[Show abstract][Hide abstract] ABSTRACT: Women who have low cobalamin (vitamin B(12)) levels are at increased risk for having children with neural tube defects (NTDs). The transcobalamin II receptor (TCblR) mediates uptake of cobalamin into cells. Inherited variants in the TCblR gene as NTD risk factors were evaluated.
Case-control and family-based tests of association were used to screen common variation in TCblR as genetic risk factors for NTDs in a large Irish group. A confirmatory group of NTD triads was used to test positive findings.
2 tightly linked variants associated with NTDs in a recessive model were found: TCblR rs2336573 (G220R; p(corr)=0.0080, corrected for multiple hypothesis testing) and TCblR rs9426 (p(corr)=0.0279). These variants were also associated with NTDs in a family-based test before multiple test correction (log-linear analysis of a recessive model: rs2336573 (G220R; RR=6.59, p=0.0037) and rs9426 (RR=6.71, p=0.0035)). A copy number variant distal to TCblR and two previously unreported exonic insertion-deletion polymorphisms were described.
TCblR rs2336573 (G220R) and TCblR rs9426 represent a significant risk factor in NTD cases in the Irish population. The homozygous risk genotype was not detected in nearly 1000 controls, indicating that this NTD risk factor may be of low frequency and high penetrance. 9 other variants are in perfect linkage disequilibrium with the associated single nucleotide polymorphisms. Additional work is required to identify the disease-causing variant. Our data suggest that variation in TCblR plays a role in NTD risk and that these variants may modulate cobalamin metabolism.
Journal of Medical Genetics 10/2010; 47(10):677-85. DOI:10.1136/jmg.2009.073775 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: High blood pressure (BP) and elevated homocysteine are reported as independent risk factors for CVD and stroke in particular. The main genetic determinant of homocysteine concentrations is homozygosity (TT genotype) for the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, typically found in approximately 10% of Western populations. The B-vitamins folate, vitamin B12 and vitamin B6 are the main nutritional determinants of homocysteine, with riboflavin more recently identified as a potent modulator specifically in individuals with the TT genotype. Although observational studies have reported associations between homocysteine and BP, B-vitamin intervention studies have shown little or no BP response despite decreases in homocysteine. Such studies, however, have not considered the MTHFR C677T polymorphism, which has been shown to be associated with BP. It has been shown for the first time that riboflavin is an important determinant of BP specifically in individuals with the TT genotype. Research generally suggests that 24 h ambulatory BP monitoring provides a more accurate measure of BP than casual measurements and its use in future studies may also provide important insights into the relationship between the MTHFR polymorphism and BP. Further research is also required to investigate the association between specific B-vitamins and BP in individuals with different MTHFR genotypes in order to confirm whether any genetic predisposition to hypertension is correctable by B-vitamin intervention. The present review will investigate the evidence linking the MTHFR C677T polymorphism to BP and the potential modulating role of B-vitamins.
Proceedings of The Nutrition Society 12/2009; 69(1):156-65. DOI:10.1017/S0029665109991728 · 5.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate associations between nonsyndromic oral clefts and biochemical measures of folate status and the MTHFR C677T variant in the United Kingdom, where there has been no folic acid fortification program.
Dietary details were obtained from the mothers of 112 cases of cleft lip with or without cleft palate (CL+/-P), 78 cleft palate only (CP) cases, and 248 unaffected infants. Infant and parental MTHFR C677T genotype was determined. Red blood cell (RBC) and serum folate and homocysteine levels were assessed in 12-month postpartum blood samples from a subset of mothers. The data were analyzed by logistic and log-linear regression methods.
There was an inverse association between CL+/-P and maternal MTHFR CT (odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.31-0.95) and TT (OR = 0.6, 95% CI = 0.21-1.50) genotypes, with similar risk estimates for CP. There was no clear association with infant MTHFR genotype. Higher levels of maternal postpartum RBC and serum folate were associated with a lower risk for CL+/-P and an increased risk for CP. Higher levels of serum homocysteine were associated with a slightly increased risk for both CL+/-P and CP.
While the inverse relation between the mother's having the MTHFR C677T variant and both CL+/-P and CP suggests perturbation of maternal folate metabolism is of etiological importance, contrasting relations between maternal postpartum levels of RBC and serum folate by type of cleft are difficult to explain.
