Elke Raum

Meta-analysis: Serum vitamin D and breast cancer risk

We reviewed and summarised observational epidemiological studies regarding the association between serum vitamin D (measured as 25(OH)D levels) and the risk of breast cancer (BC). Relevant studies published until September 2009 were identified by systematically electronic searching Ovid Medline, EMBASE and ISI Web of Knowledge databases and by cross-referencing. The following data were extracted in a standardised manner from eligible studies: first author, publication year, country, study design, characteristics of the study population, duration of follow-up, BC incidence/BC mortality according to serum 25-hydroxyvitamin D (25(OH)D) and the respective ratios, and covariates adjusted for in the analysis. All existing observational epidemiological studies that reported at least one serum 25(OH)D level in subjects in any time period before or after a diagnosis of breast cancer were included in our review. Individual and summary risk ratios (RRs) for an increase of serum 25(OH)D by 20ng/ml were calculated using meta-analysis methods. Only 25(OH)D was considered. Overall, 10 articles were included. Specific results for BC incidence were reported in nine articles and for BC mortality in one article. In meta-analyses, summary RRs (95% confidence interval (CI)) for an increase of 25(OH)D by 20ng/ml were 0.59 (0.48-0.73), 0.92 (0.82-1.04) and 0.73 (0.60-0.88) with P values of <0.001, 0.164 and 0.001 for case-control studies, nested case-control studies and both study designs combined, respectively. No indication for publication bias was found, but there was large heterogeneity between studies. In conclusion, while case-control studies with measurement of 25(OH)D after diagnosis suggest an inverse association, a statistically significant inverse association remained unconfirmed in prospective studies with measurement of 25(OH)D years before diagnosis. Further studies are needed to clarify the potential role and the relevant exposure time regarding vitamin D and breast cancer risk.

Meta‐analysis: longitudinal studies of serum vitamin D and colorectal cancer risk

Background  In 1980, Garland hypothesized that lower levels of vitamin D resulting from much weaker UV‐B radiation at higher latitudes may account for the striking geographical pattern of cancer mortality. Further research has been conducted over the past 20 years.

Epigenotyping in peripheral blood cell DNA and breast cancer risk: a proof of principle study.

Background Epigenetic changes are emerging as one of the most important events in carcinogenesis. Two alterations in the pattern of DNA methylation in breast cancer (BC) have been previously reported; active estrogen receptor-α (ER-α) is associated with decreased methylation of ER-α target (ERT) genes, and polycomb group target (PCGT) genes are more likely than other genes to have promoter DNA hypermethylation in cancer. However, whether DNA methylation in normal unrelated cells is associated with BC risk and whether these imprints can be related to factors which can be modified by the environment, is unclear. Methodology/Principal Findings Using quantitative methylation analysis in a case-control study (n = 1,083) we found that DNA methylation of peripheral blood cell DNA provides good prediction of BC risk. We also report that invasive ductal and invasive lobular BC is characterized by two different sets of genes, the latter particular by genes involved in the differentiation of the mesenchyme (PITX2, TITF1, GDNF and MYOD1). Finally we demonstrate that only ERT genes predict ER positive BC; lack of peripheral blood cell DNA methylation of ZNF217 predicted BC independent of age and family history (odds ratio 1.49; 95% confidence interval 1.12–1.97; P = 0.006) and was associated with ER-α bioactivity in the corresponding serum. Conclusion/Significance This first large-scale epigenotyping study demonstrates that DNA methylation may serve as a link between the environment and the genome. Factors that can be modulated by the environment (like estrogens) leave an imprint in the DNA of cells that are unrelated to the target organ and indicate the predisposition to develop a cancer. Further research will need to demonstrate whether DNA methylation profiles will be able to serve as a new tool to predict the risk of developing chronic diseases with sufficient accuracy to guide preventive measures.

Meta-analysis of longitudinal studies: Serum vitamin D and prostate cancer risk

AIM To review and summarize evidence from longitudinal studies on the association between serum 25-hydroxyvitamin D (25(OH)D) and the risk of prostate cancer (PC). METHODS Relevant prospective cohort studies and nested case-control studies published until July 2009 were identified by systematically searching Ovid Medline, EMBASE, and ISI Web of Knowledge databases and by cross-referencing. The following data were extracted in a standardized manner from eligible studies: first author, publication year, country, study design, characteristics of the study population, duration of follow-up, PC incidence/PC mortality according to serum vitamin D status and the respective risk ratios, and covariates adjusted for in the analysis. Due to the heterogeneity of studies in categorizing serum vitamin D levels, all results were recalculated for an increase in serum 25(OH)D by 10ng/ml. Summary odds ratios (ORs) were calculated using meta-analysis methods. RESULTS Overall, eleven original articles were included, ten of which reported on the association between serum vitamin D levels and PC incidence and one article reported on the association with PC mortality. Meta-analysis of studies on PC incidence resulted in a summary OR (95% confidence interval, CI) of 1.03 (0.96-1.11) associated with an increase of 25(OH)D by 10ng/ml (P=0.362). No indication for heterogeneity and publication bias was found. CONCLUSIONS According to available evidence from longitudinal studies, serum 25(OH)D is not associated with PC incidence.

