Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects

Conotruncal and related heart defects (CTRD) are common, complex malformations. Although there are few established risk factors, there is evidence that genetic variation in the folate metabolic pathway influences CTRD risk. This study was undertaken to assess the association between inherited (i.e., case) and maternal gene-gene interactions in this pathway and the risk of CTRD. Case-parent triads (n=727), ascertained from the Children's Hospital of Philadelphia, were genotyped for ten functional variants of nine folate metabolic genes. Analyses of inherited genotypes were consistent with the previously reported association betweenMTHFRA1298C and CTRD (adjustedP=.02), but provided no evidence that CTRD was associated with inherited gene-gene interactions. Analyses of the maternal genotypes provided evidence of aMTHFRC677T/CBS844ins68 interaction and CTRD risk (unadjustedP=.02). This association is consistent with the effects of this genotype combination on folate-homocysteine biochemistry but remains to be confirmed in independent study populations.

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Vitamins B2 and B6 and Genetic Polymorphisms Related to One-Carbon Metabolism as Risk Factors for Gastric Adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition

Cancer Epidemiology Biomarkers & Prevention ◽

10.1158/1055-9965.epi-08-1096 ◽

2010 ◽

Vol 19 (1) ◽

pp. 28-38 ◽

Cited By ~ 22

Author(s):

Simone J.P.M. Eussen ◽

Stein Emil Vollset ◽

Steinar Hustad ◽

Øivind Midttun ◽

Klaus Meyer ◽

...

Keyword(s):

Risk Factors ◽

Genetic Polymorphisms ◽

Gastric Adenocarcinoma ◽

Carbon Metabolism ◽

One Carbon Metabolism ◽

Prospective Investigation

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Relationships among folate, alcohol consumption, gene variants in one-carbon metabolism and p16INK4a methylation and expression in healthy breast tissues

Carcinogenesis ◽

10.1093/carcin/bgu219 ◽

2014 ◽

Vol 36 (1) ◽

pp. 60-67 ◽

Cited By ~ 11

Author(s):

Adana A. Llanos ◽

Ramona G. Dumitrescu ◽

Theodore M. Brasky ◽

Zhenhua Liu ◽

Joel B. Mason ◽

...

Keyword(s):

Alcohol Consumption ◽

Carbon Metabolism ◽

Gene Variants ◽

One Carbon Metabolism ◽

Breast Tissues

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Genetic Polymorphisms in Enzymes Involved in One-Carbon Metabolism and Anti-epileptic Drug Monotherapy on Homocysteine Metabolism in Patients With Epilepsy

Frontiers in Neurology ◽

10.3389/fneur.2021.683275 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shaofang Zhu ◽

Guanzhong Ni ◽

Lisen Sui ◽

Yiran Zhao ◽

Xiaoxu Zhang ◽

...

Keyword(s):

Risk Factors ◽

Carbon Metabolism ◽

Methylenetetrahydrofolate Reductase ◽

Folate Receptor ◽

Linear Regression Analysis ◽

Elevated Serum ◽

Anti Epileptic Drug ◽

Independent Risk Factors ◽

One Carbon Metabolism ◽

Patients With Epilepsy

Aims: To investigate the effects of single nucleotide polymorphisms (SNPs) in genes of one-carbon metabolism (OCM) related enzymes and anti-epileptic drug (AED) monotherapy on homocysteine (Hcy) metabolism in patients with epilepsy, and to further explore specific SNPs that may increase patients' susceptibility to the effects of AEDs on the Hcy imbalance.Method: This case-control study analyzed 279 patients with epilepsy, including patients receiving monotherapy with valproate (VPA) (n = 53), oxcarbazepine (OXC) (n = 71), lamotrigine (LTG) (n = 55), or levetiracetam (LEV) (n = 35) and patients who had not taken any AEDs (controls, n = 65) for at least 6 months. Serum levels of vitamin B12 (vit B12), folate (FA) and Hcy were measured, and 23 SNPs in 13 genes of OCM-related enzymes were genotyped in all patients.Results: Methylenetetrahydrofolate reductase (MTHFR) rs1801133 was associated with elevated serum Hcy levels in patients with epilepsy (P < 0.001), and patients presenting the TT genotype exhibited higher serum Hcy levels than patients with the CC (P < 0.001) or CT (P < 0.001) genotype. A subsequent multiple linear regression analysis showed that AED monotherapy with VPA (vs. control: P = 0.023) or OXC (vs. control: P = 0.041), and genotypes of MTHFR rs1801133 TT (vs. CC: P < 0.001; vs. CT: P < 0.001), transcobalamin 2 (TCN2) rs1801198 CC (vs. GC: P = 0.039) and folate receptor 1 (FOLR1) rs2071010 AA (vs. GA: P = 0.031) were independent risk factors for higher Hcy levels. In the subgroup analysis of patients taking OXC, we found that patients with genotypes of MTHFR rs1801133 TT (vs. CC: P = 0.001; vs. CT: P < 0.001) and TCN2 rs1801198 CC (vs. GC: P = 0.021; vs. GG: P = 0.018) exhibited higher serum Hcy levels.Conclusions: VPA, OXC, and genotypes of MTHFR rs1801133 TT, TCN2 rs1801198 CC, and FOLR1 rs2071010 AA are all independent risk factors for elevated Hcy levels in patients with epilepsy. Moreover, genotypes of MTHFR rs1801133 TT and TCN2 rs1801198 CC may increase patients' susceptibility to the effect of OXC on disrupting Hcy homeostasis.

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