Augsburg Study Research Articles

Increased serum levels of interleukin 1 receptor antagonist (IL-1ra) levels precede the onset of coronary heart disease: results from the MONICA/KORA Augsburg study

Aims: Interleukin-1β (IL-1β) represents a key proinflammatory cytokine in the development of atherosclerosis and coronary heart disease (CHD). The activity of IL-1β is counter-regulated by interleukin-1 receptor antagonist (IL-1ra), an endogenous inhibitor. Data on the relevance of circulating IL-1ra levels for cardiovascular risk are scarce and inconsistent. Therefore, this study aimed (i) to examine the association between serum IL-1ra and incident CHD in the general population and (ii) to test whether this association is explained by other inflammation-related biomarkers. Methods: This case-cohort study uses data from the population-based MONICA/KORA Augsburg cohort. During a follow-up time of 16.0 ± 5.8 years, 803 cases and 1942 non-cases were observed for the combined CHD endpoint (non-fatal myocardial infarction and coronary death before the age of 75 years). Associations between IL-1ra and incidence of CHD were assessed using Cox regression adapted for cases-cohort analyses. Results: Cases had higher IL-1ra serum levels than non-cases (geometric means [antilog of SE] 338.81 [1.02] vs. 352.59 [1.01] pg/ml; p < 0.001). The hazard ratio (95% CI) for incident CHD was 1.15 (1.02; 1.30) per standard deviation of log-transformed IL-1ra serum levels after adjustment for age, sex, anthropometric, metabolic and lifestyle factors (p = 0.022). The excess risk for CHD was attenuated by ≥10% after additional adjustment for high-sensitivity C-reactive protein, IL-6, myeloperoxidase or soluble adhesion molecules. Conclusion: Serum IL-1ra levels are positively associated with increased risk of CHD. This association may at least partially reflect a counter-regulation to subclinical inflammation, endothelial activation and oxidative stress.

Frailty in Germany: status and perspectives : Results from a workshop of the German Society for Epidemiology

A standardized, valid and comparable operationalization and assessment of frailty in population-based studies is essential in order to describe the prevalence and determinants of frailty in the population. After an introduction to the subject the main goal of a workshop at the 9th annual meeting of the German Society for Epidemiology (DGEpi) was to present approaches and results from four different studies in Germany. The following four population-based studies were used to describe frailty in Germany: the German health interview and examination survey for adults (DEGS1), the epidemiological study on the chances of prevention, early recognition and optimized treatment of chronic diseases in the older population (ESTHER), the cooperative health research in the region Augsburg (KORA Age) study and the longitudinal urban cohort ageing study (LUCAS) in Hamburg. The four studies consistently showed that frailty is widespread in older and oldest-old persons in Germany. It is obvious that frailty represents a relevant concept in Germany even if there is currently no uniform basis for operationalization. Concepts and instruments for the collation of frailty should be included in future population-based studies in order to make a better assessment of older people's health situation and to describe the unused potential for prevention in an aging society.

Individual daytime noise exposure in different microenvironments

BackgroundNumerous studies showed that chronic noise exposure modeled through noise mapping is associated with adverse health effects. However, knowledge about real individual noise exposure, emitted by several sources, is limited. ObjectivesTo explain the variation in individual daytime noise exposure regarding different microenvironments, activities and individual characteristics. Materials and methodsIn a repeated measures study in Augsburg, Germany (March 2007–December 2008), 109 individuals participated in 305 individual noise measurements with a mean duration of 5.5h. Whereabouts and activities were recorded in a diary. One-minute averages of A-weighted equivalent continuous sound pressure levels (Leq) were determined. We used mixed additive models to elucidate the variation of Leq by diary-based information, baseline characteristics and time-invariant variables like long-term noise exposure. ResultsOverall noise levels were highly variable (median: 64dB(A); range: 37–105dB(A)). Highest noise levels were measured in traffic during bicycling (69dB(A); 49–97dB(A)) and lowest while resting at home (54dB(A); 37–94dB(A)). Nearly all diary-based information as well as physical activity, sex and age-group had significant influences on individual noise. In an additional analysis restricted to times spent at the residences, long-term noise exposure did not improve the model fit. ConclusionsIndividual exposures to day-time noise were moderate to high and showed high variations in different microenvironments except when being in traffic. Individual noise levels were greatly determined by personal activities but also seemed to depend on environmental noise levels.

