Cells of a multicellular organism are genetically homogeneous but structurally and functionally heterogeneous owing to the differential expression of genes. Many of these differences in gene expression arise during development and are subsequently retained through mitosis. Stable alterations of this kind are said to be 'epigenetic', because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years has focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histone modifications. Here, we review advances in the understanding of the mechanism and role of DNA methylation in biological processes. Epigenetic effects by means of DNA methylation have an important role in development but can also arise stochastically as animals age. Identification of proteins that mediate these effects has provided insight into this complex process and diseases that occur when it is perturbed. External influences on epigenetic processes are seen in the effects of diet on long-term diseases such as cancer. Thus, epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression. The extent to which environmental effects can provoke epigenetic responses represents an exciting area of future research.

/pdf/epigenetic-regulation-of-gene-expression-how-the-genome-55fnpf16ec.pdf

Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals

Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.

/pdf/mendelian-randomization-can-genetic-epidemiology-contribute-vb0zjyrtxf.pdf

‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?

Summary Recently, we showed that homozygosity for the common 677(C→T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A→C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an Mbo II recognition site and has an allele frequency of .33. This 1298(A→C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P P P n = 86) of the NTD patients compared with 20% ( n = 403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9–4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C→T) mutation, and can be an additional genetic risk factor for NTDs.

A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?

Context Controversy and uncertainty ensue when the results of clinical research on the effectiveness of interventions are subsequently contradicted. Controversies are most prominent when high-impact research is involved. Objectives To understand how frequently highly cited studies are contradicted or find effects that are stronger than in other similar studies and to discern whether spe- cific characteristics are associated with such refutation over time. Design All original clinical research studies published in 3 major general clinical jour- nals or high-impact-factor specialty journals in 1990-2003 and cited more than 1000 times in the literature were examined. Main Outcome Measure The results of highly cited articles were compared against subsequent studies of comparable or larger sample size and similar or better con- trolled designs. The same analysis was also performed comparatively for matched stud- ies that were not so highly cited. Results Of 49 highly cited original clinical research studies, 45 claimed that the inter- vention was effective. Of these, 7 (16%) were contradicted by subsequent studies, 7 oth- ers (16%) had found effects that were stronger than those of subsequent studies, 20 (44%) were replicated, and 11 (24%) remained largely unchallenged. Five of 6 highly- cited nonrandomized studies had been contradicted or had found stronger effects vs 9 of 39 randomized controlled trials (P=.008). Among randomized trials, studies with con- tradicted or stronger effects were smaller (P=.009) than replicated or unchallenged stud- ies although there was no statistically significant difference in their early or overall cita- tion impact. Matched control studies did not have a significantly different share of refuted results than highly cited studies, but they included more studies with "negative" results. Conclusions Contradiction and initially stronger effects are not unusual in highly cited research of clinical interventions and their outcomes. The extent to which high citations may provoke contradictions and vice versa needs more study. Controversies are most common with highly cited nonrandomized studies, but even the most highly cited randomized trials may be challenged and refuted over time, especially small ones.

/pdf/contradicted-and-initially-stronger-effects-in-highly-cited-50i9s2w55w.pdf

Contradicted and Initially Stronger Effects in Highly Cited Clinical Research

Background Periconceptional use of multivitamins containing folic acid can reduce a woman's risk of having a baby with a neural-tube defect. Methods As part of a public health campaign conducted from 1993 to 1995 in an area of China with high rates of neural-tube defects (the northern region) and one with low rates (the southern region), we evaluated the outcomes of pregnancy in women who were asked to take a pill containing 400 μg of folic acid alone daily from the time of their premarital examination until the end of their first trimester of pregnancy. Results Among the fetuses or infants of 130,142 women who took folic acid at any time before or during pregnancy and 117,689 women who had not taken folic acid, we identified 102 and 173, respectively, with neural-tube defects. Among the fetuses or infants of women who registered before their last menstrual period and who did not take any folic acid, the rates of neural-tube defects were 4.8 per 1000 pregnancies of at least 20 weeks' gestation in the nort...

https://www.nejm.org/doi/pdf/10.1056/NEJM199911113412001

R. Stone

Papers

Prevention of neural tube defects: Results of the Medical Research Council vitamin study

The use of free β-hCG in antenatal screening for Down's syndrome

The use of free β-hCG in antenatal screening for Down's syndrome