Rebecca T. Emeny

Reference Intervals for Insulin-like Growth Factor-1 (IGF-I) From Birth to Senescence: Results From a Multicenter Study Using a New Automated Chemiluminescence IGF-I Immunoassay Conforming to Recent International Recommendations

CONTEXT Measurement of IGF-I is a cornerstone in diagnosis and monitoring of GH-related diseases, but considerable discrepancies exist between analytical methods. A recent consensus conference defined criteria for validation of IGF-I assays and for establishment of normative data. OBJECTIVES Our objectives were development and validation of a novel automated IGF-I immunoassay (iSYS; Immunodiagnostic Systems) according to international guidelines and establishment of method-specific age- and sex-adjusted reference intervals and analysis of their robustness. SETTING AND PARTICIPANTS We conducted a multicenter study with samples from 12 cohorts from the United States, Canada, and Europe including 15 014 subjects (6697 males and 8317 females, 0-94 years of age). MAIN OUTCOME MEASURES We measured concentrations of IGF-I as determined by the IDS iSYS IGF-I assay. RESULTS A new IGF-I assay calibrated against the recommended standard (02/254) and insensitive to the 6 high-affinity IGF binding proteins was developed and rigorously validated. Age- and sex-adjusted reference intervals derived from a uniquely large cohort reflect the age-related pattern of IGF-I secretion: a decline immediately after birth followed by an increase until a pubertal peak (at 15 years of age). Later in life, values decrease continuously. The impact of gender is small, although across the lifespan, women have lower mean IGF-I concentrations. Geographical region, sampling setting (community or hospital based), and rigor of exclusion criteria in our large cohort did not affect the reference intervals. CONCLUSIONS Using large cohorts of well-characterized subjects from different centers allowed construction of robust reference ranges for a new automated IGF-I assay. The strict adherence to recent consensus criteria for IGF-I assays might facilitate clinical application of the results.

A Genome-Wide Association Study of Depressive Symptoms

BACKGROUND Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. RESULTS The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258). CONCLUSIONS The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

Clustering of negative affectivity and social inhibition in the community: prevalence of type D personality as a cardiovascular risk marker.

Objective: To explore the prevalence of Type D personality—the combination of negative affectivity and social inhibition—in the general population and its relationship to other cardiovascular risk factors, including psychopathological symptoms. Type D personality has been identified as a prognostic risk factor for various cardiovascular disease conditions. Methods: In a representative sample of 2698 individuals (aged 35–74 years), psychological, lifestyle, and somatic risk factors were investigated with laboratory testing, self-report measures, and a clinical interview. Type D was assessed with the German Type D Scale-14. Results: The prevalence of Type D was 23.4% (95% confidence interval [CI], 21.2–25.6) in men and 26.9% (95% CI, 23.7–30.1) in women and, thus, in the range of classical risk factors (e.g., hypercholesterolemia). In age-adjusted analysis, Type D was associated with psychopathological symptoms, including depression and somatic symptom burden. With the exception of physical inactivity in both sexes, hypertension in women and hypercholesterolemia in men, Type D was not associated with classical cardiovascular risk factors. Multivariate analysis revealed depression, exhaustion, anxiety, and low self-rated health as associated with Type D in both sexes (odds ratios, 1.97–3.21 in men, 1.52–2.44 in women). Conclusions: A Type D personality disposition can be found in about a quarter of the general population, which is comparable to the prevalence of classical cardiovascular risk factors. In both sexes, an independent association to Type D appeared mainly in psychopathological symptoms. Type D constitutes a relevant and independent risk marker in the community and should receive attention in clinical practice. CAD = coronary artery disease; CHD = coronary heart disease; DS14 = Type D Scale-14; NA = negative affectivity; HADS = Hospital Anxiety and Depression Scale; KORA = Cooperative Health Research in the Augsburg Region, Germany; MI = myocardial infarction; PHQ-9 = Patient Health Questionnaire depression module; SI = social inhibition; PTSD = posttraumatic stress disorder; TNF = tumor necrosis factor.

Association between schizophrenia and common variation in neurocan (NCAN), a genetic risk factor for bipolar disorder

A recent study found genome-wide significant association between common variation in the gene neurocan (NCAN, rs1064395) and bipolar disorder (BD). In view of accumulating evidence that BD and schizophrenia partly share genetic risk factors, we tested this single-nucleotide polymorphism for association with schizophrenia in three independent patient-control samples of European ancestry, totaling 5061 patients and 9655 controls. The rs1064395 A-allele, which confers risk for BD, was significantly over-represented in schizophrenia patients compared to controls (p=2.28×10(-3); odds ratio=1.11). Follow-up in non-overlapping samples from the Schizophrenia Psychiatric GWAS Consortium (5537 patients, 8043 controls) provided further support for our finding (p=0.0239, odds ratio=1.07). Our data suggest that genetic variation in NCAN is a common risk factor for BD and schizophrenia.

