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.