rs3733890

Case-control study of 169 omphalocele cases and 761 controls examining variants in folate, vitamin B12, and homocysteine metabolism genes. Variants in transcobalamin receptor (TCblR) rs2232775 (Q8R) and methylenetetrahydrofolate reductase (MTHFR) rs1801131 (1298A>C) were significantly associated with omphalocele (TCblR OR=3.20, p=0.0017; MTHFR OR=2.04, p=0.028). Additional race-ethnicity-specific associations were found with TCN2, BHMT rs3733890, and FOLH1 variants, suggesting disruption of methylation reactions as a potential risk factor.

This family-based association study examined 14 folate pathway genes using 89 SNPs in 445 NSCLP families (317 non-Hispanic White, 128 Hispanic) to identify genetic variants contributing to nonsyndromic cleft lip and palate. Evidence for association was found with SNPs in NOS3 and TYMS in the non-Hispanic White group (rs2373929/NOS3, rs502396/TYMS, and others), and with MTR, BHMT2, MTHFS, and SLC19A1 in the Hispanic group (rs1422086/BHMT2, rs2115540/MTHFS significant after Bonferroni correction). Multiple gene-gene interactions were detected, with CBS and MTHFD1 showing the most extensive interactions. Significant interactions were also found between several SNPs and maternal smoking and one SNP (rs651646/FOLR2) with offspring sex.

This case-control study examined 21 SNPs in 13 folate and choline metabolism genes for associations with tooth agenesis (hypodontia/oligodontia) in a Polish population of 159 cases and 185 controls. The CHDH gene variant rs6445606 showed the strongest association with a protective effect (OR=0.434, p=0.0004), with individuals carrying the C allele having reduced risk of tooth agenesis. Multifactor dimensionality reduction analysis revealed a significant epistatic interaction between CHDH rs6445606 and PLD2 rs3764897 (p=0.004).

A pathway-wide association study in 425 case-parent triads examined 109 SNPs in 29 folate/one-carbon metabolism genes and 68 SNPs in 16 vitamin A metabolism genes for associations with cleft lip/palate (CL/P) and cleft palate only (CPO). Despite strong epidemiologic evidence that folic acid and vitamin A reduce cleft risk, no convincing genetic associations were found; the strongest association was FOLH1 with CPO (p=0.0008), but findings were fewer than expected by chance and inconsistent with protective effects of vitamin supplementation, suggesting vitamin metabolism gene polymorphisms do not play an etiologic role in oral facial clefts.

This family-based association study examined 12 polymorphisms in one-carbon metabolism genes (BHMT, CBS, MTHFD1, MTHFR, MTR, MTRR, SLC19A1, TCN2) and their associations with oral facial clefts in 553 Norwegian families. CBS rs234706 showed a significant maternal protective effect on cleft lip/palate risk (LRT p=0.008), with homozygous carriers of the T allele showing reduced risk (RR=0.50, 95% CI 0.26-0.96). MTHFR rs1801133 demonstrated a protective effect in the low-folate supplementation subset (RR=0.60-0.44), and maternal folic acid supplementation ≥400 μg/day was associated with 39% reduction in cleft lip/palate risk.