Katharina Nimptsch

Vitamin D–Related Genetic Variation, Plasma Vitamin D, and Risk of Lethal Prostate Cancer: A Prospective Nested Case–Control Study

BACKGROUND The association of vitamin D status with prostate cancer is controversial; no association has been observed for overall incidence, but there is a potential link with lethal disease. METHODS We assessed prediagnostic 25-hydroxyvitamin D [25(OH)D] levels in plasma, variation in vitamin D-related genes, and risk of lethal prostate cancer using a prospective case-control study nested within the Health Professionals Follow-up Study. We included 1260 men who were diagnosed with prostate cancer after providing a blood sample in 1993-1995 and 1331 control subjects. Men with prostate cancer were followed through March 2011 for lethal outcomes (n = 114). We selected 97 single-nucleotide polymorphisms (SNPs) in genomic regions with high linkage disequilibrium (tagSNPs) to represent common genetic variation among seven vitamin D-related genes (CYP27A1, CYP2R1, CYP27B1, GC, CYP24A1, RXRA, and VDR). We used a logistic kernel machine test to assess whether multimarker SNP sets in seven vitamin D pathway-related genes were collectively associated with prostate cancer. Tests for statistical significance were two-sided. RESULTS Higher 25(OH)D levels were associated with a 57% reduction in the risk of lethal prostate cancer (highest vs lowest quartile: odds ratio = 0.43, 95% confidence interval = 0.24 to 0.76). This finding did not vary by time from blood collection to diagnosis. We found no statistically significant association of plasma 25(OH)D levels with overall prostate cancer. Pathway analyses found that the set of SNPs that included all seven genes (P = .008) as well as sets of SNPs that included VDR (P = .01) and CYP27A1 (P = .02) were associated with risk of lethal prostate cancer. CONCLUSION In this prospective study, plasma 25(OH)D levels and common variation among several vitamin D-related genes were associated with lethal prostate cancer risk, suggesting that vitamin D is relevant for lethal prostate cancer.

Association between plasma 25-OH vitamin D and testosterone levels in men

Objective A small randomized controlled trial suggested that vitamin D might increase the production of testosterone in men, which is supported by experimental studies in animals and a cross‐sectional study showing positive associations between plasma 25‐hydroxyvitamin D [25(OH)D] and testosterone and concordant seasonal variation of both biomarkers.

Dietary glucosinolate intake and risk of prostate cancer in the EPIC‐Heidelberg cohort study

Glucosinolates (GLS) are secondary plant metabolites occurring in cruciferous vegetables. Their biologically active break‐down products show cancer preventive properties in animal and cell studies. So far, epidemiologic studies, using consumption of cruciferous vegetables as proxy for GLS intake, yielded inconsistent results. Here, we evaluated the association between dietary intake of GLS in comparison with consumption data of GLS‐containing foods and the risk of prostate cancer. The study population comprised 11,405 male participants of the prospective EPIC‐Heidelberg cohort study. During a mean follow‐up time of 9.4 years, 328 incident cases of prostate cancer occurred. At recruitment, habitual food consumption was assessed by a validated food frequency questionnaire, and intake of individual GLS was estimated by means of a newly compiled database on food content of GLS. Adjusted hazard ratios (HR) for prostate cancer were calculated using the Cox proportional hazard model. Median daily intake of total GLS was 7.9 mg/day (interquartile range 5.1–11.9 mg/day). The risk of prostate cancer decreased significantly over quartiles of total GLS intake (multivariate HR [4th vs. 1st quartile] 0.68, 95% CI 0.48–0.97, ptrend 0.03). Associations with GLS‐containing food intake were weaker. Among GLS subgroups, aliphatic GLS showed the strongest inverse association with cancer risk. Analyses stratified by tumor stage and grade gave hint to inverse associations for localized and low‐grade cancers. This study shows an inverse association between dietary intake of GLS and the risk of prostate cancer. Because this is the first prospective study using individual GLS intake data, confirmation in other studies is warranted.

Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg)

BACKGROUND Anticarcinogenic activities of vitamin K have been observed in animal and cell studies. OBJECTIVE On the basis of the growth inhibitory effects of vitamin K as observed in a variety of cancer cell lines, we hypothesized that dietary intake of phylloquinone (vitamin K(1)) and menaquinones (vitamin K(2)) may be associated with overall cancer incidence and mortality. DESIGN In the prospective EPIC-Heidelberg (European Prospective Investigation into Cancer and Nutrition-Heidelberg) cohort study, 24,340 participants aged 35-64 y and free of cancer at enrollment (1994-1998) were actively followed up for cancer incidence and mortality through 2008. Dietary vitamin K intake was estimated from food-frequency questionnaires completed at baseline by using HPLC-based food-composition data. Multivariate-adjusted hazard ratios (HRs) and 95% CIs were estimated by using Cox proportional hazards models. RESULTS During a median follow-up time of >10 y, 1755 incident cancer cases occurred, of which 458 were fatal. Dietary intake of menaquinones was nonsignificantly inversely associated with overall cancer incidence (HR for the highest compared with the lowest quartile: 0.86; 95% CI: 0.73, 1.01; P for trend = 0.08), and the association was stronger for cancer mortality (HR: 0.72; 95% CI: 0.53, 0.98; P for trend = 0.03). Cancer risk reduction with increasing intake of menaquinones was more pronounced in men than in women, mainly driven by significant inverse associations with prostate (P for trend = 0.03) and lung (P for trend = 0.002) cancer. We found no association with phylloquinone intake. CONCLUSION These findings suggest that dietary intake of menaquinones, which is highly determined by the consumption of cheese, is associated with a reduced risk of incident and fatal cancer.

Influence of Obesity and Related Metabolic Alterations on Colorectal Cancer Risk

Obesity and related metabolic alterations have been implicated to play a role in colorectal cancer risk. The metabolic syndrome, as assessed according to current international definitions by the key components, abdominal obesity, dyslipidemia, elevated blood pressure, and abnormal glucose metabolism, is associated with colorectal cancer. Recent studies suggest that abdominal obesity and abnormal glucose metabolism may primarily account for this association. Visceral adipose tissue is physiologically more active than subcutaneous adipose tissue and generates hormones and cytokines with inflammatory, metabolic, and direct carcinogenic potential, which may directly or indirectly increase colorectal cancer risk. Current evidence suggests that obesity acts as a risk factor for colorectal cancer by several mechanisms, including chronic low-grade inflammation, hyperinsulinemia, as well as alterations in insulin-like growth factor and adipokine concentrations. Metabolic biomarkers reflecting these processes may not only provide clues for etiological understanding of colorectal carcinogenesis but also might be an alternative way to define an “obesity phenotype” that is relevant for colorectal cancer development.

Obesity and colorectal cancer.

This review outlines the association of obesity with risk of colorectal cancer and the potential underlying mechanisms from an epidemiological perspective. Current research indicates that there is a moderate but consistently reported association between general obesity (as determined by BMI) and colorectal cancer incidence and mortality. The relative risk associated with obesity is higher for cancer of the colon than for cancer of the rectum and it is higher in men than in women. By contrast, abdominal adiposity (as determined by waist circumference or waist-to-hip ratio) is similarly strongly associated with colon cancer in men and women, suggesting that abdominal adiposity is a more important risk factor for colon cancer than general adiposity, at least in women. Putative mechanisms that may account for the link between adiposity and colorectal cancer risk include hyperinsulinemia, insulin resistance, inflammation, altered immune response, oxidative stress, as well as disturbances in insulin-like growth factors, adipokines, and sex steroids. Understanding the link between obesity and colorectal cancer may pave the way for targeted prevention of colorectal cancer morbidity and mortality.

Determinants and correlates of serum undercarboxylated osteocalcin.

Background/Aims: To assess dietary and nondietary determinants of serum undercarboxylated osteocalcin (ucOC) as a measure of vitamin K status. Methods: UcOC and total intact osteocalcin (iOC) concentrations were determined by specific ELISA tests in serum samples of 231 male and 320 female participants (18–81 years) of the representative, cross-sectional Bavarian Food Consumption Survey II. Determinants of ucOC were investigated by analysis of variance, Spearman’s rank correlation coefficients and logistic regression models. Results: Mean ucOC serum concentration was 2.46 ng/ml in men and 2.34 ng/ml in women. Corresponding means of the ratio of ucOC to iOC (ucOC/iOC) were 0.28 and 0.29. Concentrations of ucOC and iOC, as well as the ratio of ucOC/iOC, strongly depended on the participant’s age. UcOC was influenced by smoking status, sports activity, and the season when blood was collected. Dietary intake of the dominant vitamin K sources, green leafy vegetables and dairy products, as well as the plasma concentration of the carotenoid lutein were inversely associated with serum ucOC values. Conclusions: In studies using serum ucOC as a measure of vitamin K supply, determinants, especially age, need to be taken into account.

