Background:Folate is an essential nutrient that supports nucleotide synthesis and biological methylation reactions. Diminished folate status results in chromosome breakage and is associated with several diseases, including colorectal cancer. Folate status is also inversely related to plasma homocysteine concentrations-a risk factor for cardiovascular disease. Objective: We sought to gain further understanding of the genetic determinants of plasma folate and homocysteine concentrations. Because folate is required for the synthesis of thymidine from uracil, the latter accumulating and being misincorporated into DNA during folate depletion, the DNA uracil content was also measured. Design: Thirteen single nucleotide polymorphisms (SNPs) in genes involved in folate uptake and metabolism, including folate hydrolase (FOLH1), folate polyglutamate synthase (FPGS), ␥-glutamyl hydrolase (GGH), methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC1), were studied in a cohort of 991 individuals. Results: The MTHFR 677TT genotype was associated with increased plasma homocysteine and decreased plasma folate. MTHFR 1298AC and RFC1 intron 5AG polymorphisms were associated with significantly altered plasma homocysteine concentrations. The FOLH1 1561CT SNP was associated with altered plasma folate concentrations. The MTHFR 677TT genotype was associated with a Ȃ34% lower DNA uracil content (P ҃ 0.045), whereas the G allele of the GGH Ҁ124TG SNP was associated with a stepwise increase in DNA uracil content (P ҃ 0.022). Conclusion: Because the accumulation of uracil in DNA induces chromosome breaks, mutagenic lesions, we suggest that, as for MTHFR C677T, the GGH Ҁ124 TG SNP may modulate the risk of carcinogenesis and therefore warrants further attention.

Objective : The aim of this work was to fine-map the region 6q23.1, which obtained suggestive linkage signal (logarithm of the odds [LOD] score = 2.22 under a recessive model) to cleft lip with or without cleft palate (CL±P) in our previous genome-wide linkage scan to identify possible genetic variants that may contribute to CL±P. Design : We used densely spaced markers spanning the entire 6q23.1 region to test for association with CL±P in a family cohort sample. Setting : Clinical information and DNA samples were obtained from families in the Philippines at their homes or primary health care clinics. Participants : The study sample consisted of 477 subjects (224 females and 253 males), segregating isolated CL±P, from 72 living in the same area in the Philippines. Main Outcome Measure : Overtransmission of alleles to persons born with CL±P. Results : We found statistical evidence of association between a marker of TULP4 (rs651333) with CL±P (P = .00007). Conclusions : Our results further support the linkage results for the chromosome 6q region and reveal a novel candidate gene for CL±P.