The relationship between colorectal cancer (CRC) and folate metabolism is complex. Dietary folate, depending on the timing and dose, may either prevent or enhance tumour initiation and/or growth, and polymorphisms in the genes encoding folate-metabolising enzymes may also modulate risk. In this thesis, the Apcmin/+ mouse model of CRC was used to investigate the effect of nutritional and genetic disturbances in folate metabolism on tumourigenesis and to examine various mechanisms. / The reduced folate carrier I (RFC1) is responsible for the cellular uptake and intestinal absorption of folate, primarily the 5-methyltetrahydrofolate (5-methylTHF) derivative. Methionine synthase (MTR) uses 5-methylTHF to remethylate homocysteine to methionine, which may be activated and used to methylate substrates such as DNA. 5-MethylTHF is also the product of the methylenetetrahydrofolate reductase (MTHFR)-catalysed reduction of 5,10-methyleneTHF, which is also used to convert dUMP to dTMP. / Adenoma number and load were reduced in Rfc1+/-Apc min/+ mice, compared with Rfc1+/+Apc min/+ mice, but were similar in Mtr+/-Apc min/+ and Mtr+/+ Apcmin/+ mice. Neither Rfc1 nor Mtr genotype affected global DNA methylation, apoptosis or plasma homocysteine (tHcy) levels. In the experiments involving Mtr mice, dietary folate deficiency increased adenoma number, plasma tHcy, and apoptosis, and decreased global DNA methylation. Neither Mtr nor Rfc1 genotype affected the dUTP/dTTP ratio in the intestine of mice not predisposed to adenoma formation. / Adenoma number was decreased in Mthfr+/-Apc min/+ mice (compared with Mthfr+/+Apc min/+ mice) and in Mthfr+/+Apc min/+ offspring of Mthfr+/- mothers (compared with Mthfr+/+Apcmin/+ offspring of Mthfr+/+ mothers). A folate-deficient diet, when initiated prior to conception, significantly decreased adenoma number and decreased global DNA methylation. Overall, adenoma number was inversely correlated with plasma tHcy, dUTP/dTTP ratio and apoptosis. When initiated at three weeks of age, a folate-enriched diet significantly increased adenoma number in Apcmin/+ mice. In the intestines of mice not predisposed to adenoma formation, Mthfr deficiency decreased, and folic acid deficiency increased, the dUTP/dTTP ratio. / These results support the evidence that MTHFR polymorphisms are protective in CRC tumourigenesis and that depending on stage or predisposition, folate may inhibit or enhance tumour growth.

No description available.

Elevated total plasma homocysteine (tHcy) is a risk factor for cardiovascular disease and neurocognitive disease such as dementia. The B vitamins folate and B12 are the main de terminants of tHcy. tHcy concentration can also be affected by mutations in genes coding for receptors, enzymes and transporters important in the metabolism of Hcy. This thesis focuses on mutations in the genes for folate receptor-alpha and methylenetetrahydrofolate reductase (MTHFR) and the effect they have on tHcy concentrations. Six novel mutations in the gene for folate receptor-alpha were described in Paper I. Taken together they exist in a population with a prevalence of approximately 1% and thus are not unusual. There may be an association of –69dupA and –18C>T to tHcy but for the 25-bp deletion, –856C>T, –921T>C and –1043G>A there is probably no association to tHcy. Mutation screening was continued and four additional mutations, 1314G>A, 1816delC, 1841G>A and 1928C>T, were described in Paper II. The prevalences for the heterozygotes were between 0.5% and 13% in an elderly population. There was no significant difference in prevalence between the elderly subjects and patients with dementia. The 1816(–)-allele and the 1841A-allele were in complete linkage and the haplotype 1816(–)-1841A may possibly have a tHcy raising effect. The 1314G>A and 1928C>T mutations had no association to tHcy. The genotype prevalences and haplotype frequencies of the MTHFR 677C>T, 1298A>C and 1793G>A polymorphisms were determined in a population sample of Swedish children and adolescents (Paper III). The MTHFR 677T-allele was associated with increased tHcy concentrations in both children and adolescents. A small elevating effect of the 1298C-allele and a small lowering effect of the 1793A-allele could be shown. In an epidemiological sample of adults from the Canary Islands, Spain, data for serum folate and vitamin B12 were used for a broader study of the nutrigenetic impact on tHcy (Paper IV). The 677T-allele had a significant tHcy increasing effect in men but not in women. The 1298C-allele had a minor elevating effect on tHcy in men with the 677CT genotype. It was not possible to document any effect of the 1793A-allele on tHcy due to its low prevalence. A slightly superior explanatory power for the genetic impact was obtained using the MTHFR haplotypes in the analysis compared to the MTHFR 677C>T genotype-based approach in both the Swedish children and adolescents and in the Spanish adults. Therefore MTHFR haplotypes should be considered when analysing the impact of the MTHFR 677C>T, 1298A>C and 1793G>A polymorphisms on tHcy. Notwithstanding the large geographical distance between our study populations the haplotype composition is quite similar. The MTHFR 677T-allele is slightly more prevalent in Spain compared to Sweden but it has only an effect on tHcy in the Spanish men. Age, gender and factors linked to the ethnicity of the studied subjects, seem to be able to override the nutrigenetic impact of tHcy-raising genotypes or haplotypes in particular settings, such as in the Spanish women in our study. Gene-nutrient interactions on plasma tHcy levels thus may or may not exist in a certain population. The transferability of nutrigenetic findings may therefore be limited, and must be re-evaluated for each particular setting of age-gender-ethnicity.

Thesis (Ph. D.)--Oregon State University, 2008. / Includes bibliographical references. Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Thesis (Ph. D.)--Oregon State University, 2008. / Includes bibliographical references.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Kardiyoloji Anabilim Dalı, 2005. / Bibliyografya var.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Thesis (M.Sc. (Tropical Medicine))--Mahidol University, 2003.

Thesis (Ph. D.)--Case Western Reserve University, 2006. / [School of Medicine] Department of Genetics. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Thesis (M. Sc. (Pharmacy))--Rhodes University, 2006.