Prediagnostic plasma IGFBP‐1, IGF‐1 and risk of prostate cancer

Insulin‐like growth factor (IGF)−1 is associated with a higher risk of prostate cancer. IGF‐binding protein (IGFBP)−1, a marker for insulin activity, also binds IGF‐1 and inhibits its action. Data on IGFBP‐1 and prostate cancer risk are sparse and whether the IGF and insulin axes interact to affect prostate cancer carcinogenesis is unknown. We evaluated the independent and joint influence of prediagnostic plasma levels of IGFBP‐1 (fasting) and IGF‐1 on risk of prostate cancer among 957 cases and 1,021 controls with fasting levels of IGFBP‐1 and 1,709 cases and 1,778 controls with IGF‐1 nested within the Health Professionals Follow‐up Study. Unconditional logistic regression adjusting for matching factors was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Higher prediagnostic fasting IGFBP‐1 levels were associated with lower risk of prostate cancer (highest vs. lowest quartile OR = 0.67, 95% CI 0.52–0.86, ptrend = 0.003), which remained similar after adjusting for IGF‐1. Prediagnostic IGF‐1 was associated with increased risk of prostate cancer (highest vs. lowest quartile OR = 1.28, 95% CI = 1.05–1.56, ptrend = 0.01). The associations with each marker were primarily driven by lower‐grade and non‐advanced prostate cancer. Being low in IGFBP‐1 and high in IGF‐1 did not confer appreciable additional risk (pinteraction = 0.42). In summary, prediagnostic fasting IGFBP‐1 may influence prostate cancer carcinogenesis. Being low in IGFBP‐1 or high in IGF‐1 is sufficient to elevate the risk of prostate cancer.

Association of CRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk.

High blood concentrations of C‐reactive protein (CRP) have been associated with elevated risk of colorectal cancer in several prospective studies including the European Prospective Investigation into Cancer and Nutrition (EPIC), but it is unknown whether these observations reflect a causal relationship. We aimed to investigate whether CRP genetic variants associated with lifelong higher CRP concentrations translate into higher colorectal cancer risk. We conducted a prospective nested case–control study within EPIC including 727 cases diagnosed between 1992 and 2003 and 727 matched controls selected according to an incidence‐density sampling protocol. Baseline CRP concentrations were measured in plasma samples by a high sensitivity assay. Tagging single nucleotide polymorphisms (SNPs) in the CRP gene (rs1205, rs1800947, rs1130864, rs2808630, rs3093077) were identified via HapMap. The causal effect of CRP on colorectal cancer risk was examined in a Mendelian Randomization approach utilizing multiple CRP genetic variants as instrumental variables. The SNPs rs1205, rs1800947, rs1130864 and rs3093077 were significantly associated with CRP concentrations and were incorporated in a CRP allele score which was associated with 13% higher CRP concentrations per allele count (95% confidence interval 8–19%). Using the CRP‐score as instrumental variable, genetically twofold higher CRP concentrations were associated with higher risk of colorectal cancer (odds ratio 1.74, 95% confidence interval 1.06–2.85). Similar observations were made using alternative definitions of instrumental variables. Our findings give support to the hypothesis that elevated circulating CRP may play a direct role in the etiology of colorectal cancer.

Habitual intake of flavonoid subclasses and risk of colorectal cancer in 2 large prospective cohorts

Background: Flavonoids inhibit the growth of colon cancer cells in vitro. In a secondary analysis of a randomized controlled trial, the Polyp Prevention Trial, a higher intake of one subclass, flavonols, was statistically significantly associated with a reduced risk of recurrent advanced adenoma. Most previous prospective studies on colorectal cancer evaluated only a limited number of flavonoid subclasses and intake ranges, yielding inconsistent results. Objective: In this study, we examined whether higher habitual dietary intakes of flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols, and anthocyanins) were associated with a lower risk of colorectal cancer. Design: Using data from validated food-frequency questionnaires administered every 4 y and an updated flavonoid food composition database, we calculated flavonoid intakes for 42,478 male participants from the Health Professionals Follow-Up Study and for 76,364 female participants from the Nurses’ Health Study. Results: During up to 26 y of follow-up, 2519 colorectal cancer cases (1061 in men, 1458 in women) were documented. Intakes of flavonoid subclasses were not associated with risk of colorectal cancer in either cohort. Pooled multivariable adjusted RRs (95% CIs) comparing the highest with the lowest quintiles were 1.04 (0.91, 1.18) for flavonols, 1.01 (0.89, 1.15) for flavones, 0.96 (0.84, 1.10) for flavanones, 1.07 (0.95, 1.21) for flavan-3-ols, and 0.98 (0.81, 1.19) for anthocyanins (all P values for heterogeneity by sex >0.19). In subsite analyses, flavonoid intake was also not associated with colon or rectal cancer risk. Conclusion: Our findings do not support the hypothesis that a higher habitual intake of any flavonoid subclass decreases the risk of colorectal cancer.