title: Folate Deficiency and Gene Polymorphisms of MTHFR, MTR and MTRR Elevate the Hyperhomocysteinemia Risk.
abstract: BACKGROUND
  Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVDs). We aimed to investigate the joint effect of homocysteine metabolism gene polymorphisms, as well as the folate deficiency on the risk of HHcy in a Chinese hypertensive population.
  
  
  METHODS
  This study enrolled 480 hypertensive patients aged 28 - 75 from six hospitals in different Chinese regions from 9/2005 - 12/2005. Known genotypes of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G were detected by PCRRFLP methods. Serum Hcy was measured by high-performance liquid chromatography and serum folate was measured by chemiluminescent immunoassay.
  
  
  RESULTS
  MTHFR C677T and MTR A2756G can independently elevate the risk of HHcy (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA, p = 0.026, respectively), whereas MTHFR A1298C decreased HHcy risk (AC + CC vs. AA, p < 0.001) and showed a protective effect against HHcy risk. Importantly, the joint effect of these risk genotypes showed significantly higher odds of HHcy than non-risk genotypes, especially the patients with four risk genotypes. It is noteworthy that this deleterious effect was aggravated by folate deficiency. These findings were verified by generalized multifactor dimensionality reduction model (p = 0.001) and a cumulative effects model (p < 0.001).
  
  
  CONCLUSIONS
  We have first demonstrated that the joint effect of homocysteine metabolism gene polymorphisms and folate deficiency lead to dramatic elevations in the HHcy risk.
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Cheng
authors.forename: A-Jie
authors.initials: AJ
authors.lastname: Zhang
authors.forename: Shao-Xing
authors.initials: SX
authors.lastname: Dai
authors.forename: Gong-Hua
authors.initials: GH
authors.lastname: Li
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Lv
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Dahai
authors.initials: D
authors.lastname: Liu
authors.forename: Jing-Fei
authors.initials: JF
authors.lastname: Huang
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D000328:Adult; D000368:Aged; D005287:Ferredoxin-NADP Reductase; D005492:Folic Acid; D005838:Genotype; D006710:Homocysteine; D006801:Humans; D020138:Hyperhomocysteinemia; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors
chemical_list: D006710:Homocysteine; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C585801:MTR protein, human