Explore the vast range of titles available.

The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (n = 1,152 and n = 2,310) and identified signals at ABO (P < 7.9E-139) and VWF (P < 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12–2p13 (LOD score 5.3) and at the ABO locus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the “missing heritability” for other complex genetic traits.

Background Neural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk. Methods A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects. Results Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003–0.0023) were found in nine genes ( MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury) ) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing. Conclusions To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk.

In this case–control study, which used stored blood samples to compare Irish women with a history of pregnancy complicated by neural-tube defect and women with a history of pregnancy without such a complication, there was no significant association between the presence or titer of autoantibodies against the folate receptor and case status. A second case–control study using fresh samples showed similar results. These results fail to confirm a previously reported strong association between maternal folate-receptor autoantibodies and pregnancy affected by a neural-tube defect. In this case–control study, which compared Irish women with a history of pregnancy complicated by neural-tube defect and women without such a complication, there was no significant association between the presence or titer of autoantibodies against the folate receptor and case status. Although periconceptional folic acid supplementation can prevent neural-tube defects, the underlying mechanism is not well understood. 1 In 2004, a pilot study published in the Journal 2 showed that serum from 9 of 12 women (75%) with a history of a neural-tube defect–affected pregnancy (case mothers) contained autoantibodies against folate receptors, whereas autoantibodies were detected in samples from only 2 of 20 controls (10%). The hypothesis that embryonic uptake of folate might be impaired by circulating maternal folate-receptor autoantibodies presents a biologically plausible mechanism for the pathogenesis of folate-responsive neural-tube defects. Although the authors called for further studies to confirm their findings, . . .

Although a daily supplement of 400 μg 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 μg. 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 μg/ 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. We screened 323 women. 172 with red-cell folate between 150 μg/L and 400 μg/L were invited to take part in the trial. 121 women were randomly assigned placebo or 100 μg, 200 μg, or 400 μg 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. 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 μg/L (95% Cl 43-120) and 375 μg/L (354-444) in the 100 μg/day group, 130 μg/L (108-184) and 475 μg/L (432-503) in the 200 μg/day group, and 200 μg/L (125-312) and 571 μg/L (481-654) in the 400 μg/day group. A fortification programme that delivered 400 μg folic acid daily to women would protect against NTD, but at the expense of unnecessarily high exposure for many people. Delivery of 200 μg 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 μg daily, this dose taken continually, as it will be in fortified food, will also produce an important decrease in NTD.

[...]MTHFR C677T heterozygosity needs to be considered as a risk factor for other conditions where homozygosity has been shown to be associated with increased risk, for example, ischaemic heart disease. 5 Secondly, the population at risk, and the population that will benefit from food fortification, is much larger than previously believed. Based on pooled data from published studies, about 59% of the European population and 53% of the North American population have either CT or TT genotypes. 1 Both the lower folate and increased homocysteine concentrations associated with CT and TT genotypes can be corrected by folic acid, even in relatively small doses. [...]our study provides new data underscoring the importance of public health intervention programmes of folic acid supplementation and food fortification targeted at all women of childbearing age to prevent neural tube defects.

The thermolabile variant (677TT) of methylenetetrahydrofolate reductase (MTHFR) is a known risk factor for neural tube defects (NTDs). The relationship between a second MTHFR polymorphism (1298A→C) and NTD risk has been inconsistent between studies. We genotyped 276 complete NTD triads (mother, father and child affected with an NTD) and 256 controls for MTHFR 1298A→C. Our findings do not support a role for the 1298A→C polymorphism in NTDs (OR 0.85 (95% CI 0.49–1.47), p = 0.55), nor do we observe a combined effect with the 677C→T polymorphism.

The risk of neural tube defects (NTDs) is known to have a significant genetic component that could act through either the NTD patient and/or maternal genotype. The success of folic acid supplementation in NTD prevention has focused attention on polymorphisms within folate-related genes. We previously identified the 1958G>A (R653Q) polymorphism of the trifunctional enzyme MTHFD1 (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase; often referred to as ‘C1 synthase’) as a maternal risk for NTDs, but this association remains to be verified in a separate study to rule out a chance finding. To exclude this possibility, we genotyped an independent sample of mothers with a history of an NTD-affected pregnancy derived from the same Irish population. In this sample there was a significant excess of 1958AA homozygote mothers of NTD cases ( n =245) compared to controls ( n =770). The direction and magnitude of risk (odds ratio 1.49 (1.07–2.09), P =0.019) is consistent with our earlier finding. Sequencing of the MTHFD1 gene revealed that this association is not being driven by another common variant within the coding region. We have established that the MTHFD1 1958G>A polymorphism has a significant role in influencing a mother's risk of having an NTD-affected pregnancy in the Irish population.

