The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and venous thromboembolism (VTE) risk in the Chinese population has been widely reported, but results were inconsistent and underpowered. To elucidate the variable results, a meta-analysis and systematic review were performed from all case-controlled studies relating MTHFR C677T polymorphism by pooling data on them. We estimated the pooled odds ratio with its 95% confidence intervals to assess this possible association. Finally, a total of 24 studies with 2339 cases and 4048 controls were included in the current meta-analysis. Significant association was found with VTE risk for all genetic models. Subgroup analyses by type of VTE further identified the above-mentioned association in deep vein thrombosis/pulmonary embolism and splanchnic vein thrombosis. The findings from our meta-analysis support the associations of MTHFR C677T polymorphism with VTE risk in the Chinese population.
ArfvidssonBEklofBKistnerRLMasudaEMSatoDT. Risk factors for venous thromboembolism following prolonged air travel. Coach class thrombosis. Hematol Oncol Clin North Am. 2000;14(2):391–400, ix.
2.
KhareAGhoshKKulkarniBMohantyD. Thrombophilia: hereditary and acquired in cardiovascular disease. Haematologia. 2002;32
(4):293–311.
3.
CushmanM. Epidemiology and risk factors for venous thrombosis. Semin Hematol. 2007;44
(2):62–69.
4.
RogersEJChenSChanA. Folate deficiency and plasma homocysteine during increased oxidative stress. N Engl J Med. 2007;357
(4):421–422.
5.
GoyettePSumnerJSMilosR. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet. 1994;7
(2):195–200.
6.
GoyettePPaiAMilosR. Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome. 1998;9
(8):652–656.
7.
FrosstPBlomHJMilosR. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10
(1):111–113.
8.
SimoneBDe StefanoVLeonciniE. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol. 2013;28
(8):621–647.
9.
JangMJJeonYJChoiWI. The 677C > T mutation of the MTHFR gene increases the risk of venous thromboembolism in Koreans and a meta-analysis from Asian population. Clin Appl Thromb Hemost. 2013;19
(3):309–314.
10.
GohilRPeckGSharmaP. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost. 2009;102
(2):360–370.
11.
StroupDFBerlinJAMortonSC. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA. 2000;283
(15):2008–2012.
12.
QinXPengQChenZ. The association between MTHFR gene polymorphisms and hepatocellular carcinoma risk: a meta-analysis. PloS One. 2013;8
(2):e56070.
13.
HigginsJPThompsonSGDeeksJJAltmanDG. Measuring inconsistency in meta-analyses. BMJ. 2003;327
(7414):557–560.
14.
HigginsJPThompsonSG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21
(11):1539–1558.
15.
DerSimonianRLairdN. Meta-analysis in clinical trials. Control Clin Trial. 1986;7
(3):177–188.
16.
MantelNHaenszelW. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22
(4):719–748.
17.
EggerMDavey SmithGSchneiderMMinderC. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315
(7109):629–634.
18.
BeggCBMazumdarM. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50
(4):1088–1101.
19.
DuvalSTweedieR. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56
(2):455–463.
20.
ZhengYZTongJDoXPPuXQZhouBT. Prevalence of methylenetetrahydrofolate reductase C677T and its association with arterial and venous thrombosis in the Chinese population. Br J Haematol. 2000;109
(4):870–874.
21.
YinGYanLZhangZChenKJinX. C677T methylenetetrahydrofolate reductase gene polymorphism as a risk factor involved in venous thromboembolism: a population-based case-control study. Mol Med Rep. 2012;6
(6):1271–1275.
22.
LuYZhaoYLiuG. Factor V gene G1691A mutation, prothrombin gene G20210A mutation, and MTHFR gene C677T mutation are not risk factors for pulmonary thromboembolism in Chinese population. Thromb Res. 2002;106
(1):7–12.
23.
LinJSShenMCTsaiWLinB. The prevalence of C677T mutation in the methylenetetrahydrofolate reductase gene and its association with venous thrombophilia in Taiwanese Chinese. Thromb Res. 2000;97
(3):89–94.
24.
LiXMWeiYFHaoHL. Hyperhomocysteinemia and the MTHFR C677T mutation in Budd-Chiari syndrome. Am J Hematol. 2002;71
(1):11–14.
25.
HsuTSHsuLAChangCJ. Importance of hyperhomocysteinemia as a risk factor for venous thromboembolism in a Taiwanese population. A case-control study. Thromb Res. 2001;102
(5):387–395.
26.
