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Julian Little

Publications and source records attributed to Julian Little.

29 records · Page 2Linked to original sources
PubMed2004

Associations between two common variants C677T and A1298C in the methylenetetrahydrofolate reductase gene and measures of folate metabolism and DNA stability (strand breaks, misincorporated uracil, and DNA methylation status) in human lymphocytes in vivo.

OBJECTIVE: Homozygosity for variants of the methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased risk for colorectal cancer. We have investigated the relationships between two variants of the MTHFR gene (C677T and A1298C) and blood folate, homocysteine, and genomic stability (strand breakage, misincorporated uracil, and global cytosine methylation in lymphocytes) in a study of 199 subjects. RESULTS: The frequencies of homozygosity for the C677T and A1298C variants of the MTHFR gene were 12.6% and 14.6%, respectively. Plasma homocysteine, folate, vitamin B12, 5-methyltetrahydrofolate, and RBC folate were determined in the C677T genotypes. Plasma folate was significantly lower (P < 0.001) in the homozygous variants (6.7 +/- 0.6 ng/mL) compared with wild-types (8.8 +/- 0.4 ng/mL) and heterozygotes (9.1 +/- 0.5 ng/mL). Homocysteine was significantly higher (P < 0.05) in homozygous variants (13.2 +/- 1.1 micromol/L) compared with homozygous subjects (10.9 +/- 0.4 micromol/L). Homozygous variants had significantly lower (P < 0.05) RBC folate (84.7 +/- 6.3 ng/mL) compared with wild-types (112.2 +/- 5.2 ng/mL) and heterozygous individuals (125.1 +/- 6.6 ng/mL). No significant difference in RBC folate was observed between wild-types and heterozygotes. The A1298C variant did not influence plasma homocysteine, folate, 5-methyltetrahydrofolate, vitamin B12, or RBC folate. Lymphocyte DNA stability biomarkers (strand breaks, misincorporated uracil, and global DNA methylation) were similar for all MTHFR C677T or A1298C variants. CONCLUSION: Data from this study do not support the hypothesis that polymorphisms in the MTHFR gene increase DNA stability by sequestering 5,10-methylenetetrahydrofolate for thymidine synthesis and reducing uracil misincorporation into DNA.

Adult↗
PubMed2003

Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial.

BACKGROUND & AIMS: Epidemiologic and experimental studies have suggested that aspirin intake reduces the risk for colorectal carcinogenesis. However, the available data are not sufficient to serve as the basis for firm recommendations. METHODS: We randomly assigned 272 patients with a history of colorectal adenomas (at least one more than 5 mm in diameter, or more than 3) to daily lysine acetylsalicylate (160 or 300 mg/day) or placebo for 4 years. The primary end points were adenoma recurrence after 1 and 4 years. These results are those of the year 1 colonoscopy. RESULTS: Among the 238 patients who completed the year 1 colonoscopy, at least one adenoma was observed in 38 patients of the 126 (30%) in the aspirin group and in 46 of the 112 (41%) in the placebo group; relative risk was 0.73 (95% confidence interval [CI]: 0.52-1.04; P = 0.08). At least one adenoma of more than 5 mm diameter was observed in 13 patients (10%) in the aspirin group and 26 (23%) in the placebo group (P = 0.01). The corresponding numbers for adenomas more than 10 mm in diameter were one (1%) and 7 (6%) (P = 0.05). Stepwise regression showed that independent factors associated with lower adenoma recurrence are aspirin treatment (adenoma >5 mm, P = 0.01), absence of personal history of adenoma before the entry colonoscopy (P = 0.01), and initial adenomatous polyp burden less than 10 mm (P = 0.001). CONCLUSIONS: Daily soluble aspirin is associated with a reduction in the risk for recurrent adenomas found at colonoscopy 1 year after starting treatment.

Adenoma↗
PubMed2003

Colon cancer and genetic variation in folate metabolism: the clinical bottom line.

So far, evidence for the relation between folate intake and colorectal cancer has been insufficient to lead to specific public health interventions. In principle, data on the relation between genetic variation in folate metabolism and colorectal neoplasia could be used to corroborate the data on the relation between folate intake or status and the disease, strengthening the evidence base for primary prevention. Issues in considering the relation between a health outcome and genetic variation in metabolism of nutrients or other food components include knowledge of gene function, linkage disequilibrium, population stratification, study size and quality, and gene-environment interaction. Overall homozygosity for MTHFR variant genotypes is associated with a reduced risk of colorectal cancer, the opposite of what might have been expected a priori. This has led investigators to place greater emphasis on the functions of folate and methylenetetrahydrofolate reductase in DNA synthesis. Folate and related nutrients may be important after adenoma formation. A challenge for the future is to characterize the effects of multiple genes influencing folate metabolism. Limited data for colorectal cancer suggest that the effect of a low folate diet overrides the effect of genotype, but two studies of adenomas suggested the opposite. Another potential role of information on genetic variation in folate metabolism is in the management of colorectal cancer but most studies have been small, have included selected patient groups, and have made limited adjustment for potentially important factors.

Adenoma↗
PubMed2002

Reporting, appraising, and integrating data on genotype prevalence and gene-disease associations.