Genetic variants in MTHFD1 (5,10-methylenetetrahydrofolate dehydrogenase/5,10-methenyltetrahydrofolate cyclohydrolase/ 10-formyltetrahydrofolate synthetase), an important folate metabolic enzyme, are associated with a number of common diseases, including neural tube defects (NTDs). This study investigates the promoter of the human MTHFD1 gene in a bid to understand how this gene is controlled and regulated. Following a combination of in silico and molecular approaches, we report that MTHFD1 expression is controlled by a TATA-less, Initiator-less promoter and transcription is initiated at multiple start sites over a 126 bp region. We confirmed the presence of three database polymorphisms (dbSNP) by direct sequencing of the upstream region (rs1076991 C > T, rs8010584 G > A, rs4243628 G > T), with a fourth (dbSNP rs746488 A > T) not found to be polymorphic in our population and no novel polymorphisms identified. We demonstrate that a common SNP rs1076991 C > T within the window of transcriptional initiation exerts a significant effect on promoter activity in vitro. We investigated this SNP as a potential risk factor for NTDs in a large homogenous Irish population and determined that it is not an independent risk factor, but, it does increase both case (χ ² = 11.06, P = 0.001) and maternal (χ ² = 6.68, P = 0.01) risk when allele frequencies were analysed in combination with the previously identified disease-associated p.R653Q (c.1958 G > A; dbSNP rs2236225) polymorphism. These results provide the first insight into how MTHFD1 is regulated and further emphasise its importance during embryonic development.

Background Neural tube defects (NTDs), which are among the most common congenital malformations, are influenced by environmental and genetic factors. Low maternal folate is the strongest known contributing factor, making variants in genes in the folate metabolic pathway attractive candidates for NTD risk. Multiple studies have identified nominally significant allelic associations with NTDs. We tested whether associations detected in a large Irish cohort could be replicated in an independent population. Methods Replication tests of 24 nominally significant NTD associations were performed in racially/ethnically matched populations. Family-based tests of fifteen nominally significant single nucleotide polymorphisms (SNPs) were repeated in a cohort of NTD trios (530 cases and their parents) from the United Kingdom, and case-control tests of nine nominally significant SNPs were repeated in a cohort (190 cases, 941 controls) from New York State (NYS). Secondary hypotheses involved evaluating the latter set of nine SNPs for NTD association using alternate case-control models and NTD groupings in white, African American and Hispanic cohorts from NYS. Results Of the 24 SNPs tested for replication, ADA rs452159 and MTR rs10925260 were significantly associated with isolated NTDs. Of the secondary tests performed, ARID1A rs11247593 was associated with NTDs in whites, and ALDH1A2 rs7169289 was associated with isolated NTDs in African Americans. Conclusions We report a number of associations between SNP genotypes and neural tube defects. These associations were nominally significant before correction for multiple hypothesis testing. These corrections are highly conservative for association studies of untested hypotheses, and may be too conservative for replication studies. We therefore believe the true effect of these four nominally significant SNPs on NTD risk will be more definitively determined by further study in other populations, and eventual meta-analysis.

The dietary reference values for folate, as for other nutrients, are targeted to the general and supposedly normal population, not people with special needs, such as those with genetic or metabolic abnormalities or diseases. However, 5-15% of general populations are homozygous for a thermolabile variant of 5,10-methylenetetrahydrofolate reductase (C677T) which causes mild hyperhomocysteinaemia and is positively associated with the development of vascular disease and the risk of neural-tube defects. If tissue-folate status is compromised in large sectors of the population by this or other genetic variants, the present dietary reference values may need to be changed. We identified the C677T genotype and measured red-cell folate concentrations in two groups of healthy women (pregnant, 242, not pregnant, 318). We then analysed the effect of genotype on red-cell folates, which are a reliable marker for tissue folate stores. In the pregnant group there were 20 TT homozygotes, 114 wild-type CC homozygotes, and 108 CT heterozygotes. In the non-pregnant group, the numbers were 41, 148, and 129. In both pregnant and non-pregnant groups, red-cell folate was significantly lower among TT homozygous than CC homozygous women (mean 252 [95% CI 202-317] vs 347 [321-372] micrograms/L, p = 0.002 for pregnant women; 284 [250-327] vs 347 [342-372] micrograms/L, p = 0.01 for non-pregnant women). Plasma folate was also significantly lower in TT homozygous than in CC homozygous women in the pregnant group (p = 0.009) but not in the non-pregnant group. These results suggest that a substantial minority of people in general populations may have increased folate needs. Future studies may show the presence of other common genetic variants that interact with particular nutrients and place doubts on the validity of assuming \"normality\" for nutrient requirements in any general population.