[Show abstract][Hide abstract] ABSTRACT: Mildly elevated maternal plasma homocysteine (Hcy) levels (hyperhomocysteinemia) have recently been observed in some neural tube defect (NTD) pregnancies. Plasma levels of Hcy are governed by both genetic and nutritional factors and the aetiology of NTDs is also known to have both genetic and nutritional components. We therefore examined the frequency of relatively common mutations in the enzyme cystathionine β-synthase (CBS), which is one of the main enzymes that controls Hcy levels, in the NTD population. Neither the severely dysfunctional G307S CBS allele nor the recently reported 68 bp insertion/I278T CBS allele was observed at increased frequency in the cases relative to controls. We therefore conclude that loss of function CBS alleles do not account for a significant proportion of NTDs in Ireland.
[Show abstract][Hide abstract] ABSTRACT: to examine the prevalence of vitamin B12 deficiency and folate deficiency in later life in representative samples of the elderly population in the United Kingdom.
a population-based cross-sectional analysis of 3,511 people aged 65 years or older from three studies was used to estimate the age-specific prevalence of vitamin B12 deficiency and of folate deficiency. Vitamin B12 deficiency is conventionally diagnosed if serum vitamin B12 < 150 pmol/l ('low vitamin B12'). We defined 'metabolically significant vitamin B12 deficiency' as vitamin B12 < 200 pmol/l and blood total homocysteine >20 micro mol/l. Folate deficiency, which usually refers to serum folate <5 nmol/l, was defined as 'metabolically significant' if serum folate was <7 nmol/l and homocysteine >20 micro mol/l.
the prevalence of vitamin B12 deficiency, whether defined as low vitamin B12 or metabolically significant vitamin B12 deficiency increased with age in all three studies, from about 1 in 20 among people aged 65-74 years to 1 in 10 or even greater among people aged 75 years or greater. The prevalence of folate deficiency also increased with age, and was similar to that for vitamin B12 deficiencies, but only about 10% of people with low vitamin B12 levels also had low folate levels.
the high prevalence of vitamin B12 and folate deficiency observed in older people indicates a particular need for vigilance for deficiency of these vitamins. Reliable detection and treatment of vitamin deficiency could reduce the risk of deficiency-related disability in old age.
Age and Ageing 01/2004; 33(1):34-41. DOI:10.1093/ageing/afg109 · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ongoing clinical trials are investigating whether lowering plasma homocysteine reduces the risk of vascular disease. If so, food fortification with folic acid will be the likely result, and sub-optimal amounts are likely to be preferred, for safety reasons. Dose-finding studies are needed before the outcomes of these trials, to establish the benefits and risks of folic acid consumption over the widest intake range likely to be encountered.
To find the lowest dose of folic acid that effectively reduces plasma homocysteine in premenopausal women.
Double-blind, randomized placebo-controlled trial.
Women of child-bearing age (n=95) were randomly allocated to 0, 100, 200, or 400 microg/day of folic acid. Red-cell folate and plasma homocysteine were measured at baseline and after 10 weeks supplementation.
Median red cell folate levels increased significantly in the 200 microg(p=0.0001) and 400 microg(p=0.0001) groups; but not in the placebo (0 microg) (p=0.25) or the 100 microg (p=0.5) groups. Only the 200 microg and the 400 microg groups had significant decreases in plasma homocysteine, (p=0.04 and p=0.0008, respectively). However, when subjects whose initial plasma homocysteine was <8 micromol/l (already optimally low) were removed from the analysis, there were significant plasma homocysteine decreases in all three treatment groups, but not the placebo group.
In this sub-population, low doses of folic acid significantly lower plasma homocysteine. This could be achieved safely by fortification.
QJM: monthly journal of the Association of Physicians 11/2002; 95(11):733-40. DOI:10.1093/qjmed/95.11.733 · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the effect of riboflavin supplementation on plasma homocysteine (tHcy) concentrations in healthy elderly people with sub-optimal riboflavin status.
A double-blind, randomized, placebo-controlled riboflavin supplementation trial.
Community based study in Northern Ireland.