Tobacco Smoke Exposure Before, During, and After Pregnancy and Risk of Overweight at Age 6

Maternal smoking during pregnancy has been associated with overweight and obesity in childhood and is strongly correlated with childrens tobacco smoke exposure before and after pregnancy. We investigated the independent association of tobacco smoke exposure at various pre‐ and postnatal periods and overweight at age 6. A total of 1,954 children attending the 2001–2002 school entrance health examination in the city of Aachen, Germany, were included into this study. Height and weight were measured, BMI was calculated. Tobacco smoke exposure at various periods, other lifestyle and sociodemographic factors were ascertained by questionnaire. Multiple logistic regression models were used to assess the association between tobacco smoke exposure and overweight. Prevalence of overweight was 8.9%. Significant positive associations were found with maternal smoking before and during pregnancy and during the first and sixth year of life. When all smoking periods were included into one logistic model simultaneously, secondhand smoke exposure after birth remained positively associated with overweight at age 6 at either one of the two time periods (first year only: odds ratio (OR) (95% confidence interval (CI)): 2.94 (1.30–6.67), sixth year only: 2.57 (1.64–4.04), respectively) or at both (4.43 (2.24–8.76)). Exposure to tobacco smoke during the first years of life appears to be a key risk factor for development of childhood overweight.

Changes of cardiovascular risk factors and their implications in subsequent birth cohorts of older adults in Germany: a life course approach

Background To examine lifetime patterns of cardiovascular risk factors and their implications in subsequent birth cohorts of older adults in Germany, who experienced very different political and socioeconomic conditions at various phases of their lives. Design and methods Participants of the ESTHER study, a statewide cohort study conducted in Saarland, Germany, were categorized into four birth cohorts: 1925-1934, 1935-1939, 1940-1944, 1945-1952. At baseline, lifetime history of body weight, physical activity, smoking and drinking habits, and of physician-diagnosed diabetes mellitus were documented. The average BMI, the average number of hours of physical activity, prevalence of smoking and alcohol consumption between ages 20 and 50 years were assessed. The relative risks of a first diagnosis of diabetes mellitus before or at the age of 50 years by birth cohorts were assessed by multiple logistic regressions controlling for education and BMI at the age of 20. Results For both men and women, later birth cohorts had considerably worse lifestyle profiles. The frequency of diabetes mellitus up to the age of 50 years was much higher in the later than in the earlier cohorts. The increase was more pronounced among men than among women. Conclusion Women and men reaching old age in the forthcoming years have more unfavourable lifetime risk factor profiles than earlier birth cohorts. These patterns might have substantial implications for the future burden of chronic disease. Eur J Cardiovasc Prev Rehabil 14: 809-814

Genetic Variation in the Prostate Stem Cell Antigen Gene and Upper Gastrointestinal Cancer in White Individuals

BACKGROUND & AIMS An association between gastric cancer and the rs2294008 (C>T) polymorphism in the prostate stem cell antigen (PSCA) gene has been reported for several Asian populations. We set out to determine whether such an association exists in white individuals. METHODS We genotyped 166 relatives of gastric cancer patients, including 43 Helicobacter pylori-infected subjects with hypochlorhydria and gastric atrophy, 65 infected subjects without these abnormalities, 58 H pylori-negative relatives, and 100 population controls. Additionally, a population-based study of chronic atrophic gastritis provided 533 cases and 1054 controls. We then genotyped 2 population-based, case-control studies of upper gastrointestinal cancer: the first included 312 gastric cancer cases and 383 controls; the second included 309 gastric cancer cases, 159 esophageal cancer cases, and 211 controls. Odds ratios were computed from logistic models and adjusted for confounding variables. RESULTS Carriage of the risk allele (T) of rs2294008 in PSCA was associated with chronic atrophic gastritis (adjusted odds ratio [OR], 1.5; 95% confidence interval [CI]: 1.1-1.9) and noncardia gastric cancer (OR, 1.9; 95% CI: 1.3-2.8). The association was strongest for the diffuse histologic type (OR, 3.2; 95% CI: 1.2-10.7). An inverse association was observed between carriage of the risk allele and gastric cardia cancer (OR, 0.5; 95% CI: 0.3-0.9), esophageal adenocarcinoma (OR, 0.5; 95% CI: 0.3-0.9), and esophageal squamous cell carcinoma (OR, 0.4; 95% CI: 0.2-0.9). CONCLUSIONS The rs2294008 polymorphism in PSCA increases the risk of noncardia gastric cancer and its precursors in white individuals but protects against proximal cancers.

