Environmental influence on the worldwide prevalence of a 776C->G variant in the transcobalamin gene (TCN2).

BACKGROUND: A 776C-->G variant (dbSNP ID: rs1801198) in the transcobalamin gene (TCN2; MIM# 275350) decreases the cellular and plasma concentration of transcobalamin and thereby influences the cellular availability of vitamin B(12). OBJECTIVE: To evaluate the worldwide prevalence of this variant and its association with homocysteine plasma level. METHODS: The study was performed in 1433 apparently healthy subjects, including Afro-Americans and Afro-Africans and in 251 Afro-Africans participants with severe malaria. RESULTS: The frequencies of the 776G allele were the highest in China (0.607; 95% CI 0.554 to 0.659), low in West Africa (Bénin and Togo, 0.178; 0.154 to 0.206), and intermediate in France (0.445; 0.408 to 0.481), Italy (0.352; 0.299 to 0.409), Morocco (0.370; 0.300 to 0.447) and Mexico (0.374; 0.392 to 0.419). The 776G genotype was more frequent in Afro-Americans from New York (16.7; 8.4 to 30.7) and in Afro-African patients with severe malaria (6.0%; 95% CI 3.7 to 9.6) than in healthy Afro-African volunteers (p = 0.0004 and p = 0.033, respectively), while no difference was observed for MTHFR 677TT and 677T alleles. A disequilibrium of TCN2 genotype distribution was recorded in patients with severe malaria, with a twofold higher GG genotype than expected (p = 0.010). An association between the TCN2 polymorphism and homocysteine was observed only in Mexico and France, the two countries with the highest rate of low plasma concentration of vitamin B(12) (<100 pmol/l). CONCLUSION: Given the dramatic heterogeneity of the 776G allele frequency worldwide, this polymorphism may be prone to a selective pressure or confers an evolutionary advantage in confronting environmental factors, one of which is malaria.

Using Genetic and Epigenetic Markers to Improve Differential Diagnosis of Prostate Cancer and Benign Prostatic Hyperplasia by Noninvasive Methods in Mexican Patients.

BACKGROUND: Prostate cancer (PCa) is the most common malignancy in Mexican men. Serum prostate-specific antigen (PSA) is the usual noninvasive biomarker used for its detection. Its low specificity can increase the number of unnecessary prostate biopsies and the incidence of unpleasant complications for patients. The androgen-receptor gene (AR-CAG) repeat length and the percentage of promoter methylation (PPM) of genes glutathione-S-transferase P1 (GSTP1) and Ras association domain family 1 isoform A (RASSF1A) improve PCa detection. As an option for noninvasive assessment, we evaluated a combined analysis of all these biomarkers. PATIENTS AND METHODS: A total of 186 patients scheduled for biopsy were included in the present study. PSA and AR-CAG repeats were analyzed in blood samples. The PPM of GSTP1 and RASSF1A genes was estimated in prostate tissue and urinary sediment cells (USCs) and plasma DNA using quantitative methylation-specific polymerase chain reaction. The predictive values for PCa and benign prostatic hyperplasia (BPH), logistic regression analysis, receiver operating characteristic curve, and decision curve analysis were used to assess the differential diagnosis. RESULTS: Statistically significant differences between PCa and BPH patients were observed for all biomarkers, with higher positive and negative predictive values when all biomarkers were included in the analysis, attaining USC values of 89.2% and 78.0%, respectively. The differential diagnosis accuracy of PSA (area under the curve, 0.59) increased to 0.70 and 0.68, respectively, when the combined analysis of PPM of RASSF1Aplasma or GSTP1AUSC and AR-CAG repeats was performed. Decision curve analysis showed the utility of the combined analysis to decrease the number of unnecessary biopsies. CONCLUSION: The results showed that combined analysis of the proposed biomarkers in plasma and USCs significantly increased the confidence for the differential diagnosis for PCa and BPH. This noninvasive practice might help in the early detection of PCa and patient follow-up, avoiding to some extent unnecessary prostate biopsies.

Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism is heterogeneously distributed worldwide, with the highest and lowest frequencies of the T allele in Mexico and Africa, respectively, and a south-to-north gradient in Europe. Distribution of MTHFR 1298A-->C is less well known. It has been hypothesized that 677T frequency could result in part from gene-nutrient interactions. OBJECTIVE: The objective was to compare the association of 677T and 1298C alleles with plasma concentrations of homocysteine, folate, and vitamin B-12 in geographical areas with contrasting 677T allele frequencies. DESIGN: Healthy young adults (n = 1277) were recruited in Mexico City, the West African countries of Bénin and Togo, France, and Sicily (Italy). Homocysteine, folate, and vitamin B-12 were measured in plasma, and MTHFR polymorphisms were measured in genomic DNA. RESULTS: Mexico City and Sicily reported the highest and Bénin and Togo reported the lowest plasma concentrations of folate. Mexico City had the highest 677T allele prevalence and the lowest influence of 677TT genotype on homocysteine, whereas the opposite was observed in Africa. The prevalence of the 1298C allele was lowest in the Mexicans and Africans and highest in the French. The percentage of the 677T genotype was significantly associated with the folate concentrations in 677CC carriers in a univariate analysis (R = 0.976; 95% CI: 0.797, 0.996; P < 0.0002) and in a multiple regression model that included homocysteine, vitamin B-12, and age (P = 0.0002). CONCLUSION: Our data agree with the hypothesis of a gene-nutrient interaction between MTHFR 677C-->T polymorphism and folate status that may confer a selective advantage of TT-homozygous genotype when dietary intake of folate is adequate, at least in the areas studied.