Jiabi Qin1,2,3, Jinqi Li2, Fang Li2, Mengting Sun2, Tingting Wang3, Jingyi Diao2, Senmao Zhang2, Liu Luo2, Yihuan Li2, Letao Chen2, Peng Huang4, Ping Zhu5. 1. Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Er Road, Guangzhou, 510100, Guangdong, China. 2. Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, China. 3. NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China. 4. Hunan Children's Hospital, 86 Ziyuan Road, Changsha, 410007, Hunan, China. HPeng1979@163.com. 5. Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Er Road, Guangzhou, 510100, Guangdong, China. zhuping6588@163.com.
Abstract
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.
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.