rs3016432

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.

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.