Elevated particle number concentrations induce immediate changes in heart rate variability: a panel study in individuals with impaired glucose metabolism or diabetes.

BackgroundThe health effects of short-term exposure to ambient ultrafine particles in micro-environments are still under investigation.MethodsSixty-four individuals with type 2 diabetes and impaired glucose tolerance recorded ambulatory electrocardiograms over five to six hours on 191 occasions in a panel study in Augsburg, Germany. Personal exposure to particle number concentrations (PNC) was monitored for each individual on 5-minute basis concurrently and particulate matter with an aerodynamic diameter < 2.5 μm (PM2.5) was acquired from a central monitoring site on an hourly basis.ResultsMore than 11,000 5-minute intervals were available for heart rate and measures of heart rate variability including SDNN (standard deviation of NN intervals). A concurrent decrease in 5-minute SDNN of −0.56% (95% confidence limits (CI): −1.02%; −0.09%) and a 5-minute delayed increase in heart rate of 0.23 % (95% CI: 0.11%; 0.36%) was observed with an increase in personal PNC of 16,000 per cm3 in additive mixed models. Models evaluating the association of concurrent 5-minute personal PNC and of 1-hour PM2.5 showed independent effects on SDNN.ConclusionThe data suggest that freshly emitted ultrafine particles and aged fine particulate matter are both associated with changes in cardiac function in individuals with type 2 diabetes and impaired glucose tolerance in urban areas.

Mitochondrial genetic variants identified to be associated with posttraumatic stress disorder.

Despite the fact that mitochondrial dysfunctions are increasingly recognized as key components in stress-related mental disorders, very little is known about the association between posttraumatic stress disorder (PTSD) and mitochondrial variants. To identify susceptibility mitochondrial genes for PTSD, we analyzed a total number of 978 mitochondrial single-nucleotide polymorphisms (mtSNPs) in a sample of 1238 individuals participating in the KORA (Cooperative Health Research in the Region of Augsburg) study. Participants were classified with ‘no PTSD', ‘partial PTSD' or ‘full PTSD' by applying the Posttraumatic Diagnostic Scale and the Impact of Event Scale. To assess PTSD–mtSNP association while taking heteroplasmy into account, we used the raw signal intensity values measured on the microarray and applied linear regression. Significant associations were obtained between full versus no PTSD and two mtSNPs; mt8414C→T (β=−0.954±0.06, Padjusted=0.037) located in adenosine triphosphate (ATP) synthase subunit 8 (MT-ATP8) and mt12501G→A (β=−1.782±0.40, Padjusted=0.015) located in the NADH dehydrogenase subunits 5 (MT-ND5). Heteroplasmy for the two variants towards a larger number of the respective minor alleles increases the risk of having PTSD. NADH dehydrogenase and ATP synthase are both linked to the regulation of reactive oxygen species. Our results highlight the important role of the mitochondrial genome among the factors that contribute to the risk of PTSD. Mitochondrial genetic variants may be more important than has previously been assumed, leading to further insights regarding effects of existing medications, or even to the development of innovative treatments. As this is the first mitochondrial genome-wide association study for PTSDs, further analyses are needed to follow up on the present findings.

Regional Variation of Chronic Kidney Disease in Germany: Results From Two Population-Based Surveys

Background/Aims: Due to the increasing prevalence of risk factors for chronic kidney disease (CKD), kidney dysfunction becomes a major public health problem. We investigated the CKD prevalence and determined to what extent the variation of risk factors explains the different CKD prevalence in Germany. Methods: We analyzed data from 6,054 participants, aged 31 to 82 years, from the Study of Health in Pomerania (SHIP-1) in Northeast Germany and the Cooperative Health Research in the Region of Augsburg (KORA F4) Study in Southern Germany. Regional differences in selected percentiles corresponding to the cutpoints for estimated glomerular filtration rate (eGFR, <60 ml/min per 1.73 m²) and albumin-to-creatinine ratio (ACR, ≥30 mg/g) were tested using quantile regression models that adjusted for CKD risk factors. Results: The prevalence of decreased eGFR_{creatinine-cystatinC} (5.9 vs. 3.1 %, p <0.001) and albuminuria (20.2 vs. 8.8 %, p<0.001) were higher in SHIP-1 than in KORA F4. The differential distribution of risk factors explained 18-21% of the regional differences of decreased eGFR_{creatinine-cystatinC} and high ACR. Conclusions: The CKD prevalence is higher in Northeast than in Southern Germany. Differences in the prevalence of risk factors partly explain the higher disease burden of CKD in Northeast than in Southern Germany.

