| Rheumatoid arthritis(RA)is a chronic autoimmune disease characterized by persistent synovitis.At present,it is mainly believed that abnormal immune system function and persistent inflammatory reaction erosive arthritis lead to the incidence of RA.Environmental and genetic factors lead to immune disorder and inflammation,which have been widely studied.However,most of the previous studies focused on the association between genetic factors and RA,while the studies on the influence of environmental factors on RA were relatively lacking.There have been a large number of studies on the effects of heavy metals and nutrients on immune function and inflammation.On the one hand,lead,cadmium,mercury and arsenic in heavy metals are known risk factors for immune function.For example,lead and mercury have adverse effects on the metabolism of cytokines in the immune system and can cause inflammation;Previous study reported that lead and mercury have adverse effects on cytokine metabolism of the immune system and can cause inflammation;Cadmium interfered with the activity of antioxidant proteins and promotes inflammation.Nutrient elements related to malnutrition,such as manganese,selenium,copper,iron,iodine,cobalt and so on,are closely related to human immune function and inflammation.For example,oxidative stress is known to be closely related to the inflammatory response of RA,and manganese and copper are involved in the regulation of oxidative stress as important auxiliary groups of Superoxide dismutase(SOD).On the other hand,there are many complex associations between heavy metals and nutrient elements.For example,a number of animal experiments have shown that selenium can antagonize many heavy11 metals such as lead and mercury.Copper has been reported to interact with cadmium in vitro.Although some studies have conducted preliminary discussions on the association between heavy metals and nutrient elements and RA,there are defects such as a relatively single included exposure element and incomplete correction for confocal elements,and no research literature on the association between mixed exposure of multiple elements and RA disease has been retrieved.Therefore,this study aims to analyze the association between a variety of heavy metals and nutrient elements and RA through a large sample cross-sectional study,and further explore the influence of mixed exposure of multiple elements on RA based on the actual situation of coexistence of multiple exposure elements in human body.This study includes the following two parts:Section 1: The Association of Some Heavy Metals and Nutrients withRheumatoid ArthritisObjective: This section aimed to analyze the association of 4 heavy metals(lead,cadmium,mercury,arsenic)and 6 nutrient elements(manganese,selenium,copper,iron,iodine,cobalt)with the risk of RA,so as to obtain the basic characteristics of multiple elements in RA patients.Methods: A cross-sectional study was conducted based on the survey data from2001 to 2016 in NHANES,and subjects who were over 20 years of age with complete baseline and RA information were included.T-test and ANOVA were used to describe the basic characteristics of the included population,and Mann-Whitney U rank sum test was used to compare the distribution of heavy metals and nutrients between RA patients and controls.Binomial logistic regression model was used to analyze the risk of rheumatoid arthritis under different levels of exposure elements,and further stratified analysis was conducted according to gender,age and BMI to observe whether the association between exposure elements and rheumatoid arthritis was stable under different demographic characteristics.Results: A total of 35,788 subjects were included,including 2597 patients with RA and 28,061 healthy controls.The median(interquartile range)of blood lead concentration was 1.60(1.10-2.40)μg/L for RA patients,which was higher than1.25(0.79-2.00)μg/L for the control group,and was statistically significant(P<0.001).The total blood mercury level of the RA group was 0.93(0.50-1.84)μg/L,which was higher than that of the control group 0.86(0.46-1.68)μg/L,and the difference was statistically significant(P=0.009).The serum cadmium level was low overall,but the serum cadmium concentration of RA patients was 0.40(0.24-0.60)μg/L higher than that of control group 0.31(0.20-0.53)μg/L significantly.The urinary iodine concentration of RA patients was 170.00(95.00-176.20)ng/ml,which was higher than that of the control group 140.30(80.00-241.00)ng/ml,and was statistically significant(P<0.001).Similarly,serum copper