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A functional variant in MTRR intron-1 significantly increases risk of congenital heart disease in Han Chinese population
ZHAO Jianyuan 1,YANG Xueyan 2 #,GU Zhuoya 2,WANG Jue 2,DUAN Wenyuan 3,YE Zhizhou 2,SHEN Hongbing 4,SHI Kaihu 5,HOU Jia 6,HUANG Guoying 6,JIN Li 2,QIAO Bing 3,WANG Hongyan 2 *
1.The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, ShangHai 200433
2.The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University
3.Institute of Cardiovascular Disease General Hospital of Jinan Military Region
4.Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University
5.Department of Cardiac Surgery, The Second Hospital of Anhui Medical University
6.Department of Cadiology, Children's hospital, Fudan University
*Correspondence author
#Submitted by
Subject:
Funding: the 973 Program (No.2007CB500902, 2010CB529601), the National Natural Science Foundation of China(No.30872129), Doctoral Fund of Ministry of Education of China(No.20090071120037), the Commission for Science and Technology of Shanghai Municipality(No.10JC1401300), Natural Science Foundation of Shanghai Municipality(No.09ZR1404400), This work was supported by the grants from the National Science Fund for Distinguished Young Scholars (No.81025003)
Opened online:22 January 2013
Accepted by: none
Citation: ZHAO Jianyuan,YANG Xueyan,GU Zhuoya.A functional variant in MTRR intron-1 significantly increases risk of congenital heart disease in Han Chinese population[OL]. [22 January 2013] http://en.paper.edu.cn/en_releasepaper/content/4514134
 
 
Homocysteine is known to be an independent risk factor for congenital heart disease (CHD). Methionine synthase reductase (MTRR) is essential for adequate remethylation of homocysteine, which is the exclusively dominant pathway for homocysteine removal in earlier embryo development. Here we report the variant c.56+781 A>C (rs326119) in the intron-1 of MTRR significantly increases the CHD risk in Han Chinese population. In three independent case-control studies with a total of 2,340 CHD patients and 2,270 healthy control participants from different geographic areas, we observed that children carrying heterozygote AC and homozygote CC genotype have 1.40 fold (OR=1.40, 95% CI=1.23-1.59, P=2.32×10-7) and 1.84 fold (OR=1.84, 95% CI=1.54-2.20, P=2.3×10-11) increased risk for CHD than those carrying wild-type AA genotype, respectively. Both in vivo quantitative real-time PCR analysis of MTRR mRNA in cardiac tissue samples of CHD and in vitro luciferase assay in transfected cells showed that the c.56+781 C allele remarkably deceases MTRR transcription. Additionally, healthy individuals with homozygous CC genotype have significantly elevated plasma homocysteine level compared with the wild-type AA carriers. Thus, we demonstrated that MTRR c.56+781 A>C variant is an important genetic marker for the increased CHD risk through its down-regulation function on MTRR expression in the transcription stage. Our results accentuate the significance of functional SNP in non-coding region of homocysteine/folate metabolism pathway core genes for their potential contribution to the etiology of CHD.
Keywords:Congenital heart disease; Methionine synthase reductase; Single nucleotide polymorphism; Homocysteine
 
 
 

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