Association of low 25-hydroxyvitamin D levels with the frailty syndrome in an aged population: results from the KORA-age Augsburg study.

Older adults often suffer from vitamin D deficiency and from the frailty syndrome charac-terized by different physical limitations, complicating independent everyday life. Previous studies have suggested a relationship between vitamin D status and the frailty syndrome, but results have been partly inconsistent, particularly regarding the shape of the association. Therefore, our aim was to further assess the association of 25-hydroxyvitamin D (25(OH)D) serum levels and frailty in older participants. Cross-sectional population-based study. The study population included 478 men and 462 women of the KORA (COoperative health research in the Region of Augsburg)-Age study born before 1944 examined in 2009. Classification of participants into different frailty states was performed according to the following criteria: weight loss, exhaustion, physical inactivity, slowness, and weakness. PARTICIPANTS who met 1-2 or ≥ 3 of the 5 criteria were classified as prefrail or frail, respectively. Total 25(OH)D was measured in non-fasting serum samples with an enhanced chemiluminescence immunoassay. Sequential logistic regression models adjusted for age, sex, season, lifestyle factors, diseases and biomarkers including parathyroid hormone (PTH) were calculated. High levels of 25(OH)D were inversely associated with being prefrail (N=351) or frail (N=38) in the model adjusted for age, sex, season and lifestyle factors. Compared to levels <15 ng/ml, odds ratios (ORs) (95% confidence intervals (CIs) were 0.52 (0.34-0.78) for levels of 15-<20 ng/ml, 0.55 (0.37-0.81) for levels of 20-<30 ng/ml and 0.32 (0.21-0.51) for levels ≥ 30 ng/ml. Additional adjustment for potential mediators including PTH only slightly attenuated these associations. For single frailty-components, significantly decreased ORs were found for exhaustion, physical inactivity and slowness comparing 25(OH)D levels ≥ 30 ng/ml with levels <15 ng/ml. Subjects with 25(OH)D serum levels ≥ 15 ng/ml were less frequently prefrail or frail.

Job strain as a risk factor for the onset of type 2 diabetes mellitus: findings from the MONICA/KORA Augsburg cohort study.

To examine whether job strain is associated with an increased risk of subsequent Type 2 diabetes mellitus (T2DM) development in a population-based study of men and women. Data were derived from the prospective MONICA/KORA Augsburg study. We investigated 5337 working participants aged 29 to 66 years without diabetes at one of the three baseline surveys. Job strain was measured by the Karasek job content questionnaire. High job strain was defined by the quadrant approach, where high job demands combined with low job control were classified as high job strain. Continuous job strain (quotient of job demands divided by job control) was additionally analyzed as sensitivity analysis. Hazard ratios (HRs) were estimated using multivariable Cox proportional hazards models with adjustment for age, sex, survey, socioeconomic and life-style variables, parental history of diabetes, and body mass index. During a median follow-up of 12.7 years, 291 incident cases of T2DM were observed. The participants with high job strain at baseline had a 45% higher fully adjusted risk to develop T2DM than did those with low job strain (HR = 1.45 [95% confidence interval = 1.00-2.10], p = .048). On the continuous scale, more severe job strain in the magnitude of 1 standard deviation corresponded to a 12% increased fully adjusted T2DM risk (HR = 1.12 [95% confidence interval = 1.00-1.25], p = .045). Men and women who experience high job strain are at higher risk for developing T2DM independently of traditional risk factors. Preventive strategies to combat the globally increasing T2DM epidemic should take into consideration the adverse effects of high strain in the work environment.

Metabolomics approach reveals effects of antihypertensives and lipid-lowering drugs on the human metabolism.