Age- and Sex-Specific Reference Intervals Across Life Span for Insulin-Like Growth Factor Binding Protein 3 (IGFBP-3) and the IGF-I to IGFBP-3 Ratio Measured by New Automated Chemiluminescence Assays

CONTEXT Measurement of IGF-binding protein-3 (IGFBP-3) can aid the diagnosis of GH-related diseases. Furthermore, epidemiological studies suggest that IGFBP-3 and the molar IGF-I to IGFBP-3 ratio are associated with clinical end points like cancer or cardiovascular disease. However, their clinical use is limited by the lack of validated reference intervals. OBJECTIVE The objective of the study was the establishment of age- and sex-specific reference intervals for IGFBP-3 and the molar IGF-I to IGFBP-3 ratio by newly developed automated immunoassays. SETTING This was a multicenter study with samples from 11 cohorts from the United States, Canada, and Europe. PARTICIPANTS A total of 14 970 healthy subjects covering all ages from birth to senescence participated in the study. MAIN OUTCOME MEASURES Concentrations of IGFBP-3 and the IGF-I to IGFBP-3 ratio as determined by the IDS iSYS IGF-I and IGFBP-3 assays were measured. RESULTS Both the concentration of IGFBP-3 and the IGF-I to IGFBP-3 ratio are mainly determined by age. IGFBP-3 concentrations increase until the age of 22 years, with a plateau being visible between 15 and 25 years. Determined by the high peripubertal peak in IGF-I, the peak in the IGF-I to IGFBP-3 ratio occurs already around the age of 15 years, with a slightly earlier and higher peak in females. Beyond the age of 60 years, IGFBP-3 concentrations remain higher in females, whereas IGF-I as well as the IGF-I to IGFBP-3 ratio remains significantly higher in males. CONCLUSIONS We present an extensive set of assay-specific age- and sex-adjusted normative data for concentrations of IGFBP-3 and the molar IGF-I to IGFBP-3 ratio and demonstrate distinct sex specific differences across the life span.

Multimorbidität und erfolgreiches Altern

BACKGROUND The objective of the KORA-Age research consortium is to assess the determinants and consequences of multimorbidity in the elderly and to look into reasons for successful aging in the general public. PATIENTS AND METHODS In the KORA-Age cohort study 9,197 persons were included who where born in the year 1943 or before and participants of previous KORA cohort studies conducted between 1984 and 2001 (KORA: Cooperative Health Research in the Region of Augsburg). The randomized intervention study KORINNA (Coronary infarct follow-up treatment in the elderly) tested a nurse-based case management program with 338 patients with myocardial infarct and included an evaluation in health economics. RESULTS A total of 2,734 deaths were registered, 4,565 participants submitted a postal health status questionnaire and 4,127 participants were interviewed by telephone (response 76.2% and 68.9% respectively). A gender and age-stratified random sample of the cohort consisting of 1,079 persons took part in a physical examination (response 53.8%). CONCLUSION The KORA-Age consortium was able to collect data in a large population-based sample and is contributing to the understanding of multimorbidity and successful aging.

Posttraumatic stress disorder and not depression is associated with shorter leukocyte telomere length: findings from 3,000 participants in the population-based KORA F4 study.

Background A link between severe mental stress and shorter telomere length (TL) has been suggested. We analysed the impact of Posttraumatic Stress Disorder (PTSD) on TL in the general population and postulated a dose-dependent TL association in subjects suffering from partial PTSD compared to full PTSD. Methods Data are derived from the population-based KORA F4 study (2006–2008), located in southern Germany including 3,000 individuals (1,449 men and 1,551 women) with valid and complete TL data. Leukocyte TL was measured using a quantitative PCR-based technique. PTSD was assessed in a structured interview and by applying the Posttraumatic Diagnostic Scale (PDS) and the Impact of Event Scale (IES). A total of 262 (8.7%) subjects qualified for having partial PTSD and 51 (1.7%) for full PTSD. To assess the association of PTSD with the average TL, linear regression analyses with adjustments for potential confounding factors were performed. Results The multiple model revealed a significant association between partial PTSD and TL (beta = −0.051, p = 0.009) as well as between full PTSD and shorter TL (beta = −0.103, p = 0.014) indicating shorter TL on average for partial and full PTSD. An additional adjustment for depression and depressed mood/exhaustion gave comparable beta estimations. Conclusions Participants with partial and full PTSD had significantly shorter leukocyte TL than participants without PTSD. The dose-dependent variation in TL of subjects with partial and full PTSD exceeded the chronological age effect, and was equivalent to an estimated 5 years in partial and 10 years in full PTSD of premature aging.

