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Biomedical subjects

A M Molloy

Publications and source records attributed to A M Molloy.

At least 19 recordsLinked to original sources
PubMed2002

Low-dose folic acid lowers plasma homocysteine levels in women of child-bearing age.

BACKGROUND: 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. AIM: To find the lowest dose of folic acid that effectively reduces plasma homocysteine in premenopausal women. DESIGN: Double-blind, randomized placebo-controlled trial. METHODS: 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. RESULTS: 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. DISCUSSION: In this sub-population, low doses of folic acid significantly lower plasma homocysteine. This could be achieved safely by fortification.

Adult↗
PubMed2001

Elevated plasma homocysteine in early pregnancy: a risk factor for the development of severe preeclampsia.

OBJECTIVE: The aim of our study was to determine if an elevated plasma homocysteine level in early pregnancy is associated with the development of severe preeclampsia. STUDY DESIGN: Blood samples were obtained from patients attending their first antenatal visit. Cases were asymptomatic women who subsequently developed severe preeclampsia. Controls were matched for gestational age and date of sample collection. Plasma homocysteine level was measured by using fluorescence polarization immunoassay. RESULTS: There were 56 patients with severe preeclampsia from whom blood samples were obtained at a mean (+/-SD) gestation of 15.3 weeks (+/-4.04 weeks) and 112 controls at 14.9 weeks (+/-3.41 weeks). The preeclampsia cases had a mean (+/-SD) homocysteine level of 9.8 micromol/L (+/-3.3 micromol/L), whereas controls had a mean homocysteine level of 8.4 micromol/L (+/-1.9 micromol/L), P < or = .0001. CONCLUSION: Women who develop severe preeclampsia have higher plasma homocysteine levels in early pregnancy than women who remain normotensive throughout pregnancy. An elevated plasma homocysteine level in early pregnancy can increase the risk of developing severe preeclampsia by almost threefold.

Adult↗
PubMed2001

Folates and prevention of disease.

Research in the past decade has established that low or inadequate folate status may contribute to congenital malformations and the development of chronic disease in later life. Using an evidence based approach, there are clear guidelines for recommending folic acid supplementation or fortification in certain disease conditions but further proof of its efficacy is required in other circumstances. There is conclusive evidence that maternal periconceptional supplementation with folic acid prevents the majority of NTDs, probably by overcoming one or more genetically inherited metabolic blocks in folate dependent enzymes. Public health efforts to advise women to increase their folate intake have not been successful. As a result, the U.S. government passed legislation to have all flour fortified with folic acid. This intervention has had a dramatic effect on folate status in the U.S. To date, countries of the EU have not adopted mandatory fortification policies. The amino acid homocysteine is an essential intermediate in folate metabolism. Substantial evidence indicates that elevated plasma homocysteine is an independent risk factor for heart disease and stroke. Plasma homocysteine levels can be reduced by folic acid supplements. A food fortification policy would probably be an effective population strategy to reduce plasma homocysteine. However, many experts believe that this would be premature without first showing that such reduction would cause a decrease in the prevalence of cardiovascular disease. The contribution of folate to cancer risk is not well defined although there is reasonable evidence to implicate low folate status in the specific case of colorectal cancer. In particular, long-term folic acid supplementation may reduce risk of colorectal cancer substantially. Various mental disorders including Alzheimer's Disease have been associated with low folate status or elevated plasma homocysteine. While it is hard to determine if this is cause or effect, there is little doubt that if it were true then low dose folic acid intervention would be highly effective.

Cardiovascular Diseases↗
PubMed2001

The methylenetetrahydrofolate reductase (MTHFR) gene in colorectal cancer: role in tumor development and significance of allelic loss in tumor progression.