The mechanism of antihypertensive and lipid-lowering drugs on the human organism is still not fully understood. New insights on the drugs’ action can be provided by a metabolomics-driven approach, which offers a detailed view of the physiological state of an organism. Here, we report a metabolome-wide association study with 295 metabolites in human serum from 1,762 participants of the KORA F4 (Cooperative Health Research in the Region of Augsburg) study population. Our intent was to find variations of metabolite concentrations related to the intake of various drug classes and—based on the associations found—to generate new hypotheses about on-target as well as off-target effects of these drugs. In total, we found 41 significant associations for the drug classes investigated: For beta-blockers (11 associations), angiotensin-converting enzyme (ACE) inhibitors (four assoc.), diuretics (seven assoc.), statins (ten assoc.), and fibrates (nine assoc.) the top hits were pyroglutamine, phenylalanylphenylalanine, pseudouridine, 1-arachidonoylglycerophosphocholine, and 2-hydroxyisobutyrate, respectively. For beta-blockers we observed significant associations with metabolite concentrations that are indicative of drug side-effects, such as increased serotonin and decreased free fatty acid levels. Intake of ACE inhibitors and statins associated with metabolites that provide insight into the action of the drug itself on its target, such as an association of ACE inhibitors with des-Arg(9)-bradykinin and aspartylphenylalanine, a substrate and a product of the drug-inhibited ACE. The intake of statins which reduce blood cholesterol levels, resulted in changes in the concentration of metabolites of the biosynthesis as well as of the degradation of cholesterol. Fibrates showed the strongest association with 2-hydroxyisobutyrate which might be a breakdown product of fenofibrate and, thus, a possible marker for the degradation of this drug in the human organism. The analysis of diuretics showed a heterogeneous picture that is difficult to interpret. Taken together, our results provide a basis for a deeper functional understanding of the action and side-effects of antihypertensive and lipid-lowering drugs in the general population.Electronic supplementary materialThe online version of this article (doi:10.1007/s10654-014-9910-7) contains supplementary material, which is available to authorized users.

Update of the German Diabetes Risk Score and external validation in the German MONICA/KORA study

AimsSeveral published diabetes prediction models include information about family history of diabetes. The aim of this study was to extend the previously developed German Diabetes Risk Score (GDRS) with family history of diabetes and to validate the updated GDRS in the Multinational MONItoring of trends and determinants in CArdiovascular Diseases (MONICA)/German Cooperative Health Research in the Region of Augsburg (KORA) study. MethodsWe used data from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study for extending the GDRS, including 21,846 participants. Within 5 years of follow-up 492 participants developed diabetes. The definition of family history included information about the father, the mother and/or sibling/s. Model extension was evaluated by discrimination and reclassification. We updated the calculation of the score and absolute risks. External validation was performed in the MONICA/KORA study comprising 11,940 participants with 315 incident cases after 5 years of follow-up. ResultsThe basic ROC-AUC of 0.856 (95%-CI: 0.842–0.870) was improved by 0.007 (0.003–0.011) when parent and sibling history was included in the GDRS. The net reclassification improvement was 0.110 (0.072–0.149), respectively. For the updated score we demonstrated good calibration across all tenths of risk. In MONICA/KORA, the ROC-AUC was 0.837 (0.819–0.855); regarding calibration we saw slight overestimation of absolute risks. ConclusionsInclusion of the number of diabetes-affected parents and sibling history improved the prediction of type 2 diabetes. Therefore, we updated the GDRS algorithm accordingly. Validation in another German cohort study showed good discrimination and acceptable calibration for the vast majority of individuals.

