E. Kampman

Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity

Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 × 10−7. This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.

Calcium does not protect against colorectal neoplasia

&NA; Calcium could decrease risk of colorectal neoplasia by binding bowel‐irritating compounds and diminishing mucosal proliferation. This study quantitatively summarizes epidemiologic studies addressing this hypothesis and aims to explain heterogeneity between studies. Twenty‐four articles reported 43 measures of relative risks (RRs). The weighted mean, according to a random effects model, did not indicate substantial protection by calcium [RR = 0.89; 95% confidence interval (CI) = 0.79‐1.01]. Results from different studies showed substantial heterogeneity, with the “true” underlying RRs ranging from about 0.50 to 1.60. Summary RRs for cohort and case‐control studies were 0.90 and 0.88, respectively. For adenomas and carcinomas, RRs were 1.13 (95% CI = 0.91‐1.39) and 0.86 (95% CI = 0.74‐0.98), respectively, both falling within the range of betweenstudy heterogeneity. With respect to subsites, lower RRs were observed for estimates that included proximal colon as one of the subsites (RR = 0.67), whereas the RR was close to 1.0 for distal (RR = 0.97) and rectal subsites (RR = 0.99). Stratification on study characteristics and weighted regression analysis yielded RRs slightly below 1.0, with considerable heterogeneity. These results do not support the hypothesis that calcium prevents colorectal neoplasia. (Epidemiology 1996;7:590‐597)

Vegetable and animal products as determinants of colon cancer risk in Dutch men and women

To examine the relationship between colon cancer and food groups from vegetable or animal sources and their possible interactions with gender, we analyzed data from a Dutch case-control study. Dietary patterns were assessed for 232 colon cancer cases and 259 population controls. In multivariate analyses, the consumption of vegetables was associated significantly with reduced colon-cancer risk (odds ratio [OR] for highest cf lowest quartile of consumption =0.4, 95 percent confidence interval [CI]=0.2-0.7, P-trend =0.0004). Consumption of fresh red meat was associated positively with risk in women (Or=2.4, 95% CI=1.0-5.7, P-trend=0.04), especially for those with a high consumption of red meat relative to the consumption of vegetables and fruits (OR=3.1). For men, no association with consumption of fresh red meat was found OR=0.9). No clear associations were found for other products of vegetable or animal origin. The results of this Dutch case-control study support the preventive potential of a high-vegetable diet in colon cancer risk. This study suggests this may be important for women consuming a diet high in red meat.

Plasma Enterolignans Are Associated with Lower Colorectal Adenoma Risk

Lignans are biphenolic compounds that occur in foods of plant origin such as whole grains, seeds, fruits and vegetables, and beverages, such as coffee and tea. Plant lignans are converted by intestinal bacteria into the enterolignans, enterodiol and enterolactone. Enterolignans possess several biological activities, whereby they may influence carcinogenesis. We studied the associations between plasma enterolignans and the risk of colorectal adenomas in a Dutch case-control study. Colorectal adenomas are considered to be precursors of colorectal cancer. Cases (n = 532) with at least one histologically confirmed colorectal adenoma and controls (n = 503) with no history of any type of adenoma were included. Plasma enterodiol and enterolactone concentrations were measured by liquid chromatography with tandem mass spectrometry. Associations were stronger for incident than for prevalent cases. When only incident cases (n = 262) were included, high compared to low plasma concentrations of enterodiol were associated with a reduction in colorectal adenoma risk after adjustment for confounding variables. Enterodiol odds ratios (95% confidence intervals) were 1.00, 0.69 (0.42-1.13), 0.60 (0.37-0.99), and 0.53 (0.32-0.88) with a significant trend (P = 0.01) through the quartiles. Although enterolactone plasma concentrations were 10-fold higher, enterolactones reduction in risk was not statistically significant (P for trend = 0.09). Use of oral antibiotic therapy could decrease the plasma concentrations of enterolactone. Exclusion of antibiotic users resulted in similar odds ratios for both enterolignans, but the association for enterolactone became somewhat stronger (P = 0.05 versus P = 0.09). We observed a substantial reduction in colorectal adenoma risk among subjects with high plasma concentrations of enterolignans, in particular, enterodiol. These findings could be important in the prevention of colorectal adenomas. (Cancer Epidemiol Biomarkers Prev 2006;15(6):1132–6)

