【作者】 张莹；

【导师】 何美安；

【作者基本信息】 华中科技大学 ， 劳动卫生与环境卫生学， 2022， 硕士

【摘要】 目的:全氟烷基化合物（Perfluoroalkyl Substances,PFAS）是一种内分泌干扰物,在工作及生活环境中普遍存在,被人体吸收后可干扰机体血糖和脂质代谢,造成健康危害。目前PFAS与心血管疾病（Cardiovascular Disease,CVD）发生风险的关联受到广泛关注。一般人群中的横断面流行病学研究发现PFAS水平与CVD发生风险呈正相关。CVD是糖尿病主要的并发症,也是导致糖尿病患者死亡的主要原因,然而目前关于PFAS与2型糖尿病患者发生心血管疾病并发症的前瞻性关联研究十分匮乏。在PFAS中,全氟辛酸（Perfluorooctanoic Acid,PFOA）和全氟辛烷磺酸（Perfluorooctane Sulfonate,PFOS）是含量最高,且近期研究最多的两种全氟烷基化合物。因此,本研究以血清PFOA和PFOS的水平作为PFAS内暴露标志物,前瞻性地探索PFAS与2型糖尿病心血管疾病并发症发生风险的关联。方法:本研究采用巢式病例对照研究设计。研究对象基于东风-同济队列基线的糖尿病人群,共纳入989例新发CVD（749例冠心病患者和240例脑卒中患者）,并按照性别和年龄进行1:1匹配纳入989例未发生CVD的对照。利用超高效液相色谱串联质谱仪,测定研究对象基线血清的PFOA和PFOS浓度。对呈偏态分布的血清PFOA和PFOS浓度进行自然对数转换,再纳入模型分析。采用条件Logistic回归模型分析2型糖尿病患者血清PFOA和PFOS水平与CVD并发症发生风险的关联,非条件Logistic回归模型分析多种传统糖尿病和CVD危险因素与血清PFAS水平在2型糖尿病CVD并发症发生中的交互作用。结果:本研究共纳入1978例受试者（989对）,平均年龄66.27岁,其中男性占50.8%。血清PFOA与PFOS的检出率均为99.9%,其中糖尿病新发CVD组人群和对照组人群的血清PFOA浓度中位数分别为1.06 ng/m L和1.19 ng/m L、血清PFOS浓度中位数分别为12.63 ng/m L和13.54 ng/m L。对两组人群基线流行病学信息和生化指标进行比较发现:新发CVD组BMI（25.47 kg/m²）、空腹血糖水平（8.56 mmol/L）、总胆固醇（5.37 mmol/L）、甘油三酯（1.78 mmol/L）、低密度脂蛋白胆固醇（3.20mmol/L）、收缩压（138.59 mm Hg）、舒张压（78.45 mm Hg）、糖尿病病程（4年）均显著高于对照组的BMI（24.98 kg/m²）、空腹血糖水平（8.25 mmol/L）、总胆固醇（5.27mmol/L）、甘油三酯（1.62 mmol/L）、低密度脂蛋白胆固醇（3.11 mmol/L）、收缩压（133.51 mm Hg）、舒张压（76.75 mm Hg）、糖尿病病程（2.22年）,而新发CVD组的基线e GFR水平（74.86 m L/min/1.73m²）比对照组人群基线e GFR水平（76.69m L/min/1.73m²）低。此外,新发CVD组高血压患病率（75.4%）、高脂血症患病率（63.6%）、降糖药物及胰岛素使用率（51.7%）对比对照组人群高血压患病率（64.4%）、高脂血症患病率（58.1%）、降糖药物及胰岛素使用率（43.6%）相对较高。对传统糖尿病、CVD的危险因素进行校正后,血清PFOA水平与糖尿病CVD并发症发生风险呈负相关,最高分位的比值比（Odds Ratio,OR）和95%置信区间（Confidence Interval,CI）为0.66(95%CI::0.52～0.85,P_trend=0.002)。经自然对数转换后的血清PFOA值每增加一个标准差,糖尿病人新发CVD的风险降低15%（OR=0.85,95%CI:0.76～0.95）。对基线空腹血糖水平分层,结果显示在基线空腹血糖水平≥7.00 mmol/L的分组中血清PFOA水平与糖尿病新发CVD风险呈负相关,具有临界交互作用(P_交互=0.048),血清PFOA最高分位OR值为0.61(95%CI:0.45～0.82,P_trend=0.001),经自然对数转换后的血清PFOA值每增加一个标准差,糖尿病患者新发心血管疾病并发症的风险降低20%（OR=0.80,95%CI:0.70～0.91）。血清PFOS水平与糖尿病CVD并发症发生风险无显著关联,最高三分位的OR（95%CI）为0.81（0.60～1.08）。结论:血清PFOA水平与2型糖尿病CVD并发症的发生风险呈负相关,未发现血清PFOS与糖尿病人发生心血管疾病风险有关。本研究结果需要更多研究来证实并阐明其潜在的生物学机制。更多还原