Abstract P008: Ultra-Sensitive Troponin I Strongly Predicts Incident Coronary Heart Disease in the General Population Independently of Traditional Risk Factors. Results From the MONICA/KORA Augsburg Case-Cohort Study

Background: High-sensitive (hs) troponin T and I assays as well as ultrasensitive (us) troponin I enable measurement of troponins in 65% to 98% of the general population. We prospectively investigated whether increased concentrations of us-troponin I are associated with an increased risk of coronary heart disease (CHD) after controlling for traditional risk factors. Methods: We conducted a population-based case cohort study in middle-aged healthy men and women within the MONICA/KORA Augsburg studies. Serum levels of us-troponin I (Single Molecule Counting technology, Singulex) were available in 2,745 men and women including 803 incident CHD cases. Geometric mean us-troponin I was 1.56 ng/L. Mean (SD) follow-up was 16.0 (5.8) years. Results: Baseline concentrations of us-troponin I were higher in cases compared to non-cases (geometric mean 2.56 vs. 1.49 ng/L, p&lt;0.0001) and in men compared to women (geometric mean 1.93 vs. 1.27 ng/L, p&lt;0.0001). After adjustment for variables of the Framingham Risk Score, the hazard ratio (HR) with 95% confidence interval (CI) for a CHD event in the top quartile compared to the bottom quartile was 2.76 (95% CI, 1.87-4.09). After additional adjustment for alcohol intake, physical activity, and body mass index, hazard ratios remained essentially unchanged. Conclusions: Troponin I measured by an us-assay was detectable in almost all subjects. This is the first population-based prospective study with long-term follow-up showing that even modestly increased concentrations of us troponin I are strongly associated with incident CHD independently of a variety of traditional risk factors.

Regional and Neighborhood Disparities in the Odds of Type 2 Diabetes: Results From 5 Population-Based Studies in Germany (DIAB-CORE Consortium)

The objective of this study was to investigate the association between residential environment and type 2 diabetes. We pooled cross-sectional data from 5 population-based German studies (1997-2006): the Cardiovascular Disease, Living and Ageing in Halle Study, the Dortmund Health Study, the Heinz Nixdorf Recall Study, the Cooperative Health Research in the Region of Augsburg Study, and the Study of Health in Pomerania. The outcome of interest was the presence of self-reported type 2 diabetes. We conducted mixed logistic regression models in a hierarchical data set with 8,879 individuals aged 45-74 years on level 1; 226 neighborhoods on level 2; and 5 study regions on level 3. The analyses were adjusted for age, sex, social class, and employment status. The odds ratio for type 2 diabetes was highest in eastern Germany (odds ratio = 1.98, 95% confidence interval: 1.81, 2.14) and northeastern Germany (odds ratio = 1.58, 95% confidence interval: 1.40, 1.77) and lowest in southern Germany (reference) after adjustment for individual variables. Neighborhood unemployment rates explained a large proportion of regional differences. Individuals residing in neighborhoods with high unemployment rates had elevated odds of type 2 diabetes (odds ratio = 1.62, 95% confidence interval: 1.25, 2.09). The diverging levels of unemployment in neighborhoods and regions are an independent source of disparities in type 2 diabetes.

Individual Daytime Noise Exposure during Routine Activities and Heart Rate Variability in Adults: A Repeated Measures Study

Background: Epidemiological studies have demonstrated associations between noise exposure and cardiovascular events. However, there have been few studies of possible underlying mechanisms.Objectives: We examined the association between individual daytime noise exposure and heart rate variability (HRV).Methods: In a prospective panel study in Augsburg, Germany (March 2007–December 2008), 110 individuals participated in 326 electrocardiogram recordings with a mean duration of 6 hr. Five-minute averages of heart rate (HR) and HRV parameters were determined. Individual noise exposure was measured as A-weighted equivalent continuous sound pressure levels (Leq). Effects were estimated using additive mixed models adjusted for long- and short-term time trends and physical activity. Due to nonlinear exposure–response functions, we performed piecewise linear analyses with a cut-off point at 65 dB(A).Results: Concurrent increases of 5dB(A) in Leq < 65dB(A) were associated with increases in HR (percent change of mean value: 1.48%; 95% CI: 1.37, 1.60%) and the ratio of low-frequency (LF) to high-frequency (HF) power (4.89%; 95% CI: 3.48, 6.32%), and with decreases in LF (–3.77%; 95% CI: –5.49, –2.02%) and HF (–8.56%; 95% CI: –10.31, –6.78%) power. Standard deviation of normal-to-normal intervals (SDNN) was positively associated with concurrent noise < 65dB(A) (5.74%; 95% CI: 5.13, 6.36) but negatively associated with noise lagged by 5–15 min (–0.53% to –0.69%). Associations with cardiac function were less pronounced for noise ≥ 65dB(A), with some in opposite directions from associations with noise < 65dB(A). Concurrent associations were modified by sex and age.Conclusions: Individual daytime noise exposure was associated with immediate changes in HRV, suggesting a possible mechanism linking noise to cardiovascular risk. Noise at lower levels may have health consequences beyond those resulting from “fight-or-flight” responses to high levels of noise.

