Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Er Road, Guangzhou, 510100, Guangdong, China.
Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, China.
Eur J Pediatr. 2021 Oct;180(10):3181-3190. doi: 10.1007/s00431-021-04087-y. Epub 2021 Apr 29.
Although it is generally recognized that genetic and environmental factors are associated with the risk of congenital heart disease (CHD), the mechanism remains largely uncertain. This study aimed to investigate the association of maternal folate use, the time when folate use was started, and polymorphisms of the reduced folate carrier (RFC1) gene with the risk of CHD in offspring of Chinese descent, which can help provide new insight into the etiology of folate-related birth defects. A case-control study of 683 mothers of CHD patients and 740 mothers of healthy children was performed. The present study showed that mothers who did not use folate were at a significantly increased risk of CHD (OR=2.04; 95% CI: 1.42-2.93). When compared with those who started using folate prior to conception, mothers who started using folate from the first trimester of pregnancy (OR=1.90; 95% CI: 1.43-2.54) or from the second trimester of pregnancy (OR=8.92; 95% CI: 4.20-18.97) had a significantly higher risk of CHD. Maternal RFC1 gene polymorphisms at rs2236484 (AG vs AA: OR=1.79 [95% CI: 1.33-2.39]; GG vs AA: OR=1.64 [95% CI: 1.15-2.35]) and rs2330183 (CT vs CC: OR=1.54 [95% CI: 1.14-2.09]) were also significantly associated with CHD risk. Additionally, the risk of CHD was significantly decreased among mothers who had variant genotypes but used folate when compared with those who had variant genotypes and did not use folate.Conclusion: In those of Chinese descent, maternal folate use and the time when use started are significantly associated with the risk of CHD in offspring. Furthermore, maternal folate supplementation may help to offset some of the risks of CHD in offspring due to maternal RFC1 genetic variants. What is Known: • Folate use could help prevent CHD, but the relationship between the time when folate use is started and CHD has not received sufficient attention. • Studies have assessed the associations of folate metabolism-related genes with CHD, but genes involved in cellular transportation of folate, such as the RFC1 gene, have not garnered enough attention. What is New: • In those of Chinese descents, the time when folate use is started is significantly associated with the risk of CHD in offspring. • Maternal RFC1 polymorphisms were significantly associated with the risk of CHD. • Folate supplementation may help to offset some risks of CHD due to RFC1 genetic variants.
虽然人们普遍认为遗传和环境因素与先天性心脏病 (CHD) 的风险相关，但其中的机制仍很大程度上不明确。本研究旨在探究中国血统的母亲叶酸使用情况、叶酸使用起始时间以及还原叶酸载体 (RFC1) 基因多态性与后代 CHD 风险之间的关联，这有助于为叶酸相关出生缺陷的病因提供新的见解。通过对 683 名 CHD 患儿的母亲和 740 名健康儿童的母亲进行病例对照研究。本研究表明，不使用叶酸的母亲发生 CHD 的风险显著增加（OR=2.04；95%CI：1.42-2.93）。与孕前开始使用叶酸的母亲相比，从孕早期（OR=1.90；95%CI：1.43-2.54）或孕中期（OR=8.92；95%CI：4.20-18.97）开始使用叶酸的母亲发生 CHD 的风险显著更高。母亲 RFC1 基因 rs2236484（AG 与 AA：OR=1.79[95%CI：1.33-2.39]；GG 与 AA：OR=1.64[95%CI：1.15-2.35]）和 rs2330183（CT 与 CC：OR=1.54[95%CI：1.14-2.09]）多态性也与 CHD 风险显著相关。此外，与具有变异基因型但未使用叶酸的母亲相比，具有变异基因型且使用叶酸的母亲发生 CHD 的风险显著降低。结论：在中国人群中，母亲叶酸使用情况和使用起始时间与后代 CHD 风险显著相关。此外，母亲叶酸补充可能有助于抵消由于母亲 RFC1 遗传变异导致的部分后代 CHD 风险。已知情况：•叶酸使用有助于预防 CHD，但叶酸使用时间与 CHD 之间的关系尚未得到充分关注。•已有研究评估了叶酸代谢相关基因与 CHD 的关联，但细胞叶酸转运相关基因（如 RFC1 基因）尚未得到足够重视。新发现：•在中国人群中，叶酸使用时间与后代 CHD 风险显著相关。•母亲 RFC1 多态性与 CHD 风险显著相关。•叶酸补充可能有助于抵消由于 RFC1 遗传变异导致的部分 CHD 风险。
