基质金属蛋白酶2基因遗传变异与儿童青少年血压的关联分析

Association analysis between genetic variants of matrix metalloproteinase enzyme 2 gene and the blood pressure of children and adolescents

目的探讨基质金属蛋白酶2(MMP2)基因遗传变异与儿童青少年血压的关系。方法于2016年在广州市城区开展横断面调查,对4155名儿童青少年进行体格检查(包括身高、体重、血压等)、问卷调查(包括一般情况、运动情况、父母文化程度、家庭收入等),并进行遗传变异检测。采用多重线性回归模型分析MMP2基因遗传变异(rs243865和rs7201)、遗传风险评分(GRS)等级与收缩压和舒张压标化值的关联。通过逐步法分析标化体重指数(BMI)对于GRS等级与标化血压的中介效应,并采用回归模型的相乘项评价运动与GRS等级对血压的相加交互作用。结果研究共纳入4155名中小学生,男性2132名(51.3%)。小学二年级、初一和高一学生分别为1401名(33.7%)、1422名(34.2%)和1332名(32.1%),年龄分别为(8.2±0.3)、(13.1±0.4)和(16.2±0.5)岁。调整年龄、性别、父母文化程度和家庭收入后,与rs243865 TT基因型携带者比较,CC/CT基因型携带者舒张压高0.461个标准差(显性模型β=0.461,95%CI 0.199~0.723)。与rs7201 CC基因型携带者比较,AA/AC基因型携带者收缩压和舒张压分别高0.147个标准差(隐性模型β=0.147,95%CI 0.014~0.279)和0.171个标准差(隐性模型β=0.171,95%CI 0.039~0.304)。每增加1个GRS等级,收缩压升高0.151个标准差(β=0.151,95%CI 0.029~0.272),舒张压升高0.242个标准差(β=0.242,95%CI 0.120~0.363)。BMI的中介效应分别占GRS对收缩压和舒张压总效应的28.3%和12.6%。控制BMI后,GRS对舒张压的直接效应仍有统计学意义(P<0.001)。中高强度运动不足(<0.5 h/d)与GRS对收缩压存在正相加交互作用(交互项β=0.518,95%CI 0.088~0.949,P=0.018)。结论MMP2基因rs243865和rs7201遗传变异与儿童青少年血压升高存在关联,肥胖在其中可能具有中介作用,运动不足和MMP2基因遗传变异对儿童青少年收缩压具有正相加交互作用。

Objective To explore the association between genetic variants of matrix metalloproteinase enzyme 2(MMP2)gene and the blood pressure of children and adolescents.Methods This cross-sectional study was performed in 2016 and included 4155 children and adolescents in the urban area of Guangzhou.Physical examinations(including body height,weight,and blood pressure),questionnaires(including general characteristics,physical exercise,parental educational level,household income,etc.),and blood sampling were performed.Multivariable linear regression models were used to investigate the associations of MMP2 genetic variations(rs243865,rs7201)and the genetic risk score(GRS)level with standardized blood pressure.Mediating effect of standardized body mass index(BMI)was further assessed by process analysis in the association between GRS level and blood pressure,and potential additive interaction between physical activity and GRS level was analyzed using the product term in the regression model.Results A total of 4155 primary and secondary schoolchildren were finally included in the analysis,consisting of 1401(33.7%)second grade pupils of primary school,1422(34.2%)first grade pupils of middle school,and 1332(32.1%)first-grade students of senior high school.After adjusting for age,sex,parental educational level,and family income,as compared to the rs243865 TT genotype,the CC/CT genotype increased diastolic blood pressure(DBP)by 0.461 standard deviations(SD)(βfor dominant model=0.461,95%CI 0.199-0.723).When compared to the rs7201 CC genotype,the AA/AC genotype showed 0.147 SD higher systolic blood pressure(SBP)(βfor recessive model=0.147,95%CI 0.014-0.279)and 0.171 SD increased DBP(βfor recessive model=0.171,95%CI 0.039-0.304).For each increment of GRS level,SBP and DBP increased by 0.151 SD(βfor dominant model=0.151,95%CI 0.029-0.272)and 0.242 SD(β=0.242,95%CI 0.120-0.363),respectively.The mediating effect of BMI accounted for 28.3%and 12.6%of the total effect of GRS on SBP and DBP,respectively.After controlling BMI,the direct effect of GRS on DBP remained statistically significant(P<0.001).The insufficient moderate-to-vigorous physical activity(<0.5 h/d)showed a significant interaction with GRS on SBP under additive scale(βfor interaction=0.518,95%CI 0.088-0.949,P=0.018).Conclusions rs243865 and rs7201 variants in MMP2 gene are associated with the elevated blood pressure of children and adolescents.Obesity may yield a mediation role in the associations,while insufficient physical activity may have a positively additive interaction with MMP2 genetic variants.