title: A functional variant in the cystathionine β-synthase gene promoter significantly reduces congenital heart disease susceptibility in a Han Chinese population.
abstract: 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 genotypes had a 15% (odds ratio (OR) = 0.85, 95% confidence interval (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 upregulated 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.Cell Research advance online publication 18 September 2012; doi:10.1038/cr.2012.135.
authors.affiliation: 1] The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China [2] Institute of Sports Science and Technology, Administration of Sports of Anhui Province, 97 Wuhu Road, Hefei, Anhui 230001, China.
authors.forename: Jian-Yuan
authors.initials: JY
authors.lastname: Zhao
authors.forename: Xue-Yan
authors.initials: XY
authors.lastname: Yang
authors.forename: Kai-Hu
authors.initials: KH
authors.lastname: Shi
authors.forename: Shu-Na
authors.initials: SN
authors.lastname: Sun
authors.forename: Jia
authors.initials: J
authors.lastname: Hou
authors.forename: Zhi-Zhou
authors.initials: ZZ
authors.lastname: Ye
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Duan
authors.forename: Bin
authors.initials: B
authors.lastname: Qiao
authors.forename: Yi-Jiang
authors.initials: YJ
authors.lastname: Chen
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shen
authors.forename: Guo-Ying
authors.initials: GY
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Wang