From a screening sample of 101 healthy elderly people, 52 had sub-optimal riboflavin status (erythrocyte glutathione reductase activation coefficient, EGRAC>or=1.20) and were invited to participate in the study.
The intervention had two parts. Part 1 was a 12 week randomized double blind, placebo-controlled intervention with riboflavin (1.6 mg/day). Following completion of part 1, the placebo group went on to part 2 of the study which involved supplementation with folic acid (400 micro g/day) for 6 weeks followed by folic acid and riboflavin (1.6 mg/day) for a further 12 weeks, with a 16 week washout period post-supplementation. The purpose of part 2 was: (a) to address the possibility that homocysteine-lowering in response to riboflavin may be obscured by a much greater effect of folate, and that, once folate status was optimized, a dependence of homocysteine on riboflavin might emerge; and (b) to demonstrate that these subjects had homocysteine concentrations which could be lowered by nutritional intervention.
Although riboflavin supplementation significantly improved riboflavin status in both parts 1 and 2 of the study (P<0.001 for each), tHcy concentrations were unaffected (P=0.719). In contrast, folic acid supplementation (study part 2) resulted in a homocysteine lowering of 19.6% (P=0.001).
Despite the metabolic dependency of tHcy on riboflavin, it did not prove to be an effective homocysteine-lowering agent, even in the face of sub-optimal riboflavin status.
European Journal of Clinical Nutrition 10/2002; 56(9):850-6. DOI:10.1038/sj.ejcn.1601402 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fortification of food with folic acid to prevent neural-tube defects in babies also lowers plasma total homocysteine, which is a risk factor for vascular disease. We investigated the effect of folate and vitamin B12 on homocysteine concentrations. 30 men and 23 women received sequential supplementation with increasing doses of folic acid. After supplementation, the usual dependency of homocysteine on folate diminished, and vitamin B12 became the main determinant of plasma homocysteine concentration. This finding suggests that a fortification policy based on folic acid and vitamin B12, rather than folic acid alone, is likely to be much more effective at lowering of homocysteine concentrations, with potential benefits for reduction of risk of vascular disease.
The Lancet 02/2002; 359(9302):227-8. DOI:10.1016/S0140-6736(02)07439-1 · 45.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Studies investigating the relationship between plasma total homocysteine (tHcy) and vascular disease usually rely on a single measurement. Little information is available, however, on the seasonal variability of plasma tHcy. The aim of this study was to investigate the seasonal variation in fasting plasma tHcy and related B-vitamin intake and status in a group of people who did not consume fortified foods or take B-vitamin supplements.
In this longitudinal study, a group of 22 healthy people were followed for 1 year. A fasting blood sample and dietary information were collected from each individual every 3 months, i.e., at the end of each season.
There was no significant seasonal variation in plasma tHcy or in B-vitamin intake or status with the exception of red cell folate (significantly lower in spring compared with autumn or winter) and serum folate (significantly lower in spring compared with the other seasons). Although the between-person variation in plasma tHcy was high (47%), the within-person variation was low (11%). This low variation, combined with the low methodologic imprecision of 3.8%, yielded a high reliability coefficient for plasma tHcy (0.97).
Although there was a small seasonal variation in folate status, there was no corresponding seasonal variation in plasma tHcy. The high reliability coefficient for plasma tHcy suggests that a single measurement is reflective of an individual's average plasma tHcy concentration, thus indicating its usefulness as a potential predictor of disease. This, however, needs to be confirmed in different subgroups of the population.
[Show abstract][Hide abstract] ABSTRACT: Current data suggest that physiologic doses of vitamin B-6 have no significant homocysteine-lowering effect. It is possible that an effect of vitamin B-6 was missed in previous trials because of a much greater effect of folic acid, vitamin B-12, or both.
The aim of this study was to investigate the effect of low-dose vitamin B-6 supplementation on fasting total homocysteine (tHcy) concentrations in healthy elderly persons who were made replete with folate and riboflavin.
Twenty-two healthy elderly persons aged 63-80 y were supplemented with a low dose of vitamin B-6 (1.6 mg/d) for 12 wk in a randomized, double-blind, placebo-controlled trial after repletion with folic acid (400 microg/d for 6 wk) and riboflavin (1.6 mg/d for 18 wk); none of the subjects had a vitamin B-12 deficiency.
