Putative functional variants of MAPK/ERK identified by RegulomeDB were associated with knee osteoarthritis susceptibility
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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RegulomeDB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SequenomMassARRAY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。
Abstract:
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 RegulomeDB were genotyped by using SequenomMassARRAY. 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.