Fluid intake and the risk of urothelial cell carcinomas in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Results from previous studies investigating the association between fluid intake and urothelial cell carcinomas (UCC) are inconsistent. We evaluated this association among 233,236 subjects in the European Prospective Investigation into Cancer and Nutrition (EPIC), who had adequate baseline information on water and total fluid intake. During a mean follow‐up of 9.3 years, 513 first primary UCC occurred. At recruitment, habitual fluid intake was assessed by a food frequency questionnaire. Multivariable hazard ratios were estimated using Cox regression stratified by age, sex and center and adjusted for energy intake, smoking status, duration of smoking and lifetime intensity of smoking. When using the lowest tertile of intake as reference, total fluid intake was not associated with risk of all UCC (HR 1.12; 95%CI 0.86–1.45, p‐trend = 0.42) or with risk of prognostically high‐risk UCC (HR 1.28; 95%CI 0.85–1.93, p‐trend = 0.27) or prognostically low‐risk UCC (HR 0.93; 95%CI 0.65–1.33, p‐trend = 0.74). No associations were observed between risk of UCC and intake of water, coffee, tea and herbal tea and milk and other dairy beverages. For prognostically low‐risk UCC suggestions of an inverse association with alcoholic beverages and of a positive association with soft drinks were seen. Increased risks were found for all UCC and prognostically low‐risk UCC with higher intake of fruit and vegetable juices. In conclusion, total usual fluid intake is not associated with UCC risk in EPIC. The relationships observed for some fluids may be due to chance, but further investigation of the role of all types of fluid is warranted.

Blood lipid levels and prostate cancer risk; a cohort study.

It has been hypothesized that blood lipid levels might be associated with prostate cancer risk. The aim of the present study was to evaluate the association between serum total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and prostate cancer risk in a cohort study among 2842 Dutch men. By the end of follow-up, 64 incident cases of prostate cancer were identified. Serum total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides were evaluated as potential risk factors for prostate cancer using multivariable Cox proportional hazards regression models. These analyses were restricted to men who never used cholesterol-lowering drugs (2118 men, 43 cases). Higher total and higher LDL cholesterol were significantly associated with an increased risk of prostate cancer (hazards ratios (HR) and 95% confidence interval (CI) per mmolu2009l−1 were 1.39 (95% CI 1.03–1.88) and 1.42 (95% CI 1.00–2.02), respectively). Similar results were observed for aggressive prostate cancer, whereas for non-aggressive prostate cancer a significant association with HDL cholesterol was found (HR 4.28, 95% CI 1.17–15.67). The results of this study suggest that blood lipid levels may influence risk of prostate cancer. However, the exact roles of different cholesterol fractions on prostate cancer aggressiveness should be further evaluated.

Consumption of vegetables and fruit and the risk of bladder cancer in the European Prospective Investigation into Cancer and Nutrition

Previous epidemiologic studies found inconsistent associations between vegetables and fruit consumption and the risk of bladder cancer. We therefore investigated the association between vegetable and fruit consumption and the risk of bladder cancer among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Data on food consumption and complete follow‐up for cancer occurrence was available for a total of 478,533 participants, who were recruited in 10 European countries. Estimates of rate ratios were obtained by Cox proportional hazard models, stratified by age at recruitment, gender and study centre, and adjusted for total energy intake, smoking status, duration of smoking and lifetime intensity of smoking. A calibration study in a subsample was used to control for dietary measurement errors. After a mean follow‐up of 8.7 years, 1015 participants were newly diagnosed with bladder cancer. Increments of 100 g/day in fruit and vegetable consumption combined did not affect bladder cancer risk (i.e., calibrated HR = 0.98; 95%CI: 0.95–1.01). Borderline statistically significant lower bladder cancer risks were found among never smokers with increased consumption of fruit and vegetables combined (HR = 0.94 95%CI: 0.87–1.00 with increments of 100 g/day; calibrated HR = 0.92 95%CI 0.79–1.06) and increased consumption of apples and pears (hard fruit; calibrated HR = 0.90 95%CI: 0.82–0.98 with increments of 25 g/day). For none of the associations a statistically significant interaction with smoking status was found. Our findings do not support an effect of fruit and vegetable consumption, combined or separately, on bladder cancer risk.

Dietary supplement use and colorectal cancer risk: a systematic review and meta-analyses of prospective cohort studies.

