腹主动脉瘤MTHFR-MMP2基因-基因交互作用研究

MTHFR-MMP2 gene-gene interactions may increase the risk of abdominal aortic aneurysm

目的探索MTHFR-MMP2基因-基因交互作用是否影响患腹主动脉瘤(abdominal aortic aneurysm, AAA)的风险。方法基于1∶2匹配病例对照研究设计,以2011-2014年解放军总医院血管外科的AAA患者、同期同一医院及北京市房山区两地性别、年龄匹配的非AAA患者为研究对象;采用标准化问卷收集其基本人口学资料、病史及行为危险因素;开展体格检查、腹主动脉超声,并采集5 mL外周静脉血液标本对基因分型。采用传统及机器学习方法,包括条件Logistic回归、广义多因子降维(generalized multifactor dimension reduction, GMDR)、非监督式稀疏因子分析的机器学习方法(EPIstasis sparse factor analysis, EPISFA),分别在相加交互作用、相乘交互作用尺度上,探索MTHFR与MMP2基因-基因交互作用是否影响患腹主动脉瘤风险,并采用交互作用超额危险度(relative excess risk of interaction, RERI)、交互作用归因比(attributable proportion of interaction, API)、交互作用指数(the synergy index, S)3种指标评价MTHFR与MMP2间的基因-基因交互作用的方向和大小。结果 2011-2014年共纳入155组1:2的匹配病例对照(共465人)。在调整协变量后,同时在乘法和加法尺度下发现MTHFR基因与MMP2基因上多个位点(rs1132896, rs1477017, rs1992116, rs243847)可能存在拮抗交互作用(P<0.05),影响AAA风险,并在3种分析方法中彼此验证;在高维交互作用上,GMDR和EPISFA提示MTHFR-MMP2间可能存在高维交互作用,具有较高的交叉验证一致性,且结果具有统计学差异(P<0.05)。结论 MTHFR-MMP2基因间可能存在拮抗基因-基因交互作用影响患AAA风险。

Objective To explore the role of genetic interactions of MTHFR-MMP2 in risks for abdominal aortic aneurysm(AAA). Methods A 1∶2 matched case-control study was performed on the AAA patients admitted in the vascular surgery department of Chinese PLA General Hospital between 2011 and 2014, and on the non-AAA patients(control group) with matched gender and age from both the above hospital and a community of Fangshan district during the same period. Standardized questionnaires were used to collect information such as demographic characteristics, medical history and behavioral risk factors. Physical and abdominal aortic ultrasound examinations were carried out, and 5 mL peripheral venous blood samples were collected for genotyping. The interactions between MTHFR and MMP2 genes were investigated using both traditional and machine learning methods, including conditional Logistic regression model, generalized multifactor dimension reduction(GMDR) and EPI stasis sparse factor analysis(EPISFA). Whether the genetic interactions affects the risk of AAA was analyzed and determined, on additive and multiplicative scales, respectively. In addition, relative excess risk of interaction(RERI), attributable proportion of interaction(API) and synergy index(S) were adopted to assess the direction and magnitude of the genetic interactions between MTHFR and MMP2. Results A total of 465 individuals, including 155 AAA patients and 310 non-AAA subjects at a matched ratio of 1∶2 were enrolled in this study during 2011 and 2014. After adjustment of covariates, antagonistic interactions between MTHFR gene and multiple loci of MMP2 gene(rs1132896, rs1477017, rs1992116, rs243847) were found on both additive and multiplicative scales simultaneously(P<0.05), which could affect AAA risks. And the results were verified by the above 3 methods. GMDR and EPISFA results suggested that there might be high-dimensional interactions between MTHFR and MMP2, with high cross-validation consistency and significant difference(P<0.05). Conclusion There may be antagonistic gene-gene interactions between MTHFR and MMP2, and the interactions may potentially influence the risks for AAA.