NLRP3水平与冠心病风险关联的孟德尔随机化研究  

Associations between NLRP3 Levels and Coronary Artery Disease Risk:Mendelian Randomized Study

作　　者：杨珺玥 范思宇 谭颖超 智宏[2] 王莉娜[1] YANG Jun-yue;FAN Si-yu;TAN Ying-chao;ZHI Hong;WANG Li-na(School of Public Health,Southeast University,Nanjing 210009,China;ZhongDa Hospital,Southeast University,Nanjing 210009,China)

机构地区：[1]东南大学公共卫生学院,江苏南京210009 [2]东南大学附属中大医院,江苏南京210009

出　　处：《中山大学学报（医学科学版）》2022年第1期133-139,共7页Journal of Sun Yat-Sen University:Medical Sciences

基　　金：国家自然科学基金(81673259);江苏省自然科学基金(BK20161435)。

摘　　要：【目的】采用孟德尔随机化法(MR)推断炎症小体NLRP3水平与冠心病发生风险之间的关联。【方法】依托东南大学中大医院心血管内科,对经冠状动脉造影确诊的321个冠心病病例和293个正常对照的人群,进行流行病学调查与血样标本采集。采用ELISA方法测定血清NLRP3水平;采用RFLP-PCR的基因分型方法,检测研究对象的NLRP3基因rs10754558(C/G)的多态性;以NLRP3基因rs10754558(C/G)作为工具变量,结合血清学相关表型NLRP3水平,采用线性回归分析和Logistic回归分析的方法分别构建基因型-表型、基因型-疾病结局之间的关联,进而使用MR方法推断相关细胞因子(表型)与CAD发生之间的因果关联。【结果】NLRP3基因变异rs10754558(C/G)与冠心病风险间以及NLRP3水平之间的关联均具有统计学意义,回归系数β_(ZY)=0.45,β_(ZX)=2.34,进而通过孟德尔随机化法推断出的NLRP3水平与冠心病风险的关联回归系数β_(XY)=β_(ZY)/β_(ZX)=0.45/2.34=0.19,表明NLRP3水平每增加1 ng/mL水平,冠心病的风险增加20.9%(OR=e^(0.19)=1.209)。通过传统病例对照研究设计直接获得的NLRP3水平与冠心病风险的关联回归系数β_(XY)=0.03,表明NLRP3每升高1 ng/mL,个体发生CAD的风险增加了3.1%(OR=e^(0.03)=1.031,95%CI=1.003-1.058),相比MR方法推断的关联强度较小。【结论】通过孟德尔随机化法验证了炎症小体NLRP3水平与冠心病风险之间的关联,比传统关联研究更接近真实因果关联。【Objective】Using the Mendelian randomization(MR)study design to infer the causal relationship between NLRP3 levels and the risk of CAD.【Methods】Totally 321 CAD cases confirmed by coronary angiography(CAG)and 293 normal controls were included in this MR study.Serum NLRP3 levels of all the subjects were determined by ELISA.The polymorphism of NLRP3 gene rs10754558(C/G)was detected by RFLP-PCR and it was considered as the instrumental variable(Ⅳ)to evaluate the causal relationship between NLRP3 levels and CAD risks.Logistic regression analysis and Linear regression analysis were used to test the association between genotype-phenotype,genotype-disease outcome,and then MR method was used to infer the causal relationship between NLRP3 and CAD risks.【Results】The association between the NLRP3 gene rs10754558(C/G)variant and the risk of CAD and the level of NLRP3 were statistically significant.The regression coefficientsβ_(ZY)=0.45 andβ_(ZX)=2.34 respectively.The regression coefficientβ_(XY)=β_(ZY)/β_(ZX)=0.45/2.34=0.19,and then it was transformed into OR value(OR=e^(0.19)=1.209),which meant subjects with the 1 ng/mL increased of NLRP3 level had the 20.9%increased risk of CAD.And also,the traditional case-control study of the NLRP3 levels and CAD risks showed that the subjects with the 1 ng/mL increased of NLRP3 levels were associated with 3.1%increased CAD risk(β_(XY)=0.03,OR=e^(0.03)=1.031,95%CI=1.003-1.058),which was a little bit lower than that of MR result.【Conclusions】The inflammasome NLRP3 levels were associated with the increased risk of CAD in a mendelian randomization study and it might be a robust evidence than that of the traditional association study.

关 键 词：NLRP3基因 冠心病 孟德尔随机化 单核苷酸多态性 

分 类 号：R54[医药卫生—心血管疾病]