Neutropenia-related aspergillosis in non-transplant haematological patients hospitalised under ambient air versus purified air conditions.

BACKGROUND: To reduce the risk of invasive aspergillosis (IA), air purification by high-efficiency particulate air filtration and laminar air flow (HEPA/LAF) is standard of care in allogeneic blood stem cell transplantation. Its use in non-transplant haematological patients is inconsistent. OBJECTIVES: We sought to assess the incidence and outcome of pulmonary IA in non-transplant patients with life-threatening neutropenia by comparing an ambient air hospitalisation period (2008-2011) with a subsequent HEPA/LAF hospitalisation period (2012-2014). PATIENTS AND METHODS: We compared 204 consecutive patients with acute myeloid leukaemia, acute lymphoblastic leukaemia or aplastic anaemia completing 534 neutropenia-related hospitalisations under ambient air conditions with 126 such patients completing 437 neutropenia-related hospitalisations under HEPA/LAF conditions. IA was defined using the 2008 EORTC/MSG criteria. RESULTS: Within a 7-year study period, we observed one 'proven', three 'probable' and 73 'possible' IAs, most often during acute leukaemia remission induction. Their frequency rose with increasing duration of life-threatening neutropenia (1-10 days, 1.8%; >40 days, 35.2%) and concomitant severe anaemia (0 days, 3.2%; >20 days, 31.0%). Multiple logistic regression revealed a strong correlation between IA incidence and hospitalisation under HEPA/LAF conditions (odds ratio [OR], 0.368 [95% confidence interval, 0.207-0.654]; p < .001) and duration of neutropenia (OR, 1.043 [1.023-1.062] per day; p < .001) and anaemia (OR, 1.044 [1.008-1.081] per day; p = .016). IA-associated fatal outcomes were non-significantly reduced under HEPA/LAF (OR, 0.077 [0.005-1.151]; p = .063). The protective effect of HEPA/LAF was not seen under posaconazole prophylaxis (OR, 0.856 [0.376-1.950]; p = .711). CONCLUSIONS: Implementation of HEPA/LAF was associated with a significant reduction in neutropenia-related IA in non-transplant haematological patients.

Impact of shift work on the risk of depression.

We studied the association between shift work and depressive symptoms in the prospective Heinz Nixdorf Recall Study, considering various demographic, lifestyle and work-related factors. Depressive symptoms were assessed using the Center for Epidemiologic Studies-Depression (CES-D)-Scale (≥17 points defined as high symptoms) and the Patient Health Questionnaire (PHQ) with a cutoff ≥9, or prescription of an anti-depressant. The definition of shift work included work hours outside 7:00 to 18:00, whereas night work was defined as a shift including work between 0:00 and 5:00. Poisson regression with robust error variances was calculated to estimate relative risks (RR) and 95% confidence intervals (CI), adjusted for age at follow-up, diurnal preference, monthly household income and education. Analyses were stratified by sex. We performed various sensitivity and stratified analyses to test the robustness of our results. At baseline, 1,500 gainfully employed subjects, 45-73 years of age and without a history of depression, were included. Until the 5-year follow-up, 896 participants were observed, and 486 participants survived through the 10-year follow-up. Although most analyses did not reach the level of formal statistical significance, women working night shifts tended to show increased relative risks for depressive symptoms according to the PHQ (RR = 1.78; 95% CI 0.71-4.45), in particular when working night shifts for ≥20 years (RR = 2.70; 95% CI 0.48-15.4). Stratification by age group revealed no increased risks among women above 60 years of age. Stratified analyses indicated that over-commitment was associated with higher risks for depressive symptoms among women (RR = 4.59; 95% CI 0.95-22.2 in the CES-D and RR = 12.7; 95% CI 2.89-56.1 in the PHQ). Exclusion of subgroups for the purpose of sensitivity analyses generally strengthened associations in women, whereas little evidence for an increased risk of depression remained among male shift workers. In summary, negative effects on depression were suggested among female shift workers, although results were based on small numbers. Among men, we did not identify consistently increased risks for depressive symptoms in relation to shift work.

Survival analysis for AdVerse events with VarYing follow-up times (SAVVY)-estimation of adverse event risks.

BACKGROUND: The SAVVY project aims to improve the analyses of adverse events (AEs), whether prespecified or emerging, in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). