Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts - PubMed (original) (raw)

Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts

Abee L Boyles et al. Am J Med Genet A. 2008.

Abstract

Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 microg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts.

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Figures

Fig. 1

Fig. 1

Folate and one-carbon metabolic pathway. Enzymes are enclosed in ellipses and substrates are enclosed in boxes. The cell membrane is represented by the dotted ellipse. Enzymatic steps are indicated by solid lines, whereas transport functions are indicated by dashed lines. Biological functions are indicated by dotted lines. Abbreviations: 5-CH3 THF, 5-methyltetrahydrofolate; 5,10-CH = THF, 5,10-methenyltetrahydrofolate; 5,10-CH2-THF, 5,10-methylenetetrahydrofolate; 10f-THF, 10-formyltetrahydrofolate; AdoMet, _S_-adenosylmethionine; AdoHcy, _S_-adenosylhomocysteine; Cysta, cystathionine; DHF, dihydrofolate; Hcy, homocysteine; Hcy-tl, homocysteine thiolactone; Met, methionine; THF, tetrahydrofolate.

Fig. 2

Fig. 2

Relative risks of CL/P (A) and CPO (B) and their 95% confidence intervals of zero (ref), one, and two copies of each polymorphism for child’s genotype and mother’s genotype in the full dataset. Estimates are graphed vertically for each variant. Only the LRT of CBS rs234706 with CL/P for the maternal genotype was less than 0.05 (P = 0.008). The low minor allele frequency for the 68bp insertion in CBS prevented calculation of a relative risk for two copies in the child’s genotype for CL/P and in the mother’s genotype for CPO.

Fig. 2

Fig. 2

Relative risks of CL/P (A) and CPO (B) and their 95% confidence intervals of zero (ref), one, and two copies of each polymorphism for child’s genotype and mother’s genotype in the full dataset. Estimates are graphed vertically for each variant. Only the LRT of CBS rs234706 with CL/P for the maternal genotype was less than 0.05 (P = 0.008). The low minor allele frequency for the 68bp insertion in CBS prevented calculation of a relative risk for two copies in the child’s genotype for CL/P and in the mother’s genotype for CPO.

Fig. 3

Fig. 3

Relative risks of CL/P with 95% CIs and LRT P values in the full, <400, and >400 μg folate datasets. The four SNPs where any LRT _P_-value was less than 0.05 are shown: (A) CBS rs234706, (B) MTHFR rs1801133, (C) BHMT rs3733890, and (D) TCN2 rs1801198.

Fig. 3

Fig. 3

Relative risks of CL/P with 95% CIs and LRT P values in the full, <400, and >400 μg folate datasets. The four SNPs where any LRT _P_-value was less than 0.05 are shown: (A) CBS rs234706, (B) MTHFR rs1801133, (C) BHMT rs3733890, and (D) TCN2 rs1801198.

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