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

Siyue WANG; Xueying QIN; Yingqi WEI; Shangwei ZUO; Hongbo CHEN; Mengying WANG; Yao WU; Junhui WU; Xiaowen WANG; Zijing WANG; Jiating WANG; Huan YU; Yiqun WU; Tao WU; Yonghua HU

doi:10.16016/j.1000-5404.202101018

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

Monographic Reports: | 更新时间：2026-01-09

- MTHFR-MMP2 gene-gene interactions may increase the risk of abdominal aortic aneurysm
- Journal of Third Military Medical University Vol. 43, Issue 12, Pages: 1117-1125(2021)
- 作者机构：
  
  1.100191 北京，北京大学公共卫生学院流行病与卫生统计学系
  2.100000 北京，北京市疾病预防控制中心
  3.100853 北京，中国人民解放军总医院血管外科
- 作者简介：
- 基金信息：
- DOI：10.16016/j.1000-5404.202101018
  CLC： R181.3; R394.3; R654.3
- Received：31 January 2021，
  
  Revised：2021-02-16，
  
  Published：30 June 2021
- 稿件说明：
移动端阅览
Siyue WANG, Xueying QIN, Yingqi WEI, et al. MTHFR-MMP2 gene-gene interactions may increase the risk of abdominal aortic aneurysm[J]. Journal of Third Military Medical University, 2021, 43(12): 1117-1125.
DOI：

Siyue WANG, Xueying QIN, Yingqi WEI, et al. MTHFR-MMP2 gene-gene interactions may increase the risk of abdominal aortic aneurysm[J]. Journal of Third Military Medical University, 2021, 43(12): 1117-1125. DOI： 10.16016/j.1000-5404.202101018.

摘要

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(

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(

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。

Abstract

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 (

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 (

0.05).

Conclusion

There may be antagonistic gene-gene interactions between MTHFR and MMP2

and the interactions may potentially influence the risks for AAA.

关键词

Keywords

references

左尚维, 隗瑛琦, 陈峰, 等. 腹主动脉瘤危险因素的病例对照研究[J]. 北京大学学报(医学版), 2014, 46(3): 412-416. DOI: 10.3969/j.issn.1671-167X.2014.03.014.

ZUO S W, WEI Y Q, CHEN F, et al . A matched case-control study of risk factors in abdominal aortic aneurysm[J ] . J Peking Univ Heal Sci, 2014, 46(3): 412-416. DOI: 10.3969/j.issn.1671-167X.2014.03.014.

KEISLER B, CARTER C. Abdominal aortic aneurysm[J]. N Engl J Med, 1993, 329(17): 1275-1277. DOI: 10.1056/nejm199310213291715.

SCHMITZ-RIXEN T, KEESE M, HAKIMI M, et al . Ruptured abdominal aortic aneurysm-epidemiology, predisposing factors, and biology[J ] . Langenbecks Arch Surg, 2016, 401(3): 275-288. DOI: 10.1007/s00423-016-1401-8.

SIDLOFF D, STATHER P, DATTANI N. Aneurysm global epidemiology study: public health measures can further reduce abdominal aortic aneurysm mortality[J]. J Vasc Surg, 2014, 59(5): 1471. DOI: 10.1016/j.jvs.2014.03.266.

PINARD A, JONES G T, MILEWICZ D M. Genetics of thoracic and abdominal aortic diseases[J]. Circ Res, 2019, 124(4): 588-606. DOI: 10.1161/circresaha.118.312436.

WAHLGREN C M, LARSSON E, MAGNUSSON P K, et al . Genetic and environmental contributions to abdominal aortic aneurysm development in a twin population[J ] . J Vasc Surg, 2010, 51(1): 3-7;discussion7. DOI: 10.1016/j.jvs.2009.08.036.

GRETARSDOTTIR S, BAAS A F, THORLEIFSSON G, et al . Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm[J ] . Nat Genet, 2010, 42(8): 692-697.