BACKGROUND AND AIM: Folate deficiency predisposes to sporadic colorectal cancer (CRC). Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme and a polymorphism at position 677 (C677T), is associated with reduced enzyme activity. We investigated whether this functional polymorphism modulates the risk of developing CRC. METHODS: This was a retrospective case-control study. 136 unselected cases of sporadic CRC and 848 normal population controls were genotyped for the MTHFR C677T polymorphism. Tumor tissue was genotyped to assess loss of heterozygosity (LOH). RESULTS: MTHFR CT heterozygotes had a significantly increased risk of developing CRC (53.7% of CRC cases vs 38.4% of controls), odds ratio 1.86 (95% CI 1.3-2.7, p < 0.005). No increased cancer risk was observed in TT homozygotes. The MTHFR 'T' allele frequency was significantly higher in the cancer group (0.3713) as compared to controls (0.2900, p < 0.008). LOH at the MTHFR locus was observed in 18% of informative cancers, with exclusive loss of the variant 'T' allele, in all cases. CONCLUSION: In this study of a homogenous northern European population, MTHFR CT heterozygotes had an almost two-fold increased risk of developing sporadic CRC. The exclusive pattern of MTHFR allele loss in cases of LOH, suggest that functional MTHFR activity within a tumor might play an important role in the survival and progression of a colonic neoplasm.

Adenocarcinoma↗
PubMed2000

Association between historically high frequencies of neural tube defects and the human T homologue of mouse T (Brachyury).

The human T developmental gene has been implicated in the etiology of neural tube defects (NTDs) on the basis both of mouse studies of its homologue, T (Brachyury), and of allelic association in a Caucasian population. We have investigated the frequency of the T allelic variant TIVS7-2 in 218 Irish NTD case-parent triads. This population showed the same trend as previously reported, with an excess of the TIVS7-2 allele among cases. Log-linear modeling of case and maternal genotypic effects within families indicated that TIVS7-2 was elevated in cases (relative risk, RR = 1.36) but not in mothers (RR = 0.91). The TIVS7-2 allele is markedly associated with cases born before 1980 (RR = 2.09; CI = 1.23-3.55; corrected p = 0.030), but not with more recent cases (RR = 0.92). Cases carrying a TIVS7-2 allele did not show any increased tendency to be homozygous for the thermolabile variant of the folate-dependent enzyme 5,10-methylene tetrahydrofolate reductase, which is an established genetic risk factor for NTDs. Since the incidence of NTDs has declined markedly in Ireland over the last few decades, we suggest that the T-associated risk is potentiated by nutritional or environmental risk factor(s), the impact of which have been diminishing over time.

Adolescent↗
PubMed1999

Methylenetetrahydrofolate reductase thermolabile variant and oral clefts.

Folic acid can prevent neural tube defects; in some cases the mechanism is probably a correction of a metabolic defect caused by thermolabile methylenetetrahydrofolate reductase (MTHFR) found in increased frequency in cases. It is less clear whether folic acid can prevent oral clefts, in part because it is not known whether thermolabile MTHFR is more common in those with oral clefts. This study examined the prevalence of the mutation (677 C-->T) that causes thermolabile MTHFR in subjects with oral clefts from a national Irish support group, and an anonymous control group randomly selected from a neonatal screening program covering all births in Ireland. Eighty-three of 848 control subjects were homozygous (TT) thermolabile MTHFR (9.8%). This defect was almost three times as common in the 27 subjects (25.9%) with isolated cleft palate (odds ratio 3.23, 95% confidence interval 1.32 -7.86, P = 0. 02) and somewhat more common in the 66 subjects with cleft lip with or without cleft palate (15.2%, odds ratio 1.65, 95% confidence interval 0.81-3.35, P = 0.20). When the two groups with different etiologies were combined, the overall odds ratio was 2.06 (95% confidence interval 1.16-3.66, P = 0.02). In the Irish population homozygosity for the common folate-related polymorphism associated with thermolabile MTHFR is significantly more frequent in those with isolated cleft palate, and could be etiologically important. Am. J. Med. Genet. 86:71-74, 1999. Published 1999 Wiley-Liss, Inc.

Child↗
PubMed1999

Folate status and neural tube defects.

