that cigarette smoking might have a much higher effect on MS than PM2.5. Nonetheless, exposure to both PM2.5 and cigarette smoking could compound the risk of MS.

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.

Study participants and data acquisition
We acquired information relating to MS, cigarette smoking, sex, age, weight, height, alcohol drinking, exercise, marital status, educational level, secondhand smoke exposure, and duration of residence from the TWB (2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019)(2020).The TWB database is one of the human biological databases currently supplying data for biomedical research in Taiwan (61).The TWB project is a communitybased prospective study whose participants are exclusively Taiwanese adults with no personal history of cancer (62,63).At the start of the project, only Taiwanese aged 30-70 were eligible for enrolment (63).Currently, individuals between 20 and 70 years old without a diagnosis of cancer can enroll in the project (62).The TWB biobank currently contains over 30 recruitment sites all over Taiwan (62).All volunteers sign informed consent forms before enrolment.At enrolment, each volunteer fills out the TWB questionnaire, undergoes anthropometric examinations, and provides blood/urine samples for biochemical testing.The questionnaire contains information on cigarette smoking, sex, age, alcohol drinking, exercise, etc.The anthropometry examination determines weight, height, waist circumference, and blood pressure.The biochemical tests determine fasting blood glucose (FBG), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C), among others.
Currently, the TWB database lacks PM 2.5 data.Notwithstanding, the Taiwan Environmental Protection Administration (EPA) contains about 71 automated stations that record daily average PM 2.5 concentrations.We used the EPA daily average data from 2000 to 2016 and computed the annual average PM 2.5 concentrations (μg/m 3 ).The spatial-temporal variability of PM 2.5 in 349 areas in Taiwan was assessed using machine learning-coupled land-use regression (LUR) as previously described (64).The PM 2.5 data for each area was considered the exposure data for the participants' current residing there.The initial study sample was 131,498.However, we excluded 5,132 individuals with missing information for at least one variable.The final analysis included 126,366 people with complete data.The Institutional Review Board (IRB) of the Chung Shan Medical University Hospital granted ethical approval for this study (IRB: CS1-20009).

Definition of variables
MS was defined as the presence of at least three of the following metabolic markers: (1) waist circumference ≥ 90 cm in men or ≥ 80 cm in women; (2) systolic blood pressure (SBP) ≥ 130 mmHg or diastolic blood pressure (DBP) ≥ 85 mmHg; (3) FBG ≥ 100 mg/dL; (4) HDL-C < 40 mg/dL for men and < 50 mg/dL for women; (5) triglyceride (TG) ≥ 150 mg/dL.This definition was based on the guidelines of the Health Promotion Administration, Ministry of Health and Welfare, Taiwan.Mean annual PM 2.5 concentrations between 2000 and 2016 were grouped into quartiles: PM 2.5 ≤ Q1 (PM 2.5 ≤ 27.137 μg/m 3 ), Q1 < PM 2.5 ≤ Q2 (27.137 < PM 2.5 ≤ 32.589 μg/ m 3 ), Q2 < PM 2.5 ≤ Q3 (32.589 < PM 2.5 ≤ 38.205 μg/m 3 ), and PM 2.5 > Q3 (PM 2.5 > 38.205 μg/m 3 ).Smoking habits were self-reported, and individuals were categorized as current, former, or nonsmokers.Current smokers included those who smoked cigarettes for at least six months and were still smoking during the data collection period.Former smokers were those who smoked cigarettes for at least six months in the past but had quit the habit for over six months.Nonsmokers were those with no personal history of cigarette smoking.
The body mass index (BMI) was computed as weight/height squared (kg/m 2 ).The cutoff values for BMI categories were BMI < 18.5, 18.5 ≤ BMI < 24, 24 ≤ BMI < 27, and BMI ≥ 27 kg/m 2 , corresponding to normal weight, underweight, overweight, and obesity.Current drinkers were individuals who confirmed having a regular habit of consuming at least 150 mL of alcohol per week continuously for half a year or more.Former drinkers included those who drank 150 mL of alcohol per week continuously for at least half a year in the past but had quit the habit for over six months.Nondrinkers included those who drank <150 mL of alcohol per week.Physically active individuals included those who had a habit of regularly engaging in physical activities (lasting over half an hour) at least three times weekly.Exposure to secondhand smoke referred to habitual exposure to secondhand smoke for 5 min or more in an hour.For marital status, participants were regarded as being married (still married), single, divorced/separated (not yet married/divorced or separated from their spouses), or widowed (lost a partner).Educational level categories included, elementary and below, junior and senior high school, or university and above.The quartiles for the duration of residence were < 7. 58, 7.58-17.58, 17.58-29.58,and ≥ 29.58 years.

Statistical analyses
The differences in age (a continuous variable) between participants with and without MS were determined with the Student t-test.The differences in the percentage distribution of categorical variables (e.g., sex, cigarette smoking) between those with and without MS were determined using the Chi-square test.Age was presented in mean ± standard error (SE) while the categorical variables were presented as n (%).The risk of MS based on PM 2.5 , cigarette smoking, and the interaction between both exposures was determined by multivariate logistic regression.In the logistic regression model assessing the interaction between cigarette smoking and PM 2.5 on MS, the p-value was obtained by putting the interaction term (cigarette smoking*PM 2.5 ) as the main exposure (independent variable) and MS as the outcome variable.In all the regression analyses, adjustments were made for sex, age, weight, height, alcohol drinking, exercise, marital status, educational level, secondhand smoke exposure, and duration of residence.A p-value < 0.05 was set as the threshold for statistical significance.Data were managed and analyzed using SAS 9.4 (SAS Institute Inc., Cary, NC).
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 = 1.022-1.5 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/m 3 ), 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/m 3 had the highest risk of MS (OR = 1.801, 95% CI = 1.625-1.995).

Discussion
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)(16)(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 crosssectional 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 longterm 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)(55)(56)(68)(69)(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)(74)(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)(80)(81)(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).

Conclusion
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.
OR, odds ratio; CI, confidence interval; ref., reference; BMI, body mass index; NA, not applicable (the trend is nonlinear).

TABLE 3
Association between PM 2.5 and metabolic syndrome in current, former, nonsmokers.
OR, odds ratio; CI, confidence interval; ref., reference; BMI, body mass index; NA, not applicable (the trend is nonlinear).

TABLE 4
Association between cigarette smoking and metabolic syndrome stratified by PM 2.5 quartiles.

TABLE 5
Risk of metabolic syndrome based on a combination of cigarette smoking and PM 2.5 exposure.