Zhao Jian-Yuan, Yang Xue-Yan, Shi Kai-Hu, Sun Shu-Na, Hou Jia, Ye Zhi-Zhou, Wang Jue, Duan Wen-Yuan, Qiao Bin, Chen Yi-Jiang, Shen Hong-Bing, Huang Guo-Ying, Jin Li, Wang Hong-Yan
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.
Cell Res. 2013 Feb;23(2):242-253. doi: 10.1038/cr.2012.135. Epub 2012 Sep 18.
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.
同型半胱氨酸是引发多种心血管疾病的独立风险因素。从胚胎心脏细胞中清除同型半胱氨酸有两种方式：重新甲基化形成甲硫氨酸或转硫作用形成半胱氨酸。胱硫醚β-合酶（CBS）作为限速酶催化同型半胱氨酸转硫作用的第一步。在本研究中，我们在CBS基因启动子区域鉴定出一个功能性变异-4673C>G（rs2850144），该变异在由2340例先天性心脏病（CHD）患者和2270例对照组成的汉族人群中显著降低了患先天性心脏病的易感性。在合并样本中，携带杂合子CG和纯合子GG基因型的个体患CHD的风险分别比野生型CC基因型携带者降低了15%（优势比（OR）=0.85，95%置信区间（CI）=0.75 - 0.96，P = 0.011）和40%（OR = 0.60，95%CI = 0.49 - 0.73，P = 1.78×10⁻⁷）。额外的分层分析表明，CBS -4673C>G与分隔缺陷和圆锥动脉干缺陷显著相关。在人体心脏组织中对CBS mRNA水平进行的体内检测以及体外荧光素酶检测一致显示，次要的G等位基因显著增加了CBS的转录。功能分析表明，与次要G等位基因特异性相关的转录抑制因子SP1结合亲和力减弱以及CBS启动子低甲基化共同导致了CBS表达的显著上调。因此，在心脏发育关键阶段，由于CBS在某些细胞中维持低同型半胱氨酸水平，CBS基因表达遗传增加的携带者将受益于这种保护作用。这些结果揭示了CBS出人意料的作用，并突出了在心脏发育过程中清除同型半胱氨酸的重要性。《细胞研究》于2012年9月18日在线优先发表；doi:10.1038/cr.2012.135。
