Functional variant in methionine synthase reductase intron-1 significantly increases the risk of congenital heart disease in the Han Chinese population
| Autor: | Jian-Yuan Zhao, Hongyan Wang, Xue-Yan Yang, Bin Qiao, Kai-Hu Shi, Jia Hou, Jue Wang, Guoying Huang, Xiaohong Gong, Hongbing Shen, Wenyuan Duan, Li Jin, Zhi-Zhou Ye, Zhuo-Ya Gu |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Transcriptional Activation medicine.medical_specialty China Homocysteine Heart disease Genotype Polymorphism Single Nucleotide chemistry.chemical_compound Asian People Risk Factors Physiology (medical) Internal medicine Genetic variation medicine Animals Humans Myocytes Cardiac Child Cells Cultured Genetics biology business.industry Heart Septal Defects Case-control study Genetic Variation Odds ratio (Methionine synthase) reductase medicine.disease MTRR Introns Rats Ferredoxin-NADP Reductase Endocrinology HEK293 Cells chemistry Case-Control Studies biology.protein Cardiology and Cardiovascular Medicine business |
| Zdroj: | Circulation. 125(3) |
| ISSN: | 1524-4539 |
| Popis: | 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. Methods and 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. |
| Databáze: | OpenAIRE |
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