BOWN M J, JONES G T, HARRISON S C, et al . Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1[J ] . Am J Hum Genet, 2011, 89(5): 619-627. DOI: 10.1016/j.ajhg.2011.10.002.

BRADLEY D T, HUGHES A E, BADGER S A, et al . A variant in LDLR is associated with abdominal aortic aneurysm[J ] . Circ Cardiovasc Genet, 2013, 6(5): 498-504. DOI: 10.1161/CIRCGENETICS.113.000165.

JONES G T, TROMP G, KUIVANIEMI H, et al . Meta-analysis of genome-wide association studies for abdominal aortic aneurysm identifies four new disease-specific risk loci[J ] . Circ Res, 2017, 120(2): 341-353. DOI: 10.1161/CIRCRESAHA.116.308765.

KLARIN D, VERMA S S, JUDY R, et al . Genetic architecture of abdominal aortic aneurysm in the Million Veteran Program[J ] . Circulation, 2020, 142(17): 1633-1646. DOI: 10.1161/CIRCULATIONAHA.120.047544.

XIANG X, WANG S, LIU T, et al . Exploring gene-gene interaction in family-based data with an unsupervised machine learning method: EPISFA[J ] . Genet Epidemiol, 2020, 44(8): 811-824. DOI: 10.1002/gepi.22342.

SAKALIHASAN N, DEFRAIGNE J O, KERSTENNE M A, et al . Family members of patie nts with abdominal aortic aneurysms are at increased risk for aneurysms: analysis of 618 probands and their families from the Liège AAA Family Study[J ] . Ann Vasc Surg, 2014, 28(4): 787-797. DOI: 10.1016/j.avsg.2013.11.005.

HINTERSEHER I, TROMP G, KUIVANIEMI H. Genes and abdominal aortic aneurysm[J]. Ann Vasc Surg, 2011, 25(3): 388-412. DOI: 10.1016/j.avsg.2010.09.004.

CAO H, HU X H, ZHANG Q, et al . Hyperhomocysteinaemia, low folate concentrations and MTHFR C677T mutation in abdominal aortic aneurysm[J ] . Vasa, 2014, 43(3): 181-188. DOI: 10.1024/0301-1526/a000347.

STRAUSS E, WALISZEWSKI K, GABRIEL M, et al . Increased risk of the abdominal aortic aneurysm in carriers of the MTHFR 677T allele[J ] . J Appl Genet, 2003, 44(1): 85-93.

BRUNELLI T, PRISCO D, FEDI S, et al . High prevalence of mild hyperhomocysteinemia in patients with abdominal aortic aneurysm[J ] . J Vasc Surg, 2000, 32(3): 531-536. DOI: 10.1067/mva.2000.107563.

WANG X, KHALIL R A. Matrix metalloproteinases, vascular remodeling, and vascular disease[J]. Adv Pharmacol, 2018, 81: 241-330. DOI: 10.1016/bs.apha.2017.08.002.

HINTERSEHER I, BERGERT H, KUHLISCH E, et al . Matrix metalloproteinase 2 polymorphisms in a Caucasian population with abdominal aortic aneurysm[J ] . J Surg Res, 2006, 133(2): 121-128. DOI: 10.1016/j.jss.2005.12.001.

SMALLWOOD L, ALLCOCK R, VAN BOCKXMEER F, et al . Polymorphisms of the matrix metalloproteinase 9 gene and abdominal aortic aneurysm[J ] . Br J Surg, 2008, 95(10): 1239-1244. DOI: 10.1002/bjs.6345.

LOU X Y, CHEN G B, YAN L, et al . A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence[J ] . Am J Hum Genet, 2007, 80(6): 1125-1137. DOI: 10.1086/518312.

CORDELL H J. Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans[J]. Hum Mol Genet, 2002, 11(20): 2463-2468. DOI: 10.1093/hmg/11.20.2463.

