A Functional Variant in the Cystathionine b-Synthase Gene Promoter Significantly Reduces Congenital Heart Disease Susceptibility in a Han Chinese Population

ZHAO Jianyuan; YANG Xueyan; SHI Kaihu; SUN Shuna; HOU Jia; WANG Jue; YE Zhizhou; DUAN Wenyuan; CHEN Yijiang; SHEN Hongbing; QIAO Bin; HUANG Guoying; JIN Li; WANG Hongyan

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A Functional Variant in the Cystathionine b-Synthase Gene Promoter Significantly Reduces Congenital Heart Disease Susceptibility in a Han Chinese Population

ZHAO Jianyuan 1,YANG Xueyan 2 #,SHI Kaihu 3,SUN Shuna 4,HOU Jia 4,WANG Jue 2,YE Zhizhou 2,DUAN Wenyuan 5,CHEN Yijiang 6,SHEN Hongbing 7,QIAO Bin 5,HUANG Guoying 4,JIN Li 2,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.The Second Hospital of Anhui Medical University

4.Children’s Hospital of Fudan University

5.Institute of Cardiovascular Disease General Hospital of Jinan Military

6.Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University

7.Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University

*Correspondence author

#Submitted by

Subject:

Funding: the 973 Program（No.2010CB529601）, This work was supported by the grants from the National Science Fund for Distinguished Young Scholars （No.81025003）, the Program for Innovative Research Team in University（No.IRT1010）, the National Natural Science Foundation of China（No.3100542）, the Commission for Science and Technology of Shanghai Municipality（No.10JC1401300, 11XD1400900）, the Doctoral Fund of the Ministry of Education of China（No.20110071110026）, the 973 Program （No.2012CB910103）, grants from the 973 Program（No.2012CB944604）

Opened online:17 January 2013

Accepted by: none

Citation: ZHAO Jianyuan,YANG Xueyan,SHI Kaihu.A Functional Variant in the Cystathionine b-Synthase Gene Promoter Significantly Reduces Congenital Heart Disease Susceptibility in a Han Chinese Population[OL]. [17 January 2013] http://en.paper.edu.cn/en_releasepaper/content/4512567

Homocysteine is an independent risk factor for various cardiovascular diseases. There are two ways to remove homocysteine from embryonic cardiac cells: remethylation to form methionine or transsulfuration to form cysteine. Cystathionine β-synthase (CBS) catalyzes the first step of homocysteine transsulfuration as a rate-limiting enzyme. In this study, we identified a functional variant -4673C>G (rs2850144) in the CBS gene promoter region that significantly reduces the susceptibility to congenital heart disease (CHD) in a Han Chinese population consisting of 2,340 CHD patients and 2,270 controls. Individuals carrying the heterozygous CG and homozygous GG genotype had a 15% (OR=0.85, 95%CI=0.75-0.96, P=0.011) and 40% (OR=0.60, 95% CI=0.49-0.73, P=1.78×10-7) reduced risk to develop CHD than the wild-type CC genotype carriers in the combined samples, respectively. Additional stratified analyses demonstrated that CBS -4673C>G is significantly related to septation defects and conotruncal defects. In vivo detection of CBS mRNA levels in human cardiac tissues and in vitro luciferase assays consistently showed that the minor G allele significantly increased CBS transcription. A functional analysis revealed that both the attenuated transcription suppressor SP1 binding affinity and the CBS promoter hypomethylation specifically linked with the minor G allele contributed to the remarkably up-regulated CBS expression. Consequently, the carriers with genetically increased CBS expression would benefit from the protection due to the low homocysteine levels maintained by CBS in certain cells during the critical heart development stages. These results shed light on unexpected role of CBS and highlight the importance of homocysteine removal in cardiac development.

Keywords:Congenital heart disease; cystathionine β-synthase; non-coding variant; homocysteine

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