Periconceptional folic acid supplementation prevents approximately 70% of neural tube defects (NTDs). While most women carrying affected fetuses do not have deficient blood folate levels, the risk of having an NTD affected child is inversely correlated with pregnancy red cell folate levels. Current research is focused on the discovery of genetic abnormalities in folate related enzymes which might explain the role of folate in NTD prevention. The first candidate gene to emerge was the C677T variant of 5,10-methylenetetrahydrofolate reductase. Normal subjects who are homozygous for the mutation (TT) have red cell folate status some 20% lower than expected. It is now established that the prevalence of the TT genotype is significantly higher among spina bifida cases and their parents. Nevertheless, our studies show that the variant does not account for the reduced blood folate levels in many NTD affected mothers. We conclude that low maternal folate status may in itself be the most important risk factor for NTDs and that food fortification may be the only population strategy of benefit in the effort to eliminate NTDs.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1999

Methionine synthase: high-resolution mapping of the human gene and evaluation as a candidate locus for neural tube defects.

Periconceptual folate supplementation has been found to prevent the occurrence of many neural tube defects (NTDs). Consequently, genetic variation in folate metabolism genes is expected to contribute to the risk for neural tube defects. Methionine synthase catalyzes the vitamin B(12)-dependent conversion of homocysteine and 5-methyltetrahydrofolate to methionine and tetrahydrofolate. The observation that homocysteine and vitamin B(12) levels are independent predictors of NTD risk suggested that methionine synthase could be a candidate gene for NTDs. To assess the role of the MS gene in NTDs, we performed high-resolution physical mapping of the MS locus, isolated highly polymorphic markers linked to the MS gene, and tested for an association between specific MS alleles and NTDs. We mapped the MS gene to a position between 909 and 913 cR(10000) on chromosome 1 by radiation hybrid mapping. Polymorphic markers D1S1567 and D1S1568 map to locations no more than 900 and 194 kb from the MS gene, respectively. The segregation of these polymorphic markers was measured in 85 Irish NTD families. No allele of either marker showed a significant association with NTDs using the transmission disequilibrium test. A lack of association was also observed for the D1919G missense mutation within the gene. Our results suggest that inherited variation in the MS gene does not contribute to NTD risk in this population.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1999

The "thermolabile" variant of methylenetetrahydrofolate reductase and neural tube defects: An evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother.

Recent reports have implicated the "thermolabile" (T) variant of methylenetetrahydrofolate reductase (MTHFR) in the causation of folate-dependent neural tube defects (NTDs). We report herein the largest genetic study of NTD cases (n=271) and families (n=218) to date, establishing that, in Ireland, the "TT" genotype is found in 18.8% of cases versus 8.3% of controls (odds ratio 2.57; confidence interval [CI] 1.48-4.45; P=.0005). The maternal and paternal TT genotypes have intermediate frequencies of 13.8% and 11.9%, respectively, indicating that the predominant MTHFR-related genetic effect acts via the TT genotype of the developing embryo. Analysis of the 218 family triads of mother, father, and affected child with log-linear models supports this interpretation, providing significant evidence that the case TT genotype is associated with NTDs (P=.02) but no evidence of a maternal TT genotypic effect (P=. 83). The log-linear model predicted that the risk of NTDs conferred by the case TT genotype is 1.61 (CI 1.06-2.46), consistent with the paramount importance of the case TT genotype in determining risk. There is no compelling evidence for more than a modest additional risk conferred by a maternal TT genotype. These results favor a biological model of MTHFR-related NTD pathogenesis in which suboptimal maternal folate status imposes biochemical stress on the developing embryo, a stress it is ill-equipped to tolerate if it has a TT genotype.

Alleles↗
PubMed1999

The influence of 5,10 methylenetetrahydrofolate reductase genotypes on enzyme activity in placental tissue.