[Multimorbidity and successful aging: the population-based KORA-Age study].

BACKGROUND The objective of the KORA-Age research consortium is to assess the determinants and consequences of multimorbidity in the elderly and to look into reasons for successful aging in the general public. PATIENTS AND METHODS In the KORA-Age cohort study 9,197 persons were included who where born in the year 1943 or before and participants of previous KORA cohort studies conducted between 1984 and 2001 (KORA: Cooperative Health Research in the Region of Augsburg). The randomized intervention study KORINNA (Coronary infarct follow-up treatment in the elderly) tested a nurse-based case management program with 338 patients with myocardial infarct and included an evaluation in health economics. RESULTS A total of 2,734 deaths were registered, 4,565 participants submitted a postal health status questionnaire and 4,127 participants were interviewed by telephone (response 76.2% and 68.9% respectively). A gender and age-stratified random sample of the cohort consisting of 1,079 persons took part in a physical examination (response 53.8%). CONCLUSION The KORA-Age consortium was able to collect data in a large population-based sample and is contributing to the understanding of multimorbidity and successful aging.

Association between social isolation and inflammatory markers in depressed and non-depressed individuals: Results from the MONICA/KORA study

INTRODUCTION Depressed individuals not only suffer from chronic low grade inflammation, but also exhibit an inflammatory hyper-responsiveness to acute stress. We investigate whether chronic stress also induces an exaggerated inflammatory response in individuals with increased depression features. As model for chronic stress, social isolation was chosen. METHODS Interleukin (IL)-6 and hs-CRP levels were assessed in 1547 subjects (847 men and 700 women), derived from the population-based MONICA/KORA study. Standardized questionnaires were used to assess depressed mood (depression and exhaustion subscale) and social isolation (social network index). The relationship between the two inflammatory markers, social isolation and depressed mood was examined taking into account interactions social isolation × depressed mood using multivariable linear regression models, adjusted for age, BMI, smoking, alcohol, and physical activity. Analyses were performed in men and women separately. RESULTS We observed a significant interaction between depressed mood and social isolation regarding IL-6 and hs-CRP, respectively in men (p-value=0.02 for IL-6 and <0.01 for hs-CRP), evidencing a substantial synergistic effect of social isolation, and depressed mood on inflammatory responses. Furthermore, depressed and socially isolated men had highly significantly elevated IL-6 levels (geometric mean: 3.76 vs. 1.92 pg/ml, p-value <0.01) and heightened hs-CRP levels (geometric mean: 2.01 vs. 1.39 mg/l, p=0.08) in comparison with non-depressed and socially integrated men. In women, no significant associations were seen. CONCLUSION The interaction of depressed mood and social isolation elicits a substantial synergistic impact on inflammatory markers in men, but not in depressed women.

Job strain associated CRP is mediated by leisure time physical activity: results from the MONICA/KORA study.

BACKGROUND Psychological stress at work is considered a cardiac risk factor, yet whether it acts directly through neuroimmune processes, or indirectly by increasing behavioral risk factors, is uncertain. Cross-sectional associations between job strain and serum biomarkers of inflammation and endothelial dysfunction were investigated. Secondary analyses explored the role of psychosocial/cardiometabolic risk factors as mediators of job stress associated inflammation in healthy workers. METHODS Information on risk factors was obtained in standardized personal interviews of a subcohort of working participants in the MONICA/KORA population (n = 951). Work stress was measured by the Karasek job strain index. Biomarkers were measured from non-fasting venous blood. Multivariate regression analyses were used to examine the association of job strain with inflammatory biomarkers. Mediation analysis (Sobel test) was used to determine the effect of psychosocial risk factors on the association between job strain and C-reactive protein (CRP). RESULTS High job strain was reported by half (n = 482, 50.7%) of the study participants. While workers with high job strain were more likely to have adverse workplace conditions (competition with coworkers, job dissatisfaction and insecurity), sleeping problems, depressive symptoms, a Type A personality, and be physically inactive, no differences in cardiometabolic risk factors were detected. A strong and robust association between job strain and CRP was observed in age and sex adjusted models, as well as models adjusted for classic coronary heart disease risk factors (β = 0.39, p = 0.006 and β = 0.27, p = 0.03, respectively). Adjustment for physical activity abrogated this effect (β = 0.23, p = 0.07), and a mediating effect of physical activity on stress-associated inflammation was demonstrated (p = 0.04). CONCLUSIONS The analyses provide evidence for both a direct and an indirect effect of job strain on inflammation.