Jane Christensen

A Reverse J-Shaped Association of All-Cause Mortality with Serum 25-Hydroxyvitamin D in General Practice: The CopD Study

CONTEXT Optimal levels of vitamin D have been a topic of heavy debate, and the correlation between 25-hydroxyvitamin D [25(OH)D] levels and mortality still remains to be established. OBJECTIVE The aim of the study was to determine the association between all-cause mortality and serum levels of 25(OH)D, calcium, and PTH. DESIGN AND SETTING We conducted a retrospective, observational cohort study, the CopD Study, in a single laboratory center in Copenhagen, Denmark. PARTICIPANTS Serum 25(OH)D was analyzed from 247,574 subjects from the Copenhagen general practice sector. In addition, serum levels of calcium, albumin-adjusted calcium, PTH, and creatinine were measured in 111,536; 20,512; 34,996; and 189,496 of the subjects, respectively. MAIN OUTCOME MEASURES Multivariate Cox regression analysis was used to compute hazard ratios for all-cause mortality. RESULTS During follow-up (median, 3.07 yr), 15,198 (6.1%) subjects died. A reverse J-shaped association between serum level of 25(OH)D and mortality was observed. A serum 25(OH)D level of 50-60 nmol/liter was associated with the lowest mortality risk. Compared to 50 nmol/liter, the hazard ratios (95% confidence intervals) of all-cause mortality at very low (10 nmol/liter) and high (140 nmol/liter) serum levels of 25(OH)D were 2.13 (2.02-2.24) and 1.42 (1.31-1.53), respectively. Similarly, both high and low levels of albumin-adjusted serum calcium and serum PTH were associated with an increased mortality, and secondary hyperparathyroidism was associated with higher mortality (P < 0.0001). CONCLUSION In this study from the general practice sector, a reverse J-shaped relation between the serum level of 25(OH)D and all-cause mortality was observed, indicating not only a lower limit but also an upper limit. The lowest mortality risk was at 50-60 nmol/liter. The study did not allow inference of causality, and further studies are needed to elucidate a possible causal relationship between 25(OH)D levels, especially higher levels, and mortality.

Healthy Aspects of the Nordic Diet Are Related to Lower Total Mortality

Health-promoting effects of the Mediterranean diet have been in focus for decades, whereas less interest has been given to existing healthy dietary habits within other Western cultures. The aim of the study was to develop a food index based on traditional Nordic food items with expected health-promoting effects and relate this to all-cause mortality in a cohort of Danes. Detailed information about diet, lifestyle, and anthropometry was provided by 57,053 Danes aged 50-64 y. During 12 y of follow-up, 4126 of the cohort participants died. A healthy Nordic food index, consisting of traditional Nordic food items with expected health-promoting effects (fish, cabbages, rye bread, oatmeal, apples and pears, and root vegetables), was extracted and associated with mortality by Cox proportional hazard models. Mortality rate ratios (MRR) with 95% CI were used to associate the index to mortality. In an adjusted model, a 1-point higher index score was associated with a significantly lower MRR for both men [0.96 (0.92-0.99)] and women [0.96 (0.92-1.00)] (P = 0.03). When the index components were evaluated separately, whole grain rye bread intake was the factor most consistently associated with lower mortality in men. In conclusion, an index based on traditional healthy Nordic foods was found to be related to lower mortality among middle-aged Danes, in particular among men. This study indicates that traditional, healthy food items should be considered before public recommendations for major dietary changes are made.

Lifelong Cancer Incidence in 47 697 Patients Treated for Childhood Cancer in the Nordic Countries

BACKGROUND The pattern of cancer in long-term survivors from childhood cancer has not been investigated comprehensively. METHODS We obtained a cohort of 47,697 children and adolescents aged 0-19 years with cancer as defined by the country-wide cancer registries of Denmark, Finland, Iceland, Norway, and Sweden during 1943-2005. Cohort members were followed through age 79 years for subsequent primary cancers notified to the registries, and the age-specific risk pattern of the survivors was compared with that of the national populations using country and sex standardized incidence ratios (SIRs). We used a multiplicative Poisson regression model to estimate relative risk of cancer for attained age, with adjustment for calendar period and age at diagnosis of primary cancer. We also calculated excess absolute risk (EAR) attributable to status as childhood cancer survivor and determined the cumulative incidence of second primary cancer as a function of attained age for three subcohorts defined by period of treatment for childhood cancer. RESULTS A total of 1180 asynchronous second primary cancers were observed in 1088 persons, yielding an overall SIR of 3.3 (95% confidence interval = 3.1 to 3.5). The relative risk was statistically significantly increased in all age groups, even for cohort members approaching 70 years of age. The EAR for second primary cancer among survivors increased gradually from one additional case per 1000 person-years of observation in early life to six additional cases per 1000 person-years in the age group 60-69 years. For children treated in the prechemotherapy era (1943-1959), the cumulative risk for a second primary cancer reached 18%, 34%, and 48% at ages 60, 70, and 80 years, respectively. The age-specific incidence rates were highest for cohort members treated in the era of intensive, multiple-agent chemotherapy (1975-2005). CONCLUSION Survivors of childhood cancer have a persistent excess risk for a second primary cancer throughout their lives, accompanied by continuous changes in the risk of cancers at specific sites.