Physical activity is inversely associated with multimorbidity in elderly men: Results from the KORA-Age Augsburg Study

ObjectivePhysical activity is suggested to play a key role in the prevention of several chronic diseases. However, data on the association between physical activity and multimorbidity are lacking. MethodsUsing data from 1007 men and women aged 65–94years who participated in the population-based KORA (Cooperative Health Research in the Region of Augsburg)-Age project conducted in Augsburg/Germany and two adjacent counties in 2008/09, 13 chronic conditions were identified, and physical activity scores were calculated based on the self-reported physical activity scale for the elderly (PASE). Multivariable sex-specific logistic regression was applied to determine the association of the continuous physical activity score with multimorbidity (≥2 out of 13 diseases). ResultsPhysical activity (mean PASE score±SD) was higher in men (125.1±59.2) than in women (112.2±49.2). Among men, the odds ratio (OR) for multimorbidity was 0.73 (95% CI: 0.60–0.90) for a 1 standard deviation increase of the PASE score. No significant results could be observed for women (OR: 1.05; 95% CI: 0.83–1.33). ConclusionWe demonstrated an inverse association between physical activity and multimorbidity among men. Further prospective studies have to confirm the temporality of effects.

A Variant In the Abo Gene Explains the Variation in Soluble E-Selectin Levels—Results from Dense Genotyping in Two Independent Populations

BackgroundElevated soluble (s) E-selectin levels have been associated with various cardiovascular diseases. Recently, genetic variants in the ABO blood group have been related to E-selectin levels in a small cohort of patients with type 1 diabetes. We evaluated whether this association is reproducible in two large samples of Caucasians.Methodology/ Principal FindingsData of the present study was drawn from the population-based MONICA/KORA Augsburg study (n = 1,482) and the patients-based LURIC study (n = 1,546). A high-density genotyping array (50K IBC Chip) containing single-nucleotide polymorphisms (SNPs) from E-selectin candidate genes selected on known biology of E-selectin metabolism, mouse genetic studies, and human genetic association studies, was used for genotyping. Linear regression analyses with adjustment for age and sex (and survey in KORA) were applied to assess associations between gene variants and sE-selectin concentrations. A number of 12 SNPs (in KORA) and 13 SNPs (in LURIC), all from the ABO blood group gene, were significantly associated with the log-transformed concentration of E-selectin. The strongest association was observed for rs651007 with a change of log-transformed sE-selectin per one copy of the minor allele of −0.37 ng/ml (p = 1.87×10−103) in KORA and −0.35 ng/ml (p = 5.11×10−84) in LURIC. Inclusion of rs651007 increased the explained sE-selectin variance by 0.256 in KORA and 0.213 in LURIC. All SNPs had minor allele frequencies above 20% showing a substantial gene variation.Conclusions/ SignificanceOur findings in two independent samples indicate that the genetic variants at the ABO locus affect sE-selectin levels. Since distinct genome-wide association studies linked the ABO gene with myocardial infarction (MI) in the presence of coronary atherosclerosis and with coronary artery disease, these findings may not only enhance our understanding of adhesion molecule biology, but may also provide a focus for several novel research avenues.

