MAPK/ERK通路基因遗传变异和膝关节骨性关节炎遗传易感性的关联研究  

Putative functional variants of MAPK/ERK identified by Regulome DB were associated with knee osteoarthritis susceptibility

作　　者：王珂杰[1] 许晨阳 张益舸 陈海峰 丁文鸽[1] 戴小宇 Wang Kejie;Xu Chenyang;Zhang Yige;Chen Haifeng;Ding Wenge;Dai Xiaoyu(Department of Orthopaedics, Changzhou No. 1 People＇s Hospital, Changzhou 213003, China)

机构地区：[1]常州市第一人民医院骨科,江苏常州213003

出　　处：《南京医科大学学报（自然科学版）》2018年第6期781-785,共5页Journal of Nanjing Medical University(Natural Sciences)

基　　金：国家自然科学基金(81272017);常州市卫计委指导性课题(wz201514)

摘　　要：目的:探讨丝裂原活化蛋白激酶/细胞外信号调节蛋白激酶(MAPK/ERK)通路基因遗传变异与中国汉族人群膝关节骨性关节炎(knee osteoarthritis,KOA)发病风险的相关性。方法:采用病例对照研究设计,纳入278例膝关节骨性关节炎和年龄、性别匹配的289例健康对照,应用Regulome DB数据库筛选MAPK/ERK通路4个基因(MEK1/2和ERK1/2)的潜在功能位点,使用Sequenom Mass ARRAY平台对得到的5个位点进行基因分型。随后使用单因素和多因素Logistic回归模型分析遗传变异与骨性关节炎之间的关联及其强度。结果:单因素分析结果显示,丝裂原活化蛋白激酶激酶2(mitogen-activated protein kinase kinase 2,MEK2)基因的多态性位点rs350911与KOA发病风险在隐性模型(TT vs.TC+CC)中具有统计学关联(OR=2.62,95%CI:1.70~4.02,P<0.01)。基于多因素模型调整年龄、性别、体重指数(body mass index,BMI)等因素后,rs350911仍与KOA发病风险相关联(OR=2.72,95%CI:1.75~4.22,P<0.01)。分层分析显示MEK2的rs350911等位基因效应在男性,BMI<25 kg/m2,低K-L分级(1-2级)组中显著关联(P<0.05),且在性别分层时异质性检验有统计学意义(P=0.01),提示该位点对KOA的作用存在性别差异,与性别存在基因环境交互作用。结论:MEK2 rs350911与中国汉族人群膝关节骨性关节炎发病风险增加有关,有望为膝关节骨性关节炎的诊断和治疗提供新靶点。Objective：To investigate the relationship of genetic variations in MAPK/ERK pathway with knee osteoarthritis risk.Methods：A case-control study was conducted including 278 patients with knee osteoarthritis and 289 age and sex matched healthy controls. A total of 5 potentially functional variations in MAPK/ERK pathyway（MEK1,MEK2,ERK1 and ERK2）selected by Regulome DB were genotyped by using Sequenom Mass ARRAY. Univariate and multivariate logistic regression models were used to evaluate the association and its strength. Results：In univariate analysis,rs350911 of MEK2 was significantly associated with knee osteoarthritis in recessive model（TT vs. TC＋CC）（OR=2.62,95% CI：1.70-4.02,P〈0.01）. After adjustment for age,gender and BMI,the associations remain significant（OR=2.72,95% CI：1.75-4.22,P 0.01）. The stratification analyses revealed that the effect of rs350911 on knee osteoarthritis was significant in male,lower BMI（〈25 kg/m2）,and lower Kellgren-Lawrence grade（1-2）（all P〈0.05）. P value for heterogeneity test was 0.01 in different gender group. Conclusion：The results indicate that potential functional genetic variation in MAPK/ERK plays an important role in the pathogenesis of knee osteoarthritis.

关 键 词：膝关节骨性关节炎 丝裂原活化蛋白激酶 细胞外信号调节蛋白激酶 遗传变异 多态性 

分 类 号：R584.3[医药卫生—内分泌]