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Genetic and environmental determinants of plasma total homocysteine levels: impact of population-wide folate fortification.

ABSTRACT: Folate metabolism is an important target for drug therapy. Drug-induced inhibition of folate metabolism often causes an elevation of plasma total homocysteine (tHcy). Plasma tHcy levels are influenced by several nongenetic (e.g. folate intake, age, smoking) as well as genetic factors. Over the last decade, several countries have implemented a nationwide folate fortification program of all grain products. This investigation sought to determine the impact of folate fortification on the relative contribution of environmental and genetic factors to the variability of plasma tHcy.Two cohorts were compared in this study, one from the United States (with folate fortification, n=281) and one from Austria (without folate fortification, n=139). Several environmental factors as well as previously identified gene variants important for tHcy levels (MTHFR C677T, MTHFR A1298C, MTRR A66G) were examined for their ability to predict plasma tHcy in a multiple linear regression model.Nongenetic, environmental factors had a comparable influence on plasma tHcy between the two cohorts (R: approximately 0.19). However, after adjusting for other covariates, the tested gene variants had a substantially smaller impact among patients from the folate-fortified cohort (R=0.021) compared with the nonfolate-fortified cohort (R=0.095). The MTHFR C677T polymorphism was the single most important genetic factor. Male sex, smoking, and folate levels were important predictors for nonfolate-fortified patients; age was for folate-fortified patients.Population wide folate fortification had a significant effect on the variability of plasma tHcy and reduced the influence of genetic factors, most importantly the MTHFR 677TT genotype, and may be an important confounder for a personalized drug therapy.

SUBMITTER: Nagele P

PROVIDER: S-EPMC3116052 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Genetic and environmental determinants of plasma total homocysteine levels: impact of population-wide folate fortification.

Nagele Peter P Meissner Konrad K Francis Amber A Födinger Manuela M Saccone Nancy L NL

Pharmacogenetics and genomics 20110701 7

<h4>Objectives</h4>Folate metabolism is an important target for drug therapy. Drug-induced inhibition of folate metabolism often causes an elevation of plasma total homocysteine (tHcy). Plasma tHcy levels are influenced by several nongenetic (e.g. folate intake, age, smoking) as well as genetic factors. Over the last decade, several countries have implemented a nationwide folate fortification program of all grain products. This investigation sought to determine the impact of folate fortification ...[more]

PMID: 21597397

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Project description:PurposeThis study aimed to identify and quantify the association and investigate whether serum vitamin B12 alone or vitamin B12 combined with folate and plasma total homocysteine (tHcy) levels could be used to predict the risk of acute ischemic stroke.Materials and methodsThis retrospective case-control study was conducted in the Department of Neurology, First Affiliated Hospital of Chongqing Medical University. It included 259 inpatients experiencing their first-ever acute ischemic stroke and 259 age-matched, sex-matched healthy controls. Patients were categorized into groups based on the etiology of their stroke: large-artery atherosclerosis (LAAS, n = 126), cardio embolism (CEI, n = 35), small vessel disease (SVD, n = 89), stroke of other determined etiology (ODE, n = 5), and stroke of undetermined etiology (UDE, n = 4). The associations of serum vitamin B12, folate, and plasma tHcy levels with the risk of ischemic stroke were evaluated using multivariable logistic regression analysis. Receiver operator characteristic (ROC) curves were used to assess the diagnostic power of vitamin B12, folate, and tHcy levels for ischemic stroke.ResultsSerum vitamin B12 and folate levels were significantly lower in ischemic stroke patients compared to controls, while plasma tHcy levels were significantly higher. The first quartile of serum vitamin B12 levels was significantly associated with an increased risk of LAAS (aOR = 2.289, 95% CI = 1.098-4.770), SVD (aOR = 4.471, 95% CI = 1.110-4.945) and overall ischemic stroke (aOR = 3.216, 95% CI = 1.733-5.966). Similarly, the first quartile of serum folate levels was associated with an increased risk of LAAS (aOR = 3.480, 95% CI = 1.954-6.449), CEI (aOR = 2.809, 95% CI = 1.073-4.991), SVD (aOR = 5.376, 95% CI = 1.708-6.924), and overall ischemic stroke (aOR = 3.381, 95% CI = 1.535-7.449). The fourth quartile of tHcy levels was also significantly associated with an increased risk of LAAS (aOR = 2.946, 95% CI = 1.008-5.148), CEI (aOR = 2.212, 95% CI = 1.247-5.946), SVD (aOR = 2.957, 95% CI = 1.324-6.054), and overall ischemic stroke (aOR = 2.233, 95% CI = 1.586-4.592). For predicting different types of ischemic stroke, vitamin B12 alone demonstrated the best diagnostic value for SVD, evidenced by a sensitivity of 71.0% and negative predictive value of 90.3%, along with the highest positive likelihood ratio (+ LR) for SVD. Vitamin B12 + tHcy + folate are valuable in predicting different types of ischemic stroke, with the most significant effect observed in SVD, followed by LAAS, and the weakest predictive effect in CEI. Additionally, vitamin B12 alone in combination with other indicators, such as folate alone, tHcy alone, and folate + tHcy could reduce negative likelihood ratio (-LR) and improve + LR.ConclusionsVitamin B12 was an independent risk factor for acute ischemic stroke. The risk calculation model constructed with vitamin B12 + tHcy + folate had the greatest diagnostic value for SVD.

Project description:There is widespread vitamin and mineral deficiency problem in Tanzania with known deficiencies of at least vitamin A, iron, folate and zinc, resulting in lasting negative consequences especially on maternal health, cognitive development and thus the nation's economic potential. Folate deficiency is associated with significant adverse health effects among women of reproductive age, including a higher risk of neural tube defects. Several countries, including Tanzania, have implemented mandatory fortification of wheat and maize flour but evidence on the effectiveness of these programs in developing countries remains limited. We evaluated the effectiveness of Tanzania's food fortification program by examining folate levels for women of reproductive age, 18-49 years. A prospective cohort study with 600 non-pregnant women enrolled concurrent with the initiation of food fortification and followed up for 1 year thereafter. Blood samples, dietary intake and fortified foods consumption data were collected at baseline, and at 6 and 12 months. Plasma folate levels were determined using a competitive assay with folate binding protein. Using univariate and multivariate linear regression, we compared the change in plasma folate levels at six and twelve months of the program from baseline. We also assessed the relative risk of folate deficiency during follow-up using log-binomial regression. The mean (±SE) pre-fortification plasma folate level for the women was 5.44-ng/ml (±2.30) at baseline. These levels improved significantly at six months [difference: 4.57ng/ml (±2.89)] and 12 months [difference: 4.27ng/ml (±4.18)]. Based on plasma folate cut-off level of 4 ng/ml, the prevalence of folate deficiency was 26.9% at baseline, and 5% at twelve months. One ng/ml increase in plasma folate from baseline was associated with a 25% decreased risk of folate deficiency at 12 months [(RR = 0.75; 95% CI = 0.67-0.85, P<0.001]. In a setting where folate deficiency is high, food fortification program with folic acid resulted in significant improvements in folate status among women of reproductive age.

Dataset Information

Genetic and environmental determinants of plasma total homocysteine levels: impact of population-wide folate fortification.

Publications

Genetic and environmental determinants of plasma total homocysteine levels: impact of population-wide folate fortification.

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