Meta-Prediction of MTHFR Gene Polymorphism and Air Pollution on the Risks of Congenital Heart Defects Worldwide: A Transgenerational Analysis

Yang, Hsiao Ling; Yang, Ya Ling; Yu, Chong Ho; Shiao, S. Pamela K.

doi:10.3390/ijerph15081660

Cited by 10 publications

(9 citation statements)

References 64 publications

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“…In MTHFR , which encodes methylenetetrahydrofolate reductase, 2 polymorphisms, C677T and A1298C, have been investigated. Eleven meta-analyses have investigated the association of congenital diseases with C677T, 54 55 56 57 58 59 60 61 62 63 64 All meta-analyses analyzed the risk of CHD and only 1 study examined both congenital heart disease and orofacial cleft. Three studies showed no significant association between C677T and congenital heart disease, while 7 studies described a positive association with these conditions.…”

Section: Resultsmentioning

confidence: 99%

“…However, Chen et al 54 reported 2 negative ORs, for the recessive model and for the homozygote model, each based on 6 case-control studies. Yang et al 57 conducted a meta-analysis using 42 studies; both MTHFR C677T and A1298C polymorphisms were associated with the risk of CHD. 56 A TT model (pooled RR, 1.30; 95% CI, 1.14–1.48) and a TT+CT model (pooled RR, 1.09; 95% CI, 1.04–1.14) showed a significant positive relationship with congenital heart disease.…”

Section: Resultsmentioning

confidence: 99%

“… 64 Five studies have identified associations with the A1298C polymorphism. 55 56 57 64 65 All 5 studies considered congenital heart disease, while only Verkleij-Hagoort et al 64 further analyzed orofacial cleft. Moreover, all 5 studies showed an increasing effect of A1298C on CHD.…”

Section: Resultsmentioning

confidence: 99%

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Environmental and Genetic Risk Factors of Congenital Anomalies: an Umbrella Review of Systematic Reviews and Meta-Analyses

et al. 2021

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Background The prevalence of congenital anomalies in newborns in South Korea was 272.9 per 100,000 in 2005, and 314.7 per 100,000 in 2006. In other studies, the prevalence of congenital anomalies in South Korea was equivalent to 286.9 per 10,000 livebirths in 2006, while it was estimated 446.3 per 10,000 births during the period from 2008 to 2014. Several systematic reviews and meta-analyses analyzing the factors contributing to congenital anomalies have been reported, but comprehensive umbrella reviews are lacking. Methods We searched PubMed, Google Scholar, Cochrane, and EMBASE databases up to July 1, 2019, for systematic reviews and meta-analyses that investigated the effects of environmental and genetic factors on any type of congenital anomalies. We categorized 8 subgroups of congenital anomalies classified according to the 10th revision of the International Statistical Classification of Diseases (ICD-10). Two researchers independently searched the literature, retrieved the data, and evaluated the quality of each study. Results We reviewed 66 systematic reviews and meta-analyses that investigated the association between non-genetic or genetic risk factors and congenital anomalies. Overall, 269 associations and 128 associations were considered for environmental and genetic risk factors, respectively. Congenital anomalies based on congenital heart diseases, cleft lip and palate, and others were associated with environmental risk factors based on maternal exposure to environmental exposures (air pollution, toxic chemicals), parental smoking, maternal history (infectious diseases during pregnancy, pregestational and gestational diabetes mellitus, and gestational diabetes mellitus), maternal obesity, maternal drug intake, pregnancy through artificial reproductive technologies, and socioeconomic factors. The association of maternal alcohol or coffee consumption with congenital anomalies was not significant, and maternal folic acid supplementation had a preventive effect on congenital heart defects. Genes or genetic loci associated with congenital anomalies included MTHFR , MTRR and MTR , GATA4 , NKX2-5 , SRD5A2 , CFTR, and 1p22 and 20q12 anomalies. Conclusion This study provides a wide perspective on the distribution of environmental and genetic risk factors of congenital anomalies, thus suggesting future studies and providing health policy implications.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Environmental and Genetic Risk Factors of Congenital Anomalies: an Umbrella Review of Systematic Reviews and Meta-Analyses

et al. 2021

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“…Numerous studies have investigated the association between the MTHFR C677T polymorphism and the risk of CHDs, but the results have been inconsistent (Hobbs et al, 2005; Zhu et al, 2006; Brandalize et al, 2009; Božović et al, 2011). Meta-analyses showed that maternal MTHFR C677T polymorphism may contribute to the risk of CHDs (Wang et al, 2013; Xuan et al, 2014; Yang et al, 2018). Research on the relationship between the maternal MTHFR genotype and the development of CHD in children with DS has also yielded conflicting results (Brandalize et al, 2009; Hobbs et al, 2010; Božović et al, 2011; Elsayed et al, 2014; Coppedè, 2015).…”