【Abstract】 Objective:Perfluoroalkyl Substances（PFAS）are endocrine disruptors which are widely used in working and living environments.After being absorbed by human body,they can interfere glucose and lipid metabolism,thus causing harm to human health.At present,the association between PFAS and the risk of Cardiovascular Disease（CVD）has attracted extensive attention.Some cross-sectional epidemiological studies have shown that PFAS is positively related with incident CVD.CVD is a major complication and cause of death among patients with diabetes,but there are few prospective studies on the association between PFAS and cardiovascular disease complications among patients with type 2diabetes.Perfluorooctanoic Acid（PFOA）and Perfluorooctane Sulfonate（PFOS）are the two fluorides that have been studied most recently.Therefore,in this study,serum PFOA and PFOS levels were used as internal exposure markers to explore the relationship between serum PFAS levels and incident cardiovascular complications among patients with type 2diabetes.Methods:A nested case-control study design was used in this study.Based on Dongfeng-Tongji cohort,a total of 989 patients with CVD（749 patients with coronary heart disease and 240 patients with stroke）and 989 controls free of CVD and tumor were 1:1matched on sex and age（within 2 years）.Incident cardiovascular disease among the diabetic population,including coronary heart disease and stroke,was defined as the outcome.The concentrations of serum PFOA and PFOS at baseline were determined by High Performance Liquid Chromatography Coupled with Mass Spectrometry.The baseline serum PFOA and PFOS levels with skewness distribution were logarithmically transformed and then included into the model for analysis.Conditional Logistic regression model was used to analyze the relationship between serum PFOA and PFOS levels and incident CVD among patients with type 2 diabetes mellitus,and unconditional Logistic regression model was used to analyze the interaction between various diabetes or CVD traditional risk factors and serum PFOA or PFOS levels in the occurrence of CVD complications among patients with type 2 diabetes mellitus.Results:A total of 1978 subjects（989 pairs）were included in this study,with an average age of 66.27 years,of which 50.8%were males.The detection rates of serum PFOA and PFOS were both 99.9%.And the median serum PFOA concentrations were 1.06 ng/m L and 1.19 ng/m L,while the median serum PFOS concentrations were 12.63 ng/m L and 13.54ng/m L,in the diabetic group and the control group respectively.Compare epidemiological information and biochemical indexes of baseline population:in group with CVD complications,BMI（25.47 kg/m²）,FPG（8.56 mmol/L）,total cholesterol（5.37 mmol/L）,triglyceride（1.78 mmol/L）,LDLC（3.20 mmol/L）,SBP（138.59 mm Hg）,DBP（78.45mm Hg）,diabetes duration（4 years）were significantly higher than those in control group,BMI（24.98 kg/m²）,FPG（8.25 mmol/L）,total cholesterol（5.27 mmol/L）,triglyceride（1.62mmol/L）,LDLC（3.11 mmol/L）,SBP（133.51 mm Hg）,DBP（76.75 mm Hg）,diabetes duration（2.22 years）.Meanwhile,e GFR levels at baseline were lower in the group with CVD complications（74.86 m L/min/1.73m²）than in the control group（76.69m L/min/1.73m²）.In addition,the prevalence of hypertension（75.4%）,hyperlipidemia（63.6%）,and the usage rate of hypoglycemic drugs and insulin（51.7%）in group with new CVD complications was higher than that in control group hypertension（64.4%）,hyperlipidemia（58.1%）,and the usage rate of hypoglycemic drugs and insulin（43.6%）.After adjusting for diabetes and cardiovascular traditional disease risk factors,serum PFOA levels were negatively correlated with the incident CVD complications among paticents with type 2 diabetes,with the highest tertile of Odds Ratios（ORs）value was 0.66(95%CI:0.52～0.85,P_trend=0.002)compared with the first tertile.For each 1 SD increase in serum Ln-PFOA,the risk of CVD complications was reduced by 15%,ORs value was 0.85（95%CI:0.76～0.95）.In the stratified analysis of baseline fasting glucose levels,the negative association between serum PFOA levels and diabetic cardiovascular disease was only found in the group with higher baseline glucose levels(P_interaction=0.048).In the group with baseline fasting glucose levels≥7.00 mmol/L,The third tertile of OR value was 0.61(95%CI:0.45～0.82,P_trend=0.001),and the risk of cardiovascular disease complications decreased by 20%for each one standard deviation increase in serum Ln-PFOA,ORs value was 0.80（95%CI:0.70～0.91）.However,there was no significant correlation between t serum PFOS levels and the incident diabetic CVD complications,with the highest tertile of ORs was 0.81（95%CI:0.60～1.08）.The stratified analysis results of different population groups maintained no significant correlation.Conclusions:Serum PFOA levels are inversely associated with the incident cardiovascular complications among paticents with type 2 diabetes mellitus.But further research is needed to confirm this relationship and clarify the underlying mechanisms.更多还原