Use of dietary supplements is rising in countries where colorectal cancer is prevalent. We conducted a systematic literature review and meta‐analyses of prospective cohort studies on dietary supplement use and colorectal cancer risk. We identified relevant studies in Medline, Embase and Cochrane up to January 2013. Original and peer‐reviewed papers on dietary supplement use and colorectal cancer, colon cancer, or rectal cancer incidence were included. “Use‐no use”(U‐NU), “highest‐lowest”(H‐L) and “dose‐response”(DR) meta‐analyses were performed. Random‐effects models were used to estimate summary estimates. In total, 24 papers were included in the meta‐analyses. We observed inverse associations for colorectal cancer risk and multivitamin (U‐NU: RRu2009=u20090.92; 95% CI: 0.87,0.97) and calcium supplements (U‐NU: RRu2009=u20090.86; 95% CI: 0.79,0.95; H‐L: RRu2009=u20090.80; 95% CI: 0.70,0.92; DR: for an increase of 100 mg/day, RRu2009=u20090.96; 95% CI: 0.94,0.99). Inconsistent associations were found for colon cancer risk and supplemental vitamin A and vitamin C, and for colorectal cancer risk and supplemental vitamin D, vitamin E, garlic and folic acid. Meta‐analyses of observational studies suggest a beneficial role for multivitamins and calcium supplements on colorectal cancer risk, while the association with other supplements and colorectal cancer risk is inconsistent. Residual confounding of lifestyle factors might be present. Before recommendations can be made, an extensive assessment of dietary supplement use and a better understanding of underlying mechanisms is needed.

No effect of folic acid supplementation on global DNA methylation in men and women with moderately elevated homocysteine

A global loss of cytosine methylation in DNA has been implicated in a wide range of diseases. There is growing evidence that modifications in DNA methylation can be brought about by altering the intake of methyl donors such as folate. We examined whether long-term daily supplementation with 0.8 mg of folic acid would increase global DNA methylation compared with placebo in individuals with elevated plasma homocysteine. We also investigated if these effects were modified by MTHFR C677T genotype. Two hundred sixteen participants out of 818 subjects who had participated in a randomized double-blind placebo-controlled trial were selected, pre-stratified on MTHFR C677T genotype and matched on age and smoking status. They were allocated to receive either folic acid (0.8 mg/d; nu200a=u200a105) or placebo treatment (nu200a=u200a111) for three years. Peripheral blood leukocyte DNA methylation and serum and erythrocyte folate were assessed. Global DNA methylation was measured using liquid chromatography-tandem mass spectrometry and expressed as a percentage of 5-methylcytosines versus the total number of cytosine. There was no difference in global DNA methylation between those randomized to folic acid and those in the placebo group (differenceu200a=u200a0.008, 95%CIu200a=u200a−0.05,0.07, Pu200a=u200a0.79). There was also no difference between treatment groups when we stratified for MTHFR C677T genotype (CC, nu200a=u200a76; CT, nu200a=u200a70; TT, nu200a=u200a70), baseline erythrocyte folate status or baseline DNA methylation levels. In moderately hyperhomocysteinemic men and women, long-term folic acid supplementation does not increase global DNA methylation in peripheral blood leukocytes. ClinicalTrials.gov NCT00110604

Reproductive and hormonal factors in male and female colon cancer

We analysed data from a case-control study in the Netherlands in order to investigate whether reproductive events and hormonal factors are similarly related to colon cancer risk in men and women after adjustment for dietary factors. In total, 232 colon cancer cases (102 women, 130 men) and 259 controls (123 women, 136 men) were interviewed about life style, medical conditions and usual dietary patterns, using a structured dietary history technique. In women, age at first childbirth was positively associated with colon cancer risk (odds ratio (OR) age ≥ 26 vs < 26 years, 1.7; 95% confidence interval (CI), 0.9–3.3). Women with three or more children were at reduced risk compared with women with one or two children (OR, 0.6; 95% CI, 0.3–1.1). When women had had their first child after the age of 26 years, parity was observed to be important (for one or two children vs ≥ three children: OR, 2.8; 95% CI, 1.1–7.0). For men, opposite but non-significant associations were found. Adjustment for dietary patterns and other risk factors did not change the estimates markedly. Of the hormonal factors, late age at menarche decreased risk (OR, 0.5; 95% CI, 0.3–0.9) while late age at natural menopause slightly increased risk. Our study provides additional support for the role of reproductive status in the aetiology of colon cancer in women, independently of dietary factors.