Alcohol intake and breast cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC)

ObjectiveMost epidemiologic studies have suggested an increased risk of breast cancer with increasing alcohol intake. Using data from 274,688 women participating in the European Prospective Investigation into Cancer and Nutrition study (EPIC), we investigated the relation between alcohol intake and the risk of breast cancer.MethodsIncidence rate ratios (IRRs) based on Cox proportional hazard models were calculated using reported intake of alcohol, recent (at baseline) and lifetime exposure. We adjusted for known risk factors and stratified according to study center as well as potentially modifying host factors.ResultsDuring 6.4 years of follow up, 4,285 invasive cases of breast cancer within the age group 35–75 years were identified. For all countries together the IRR per 10 g/day higher recent alcohol intake (continuous) was 1.03 (95% confidence interval (CI): 1.01–1.05). When adjusted, no association was seen between lifetime alcohol intake and risk of breast cancer. No difference in risk was shown between users and non-users of HRT, and there was no significant interaction between alcohol intake and BMI, HRT or dietary folate.ConclusionThis large European study supports previous findings that recent alcohol intake increases the risk of breast cancer.

Association of adherence to lifestyle recommendations and risk of colorectal cancer: a prospective Danish cohort study

Objectives To evaluate the association between a simple lifestyle index based on the recommendations for five lifestyle factors and the incidence of colorectal cancer, and to estimate the proportion of colorectal cancer cases attributable to lack of adherence to the recommendations. Design Prospective cohort study. Setting General population of Copenhagen and Aarhus, Denmark. Participants 55 487 men and women aged 50-64 years at baseline (1993-7), not previously diagnosed with cancer. Main outcome measure Risk of colorectal cancer in relation to points achieved in the lifestyle index (based on physical activity, waist circumference, smoking, alcohol intake, and diet (dietary fibre, energy percentage from fat, red and processed meat, and fruits and vegetables)) modelled through Cox regression. Results During a median follow-up of 9.9 years, 678 men and women had colorectal cancer diagnosed. After adjustment for potential confounders, each additional point achieved on the lifestyle index, corresponding to one additional recommendation that was met, was associated with a lower risk of colorectal cancer (incidence rate ratio 0.89 (95% confidence interval 0.82 to 0.96). In this population an estimated total of 13% (95% CI 4% to 22%) of the colorectal cancer cases were attributable to lack of adherence to merely one additional recommendation among all participants except the healthiest. If all participants had followed the five recommendations 23% (9% to 37%) of the colorectal cancer cases might have been prevented. Results were similar for colon and rectal cancer, but only statistically significant for colon cancer. Conclusions Adherence to the recommendations for physical activity, waist circumference, smoking, alcohol intake, and diet may reduce colorectal cancer risk considerably, and in this population 23% of the cases might be attributable to lack of adherence to the five lifestyle recommendations. The simple structure of the lifestyle index facilitates its use in public health practice.

Hormone replacement therapy in relation to breast carcinoma incidence rate ratios: A prospective danish cohort study

The goal of the current study was to investigate the relation between hormone replacement therapy (HRT) and breast carcinoma in a prospective study cohort. Particular attention was paid to the type of HRT used and to the association of HRT type with estrogen receptor status and tumor histology.

Intake of whole grain in Scandinavia: Intake, sources and compliance with new national recommendations

Aims: The aim of the present study was to describe the intake of whole grain (WG) in Norway, Sweden and Denmark, and to investigate what proportion of the study population that met the new WG recommendation (75 g WG/day per 10 MJ). Methods: Descriptive study. Data is from one 24h dietary recall (24HDR) collected in 1995–2000 from a subset (n = 8,702) of the large Scandinavian cohort “HELGA” consisting of participants aged 30–65 years from three cohorts. Results: The mean WG intake was far below the recommended level. Between 16% (Danish men) and 35% (Norwegian women) consumed at least the recommended intake of WG. Among women, the median intake of WG products (g WG products/day) was 114 g/day in Norway and 108 g/day in Denmark, whereas the intake was much lower in Sweden (64 g/day). For women, the median intake of WG in absolute amounts (g WG/day) was again highest in Norway (44 g/day), but lower in both Sweden (35 g/day) and Denmark (31 g/day). For men (no data available for Norwegian men), the intake of WG products was higher in Denmark (138 g/day) compared to Sweden (79 g/day), but when looking at the WG intake in absolute amounts, the intake was highest in Sweden (49 g/day) compared to Denmark (41 g/day). Conclusions: The present study described the intake of WG as well as the sources of WG in Norway, Sweden and Denmark. Between 16% and 35% met the new recommendations on intake of WG.

Tobacco smoke and bladder cancer-in the European prospective investigation into cancer and nutrition

The purpose of the present study was to investigate the association between smoking and the development of bladder cancer. The study population consisted of 429,906 persons participating in the European Prospective Investigation into Cancer and Nutrition (EPIC), 633 of whom developed bladder cancer during the follow‐up period. An increased risk of bladder cancer was found for both current‐ (incidence rate ratio 3.96, 95% confidence interval: 3.07–5.09) and ex‐ (2.25, 1.74–2.91) smokers, compared to never‐smokers. A positive association with intensity (per 5 cigarettes) was found among current‐smokers (1.18, 1.09–1.28). Associations (per 5 years) were observed for duration (1.14, 1.08–1.21), later age at start (0.75, 0.66–0.85) and longer time since quitting (0.92, 0.86–0.98). Exposure to environmental tobacco smoke (ETS) during childhood increased the risk of bladder cancer (1.38, 1.00–1.90), whereas for ETS exposure as adult no effect was detected. The present study confirms the strong association between smoking and bladder cancer. The indication of a higher risk of bladder cancer for those who start smoking at a young age and for those exposed to ETS during childhood adds to the body of evidence suggesting that children are more sensitive to carcinogens than adults.

A Reverse J-Shaped Association Between Serum 25-Hydroxyvitamin D and Cardiovascular Disease Mortality: The CopD Study

CONTEXT Cardiovascular disease is the major cause of death in the Western world, but the association between 25-hydroxyvitamin D [25(OH)D] levels and the risk of cardiovascular disease mortality remains unclear. OBJECTIVE The objective of the study was to determine the association between cardiovascular, stroke, and acute myocardial infarct mortality and serum levels of 25(OH)D. DESIGN This was an observational cohort study, the Copenhagen vitamin D study, data from a single laboratory center in Copenhagen, Denmark. Follow-up was from 2004 to 2011. SETTING Serum 25(OH)D was analyzed from 247 574 subjects from the Copenhagen general practice sector. PARTICIPANTS Examination of the association 25(OH)D levels and mortality from cardiovascular disease, stroke, and acute myocardial infarct was performed among 161 428 women and 86 146 men. MAIN OUTCOME MEASURES A multivariate Cox regression analysis was used to compute hazard ratios for cardiovascular, stroke, and acute myocardial infarct mortality. RESULTS Of 247 574 subjects, a total of 16 645 subjects died in the ensuing 0-7 years. A total of 5454 died from cardiovascular disease including 1574 from stroke and 702 from acute myocardial infarct. The 25(OH)D level of 70 nmol/L was associated with the lowest cardiovascular disease mortality risk. Compared with that level, the hazard ratio for cardiovascular disease mortality was 2.0 [95% confidence interval (CI) 1.8-2.1] at the lower extreme (∼ 12.5 nmol/L) with a higher risk for men [2.5 (95% CI 2.2-2.9)] than for women [1.7 (95% CI 1.5-1.9)]. At the higher extreme (∼ 125 nmol/L), the hazard ratio of cardiovascular disease mortality was 1.3 (95% CI 1.2-1.4), with a similar risk among men and women. Results were similar for stroke and acute myocardial subgroups. CONCLUSIONS In this large observational study, low and high levels of 25(OH)D were associated with cardiovascular disease, stroke, and acute myocardial mortality in a nonlinear, reverse J-shaped manner, with the highest risk at lower levels. Whether this was a causal or associational finding cannot be determined from our data. There is a need for randomized clinical trials that include information on the effects of 25(OH)D levels greater than 100 nmol/L.

Polymorphisms in genes involved in the inflammatory response and interaction with NSAID use or smoking in relation to lung cancer risk in a prospective study.

Lung cancer risk was investigated in relation to single nucleotide polymorphisms in genes involved in the inflammatory response. The aim was to see if polymorphisms modifying the inflammatory response are associated with risk of lung cancer and if there were interactions between the same polymorphism and factors, which modify an inflammatory response, such as smoking status, duration, and intensity, and use of NSAID. The functional SNPs IL-1B T-31C, IL6 G-174C, IL8 T-251A, IL10 C-592T, COX2 C8473T, COX2 A-1195G and PPARgamma2 Pro(12)Ala were included. A case-cohort study including 428 lung cancer cases and a sub-cohort of 800 persons was nested within a population-based prospective study of 57,053 individuals. Variant allele carriers of IL-1B T-31C were at increased risk of lung cancer (IRR=1.51, 95% CI=1.08-2.12). There was interaction between the polymorphism COX-2 T8473C and smoking status. Thus, non-smoking variant allele carriers were at 5.75-fold (95% CI=1.25-26.43) higher risk of lung cancer than for homozygous wild type allele carriers. Lung cancer risk was similar for all genotype carriers among past and current smokers. There were, however, very few non-smoking lung cancer cases. There was interaction between IL-1B T-31C, COX-2 A-1195G and PPARgamma2 Pro(12)Ala and NSAID use in relation to lung cancer risk. For the two latter, NSAID use was only associated with a lower cancer risk among homozygous wild type allele carriers. p for interaction was 3 x 10(-6) for COX-2 A-1195G and 9 x 10(-5) for PPARgamma2 Pro(12)Ala. The results suggest that NSAID use may modify risk of lung cancer differently depending on the genotype.