Section: Discussionmentioning

confidence: 99%

Maternal LINE-1 DNA Methylation and Congenital Heart Defects in Down Syndrome

et al. 2019

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Background: Down syndrome (DS) is one of the most common chromosomal abnormalities associated with congenital heart defects (CHD), with approximately 40 to 60% of cases showing cardiac defects. This study assessed (i) the association between maternal LINE-1 methylation and the occurrence of CHDs in children with DS and (ii) the impact of endogenous maternal factors (MTHFR C677T polymorphism and maternal age) and exogenous maternal factors (cigarette smoking, alcohol intake, medication use, body mass index and dietary habits such as folate intake) on maternal LINE-1 methylation and on the occurrence of CHD in children with DS.Patients and Methods: The study included 90 mothers of children with DS of maternal origin (49% DS-CHD+ mothers/51% DS-CHD− mothers). LINE-1 DNA methylation was analyzed in peripheral blood lymphocytes by quantification of LINE-1 methylation using the MethyLight method. MTHFR C677T polymorphism genotyping was performed using PCR-RFLP.Results: LINE-1 methylation was not significantly different between DS-CHD+ and DS-CHD− mothers (P = 0.997). Combination of MTHFR C677T genotype/diet and BMI were significant independent predictors of LINE-1 DNA methylation in DS-CHD+ mothers (β −0.40, P = 0.01 and β −0.32, P = 0.03, respectively). In the analyzed multivariate model (model P = 0.028), these two factors explained around 72% of the variance in LINE-1 DNA methylation in mothers of children with DS and CHD. The group with the highest BMI (≥30 kg/m2) had significantly lower LINE-1 methylation than the group with normal BMI (Bonferroni post hoc P = 0.03) and the overweight group (Bonferroni post hoc P = 0.04). The lowest LINE-1 DNA methylation values were found in DS-CHD+ mothers with the CT+TT genotype and a low-folate diet; the values were significantly lower than the values in mothers with the CC genotype and a folate-rich diet (Bonferroni post hoc P = 0.04).Conclusion: Association between maternal LINE-1 methylation and CHD in children with DS was not found. Study showed that the MTHFR genotype/diet combination and BMI were significantly associated with LINE-1 methylation in mothers of children with DS-CHD+. These results highlight the need for a multifactorial approach to assess the roles of endogenous and exogenous maternal factors in maternal LINE-1 DNA methylation and the consequent pathologies in children. More extensive studies in a larger sample may help elucidate these relationships.

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“…Few studies have examined gene-environment interactions to identify those who may be more susceptible to the effects of air pollution with respect to risk of birth defects. One recent study performed a meta-prediction analysis to compare countries with different proportions of methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and air pollution exposure and risk of congenital heart defects (Yang, Yang, Yu, & Shiao, 2018). This study observed percentages of the TT and CT genotypes, relative to the CC genotype of the MTHFR gene, were increased in countries with higher levels of air pollution, with a trend of increased congenital heart defects risks with higher levels of air pollution.…”

Section: Introductionmentioning

confidence: 99%

Gene–environment interactions between air pollution and biotransformation enzymes and risk of birth defects

Padula

Yang

Schultz

et al. 2021

Birth Defects Research

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Genetic and environmental factors have been observed to influence risks for birth defects, though few studies have investigated gene-environment interactions. Our aim was to examine the interaction terms of gene variants in biotransformation enzyme pathways and air pollution exposures in relation to risk of several structural birth defects. We evaluated the role of ambient air pollutant exposure (nitrogen dioxide [NO 2 ], nitrogen oxide, carbon monoxide, particulate matter <10 [PM 10 ] and <2.5 [PM 2.5 ] microns) during pregnancy and 104 gene variants of biotransformation enzymes from infant bloodspots or buccal cells in a California population-based case-control study in 1997-2006. Cases included cleft lip with or without cleft palate (N = 206), gastroschisis (N = 94), tetralogy of Fallot (N = 69), and dextro-transposition of the great arteries (d-TGA; N = 40) and were compared to 208 nonmalformed controls.Overall, the results were not consistent, though did highlight some associations for further investigation as indicated by Wald chi-square test p value <.1.Increased risk of cleft lip was associated with exposure to high PM 10 and two CYP gene variants. High PM 2.5 and the variant of SLCO1B1 was associated with increased risk of teratology of Fallot. Higher NO 2 and two gene variants, CYP2A6 and SLC01B1, were associated with increased risk of d-TGA. Results for gastroschisis were inconsistent in direction and across pollutants. These exploratory results suggest that some individuals based on their genetic background may be more susceptible to the adverse effects of air pollution.

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Meta-Prediction of MTHFR Gene Polymorphism and Air Pollution on the Risks of Congenital Heart Defects Worldwide: A Transgenerational Analysis

Cited by 10 publications

References 64 publications

Environmental and Genetic Risk Factors of Congenital Anomalies: an Umbrella Review of Systematic Reviews and Meta-Analyses

Environmental and Genetic Risk Factors of Congenital Anomalies: an Umbrella Review of Systematic Reviews and Meta-Analyses

Maternal LINE-1 DNA Methylation and Congenital Heart Defects in Down Syndrome

Gene–environment interactions between air pollution and biotransformation enzymes and risk of birth defects

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