Low Levels of Serum 25-Hydroxyvitamin D Are Associated with Increased Risk of Myocardial Infarction, Especially in Women: Results from the MONICA/KORA Augsburg Case-Cohort Study

A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system. Therefore, we thought to prospectively assess the association between serum 25-hydroxyvitamin D, the most commonly used index of vitamin D status, and incident coronary heart disease. We measured serum levels of 25[OH]D in 1783 healthy middle-aged subjects (964 men, 819 women) in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg studies. A total of 298 coronary heart disease cases were identified over a mean follow-up period of 11 yr. After adjustment for age, survey, and season of blood sampling, the hazard ratio (HR) and 95% confidence interval comparing tertile extremes of serum levels of 25[OH]D was 0.32 (0.16-0.65) (P for trend = 0.001) in women and 0.56 (0.38-0.82) (P for trend = 0.005) in men. Further adjustment for traditional cardiovascular risk factors slightly attenuated the association in women [HR 0.39 (0.18-0.84); P for trend = 0.013], whereas it became nonsignificant in men [HR 0.76 (0.49-1.17); P for trend = 0.215]. After additional adjustment for C-reactive protein, IL-6, soluble intercellular adhesion molecule-1, and interferon-γ-inducible protein-10, the association still remained significant in women [HR 0.42 (0.19-0.93); P for trend = 0.028], and it was further reduced in men [HR 0.84 (0.52-1.35); P for trend = 0.461]. Our findings suggest that higher vitamin D levels are associated with decreased risk of coronary heart disease. This effect is more pronounced in women than in men. Further clinical and experimental studies are needed to investigate the sex differences and whether vitamin D supplementation could contribute to the prevention of coronary heart disease.

Abstract P173: Serum 25-hydroxyvitamin D and Mortality in Middle-aged Men and Women: Results from the MONICA/KORA Augsburg Study

Background: Recent studies found an inverse association between vitamin D status and both morbidity and mortality from major chronic diseases such as cardiovascular diseases (CVD) and cancer. In contrast, some studies have suggested adverse health effects such as increased all-cause mortality at the high end of vitamin D levels. Therefore, the aim of the present study was to further elucidate the relationship between 25-hydroxyvitamin D (25[OH]D) and all-cause as well as CVD and non-CVD mortality. Methods: Our study population comprised 851 men and 774 women aged 35-74 years at baseline selected randomly, stratifying by sex and survey out of 9,531 subjects with available blood samples. All had participated in at least one of the three population-based MONICA/KORA Augsburg surveys between 1984-1995. Participants were followed-up for a mean of 16.8 ± 5.4 years. During this period 197 persons died from CVD (ICD9 390-459, 798) and 226 from non-cardiovascular causes. For three participants the cause of death was missing. 25[OH]D was measured in serum samples collected at baseline using an enzyme immunoassay from IDS, Frankfurt. Results: After adjustment for age, sex, survey, and season of blood sampling we observed a significant inverse association between serum 25[OH]D and all-cause mortality. The hazard ratio (HR) and 95% confidence interval (CI) comparing subjects with levels &gt;75 nmol/l to those with levels ≤25 nmol/l was 0.59 (0.38-0.93); P trend =0.007 across the following four categories: ≤25 nmol/l; &gt;25-≤50 nmol/l; &gt;50-≤75 nmol/l; &gt;75 nmol/l, assigning the median value within each category to the respective category. Further adjustment for BMI, education and lifestyle factors attenuated the association and it became non-significant (HR [95% CI]: 0.78 [0.48-1.27]; P trend =0.205). For CVD mortality, we also observed an inverse association which persisted after adjustment for the above mentioned confounders (HR [95% CI]: 0.49 [0.21-1.11]; P trend =0.012). After further multivariable adjustment including potential intermediate risk factors such as systolic blood pressure, total cholesterol/HDL-cholesterol, diabetes and markers of inflammation the association became non-significant (HR [95% CI]: 0.63 [0.26-1.51]; P trend =0.122). We did not observe any significant association between 25[OH]D and non-CVD mortality regardless of the degree of adjustment. However, there was a trend towards increased non-CVD mortality in women with 25[OH]D &gt;75 nmol/l compared to those with concentrations ≤25 nmol/l (HR [95% CI]: 2.87 [0.99-8.33]; P trend =0.111 for the fully adjusted model). Conclusions: Our data indicate that vitamin D status is inversely related to CVD mortality. However, before large scale measures to improve vitamin D status should be initiated, further studies should evaluate potentially harmful effects of very high levels of 25[OH]D on other outcomes especially among women.

