Background Folate plays a critical role in DNA synthesis, fetal development, and epigenomic regulation and its deficiencies can lead to several health defects, including adverse pregnancy outcomes and congenital heart defects (CHDs). Folic acid supplementation represents a low-cost, high-impact preventive strategy in maternal and child health, with particular relevance for underserved and high-risk populations. Method Five one carbon metabolism gene variants (rs1801131, rs1801133 of MTHFR; rs1805087 of MTR; rs526934 of TCN1; rs2236225 of MTHFD1) with minor allele frequency > 0.1 were genotyped in 674 non-syndromic CHD cases (including 449 families) and 356 pooled controls. The data were analyzed for case–control associations, parental transmission patterns, and correlations with nutritional status. Results Among the genetic variants analyzed, rs2236225 showed a strong allelic association with congenital heart disease (CHD) across all cases (A vs. G, p = 0.0003; OR = 1.4 [95% CI: 1.17–1.69]). This association was primarily driven by the ‘A’ allele, which emerged as a significant risk factor, especially within the acyanotic subgroup (A vs. G, p = 0.0001; OR = 1.47 [95% CI: 1.20–1.79]), and more specifically in ventricular septal defect (VSD) cases (A vs. G, p = 0.0003; OR = 1.5 [95% CI: 1.20–1.89]). A homozygous excess of genotypes was observed in Acyanotic group (AA vs GG, p = 0.0001; OR = 2.27[95% CI: 1.5─3.43]. Other Allelic association with ASD (p = 0.04); TOF (p = 0.02) and cyanotic group (p = 0.05) along with other genetic models was also noted. These findings underscore the potential involvement of rs2236225 in CHD pathogenesis and warrant further investigation into its clinical relevance. The MTHFR haplotype rs1801131–rs1801133 (CA) showed a significant association with CHD in both case–control and transmission disequilibrium analyses (p = 0.03), although neither SNP was independently significant. The common allele of rs1805087 was associated with CHD overall (p = 0.007; AG vs. AA), with a stronger effect observed in cyanotic cases (p = 0.005). Furthermore, this allele showed significant associations with maternal transmission (p = 0.01) and folic acid supplementation (p = 0.02), suggesting a gene-environment interaction. The rare allele of rs526934 exibited a dominant effect in acyanotic CHD cases (GG + AG vs. AA, p = 0.004). It also showed significant associations under a dominant model in VSD (p = 0.01) and ASD (p = 0.03). Conclusion This dual-model study from North India offers a comprehensive evaluation of functional folate pathway gene variants in a large CHD cohort and suggest a complex interplay between genetic susceptibility and environmental factors, supporting a polygenic or gene–environment interaction model. Further validation in larger, well-characterized cohorts, incorporating additional variants, is essential to clarify the contribution of folate pathway polymorphisms to CHD aetiology.

Congenital heart disease and folate pathway gene polymorphisms: findings from a North Indian cohort

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2026年1月17日

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Prachi Kukshal,
Shadab Ahamad,
Radha Joshi,
Ajay Kumar,
Subramanian Chellappan

摘要

Background

Folate plays a critical role in DNA synthesis, fetal development, and epigenomic regulation and its deficiencies can lead to several health defects, including adverse pregnancy outcomes and congenital heart defects (CHDs). Folic acid supplementation represents a low-cost, high-impact preventive strategy in maternal and child health, with particular relevance for underserved and high-risk populations.

Method

Five one carbon metabolism gene variants (rs1801131, rs1801133 of MTHFR; rs1805087 of MTR; rs526934 of TCN1; rs2236225 of MTHFD1) with minor allele frequency > 0.1 were genotyped in 674 non-syndromic CHD cases (including 449 families) and 356 pooled controls. The data were analyzed for case–control associations, parental transmission patterns, and correlations with nutritional status.

Results

Among the genetic variants analyzed, rs2236225 showed a strong allelic association with congenital heart disease (CHD) across all cases (A vs. G, p = 0.0003; OR = 1.4 [95% CI: 1.17–1.69]). This association was primarily driven by the ‘A’ allele, which emerged as a significant risk factor, especially within the acyanotic subgroup (A vs. G, p = 0.0001; OR = 1.47 [95% CI: 1.20–1.79]), and more specifically in ventricular septal defect (VSD) cases (A vs. G, p = 0.0003; OR = 1.5 [95% CI: 1.20–1.89]). A homozygous excess of genotypes was observed in Acyanotic group (AA vs GG, p = 0.0001; OR = 2.27[95% CI: 1.5─3.43]. Other Allelic association with ASD (p = 0.04); TOF (p = 0.02) and cyanotic group (p = 0.05) along with other genetic models was also noted. These findings underscore the potential involvement of rs2236225 in CHD pathogenesis and warrant further investigation into its clinical relevance.

The MTHFR haplotype rs1801131–rs1801133 (CA) showed a significant association with CHD in both case–control and transmission disequilibrium analyses (p = 0.03), although neither SNP was independently significant.

The common allele of rs1805087 was associated with CHD overall (p = 0.007; AG vs. AA), with a stronger effect observed in cyanotic cases (p = 0.005). Furthermore, this allele showed significant associations with maternal transmission (p = 0.01) and folic acid supplementation (p = 0.02), suggesting a gene-environment interaction.

The rare allele of rs526934 exibited a dominant effect in acyanotic CHD cases (GG + AG vs. AA, p = 0.004). It also showed significant associations under a dominant model in VSD (p = 0.01) and ASD (p = 0.03).

Conclusion

This dual-model study from North India offers a comprehensive evaluation of functional folate pathway gene variants in a large CHD cohort and suggest a complex interplay between genetic susceptibility and environmental factors, supporting a polygenic or gene–environment interaction model. Further validation in larger, well-characterized cohorts, incorporating additional variants, is essential to clarify the contribution of folate pathway polymorphisms to CHD aetiology.