MTHFR C677T Polymorphism and Risk of Congenital Heart Defects: Evidence from 29 Case-Control and TDT Studies

BackgroundMethylenetetrahydrofolate reductase (MTHFR) is an important enzyme for folate metabolism in humans; it is encoded by the MTHFR gene. Several studies have assessed the association between MTHFR C677T polymorphism and the risk of congenital heart defects (CHDs), while the results were inconsistent. Methods and FindingsMultiple electronic databases were searched to identify relevant studies published up to July 22, 2012. Data from case-control and TDT studies were integrated in an allelic model using the Catmap and Metafor software. Twenty-nine publications were included in this meta-analysis. The overall meta-analysis showed significant association between MTHFR C677T polymorphism and CHDs risk in children with heterogeneity (Pheterogeneity = 0.000) and publication bias (Pegger = 0.039), but it turned into null after the trim-and-fill method was implemented (OR = 1.12, 95% CI = 0.95–1.31). Nevertheless, positive results were obtained after stratified by ethnicity and sample size in all subgroups except the mixed population. For mothers, there was significant association between the variant and CHDs without heterogeneity (Pheterogeneity = 0.150, OR = 1.16, 95% CI = 1.05–1.29) and publication bias (Pegger = 0.981). However, the results varied across each subgroup in the stratified analysis of ethnicity and sample size. ConclusionsBoth infant and maternal MTHFR C677T polymorphisms may contribute to the risk of CHDs.

背景 亚甲基四氢叶酸还原酶（Methylenetetrahydrofolate reductase, MTHFR）是人体叶酸代谢过程中的关键酶，由MTHFR基因编码。既往多项研究探讨了MTHFR C677T基因多态性与先天性心脏病（congenital heart defects, CHDs）发病风险的关联，但所得研究结果并不一致。方法与结果 本研究检索了截至2012年7月22日发表的所有相关电子数据库文献，采用Catmap与Metafor软件，基于等位基因模型整合病例对照研究及传递不平衡检验（Transmission/Disequilibrium Test, TDT）的相关数据。最终纳入29篇文献开展本次荟萃分析。整体荟萃分析结果显示，MTHFR C677T基因多态性与儿童先天性心脏病发病风险存在显著关联，但存在明显异质性（异质性检验P值=0.000）与发表偏倚（Egger检验P值=0.039）；经修剪-填充（trim-and-fill）法校正后，该关联不再具有统计学意义（比值比OR=1.12，95%置信区间CI=0.95–1.31）。不过，按种族与样本量进行的亚组分析显示，除混合人群亚组外，其余亚组均得到阳性结果。针对母亲群体的分析表明，该基因变异与先天性心脏病发病风险存在显著关联，且无异质性（异质性检验P值=0.150，OR=1.16，95%CI=1.05–1.29），无明显发表偏倚（Egger检验P值=0.981）；但在按种族与样本量开展的分层亚组分析中，各亚组结果存在差异。结论 婴儿与母亲的MTHFR C677T基因多态性均可能与先天性心脏病的发病风险相关。