Folic acid supplementation lowered fasting tHcy by 19.6% (P < 0.001). After folic acid supplementation, baseline tHcy concentrations ranged from 6.22 to 23.52 micromol/L and 10 subjects had suboptimal vitamin B-6 status (plasma pyridoxal-P < 20 nmol/L). Two-way analysis of variance showed that the significant improvement in vitamin B-6 status in response to vitamin B-6 supplementation (on the basis of both pyridoxal-P: and the erythrocyte aspartate aminotransferase activation coefficient) was reflected in a significant reduction in plasma tHcy of 7.5%.
Low-dose vitamin B-6 effectively lowers fasting plasma tHcy in healthy subjects who are both folate and riboflavin replete. This suggests that any program aimed at the treatment or prevention of hyperhomocysteinemia should include vitamin B-6 supplementation.
American Journal of Clinical Nutrition 05/2001; 73(4):759-64. · 6.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A moderate elevation in plasma total homocysteine (tHcy) has been established as an independent risk factor for vascular disease. An important exogenous source of homocysteine is methionine found in foods rich in animal protein. We investigated the response of tHcy to fluctuations in methionine intake in a cross-over intervention trial (two arms). Healthy men (n = 52; 19-29 y) were screened for habitual methionine intake using a food-frequency questionnaire. Subjects in the top quartile for methionine intake (n = 13), with a baseline fasting tHcy of 7.01 +/- 1.84 micromol/L (mean +/- SD), were randomly assigned to receive either a low-methionine intervention diet for 1 wk followed by a control diet for 1 wk or vice-versa. Simultaneously, those in the bottom quartile for methionine intake (n = 11), with a fasting plasma tHcy of 9.79 +/- 7. 20 micromol/L (mean +/- SD), received either a high methionine intervention diet for 1 wk followed by a control diet or vice-versa. All subjects had serum folate, red-cell folate, serum vitamin B-12 and plasma pyridoxal phosphate (PLP) concentrations within normal ranges. During the intervention, subjects in the top quartile for methionine intake reduced their daily methionine intake 79%, from 1969 +/- 639 to 407 +/- 83 mg/d (P: </= 0.001), and those in the bottom quartile almost doubled their methionine intake, from 1155 +/- 401 to 2112 +/- 379 mg/d (P: </= 0.001). Despite these changes in methionine intake, no corresponding changes in plasma tHcy were observed. These results suggest that in the absence of an obvious deficiency of relevant B-vitamins, fasting plasma tHcy is unaffected by intermediate-term fluctuations (up to 100% of usual intake) in dietary methionine.
Journal of Nutrition 12/2000; 130(11):2653-7. · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To estimate the rate of folate catabolism in pregnant and nonpregnant women and to derive the recommended dietary allowance for folate.
Prospective, observational study.
Rotunda Hospital, Dublin. WOMEN: Twenty-four healthy gravid women were studied once during each trimester and postpartum. Twenty-five nonpregnant controls were assessed before and after folic acid supplementation.
Women provided 24-hour urine collections while adhering to a strict dietary regimen containing no exogenous folate catabolites.
Urinary levels of p-acetamidobenzoylglutamate and p-aminobenzoylglutamate were measured by high pressure liquid chromatography.
The 24-hour excretion of folate catabolites, expressed as mean [95% CI] folate equivalents in microg) progressively increased during pregnancy. A peak was reached in the third trimester (349.1 microg [308.1 to 390.1]) where the rate was more than twice the rate in the nonpregnant control group (136.4 microg [112.4 to 160.4]) (P < 0.001). Based on our results the recommended dietary allowance for folate in nonpregnant women should be 250 microg and this should rise during pregnancy to 430 microg in the second trimester and 540 microg in the third trimester.
The rate of folate catabolism progressively increases during pregnancy reaching a peak in the third trimester at the time of maximal fetal growth. The increased demand for folate during pregnancy appears to be due to the accelerated breakdown of the vitamin because of its participation in cellular biosynthesis. These results provide a quantitative basis for the current debate on the appropriate recommended dietary allowance for folate in both pregnant and nonpregnant women.
BJOG An International Journal of Obstetrics & Gynaecology 10/2000; 107(9):1149-54. · 3.45 Impact Factor