OBJECTIVE: To study the effects of heterozygosity and homozygosity for the C677T mutation of the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene on the activity of this enzyme in placental tissue from pregnancies not affected by neural tube defect. DESIGN: Placental tissue was genotyped for the C677T variants of MTHFR. Total enzyme activity and residual activity after heating to 46 degrees C for 5 minutes was then measured. SETTING: A teaching hospital. SAMPLE: Placental samples (n = 200), one from each of 200 uncomplicated term deliveries. MAIN OUTCOME MEASURES: Total and residual enzyme activity for MTHFR. RESULTS: Placentae heterozygous for the C677T mutation of the MTHFR gene had significantly lower total enzyme activity than those without the mutation; the lowest activity occurred in homozygotes for the mutation. The same pattern was seen in relation to enzyme activity after heating. CONCLUSION: This study demonstrates that reduced enzyme activity is associated with the C677T variant of MTHFR in placental tissue. This is an important metabolic step in folic acid metabolism and pro-

Biomarkers↗
PubMed1998

Low blood folates in NTD pregnancies are only partly explained by thermolabile 5,10-methylenetetrahydrofolate reductase: low folate status alone may be the critical factor.

Thermolabile 5,10-methylenetetrahydrofolate reductase (MTHFR) is the first folate-related variant to be associated with an increased risk of neural tube defects (NTDs). The variant causes high plasma homocysteine levels and reduced red cell folate (RCF) levels, both of which have also been linked to an increased risk of NTDs. We examined the relationship between folate status and presence of the common mutation MTHFR C677T in 82 NTD-affected and 260 control mothers. Homozygosity for the TT genotype was associated with very low folate status among both the cases (n = 13) and the controls (n = 21). However, after exclusion of TT homozygotes, only 10% of the remaining 240 controls had RCF levels less than 200 microg/L compared with 29% of the 69 cases (odds ratio, 3.67; 95% confidence interval, 1.88-7.18; P < 0.001), and those with RCF less than 150 microg/L had eight times higher risk of NTD than subjects with levels over 400 microg/L. Plasma homocysteine levels of non-TT cases were also higher than those of controls (P = 0.047). This study shows that homozygosity for the C677T MTHFR variant cannot account for reduced blood folate levels in many NTD-affected mothers. Thus, a strategy of genetic screening of all childbearing women for this variant would be ineffective as a method of primary prevention of NTDs. The data suggest that low maternal folate status is itself the major determinant of NTD risk, or else that other folate-dependent genetic variants confer risk through the reduction of folate levels. These results emphasize the importance of a food-fortification program as a population strategy for reducing the occurrence of NTDs.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1997

Minimum effective dose of folic acid for food fortification to prevent neural-tube defects.

BACKGROUND: Although a daily supplement of 400 micrograms folic acid has been shown to prevent neural-tube defects (NTD), most women do not take the recommended supplement. Thus, food fortification is to be introduced in the USA and is being considered in the UK. Because of safety concerns, the USA has chosen a level of fortification that will increase the average woman's intake by only 100 micrograms. Such an increase, although safe, may be ineffective; but a trial to assess its efficacy would be unethical. Because women with red-cell folate concentrations above 400 micrograms/L have a very low risk of NTD, we undertook a randomised trial of several folic acid doses to find out how much is needed to reach this protective concentration. METHODS: We screened 323 women. 172 with red-cell folate between 150 micrograms/L and 400 micrograms/L were invited to take part in the trial. 121 women were randomly assigned placebo or 100 micrograms, 200 micrograms, or 400 micrograms daily of additional folic acid. Compliance was monitored by having the women sign a dated sheet when taking the tablet. 95 women completed the 6-month study. FINDINGS: There were significant increases in red-cell folate in all folic acid groups. The placebo group showed no significant change. The median incremental changes and median post-treatment concentrations were 67 micrograms/L (95% CI 43-120) and 375 micrograms/L (354-444) in the 100 micrograms/day group, 130 micrograms/L (108-184) and 475 micrograms/L (432-503) in the 200 micrograms/day group, and 200 micrograms/L (125-312) and 571 micrograms/L (481-654) in the 400 micrograms/day group. INTERPRETATION: A fortification programme that delivered 400 micrograms folic acid daily to women would protect against NTD, but at the expense of unnecessarily high exposure for many people. Delivery of 200 micrograms daily is also effective against NTD and safer for the general population. Based on projections from the positive folate balance in the group that received 100 micrograms daily, this dose taken continually, as it will be in fortified food, will also produce an important decrease in NTD.

Adult↗