Risk gene variants for nicotine dependence in the CHRNA5–CHRNA3–CHRNB4 cluster are associated with cognitive performance†‡§¶

Recent studies strongly support an association of the nicotinic acetylcholine receptor gene cluster CHRNA5–CHRNA3–CHRNB4 with nicotine dependence (ND). However, the precise genotype–phenotype relationship is still unknown. Clinical and epidemiological data on smoking behavior raise the possibility that the relevant gene variants may indirectly contribute to the development of ND by affecting cognitive performance in some smokers who consume nicotine for reasons of “cognition enhancement.” Here, we tested seven single nucleotide polymorphisms (SNPs) rs684513, rs637137, rs16969968, rs578776, rs1051730, rs3743078, rs3813567 from the CHRNA5–CHRNA3–CHRNB4 gene cluster for association with ND, measures of cognitive performance and gene expression. As expected, we found all SNPs being associated with ND in three independent cohorts (KORA, NCOOP, ESTHER) comprising 5,561 individuals. In an overlapping sample of 2,186 subjects we found three SNPs (rs16969968, rs1051730, rs3743078) being associated with cognitive domains from the Wechsler‐Adult‐Intelligence Scale (WAIS‐R)—most notably in the performance subtest “object assembly” and the verbal subtest “similarities.” In a refined analysis of a subsample of 485 subjects, two of these three SNPs (rs16969968, rs1051730) were associated with n‐back task performance/Continuous Performance Test. Furthermore, two CHRNA5 risk alleles (rs684513, rs637137) were associated with CHRNA5 mRNA expression levels in whole blood in a subgroup of 190 subjects. We here report for the first time an association of CHRNA5–CHRNA3–CHRNB4 gene variants with cognition possibly mediating in part risk for developing ND. The observed phenotype–genotype associations may depend on altered levels of gene expression.

Meta-analysis: Circulating vitamin D and ovarian cancer risk.

OBJECTIVE To review and summarize evidence from longitudinal studies on the association between circulating 25 hydroxyvitamin D (25(OH)D) and the risk of ovarian cancer (OC). METHODS Relevant prospective cohort studies and nested case-control studies were identified by systematically searching Ovid Medline, EMBASE, and ISI Web of Knowledge databases and by cross-referencing. The following data were extracted in a standardized manner from eligible studies: first author, publication year, country, study design, characteristics of the study population, duration of follow-up, OC incidence according to circulating vitamin D status and the respective relative risks, and covariates adjusted for in the analysis. Due to the heterogeneity of studies in categorizing circulating vitamin D levels, all results were recalculated for an increase of circulating 25(OH)D by 20ng/ml. Summary relative risks (RRs) were calculated using meta-analysis methods. RESULTS Overall, ten individual-level studies were included that reported on the association between circulating vitamin D levels and OC incidence. Meta-analysis of studies on OC incidence resulted in a summary RR (95% confidence interval, CI) of 0.83 (0.63-1.08) for an increase of 25(OH)D by 20ng/ml (P=0.160). No indication for heterogeneity and publication bias was found. CONCLUSIONS A tentative inverse association of circulating 25(OH)D with OC incidence was found, which did not reach statistical significance but which requires clarification by additional studies due to potentially high clinical and public health impact.

Epidemiology of chronic kidney disease: results from a population of older adults in Germany.

OBJECTIVE To determine prevalences and stages of chronic kidney disease (CKD), and evaluate association of CKD with related covariables in a large population of older adults. METHODS This cross-sectional analysis included 9806 participants of a general health check-up aged 50-74 years in Germany. We performed multivariate analysis to identify association of CKD with related covariables. Partial spearman correlations of eGFR with related biomarkers were calculated. RESULTS Overall, 17.4% of subjects had CKD. Prevalences of stages 1, 2, 3, 4/5 CKD were 4.6%, 4.7%, 17.0% and 0.4%, respectively. Prevalence of CKD increased with age and peaked in age 70-74 years with 23.9%. In multivariable analysis of older age, female, self-reported history of cardiovascular diseases, diabetes and statin usage were independently associated with increased risk for CKD. Significant correlations were found between eGFR and serum cystatin C (-0.28), C-reactive protein (-0.04), fasting glucose (0.12), HbA(1c) (-0.06), total cholesterol (-0.32), and triglycerides (-0.07) after adjustment for covariates. CONCLUSIONS This study shows a high prevalence of CKD among older adults. It highlights the association of eGFR with history of cardiovascular diseases, glycemic markers, and cardiovascular risk factors and may point to further possible targets in early prevention of CKD.