HsuLAKoYLWangSM. The C677T mutation of the methylenetetrahydrofolate reductase gene is not associated with the risk of coronary artery disease or venous thrombosis among Chinese in Taiwan. Hum Hered. 2001;51
(1-2):41–45.
27.
HoCH. Prevalence of prothrombin 20210A allele and methylenetetrahydrofolate reductase C677T genetic mutations in the Chinese population. Ann Hematol. 2000;79
(5):239–242.
GaoWWangYSZhangPWangHY. MTHFR C677T mutation in central retinal vein occlusion: a case-control study in Chinese population. Thromb Res. 2008;121
(5):699–703.
30.
DongNWangBChuLXiaoL. Plasma homocysteine concentrations in the acute phase after central retinal vein occlusion in a Chinese population. Curr Eye Res. 2013;38
(11):1153–1158.
31.
YuHdZhengHQiHLianJhHeYDongZm. Study on the association of polymorphisms in homocysteine metabolism related enzymes with deep venous thrombosis. Chin J Med Genet. 2006;23
(6):635–639.
32.
WangM-tLiQHanF-lYaoX-p. Relationship of plasma homocysteine and folic acid levels and 5,10-methylenetetrahydrofolate reductase gene mutation with venous thromboembolism. Chinese J Intern Med. 2004;43
(8):591–594.
33.
QiuLYanSkSongYh. Hyperhomocysteinemia and deep-vein thrombosis. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae. 2003;25
(6):706–709.
34.
GuoCGuoQGongY. The C677T mutation in the methylenetetrahydrofolate reductase gene and its association with deep vein thrombophilia in Shandong Hans. Chin J Med Genet. 2002;19
(4):295–297.
35.
KailibinuerAMahemutiAXiaY-nHuX-m. Association between gene polymorphisms of methylenetetrahydrofolate reductase and plasma homocysteine in Uygur patients with venous thromboembolism. Zhonghua Xin Xue Guan Bing Za Zhi. 2012;40
(12):1030–1036.
ZhouYBXuKLiuRBXiaoL. An association study of methylenetetrahydrofolate reductase gene polymorphism with deep venous thrombosis. Chin J Thromb Hemost. 2003;9(2):52–55.
38.
ZhouWM. Relationship between genetic polymorphism of MTHFR C677T and lower extremeities deep venous thrombosis. J Nanchang University Medical Science. 2010;12(50):70–73.
39.
YeYPWangCLiuYMHuangXXPangBS. Relationship between methylenetetrahydrofolate reductase C677T gene polymorphism and hyperhomocysteinmia and pulmonary thromboembolism. J Capital Univ Med Sci. 2004;25(03):321–325.
40.
WangXDZhangDX. The association of the cholesteryl ester transfer protein TaqIB and methylenetetrahydrofolate reductase C677T polymorphism with central retinal vein occlusion. Shaanxi Med J. 2011;40(10):1352–1354.
41.
TianHXuHZuMHPeiDS. Correlation of MTHFR C677T gene polymorphism plasma and Hcy levels in young patients with hepatic vein obstruction. J Intervent Radiol. 2012;21(01):62–65.
42.
MeiL. Methylenetetrahydrofolate reductase gene poly morphism and deep-vein thrombosis. Chin Foreign Med Res. 2010;19(08):21–22.
43.
LinSRCaiXHLiuQC. Correlection between methylenetetrahydrofolate reductase C677T polymorphism and deep venous thrombosis in Han population of Fujian province. J Shaanxi Coll Trad Chin Med. 2009;10(1):45–46, 49.
44.
GuentherBDSheppardCATranPRozenRMatthewsRGLudwigML. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nature Struct Biol. 1999;6
(4):359–365.
45.
Den HeijerMLewingtonSClarkeR. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. J Thromb Haemost. 2005;3
(2):292–299.
46.
BottoLDYangQ. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000;151
(9):862–877.
47.
De MarcoPCalevoMGMoroniA. Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population. J Hum Genet. 2002;47
(6):319–324.
48.
PepeGCamacho VanegasOGiustiB. Heterogeneity in world distribution of the thermolabile C677T mutation in 5,10-methylenetetrahydrofolate reductase. Am J Hum Genet. 1998;63
(3):917–920.
49.
KlerkMVerhoefPClarkeR. MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002;288
(16):2023–2031.
50.
QuinlivanEPGregoryJFIII. Effect of food fortification on folic acid intake in the United States. Am J Clin Nutr. 2003;77
(1):221–225.