concentration was 113.40(103.30-133.60)μg/d L in patients and significantly higher than 111.50(95.70-130.00)μg/d L in controls.Serum manganese concentrations of 8.71(6.75-11.10)μg/L and serum selenium concentrations of 193.19(176.47-206.48)μg/L in RA patients were significantly lower than those in control group 9.07(7.41-11.17)μg/L and 194.54(179.84-209.11)μg/L.In the regression analysis,the OR(95% CIs)of RA risk in the third and highest blood lead quartile group was 1.38(1.08-1.75)and 1.37(1.06-1.77),after adjusting for confounding factors,with a significant linear trend,taking the people in the lowest quartile of blood lead level as 1.00 erence.The risk of developing lead in the third and highest quartile women was 1.41(1.03-1.95)and 1.36(1.01-1.84),compared with the lowest quartile women after sex stratification,while the association was at a statistically significant margin in men.The association between blood total Mercury(THg)and RA in the subsample population was at a significant margin.The risk of group that blood THg in the highest quartile was 1.22(0.99-1.49)compared with that in the first quartile group,after adjusting for several confoundings,but the trend test was significant.The risk of RA was 1.40(1.01-1.93)in men with THg highest quartile compared with lower quartile.The subjects were grouped by urinary iodine quartile level,the risk in second,third,and highest quartile populations were 1.41(1.07-1.85),1.67(1.25-2.23),and 1.72(1.27-2.34),compared with the people in the lowest quartile of urinary iodine.After gender stratification,such a significant association only existed in female population.Only part of other nutrients was significantly associated with RA after sex stratification.The risk of RA was 1.36(1.01-1.84)for women in serum manganese highest quartile compared with the lowest quartile.The risk of RA was 1.40(1.01-1.93)in men with serum copper levels in the highest quartile compared with the lowest quartile.Similarly,the risk was 2.61(1.41-4.80)for men in the highest quartile compared with the lowest quartile for urinary cobalt levels.Conclusions: The results of this study indicate that the levels of urinary iodine,blood lead,blood total mercury,urine cobalt,serum copper and serum manganese all had positive effects on the risk of rheumatoid arthritis,and there are gender differences.Section 2: The Joint Effect of Six Elements for Rheumatoid ArthritisObjective: This section aimed to examine the joint effect of mixture,which included lead,mercury,manganese,copper,iodine and cobalt,for rheumatoid arthritis.Methods: Six elements were selected based on the Binary Logistic Regression results obtained in the first part.In the second part,subjects who didn’t have complete exposure information of six elements were excluded based on the original included population,and Spearman correlation analysis was used to explore the relationship between various elements.The Weighted Quantile Sum(WQS)regression model of multiple exposure elements and the risk of rheumatoid disease was established,and regression analysis was performed between WQS and RA to observe the correlation between joint exposure load and RA.We also analyzed by age,sex and BMI subgroup to explore whether these demographic variables affected the association between the WQS representing the joint exposure load and RA.Results: A total of 2109 subjects were included in the mixed-effect analysis,including 122 RA patients and 1987 healthy controls.The subjects with complete exposure information of six elements were screened out from the people included in the first part.The WQS model was established to analyze the mixed effects of multi-element exposure on RA,and the results showed that iodine exposure had the highest contribution of 44.48%,followed by lead(16.84%),mercury(16.32%)and cobalt(14.67%),while copper and manganese had the lower contribution.Logistic regression analysis was performed on the WQS of joint exposure of the six elements and RA,and it was found that the risk of RA increased by 67% with each increase of WQS unit.The results of subgroup analysis showed that age and BMI all affected the association between joint exposure and RA.Conclusion: In this study,the risk of RA would increase with the increase of the exposure level of the mixture of 6 elements which included lead,mercury,manganese,copper,iodine and cobalt.We also find that iodine,lead and mercury contributed a great deal to this mixed effect,and age and BMI may affect the association between this joint effect and RA. |
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