The recent completion of the first draft of the human genome sequence and advances in technologies for genomic analysis are generating tremendous opportunities for epidemiologic studies to evaluate the role of genetic variants in human disease. Many methodological issues apply to the investigation of variation in the frequency of allelic variants of human genes, of the possibility that these influence disease risk, and of assessment of the magnitude of the associated risk. Based on a Human Genome Epidemiology workshop, a checklist for reporting and appraising studies of genotype prevalence and studies of gene-disease associations was developed. This focuses on selection of study subjects, analytic validity of genotyping, population stratification, and statistical issues. Use of the checklist should facilitate the integration of evidence from these studies. The relation between the checklist and grading schemes that have been proposed for the evaluation of observational studies is discussed. Although the limitations of grading schemes are recognized, a robust approach is proposed. Other issues in the synthesis of evidence that are particularly relevant to studies of genotype prevalence and gene-disease association are discussed, notably identification of studies, publication bias, criteria for causal inference, and the appropriateness of quantitative synthesis.

Case-Control Studies↗
PubMed2002

Relation of childhood brain tumors to exposure of parents and children to tobacco smoke: the SEARCH international case-control study. Surveillance of Environmental Aspects Related to Cancer in Humans.

The etiology of childhood brain tumors (CBTs) remains unknown. Tobacco smoke contains several known carcinogens and can induce DNA adducts in human placenta and hemoglobin adducts in fetuses. We present the results of an international case-control study to evaluate the association between CBTs and exposure of parents and children to cigarette smoke. The study was undertaken as part of the SEARCH program of the IARC. Nine centers in 7 countries were involved. The studies mainly covered the 1980s and early 1990s. Cases (1,218, ages 0-19 years) were children newly diagnosed with a primary brain tumor; there were 2,223 population-based controls. Most mothers who agreed to participate were interviewed in person at home. Odds ratios (ORs) were calculated by unconditional logistic regression, adjusted for age, sex and center, for all types of CBT combined, 4 CBT histotypes, 5 age groups and each center. There was no association between the risk of brain tumors in the child and parental smoking prior to pregnancy, maternal smoking or regular exposure to others' cigarette smoke during pregnancy at home or at work, or passive smoking by the child during the first year of life. These results did not change considering the child's age at diagnosis, the histologic type of tumor or center.

Adolescent↗
PubMed2002

Asymptomatic colorectal neoplasia and fecal characteristics: a case-control study of subjects participating in the nottingham fecal occult blood screening trial.

PURPOSE: The results of previous studies of colorectal neoplasia and fecal composition have been inconsistent, in part because the cases have been symptomatic and the studies small. We sought to test hypotheses relating to fecal bile acids, calcium, and pH in a large sample of asymptomatic subjects who had participated in fecal occult blood screening. METHODS: Fecal samples were obtained from 45 cases of cancer, 129 subjects with adenoma, 167 fecal occult blood-negative controls and 155 fecal occult blood-positive subjects in whom no cancer or adenoma was found. Concentrations of fecal bile acids, steroids, calcium, and pH were assessed blind to case-control status and compared between cases and 1) fecal occult blood-negative controls and 2) fecal occult blood-positive subjects. RESULTS: No association between colorectal cancer and fecal bile acids or pH was observed. Although there was no overall association between colorectal adenomas and fecal bile acids or pH, villous adenomas were associated with increasing concentrations of major bile acids and decreasing concentration of minor bile acids, and there was a suggestion of an inverse association with an acid pH. High levels of fecal calcium were associated with a reduced risk of both colorectal cancer and adenoma, but this was not statistically significant. CONCLUSION: The study does not support an association between colorectal cancer and fecal bile acids or pH. However, there is evidence that increases in major bile acids are associated with villous adenomas.

Adenoma↗
PubMedDate not supplied

An epidemiologic assessment of genomic profiling for measuring susceptibility to common diseases and targeting interventions.

PURPOSE: The current clinical value of genomic profiling (testing for genotypes at multiple loci) for assessing susceptibility to common diseases and targeting behavioral and medical interventions is questionable. As common diseases result from many gene-environment interactions, epidemiologic studies should be used to examine the value of genomic profiling in terms of clinical validity (future disease positive and negative predictive value stratified by exposure), clinical utility (targeted interventions to reduce disease risk among persons with the profile) and public health utility (comparing reduction of disease burden in the population based on genomic profiling to population-wide interventions). METHODS: We investigate these parameters for a hypothetical common disease (5% lifetime risk), for which 3 genetic variants at different loci and one environmental exposure are risk factors. RESULTS: We show that even for modest effects of each variant alone (risk ratios from 1.5-3.0) and modest interactions between the exposure and the genes, the disease predictive value for people with 2 or more variants (especially 3) can be quite high (50-100%) in the presence of a modifiable exposure. Individual risks can then be reduced by targeted exposure intervention among persons with the genotype. However, the predictive value for multiple genotypes is much lower for rarer diseases (< 1 per 1000). Also, with increasing number of genes in a profile, the population impact of disease reduction for targeted intervention based on genotype will be smaller, especially for rare genotypes, weak associations, and weak interactions. CONCLUSION: To assess the value of genomic profiling, well-designed epidemiologic studies are needed to quantify disease risks, in addition to costs, benefits, and risks for testing and interventions.

DNA Fingerprinting↗