Polymorphism of the cyclin D1 gene, CCND1, and risk for incident sporadic colorectal adenomas.

Cyclin D1, encoded by the CCND1 gene and activated by the adenomatous polyposis coli-beta-catenin-T-cell factor/lymphoid enhancing factor pathway, induces G(1) to S-phase cell cycle transition, promoting cell proliferation. A recently described codon 242, exon 4, G to A single nucleotide polymorphism (A870G) produces a longer half-life cyclin D1. To investigate whether CCND1 genotype influences risk for colorectal adenoma, we genotyped CCND1 by PCR/RFLP on 161 incident sporadic adenoma cases and 213 controls ages 30-74 years in a North Carolina colonoscopy-based case-control study. At least one polymorphic A allele was found in 68% of cases and 60% of controls. Having an A allele was associated with increased risk for adenoma: the age- and sex-adjusted odds ratio (OR) was 1.5 [95% confidence interval (CI) 1.0-2.4], a finding that was stronger for those whose adenomas were multiple (OR 2.9, 95% CI 1.4-6.0), larger (>or=1 cm; OR 2.4, 95% CI 1.2-4.8), had moderate to severe dysplasia (OR 2.1, 95% CI 1.1-3.8), or were in the right side of the colon (OR 3.6, 95% CI 1.3-10.0). Joint risk factor multivariate analyses revealed stronger positive associations among those who were older (>57 years; OR 2.8, 95% CI 1.4-5.5), male (OR 2.8, 95% CI 1.3-5.7), currently smoked (OR 2.7, 95% CI 1.3-5.7), or currently drank alcohol (OR 2.2, 95% CI 1.2-4.2) if they had an A allele and stronger inverse associations among those who used nonsteroidal anti-inflammatory drugs (OR 0.4, 95% CI 0.2-0.9) or had higher calcium intakes (OR 0.4, 95% CI 0.2-0.9) if they had no A allele. These data support the hypothesis that the CCND1 A870G polymorphism may increase risk for colorectal neoplasms.

Calcium, vitamin D, and risk for colorectal adenoma: dependency on vitamin D receptor BsmI polymorphism and nonsteroidal anti-inflammatory drug use?

Previous epidemiological studies have been inconclusive in demonstrating an inverse association among calcium, vitamin D, and risk for colorectal adenoma. The purpose of this analysis was to evaluate the associations among calcium and vitamin D and risk for incident, sporadic colorectal adenoma according to the vitamin D receptor BsmI polymorphism and nonsteroidal anti-inflammatory drug (NSAID) use. We analyzed data from a colonoscopy-based case-control study (n = 177 cases, 228 controls) conducted in North Carolina between 1995 and 1997. Adjusted odds ratios (ORs) comparing participants in the highest to those in the lowest tertiles of total calcium and vitamin D intakes were 0.64 [95% confidence interval (CI), 0.35-1.15], P(trend) = 0.14 and 0.69 (95% CI, 0.41-1.18), and P(trend) = 0.19, respectively. Adjusted ORs for those in the upper tertile of total calcium intake relative to those in the lower were 0.25 (95% CI, 0.08-0.80) among those who had a Bb genotype, 0.57 (95% CI, 0.18-1.82) among those who had a bb genotype, and 0.36 (95% CI, 0.15-0.85) among those who did not take NSAIDs. The ORs for the highest tertile of calcium intake was 0.05 (95% CI, 0.01-0.41), P(trend) < 0.01 among those who were Bb and did not take NSAIDs, and 0.16 (95% CI, 0.02-1.36), P(trend) = 0.47 among those who were bb and did not take NSAIDs. These data support the hypotheses that higher calcium intakes may decrease risk for colorectal neoplasms, and that such a relationship is more readily detectable among those who do not take NSAIDs, and may be strongest among those who have at least one vitamin D receptor BsmI b allele.

Physical activity and reduced risk of incident sporadic colorectal adenomas: observational support for mechanisms involving energy balance and inflammation modulation.

To investigate the role of physical activity, energy balance, and inflammation on the risk of incident sporadic colorectal adenoma, the authors conducted a community- and colonoscopy-based case-control study (n = 177 cases, n = 228 controls) in Winston-Salem and Charlotte, North Carolina, from 1995 to 1997. Participants reported energy intake by a semiquantitative food frequency questionnaire, daily physical activity levels by a standardized questionnaire, and anthropometrics by self-assessment. The odds ratios for adenomas comparing the highest and lowest quantiles of exposure were 0.63 (95% confidence interval (CI): 0.34, 1.17) for physical activity, 0.80 (95% CI: 0.37, 1.73) for total energy intake, 0.70 (95% CI: 0.37, 1.34) for body mass index, 1.46 (95% CI: 0.73, 2.92) for waist/hip ratio, and 2.40 (95% CI: 1.24, 4.63) for height. For the combined effects of these factors, risk was particularly low for those with higher physical activity and low waist/hip ratio (odds ratio = 0.37, 95% CI: 0.18, 0.75) or shorter stature (odds ratio = 0.32, 95% CI: 0.16, 0.62). The inverse effect of physical activity was apparent only among those not taking nonsteroidal antiinflammatory drugs (odds ratio = 0.49, 95% CI: 0.25, 0.94). These findings add further evidence that physical activity and overall patterns indicating positive energy balance increase the risk of adenoma. Furthermore, the results suggest indirectly that biologic mechanisms related to inflammation may play a role in the beneficial effect of physical activity on the risk of incident adenoma.

Folate intake, MTHFR C677T polymorphism, alcohol consumption, and risk for sporadic colorectal adenoma (United States).

OBJECTIVE: The purpose of this study was to investigate whether folate intake is associated with risk for incident sporadic colorectal adenoma, and whether the association differs according to methylenetetrahydrofolate reductase (MTHFR) genotypes or is modified by intakes of alcohol or other micronutrients in the folate metabolism pathway. METHODS: The authors analyzed data from a colonoscopy-based case-control study (n = 177 cases, 228 controls) conducted in North Carolina between 1995 and 1997. RESULTS: The multivariate-adjusted odds ratio (OR) comparing the highest to lowest tertile of total folate intake was 0.61 (95% confidence interval [CI] 0.35-1.05); for MTHFR C677T polymorphism CT and TT genotypes relative to the CC genotype they were, respectively, 1.09 (CI: 0.71-1.66) and 0.68 (CI: 0.29-1.61); and for heavy drinkers (> 3 drinks/week) compared to non-drinkers it was 1.67 (CI: 1.00-2.81). The multivariate-adjusted ORs comparing the highest to lowest tertile of total folate intake according to those with the MTHFR CC, CT, and TT genotypes, were, respectively, 0.65 (CI: 0.30-1.39), 0.57 (CI: 0.23-1.44), and 0.22 (CI: 0.02-3.19). For those in the lowest tertile of folate intake who drank more than three drinks a week compared to those who were in the highest tertile of folate intake and did not drink alcohol the OR was 6.54 (CI: 1.96-21.80). There was no substantial evidence for interactions of folate with intakes of methionine, vitamins B2, B6, or B12. CONCLUSIONS: These data are consistent with hypotheses and previous findings that higher folate intake may reduce risk for colorectal neoplasms, perhaps especially among those who consume more alcohol.