Abstract P265: Physical Activity is Inversely Associated with Multimorbidity in Men: Results from the Population-Based KORA-Age Augsburg Study

Background: The co-occurrence of two or more chronic diseases in one individual, commonly known as multimorbidity, has become a major public health problem among the elderly. Physical activity has proven to be an essential means to mitigate chronic morbidity and disability. Therefore, we hypothesized that physical activity was inversely associated with multimorbidity. Currently, epidemiological studies addressing this research question are lacking. Methods: Using data from 1,007 men and women aged 65–94 years who participated in the population-based KORA-Age project conducted in Augsburg/Germany and two adjacent counties in 2009, thirteen chronic conditions were identified through a standardized telephone interview and a self-administered questionnaire. Physical activity scores were calculated based on the self-reported physical activity scale for the elderly (PASE), comprised of occupational, household and leisure activity items. Sex-specific logistic regression adjusted for age, BMI, education, and nutritional status was applied to determine the relation of the continuous physical activity score and multimorbidity (yes/no). Results: Multimorbidity was prevalent in 62.3% and 68.5% for men and women, respectively. Physical activity (mean PASE score ± SD) was higher in men (125.1 ± 59.2) than in women (112.2 ± 49.2). Among men, the OR for multimorbidity was 0.57 (95% CI: 0.41–0.78) for a 100-unit increase in the PASE score. No significant results could be observed for women (OR: 1.17; 95% CI: 0.73–1.89) (p-value for sex interaction=0.271). Additional analyses of physical activity quartiles showed that the effect among men were mainly observed in the highest quartile versus the lower ones (Figure 1). Conclusion: Our data suggest an inverse association between physical activity and multimorbidity in men, but not in women. Physical activity may counteract the development or progression of chronic diseases in men; further large population-based studies are needed to explore the possible sex-differences.

RANTES/CCL5 and Risk for Coronary Events: Results from the MONICA/KORA Augsburg Case-Cohort, Athero-Express and CARDIoGRAM Studies

BackgroundThe chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events.Methods and FindingsWe conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75–1.42] and 1.11 [0.81–1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (>22,000 cases, >60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years).ConclusionsHigh RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies.

Abstract 17135: Serum 25-Hydroxyvitamin D Deficiency Increases Risk of Myocardial Infarction: Results From the Prospective Monica/Kora Augsburg Case-Cohort Study

Background: A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. Circulating 25-hydroxyvitamin D3 (25[OH]D), the most commonly used index of vitamin D status, is converted to the active hormone 1,25-dihydroxyvitamin D3 (1,25[OH]2D), which, operating through the vitamin D receptor, inhibits in vitro cell proliferation, induces differentiation and apoptosis, and may protect against coronary heart disease (CHD). Therefore, the aim was to prospectively assess the association between serum (25[OH]D) concentrations and incident CHD. Methods: Using a case-cohort design, serum levels of (25[OH]D) were measured in 1,783 subjects (964 men, 819 women) selected from a source population of 9,300 middle-aged participants in the population-based MONICA/KORA Augsburg studies. Results: A total of 298 CHD cases (225 male, 73 female) were identified over an 11-year average follow-up period. We found a significant interaction of the effects of vitamin D with sex. After adjustment for age, survey, and season of blood sampling, the hazard ratio (HR) and 95% confidence interval (CI) comparing tertile extremes of serum levels of (25[OH]D) was 0.32 (0.16-0.65) (p for trend=0.001) in women, and 0.56 (0.38-0.82) (p-trend=0.005) in men. Further adjustment for standard cardiovascular risk factors (including BMI, smoking, physical activity, alcohol, systolic blood pressure, total cholesterol/HDL-cholesterol ratio, and parental history) slightly attenuated the association in women (HR: 0.39 [0.18-0.84] p-trend=0.013, and strongly in men (HR: 0.76 [0.49-1.17] p-trend=0.215). After additional adjustment for C-reactive protein, interleukin-6, ICAM-1, and IP-10, the effect remained significant in women (HR: 0.42 [0.19-0.93] p-trend=0.028) while it was further reduced in men (HR: 0.84 [0.52-1.35] p-trend=0.461). Conclusions: Our findings suggest that higher vitamin D status is associated with decreased risk of CHD. This effect seems to be particularly pronounced in women. Further clinical and experimental studies are needed to investigate the sex differences and whether or not correction of vitamin D deficiency could contribute to the prevention of CHD.