Wang Jue, Zhao Jian-Yuan, Wang Feng, Peng Qian-Qian, Hou Jia, Sun Shu-Na, Gui Yong-Hao, Duan Wen-Yuan, Qiao Bin, Wang Hong-Yan
The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
Children's Hospital Shanghai, Fudan University, Shanghai, China.
PLoS One. 2014 Feb 12;9(2):e88332. doi: 10.1371/journal.pone.0088332. eCollection 2014.
Genome-wide association studies on components of the one-carbon metabolic pathway revealed that human vitamin B12 levels could be significantly influenced by variations in the fucosyltransferase 2 (FUT2), cubilin (CUBN), and transcobalamin-I (TCN1) genes. An altered vitamin B12 level is an important factor that disturbs the homeostasis of the folate metabolism pathway, which in turn can potentially lead to the development of congenital heart disease (CHD). Therefore, we investigated the association between the variants of vitamin B12-related genes and CHD in Han Chinese populations.
Six variants of the vitamin B12-related genes were selected for analysis in two independent case-control studies, with a total of 868 CHD patients and 931 controls. The variant rs11254363 of the CUBN gene was associated with a decreased risk of developing CHD in both the separate and combined case-control studies. Combined samples from the two cohorts had a significant decrease in CHD risk for the G allele (OR = 0.48, P = 1.7×10⁻⁵) and AG+GG genotypes (OR = 0.49, P = 4×10⁻⁵), compared with the wild-type A allele and AA genotype, respectively.
Considering the G allele of variant rs11254363 of the CUBN gene was associated with an increased level of circulating vitamin B12. This result suggested that the carriers of the G allele would benefit from the protection offered by the high vitamin B12 concentration during critical heart development stages. This finding shed light on the unexpected role of CUBN in CHD development and highlighted the interplay of diet, genetics, and human birth defects.
全基因组关联研究针对一碳代谢途径的组成部分展开，结果显示，岩藻糖基转移酶2（FUT2）、内因子结合蛋白（CUBN）和钴胺素I（TCN1）基因的变异可能会对人体维生素B12水平产生显著影响。维生素B12水平的改变是扰乱叶酸代谢途径稳态的一个重要因素，进而可能导致先天性心脏病（CHD）的发生。因此，我们研究了维生素B12相关基因变异与中国汉族人群CHD之间的关联。
在两项独立的病例对照研究中，选取了6个维生素B12相关基因的变异进行分析，共有868例CHD患者和931例对照。在单独及合并的病例对照研究中，CUBN基因的rs11254363变异均与CHD发病风险降低相关。与野生型A等位基因和AA基因型相比，两个队列的合并样本中，G等位基因（OR = 0.48，P = 1.7×10⁻⁵）以及AG + GG基因型（OR = 0.49，P = 4×10⁻⁵）的CHD风险均显著降低。
鉴于CUBN基因rs11254363变异的G等位基因与循环维生素B12水平升高相关。这一结果表明，G等位基因携带者在心脏发育关键阶段会因高浓度维生素B12提供的保护而受益。这一发现揭示了CUBN在CHD发生过程中的意外作用，并突出了饮食、遗传学和人类出生缺陷之间的相互作用。
