title: Functional variant in methionine synthase reductase intron-1 significantly increases the risk of congenital heart disease in the Han Chinese population.
abstract: BACKGROUND
  Homocysteine is known to be an independent risk factor for congenital heart disease (CHD). Methionine synthase reductase (MTRR) is essential for the adequate remethylation of homocysteine, which is the dominant pathway for homocysteine removal during early embryonic development.
  
  
  RESULTS
  Here, we report that the c.56+781 A>C (rs326119) variant of intron-1 of MTRR significantly increases the risk of CHD in the Han Chinese population. In 3 independent case-control studies involving a total of 2340 CHD patients and 2270 healthy control participants from different geographic areas, we observed that patients carrying the heterozygous AC and homozygous CC genotype had a 1.40-fold (odds ratio=1.40; P=2.32×10(-7)) and 1.84-fold (odds ratio=1.84; P=2.3×10(-11)) increased risk, respectively, of developing CHD than those carrying the wild-type AA genotype. Both in vivo quantitative real-time polymerase chain reaction analysis of MTRR mRNA in cardiac tissue samples from CHD patients and in vitro luciferase assays in transfected cells demonstrated that the c.56+781 C allele profoundly decreased MTRR transcription. Further analysis demonstrated that the c.56+781 C allele manifested reduced CCAAT/enhancer binding protein-α binding affinity. In addition, healthy individuals with the homozygous CC genotype had significantly elevated levels of plasma homocysteine compared with the wild-type AA carriers.
  
  
  CONCLUSIONS
  We have demonstrated that the MTRR c.56+781 A>C variant is an important genetic marker for increased CHD risk because this variant results in functionally reduced MTRR expression at the transcriptional level. Our results accentuate the significance of functional single-nucleotide polymorphisms in noncoding regions of the homocysteine/folate metabolism pathway core genes for their potential contributions to the origin of CHD.
authors.affiliation: State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Jian-Yuan
authors.initials: JY
authors.lastname: Zhao
authors.forename: Xue-Yan
authors.initials: XY
authors.lastname: Yang
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Gong
authors.forename: Zhuo-Ya
authors.initials: ZY
authors.lastname: Gu
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Duan
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.forename: Zhi-Zhou
authors.initials: ZZ
authors.lastname: Ye
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shen
authors.forename: Kai-Hu
authors.initials: KH
authors.lastname: Shi
authors.forename: Jia
authors.initials: J
authors.lastname: Hou
authors.forename: Guo-Ying
authors.initials: GY
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Bin
authors.initials: B
authors.lastname: Qiao
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000328:Adult; D000818:Animals; D044466:Asian People / Q000235:genetics* / Q000706:statistics & numerical data*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002681:China / Q000453:epidemiology; D005287:Ferredoxin-NADP Reductase / Q000235:genetics* / Q000378:metabolism; D014644:Genetic Variation; D005838:Genotype; D057809:HEK293 Cells; D006343:Heart Septal Defects / Q000208:ethnology* / Q000235:genetics* / Q000378:metabolism; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007438:Introns / Q000235:genetics; D032383:Myocytes, Cardiac / Q000166:cytology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051381:Rats; D012307:Risk Factors; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D006710:Homocysteine; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase