Kilian Rapp

γ-Glutamyltransferase as a Risk Factor for Cardiovascular Disease Mortality: An Epidemiological Investigation in a Cohort of 163 944 Austrian Adults

Background— There is evidence from recent studies that γ-glutamyltransferase (GGT) is likely to be associated with cardiovascular disease (CVD). However, few studies to date with sufficient sample size and follow-up investigated the association of GGT with CVD mortality. Methods and Results— The relation of GGT to the risk of death from CVD was examined in a cohort of 163 944 Austrian adults that was monitored for up to 17 years. To evaluate GGT as an independent predictor, Cox proportional hazards models were calculated, which adjusted for established risk factors. In both men and women, high GGT was significantly (P<0.001) associated with total mortality from CVD, showing a clear dose-response relationship. Adjusted hazard ratios (95% CI) per log GGT increase were 1.66 (1.40 to 1.98) in men and 1.64 (1.36 to 1.97) in women. In men, subgroup analyses showed that high GGT was positively associated with incident fatal events of chronic forms of coronary heart disease (P=0.009), congestive heart failure (P<0.001), and hemorrhagic (P=0.01) and ischemic stroke (P<0.001). No significant associations were observed for acute myocardial infarction (P=0.16). In women, hazard ratios suggested associations in all subgroups; however, for hemorrhagic and ischemic stroke they were not statistically significant (P=0.09 and P=0.07, respectively). In addition, subgroup analyses stratified by age revealed a stronger relationship of GGT in younger participants. Hazard ratios for total CVD were 2.03 (1.53 to 2.69) in men and 2.60 (1.53 to 4.42) in women younger than 60 years. Conclusions— This study demonstrates in a large, prospectively observed cohort that GGT is independently associated with cardiovascular mortality.

Obesity and incidence of cancer : a large cohort study of over 145,000 adults in Austria

We investigated the relation of overweight and obesity with cancer in a population-based cohort of more than 145 000 Austrian adults over an average of 9.9 years. Incident cancers (n=6241) were identified through the state cancer registry. Using Cox proportional-hazards models adjusted for smoking and occupation, increases in relative body weight in men were associated with colon cancer (hazard rate (HR) ratio 2.48; 95% confidence interval (CI): 1.15, 5.39 for body mass index (BMI) ⩾35 kg m−2) and pancreatic cancer (HR 2.34, 95% CI: 1.17, 4.66 for BMI>30 kg m−2) compared to participants with normal weight (BMI 18.5–24.9 kg m−2). In women, there was a weak positive association between increasing BMI and all cancers combined, and strong associations with non-Hodgkins lymphomas (HR 2.86, 95% CI: 1.49, 5.49 for BMI⩾30 kg m−2) and cancers of the uterine corpus (HR 3.93, 95% CI: 2.35, 6.56 for BMI⩾35 kg m−2). Incidence of breast cancer was positively associated with high BMI only after age 65 years. These findings provide further evidence that overweight is associated with the incidence of several types of cancer.

Cost of falls in old age: a systematic review.

SummaryThe purpose of this study was to review the evidence of the economic burden of falls in old age. This review showed that falls are a relevant economic burden. Efforts should be directed to fall-prevention programmes.IntroductionFalls are a common mechanism of injury and a leading cause of costs of injury in the elderly. The purpose of this study was to review for the first time the evidence of the economic burden caused by falls in old age.MethodsA systematic review was conducted in the databases of PubMed, of the Centre for Reviews and Dissemination and in the Cochrane Database of Systematic Reviews until June 2009. Studies were assessed for inclusion, classified and synthesised. Costs per inhabitant, the share of fall-related costs in total health care expenditures and in gross domestic products (GDP) were calculated. If appropriate, cost data were inflated to the year 2006 and converted to US Dollar (USD PPP).ResultsA total of 32 studies were included. National fall-related costs of prevalence-based studies were between 0.85% and 1.5% of the total health care expenditures, 0.07% to 0.20% of the GDP and ranged from 113 to 547 USD PPP per inhabitant. Direct costs occurred especially in higher age groups, in females, in hospitals and long-term care facilities and for fractures. Mean costs per fall victim, per fall and per fall-related hospitalisation ranged from 2,044 to 25,955; 1,059 to 10,913 and 5,654 to 42,840 USD PPP and depended on fall severity. A more detailed comparison is restricted by the limited number of studies.ConclusionFalls are a relevant economic burden to society. Efforts should be directed to economic evaluations of fall-prevention programmes aiming at reducing fall-related fractures, which contribute substantially to fall-related costs.

Blood Glucose and Risk of Incident and Fatal Cancer in the Metabolic Syndrome and Cancer Project (Me-Can): Analysis of Six Prospective Cohorts

Tanja Stocks and colleagues carry out an analysis of six European cohorts and confirm that abnormal glucose metabolism is linked with increased risk of cancer overall and at specific sites.

Serum uric acid is an independent predictor for all major forms of cardiovascular death in 28,613 elderly women: a prospective 21-year follow-up study.

BACKGROUND The role of serum uric acid (SUA) as a risk factor for cardiovascular disease (CVD) remains controversial. Little is known about its predictive value for mortality from congestive heart failure (CHF) and stroke, particularly in elderly, post-menopausal women. METHODS The relation of SUA to risk of death from total CVD, CHF, stroke and coronary heart disease (CHD) was examined prospectively in a large cohort of 28613 elderly Austrian women (mean age 62.3 years), followed-up for a median of 15.2 years. Adjusted Cox proportional hazards models were calculated to evaluate SUA as an independent predictor for fatal CVD events. RESULTS SUA in the highest quartile (>or=5.41 mg/dL) was significantly associated with mortality from total CVD (p<0.0001), showing a clear dose-response relationship; the adjusted hazard ratio (95%CI) in comparison to the lowest SUA quartile was 1.35 (1.20-1.52). In subgroup analyses SUA was independently predictive for deaths from acute and subacute (p<0.0001) and chronic forms (p=0.035) of CHD, yielding adjusted hazard ratios for the highest versus lowest SUA quartile of 1.58 (1.19-2.10) and 1.25 (1.01-1.56), respectively. SUA was further significantly related to fatal CHF (p<0.0001) and stroke (p=0.018); the adjusted hazard ratios for the highest versus lowest SUA quartile were 1.50 (1.04-2.17) and 1.37 (1.09-1.74), respectively. CONCLUSIONS These findings, for the first time, demonstrate that SUA is an independent predictor for all major forms of death from CVD including acute, subacute and chronic forms of CHD, CHF and stroke in elderly, post-menopausal women.

Associations of adipokines with asthma, rhinoconjunctivitis, and eczema in German schoolchildren.

There is growing evidence for an association between obesity and asthma, but little is known about the underlying mechanisms. We hypothesized that high plasma leptin and low plasma adiponectin concentrations might be related to asthma and allergies in children. Plasma leptin and adiponectin concentrations were measured in a cross‐sectional study involving 462 children aged 10 years. Information on disease symptoms and diagnosis was collected by parental questioning. Multivariate linear and logistic regression models were used to assess the association between biomarkers and disease. High leptin levels were associated with increased lifetime prevalence of asthma [odds ratio (OR): 3.76; 95% confidence interval (CI): 1.42–9.92]. The relationship was particularly strong for non‐atopic asthma (OR: 5.51; 95% CI: 1.99–17.51). No associations were observed between plasma leptin levels and hay fever, and rhinoconjunctivitis. Low adiponectin levels were associated with increased prevalence of both symptoms of atopic dermatitis (OR: 3.23; 95% CI: 1.28–7.76) and ever‐diagnosed eczema (OR: 2.35; 95% CI: 1.13–4.89). In girls and non‐atopic children, stronger associations for both leptin and adiponectin levels with asthma than in boys and atopic children were observed. These results suggest that adipokines may contribute to increased asthma and allergy risk in obese subjects. Stronger associations among girls with non‐atopic asthma may indicate diverse pathological mechanisms.

Hip fractures in institutionalized elderly people: incidence rates and excess mortality.

It is assumed that nursing homes are the setting with the highest incidence of hip fractures. This observation is, however, based on very little data. The aim of this study was to analyze hip fracture rates and the associated excess mortality in a large nursing home population. A cohort of >69,000 women and men newly admitted to German nursing homes were used to calculate sex‐ and age‐specific incidence rates of hip fractures. To calculate excess mortality, a retrospective cohort study was conducted. To each patient with a hip fracture (n = 4342), four residents without hip fracture (n = 17,368) were matched by sex, age, and level of care (measure for the need of care). Hazard regression models were applied. During 91,850 person‐years, 4342 hip fractures were observed. The crude incidence rates for hip fractures were 50.8/1000 person‐years in women and 32.7/1000 person‐years in men. The incidence rates increased with increasing age categories and were highest in the first months after admission to the nursing home. Increasing care need reduced the risk of hip fracture. Mortality in patients with a hip fracture was increased (women: hazard rate ratio for the first 3 mo after fracture, 1.72; 95% CI, 1.59–1.86; men: hazard ratio, 2.14; 95% CI, 1.80–2.53), but excess mortality was limited to the first months after injury. Data are presented for hip fracture rates and excess mortality after a hip fracture. Our results have implications on the timing and the allocation of specific measures for hip fracture prevention.

Longitudinal change in serum gamma-glutamyltransferase and cardiovascular disease mortality: a prospective population-based study in 76,113 Austrian adults.

Objective—The purpose of this study was to investigate the association of longitudinal change in serum γ-glutamyltransferase (GGT) with mortality from cardiovascular disease (CVD). Methods and Results—A population-based cohort of 76 113 Austrian men and women with 455 331 serial GGT measurements was prospectively followed-up for a median of 10.2 years after assessment of longitudinal GGT change during an average period of 6.9 years. Cox proportional hazards regression with time-varying covariates was used to evaluate GGT change as an independent predictor for CVD death. Independently of baseline GGT and other classical CVD risk factors, a pronounced increase in GGT (7-year change >9.2 U/L) was significantly associated with increased total CVD mortality in men (P=0.005); the adjusted hazard ratio (95% confidence interval) in comparison to stable GGT (7-year change −0.7 to 1.3 U/L) was 1.40 (1.09 to 1.81). Similarly, total CVD risk was elevated for increasing GGT in women, although effects were less pronounced and statistically significant only in subanalyses regarding coronary heart disease. Age of participants significantly modified the relation between GGT change and CVD mortality, with markedly stronger associations to be observable for younger individuals. Conclusion—Our study is the first to demonstrate that a longitudinal increase in GGT, independently of baseline GGT and even within its normal range, significantly increases risk of fatal CVD.

Association of γ-Glutamyltransferase and Risk of Cancer Incidence in Men: A Prospective Study

Although several epidemiologic studies have shown that gamma-glutamyltransferase (GGT) is independently associated with cardiovascular disease and all-cause mortality, its relationship with cancer incidence remains widely unexplored. In several experimental models, the ability of cellular GGT to modulate crucial redox-sensitive functions has been established, and it thus may play a role in tumor progression, as has been repeatedly suggested. We prospectively investigated the association between GGT and risk of overall and site-specific cancer incidence in a large population-based cohort of 79,279 healthy Austrian men with serial GGT measurements. Median follow-up was 12.5 years. Adjusted Cox proportional hazards models were calculated to evaluate GGT as an independent predictor for cancer incidence, and nonparametric regression splines were fitted to flexibly capture the dose-response relationship. Elevated GGT significantly increased overall cancer risk, showing a clear dose-response relationship (P for GGT log-unit increase < 0.0001; P for trend < 0.0001). In comparison with the reference GGT concentration (25 units/L), we found adjusted relative risks (95% confidence intervals) equalling 1.19 (1.15-1.22) for GGT concentrations of 60 units/L, 1.32 (1.28-1.36) for 100 units/L, 1.67 (1.60-1.75) for 200 units/L, and 2.30 (2.14-2.47) for 400 units/L. In cancer site-specific models, GGT was significantly associated with malignant neoplasms of digestive organs, the respiratory system/intrathoracic organs, and urinary organs (all P < 0.0001). Age of participants significantly modified the association of GGT and cancer risk (P < 0.001), revealing markedly stronger associations in participants ages </=65 years. Our findings, for the first time, show that elevated GGT is significantly associated with increased cancer risk in men.

Cohort Profile: The Metabolic syndrome and Cancer project (Me-Can)

Background: A large number of prospective studies have shown that overweight and diabetes are related to an increased risk of many cancers, including colorectal cancer. In contrast, diabetes has been related to a decreased risk of prostate cancer, and overweight has been related to an increased risk of fatal, but not of incident, prostate cancer. Data from studies on metabolic factors related to overweight and diabetes, and the association with cancer risk, are limited. Aim: The aim of this thesis was to study metabolic factors in relation to risk of prostate cancer (paper I and III), colorectal cancer (paper II and V), and cancer overall (paper VI). Methods: Study designs were i) case-control studies, nested within the Northern Sweden Health and Disease Cohort (paper I and II), and ii) cohort studies of the Swedish Construction Workers cohort (paper III), and the Metabolic syndrome and Cancer project (Me-Can) comprising seven European cohorts (paper V and VI). Paper IV was a descriptive paper of Me-Can. Results, prostate cancer: In paper I, increasing levels of several factors related to insulin resistance (insulin, insulin resistance index, leptin, HbA1c, and glucose) were associated with a decreased risk of overall incident prostate cancer, and the associations were stronger for non-aggressive tumours. In paper III, increasing levels of blood pressure was associated with a significant decreased risk of overall incident prostate cancer and of non-aggressive tumours. Body mass index (BMI) was significantly positively related to fatal prostate cancer. Results, colorectal cancer: In paper II, obesity, hypertension, and hyperglycaemia, were associated with an increased risk of colorectal cancer, and presence of two or three of these factors was associated with a higher risk than the presence of one single factor. In paper V, BMI was associated with a significant linear positive association with risk of colorectal cancer in men and women, and significant positive associations were also found in men for blood pressure and triglycerides. A high metabolic syndrome score, based on levels of BMI, blood pressure, glucose, cholesterol, and triglycerides, was associated with a significant increased risk of colorectal cancer in men and women. The association was stronger than for any of the factors in single, but there was no evidence of a positive interaction between these metabolic factors. Results, cancer overall: Blood glucose was significantly positively associated with risk of incident and fatal cancer overall, and at several specific sites. The associations were stronger in women than in men, and for fatal than for incident cancer. Conclusions: Results from these studies indicate that elevated blood glucose is related to an increased risk of cancer overall and at several specific sites, and further, that overweight and metabolic aberrations increase the risk of colorectal cancer in an additive way. The association with prostate cancer seems to be more complex; insulin resistance and high blood pressure were in our studies related to a decreased risk of overall incident prostate cancer and of non-aggressive tumours, whereas overweight increased the risk of fatal prostate cancer.