Cytokines And The Risk Of Cardiovascular Disease Among Xinjiang Kazakhs: A Cohort Study

Objective:To analyze whether cytokines are associated with increased risk of cardiovascular diseases（CVD）and the value of cytokines to predict CVD risk among the Kazak population of Xinjiang.Methods:A four-stage stratified（prefecture-county-township-village）random cluster sampling method was adopted to select six villages in Xinyuan County as the epidemiological investigation.The baseline survey was carried out from 2010 to 2012 and follow-up surveys were conducted in 2013,2016 and 2017.All participants were followed up for the incident CVD via questionnaires and outcome events were confirmed by local hospital medical records,social security information and death registration.After excluding individuals with CVD or missing data or acute inflammatory disease and those who were lost to follow-up,a total of 1508 participants were recruited into the study.Baseline characteristics were compared using theχ2 test and Wilcoxon rank sum test.Multivariable Cox regression analysis,a least absolute shrinkage and selection operator penalized regression analysis,and restricted cubic splines were applied to evaluate the association between cytokines and CVD.Stratified analysis and a term of the product of two variables in cox regression were used to examine joint effects and interactions of traditional risk factors and cytokines or different kinds of cytokines.Relative excess risk due to interaction,attributable proportion due to interaction or synergy index were applied to evaluate the additive interaction.The area under the receiver operating characteristic curve,net reclassification index（NRI）,and overall discrimination index（IDI）were used to estimate the value of cytokines for predicting CVD.Results:1.A total of 1508 subjects were included in the analysis,with the median（interquartile range）age was45.00（36.00–53.00）,among which 662（43.90%）were male.The median levels of interleukin-6（IL-6）,high-sensitive C-reactive protein（hs-CRP）,free fatty acids（FFA）,adiponectin（APN）were 32.69（interquartile range 16.33-98.07）pg/m L,325.86（interquartile range 28.02-1231.21）pg/m L,0.50（interquartile range 0.33-0.79）mmol/L,29.40（interquartile range 11.08-101.70）ng/m L respectively.2.The mean follow-up time was 5.18 years,for a total of 7818.27 person-years of follow-up.There were altogether 203 incident CVD during follow-up and the incidence rate was 25.96/per 1000 person-years.The cytokines were separately included into a Cox regression model.After adjusted by age,sex,smoking,drinking,systolic blood pressure,diastolic blood pressure,diabetes,total cholesterol,triglycerides,low-density lipoprotein cholesterol,high-density lipoprotein cholesterol and body mass index,low APN and high IL-6 were independent risk factors for CVD.The adjusted HRs of APN in Q₂,Q₃ and Q₄ compared with Q₁were 0.88（0.64,1.21）,0.71（0.51,0.98）and 0.67（0.48,0.95）,respectively(P_trend<?0.05);The adjusted HRs of IL-6 in Q₂,Q₃ and Q₄ compared with Q₁ were 1.53（0.96,2.45）,2.23（1.42,3.50）,1.78（1.13,2.81）,respectively(P_trend=0.064);The adjusted HRs of APN and IL-6 were 0.79（0.73,0.86）、1.13（1.05,1.21）,respectively.FFA and hs-CRP were not associated with the risk of CVD.The results were consistent with the single cytokine models when four cytokines were jointly included in LASSO regression.3.Restricted cubic spline analysis showed an inverse linear association between APN(P_overall<0.001,P_linear=0.078)and CVD risk and a positive non-linear association between IL-6 and CVD risk(P_overall<0.001,P_linea=0.025)after multivariate adjustment.4.Combined effects analysis showed that the coexistence of low APN and high IL-6（or smoking,diabetes,hypertension,dyslipidemia,overweight and obesity）increased the risk of CVD.The coexistence of IL-6 and smoking（or hypertension,dyslipidemia,overweight and obesity）also increased the risk of CVD（all P<0.05）.5.There was a multiplicative interaction between IL-6 and dyslipidemia,and IL-6 had no multiplicative and additive interaction with APN（or smoking,drinking,diabetes,hypertension,overweight and obesity）;APN had no multiplicative and additive interaction with smoking（or alcohol consumption,diabetes,hypertension,dyslipidemia,overweight and obesity）.6.APN can improve the prediction ability of the Framingham model for CVD risk（NRI=0.294,P<0.001;IDI=0.017,P<0.001）;IL-6 did not result in significant NRI and IDI.Conclusions:1.The cumulative incidence of CVD was 13.50%（203/1508）,and the incidence density of CVD was25.96/1000 person-years（203/7818.27 person-years）in Kazakh population,which was higher than the national incidence.2.Low APN and high IL-6 were dependent CVD risk factors.APN was associated with CVD risk in a linear manner while IL-6 was non-linear.3.The coexistence of low APN and high IL-6 increased the risk of CVD.The coexistence of traditional risk factors and low APN or high IL-6 also increased the risk of CVD.4.There was a multiplicative interaction between serum IL-6 and dyslipidemia.5.APN can improve the prediction ability of the Framingham model for CVD risk and had a good predictive value for the risk of CVD.