ROTHMAN K J, GREENLAND S. Modern epidemiology[M]. 3rd ed. Philadelphia: Lippincot Williams&Wilkins, 2008: 94-113.

袁悦, 李楠, 任爱国, 等. 流行病学研究中相加和相乘尺度交互作用的分析[J]. 现代预防医学, 2015, 42(6): 961-965, 975.

YUAN Y, LI N, REN A G, et al . Analysis of the application of the additive model and the multiplicative statistical model in biologial interaction[J ] . Mod Prev Med, 2015, 42(6): 961-965, 975.

KNOL M J, VAN DER TWEEL I, GROBBEE D E, et al . Estimating interaction on an additive scale between continuous determinants in a logistic regression model[J ] . Int J Epidemiol, 2007, 36(5): 1111-1118. DOI: 10.1093/ije/dym157.

LI W, REICH J. A complete enumeration and classification of two-locus disease models[J]. Hum Hered, 2000, 50(6): 334-349. DOI: 10.1159/000022939.

邱宏, 余德新, 王晓蓉, 等. logistic回归模型中交互作用的分析及评价[J]. 中华流行病学杂志, 2008, 29(9): 934-937. DOI: 10.3321/j.issn: 0254-6450.2008.09.019.

QIU H, IGNATIUS T S, WANG X R, et al . Study on the interaction under logistic regression modeling[J ] . Chin J Epidemiol, 2008, 29(9): 934-937. DOI: 10.3321/j.issn: 0254-6450.2008.09.019.

ASSMANN S F, HOSMER D W, LEMESHOW S, et al . Confidence intervals for measures of interaction[J ] . Epidemi ology, 1996, 7(3): 286-290. DOI: 10.1097/00001648-199605000-00012.

HU J K, WANG X, WANG P. Testing gene-gene interactions in genome wide association studies[J]. Genet Epidemiol, 2014, 38(2): 123-134. DOI: 10.1002/gepi.21786.

YANG Y, HE C, OTT J. Testing association with interactions by partitioning Chi-squares[J]. Ann Hum Genet, 2009, 73(1): 109-117. DOI: 10.1111/j.1469-1809.2008.00480.x.

吴同, 冉柳毅, 靳佳佳, 等. 脑源性神经营养因子基因和神经营养性酪氨酸激酶受体Ⅱ型基因交互作用与青年自杀未遂行为的关系[J]. 第三军医大学学报, 2019, 41(11): 1065-1069. DOI: 10.16016/j.1000-5404.201811215.

WU T, RAN L Y, JIN J J, et al . Association of interaction between brain-derived neurotrophic factor gene and neurotrophic tyrosine kinase receptor type 2 gene with suicide attempt in middle and later adolescents[J ] . J Third Mil Med Univ, 2019, 41(11): 1065-1069. DOI: 10.16016/j.1000-5404.201811215.

YI X, LIN J, LUO H, et al . Interactions among variants in TXA2R, P2Y12 and GPⅢa are associated with carotid plaque vulnerability in Chinese population[J ] . Oncotarget, 2018, 9(25): 17597-17607. DOI: 10.18632/oncotarget.24801.

HALAZUN K J, BOFKIN K A, ASTHANA S, et al . Hyperhomocysteinaemia is associated with the rate of abdominal aortic aneurysm expansion[J ] . Eur J Vasc Endovascular Surg, 2007, 33(4): 391-394. DOI: 10.1016/j.ejvs.2006.10.022.

范义川. 甲硫氨酸诱导高同型半胱氨酸血症在腹主动脉瘤发病中的作用及分子机制的实验性研究[D]. 沈阳: 中国医科大学, 2019.

FAN Y C. Role of methionine-induced hyperhomocysteinemia in the pathogenesis of abdominal aortic aneurysm and its molecular mechanisms[D]. Shenyang: China Medical University, 2019.

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