Study On The Relationship Between Tobacco Smoke Exposure And Serum NLRP3 And Metabolic Syndrome

Objective:To evaluated the relationship between tobacco smoke exposure,serum nod-like receptor protein 3(NLRP3)concentration,and metabolic syndrome(MS).To explore the role of NLRP3 in smoking-induced MS.And further explore the biological interaction between tobacco smoke exposure and serum NLRP3.Explore the pathogenesis of smoking and MS,and to provide theoretical basis for the prevention,treatment and early detection of MS.Methods:The basic health information of the workers was collected in the way of examination,and the health examination information was provided by the medical personnel of the cooperative hospital.Collected the morning urine and blood samples,and eventually enrolled 637 participants.The levels of three tobacco metabolites(Nicotine,Cotinine,Trans-3’-hydroxycotinine)were detected by high performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS).The concentration of NLRP3 in human serum was determined by Enzyme Linked Immunosorbent Assay(ELISA).The International Diabetes Union(IDF,2005)was used to identify the patients with MS in participants.The relationship between the exposure level of tobacco smoke and NLRP3 concentration and the MS was studied by using the regression model with classification variables,including smoking status,daily smoking quantity,smoking index and passive smoking frequency.The correlation analysis of three tobacco metabolites was carried out by using Spearman rank correlation.Tobacco metabolites were used to study the relationship between tobacco metabolites in workers’ urine and whether they suffered from MS by logistic regression model in the form of continuous variable and classified variable.Tobacco metabolites were introduced into generalized linear model to investigate the relationship between tobacco metabolites and serum NLRP3 in urine of workers in the form of continuous variable and classified variable.The serum NLRP3 was introduced into logistic regression model to investigate the relationship between the concentration of NLRP3 and MS in workers in the form of continuous variable,quartile group and tertiles group.The linear trend test was carried out and the dose response relationship was fitted by the restricted cubic spline function.The role of NLRP3 in the relationship between tobacco metabolites and whether or not there is MS was evaluated by using the analysis of mediating effect.The interaction between tobacco smoke exposure and serum NLRP3 was studied by additive interaction model.Results:1.There were more smokers in MS workers,more smokers more than 15 cigarettes per day,and more smokers smoking index more than 280 cigarettes per year than non-MS workers.The urinary nicotine,cotinine,trans-3’-hydroxycotinine concentration and the median serum NLRP3 concentration in MS workers were higher than those in non-MS workers.2.Compared with non-smokers,the serum NLRP3 of smokers increased by 0.205 ng/ml(95% CI: 0.016,0.394),and the risk of MS increased by 2.14 times(95% CI: 1.32,3.46).Compared with non-smokers,the serum NLRP3 of workers with more than 15 cigarettes per day increased by 0.432 ng/ml(95%CI:0.210,0.655),and the risk of MS increased by 2.12times(95%CI: 1.24,3.62).Compared with the non-smokers,the serum NLRP3 of workers with smoking index > 280 years increased by 0.236 ng/ml(95% CI: 0.002,0.470),and the risk of metabolic syndrome increased by 2.04 times(95% CI: 1.15,3.62).For the frequency of passive smoking,no effect on the increase of serum NLRP3 and the increased risk of MS was found.3.There was a strong correlation between urinary nicotine,cotinine and trans-3’-hydroxycotinine.4.The increased of the three tobacco metabolites concentration in workers’ urine was related to the MS and there was a dose response relationship(P＿trend<0.05).The serum NLRP3 of workers with urine nicotine ≥ 100 ng/mL increased by 0.284 ng/ml(P = 0.002)compared with workers with urine nicotine < 100 ng/ml,and the risk of MS increased by2.20 times(95% CI: 1.40,3.45)concurrently.The serum NLRP3 of workers with urine cotinine ≥ 100 ng/mL increased by 0.190 ng/ml(P = 0.036)compared with workers with urine cotinine < 100 ng/ml,and the risk of MS increased by 2.18 times(95% CI: 1.39,3.41)concurrently.The serum NLRP3 of workers with urine trans 3’-hydroxycotinine ≥ 100 ng/ml increased by 0.199 ng/ml(P = 0.028)than workers with urine trans 3’-hydroxycotinine <100 ng/ml,and the risk of MS increased by 2.34 times(95% CI: 1.49,3.67)concurrently.5.The increased of serum NLRP3 in workers was related to the risk of MS and there was a dose response relationship(P＿trend=0.020,P for nonlinear = 0.398).Each a ln-unit increase of serum NLRP3 was related to 1.74 times(95% CI: 1.04,2.90)increase of risk for MS.Each one interquartile range increase of serum NLRP3 was related to 1.25 times(95%CI:1.02,1.53)increase of risk for MS.Compared with the serum NLRP3 concentration T1 group,the risk for MS in the serum NLRP3 T3 group increased by 1.78 times(95%CI: 1.04,3.04).6.The mediated effect of NLRP3 concentration between smoking and MS was 11.1%(3.0%,33.2%)(P = 0.039).The mediated effect of serum NLRP3 concentration on nicotine and MS was 15.1%(4.3%,41.7%)(P = 0.024),and the mediated effect of serum NLRP3 concentration on trans 3’-hydroxycotinine and MS was 16.3%(3.3%,52.5%)(P = 0.041).7.The risk of smoking combined with high serum NLRP3 exposure was greater than that of individual effects and their sum,and there was additive interaction(RERI = 2.613,AP = 0.483,S = 2.454).The risk of MS in the smoking-high serum NLRP3 group was 3.39 times higher than that in the non-smokers-low serum NLRP3 group(OR = 5.41,95% CI:2.50,11.73).Among all patients with MS,76.9% of the MS was caused by the interaction between smoking and high serum NLRP3(AP = 0.483,95%CI: 0.082,0.884).The combined effect of high urinary tobacco metabolites and high serum NLRP3 concentration on the risk of MS was greater than the individual effect and its sum,and there was an additive interaction.8.Further analysis found that smoking and serum NLRP3 were mainly related to high triglycerides.The association remained significant after adjusting for other MS related measures.Conclusion:1.Both nicotine,cotinine and trans-3’-hydroxycotinine in urine was a good biomarker for tobacco smoke exposure.2.Both smoking and increased serum NLRP3 could increase the risk of MS,and a small part of MS caused by exposure to tobacco smoke was due to the inflammatory response induced by NLRP3.3.The combined exposure of smoking and high serum NLRP3 had a biological interaction effect on MS,and elevated NLRP3 may increase the risk of MS in people with high exposure to tobacco smoke.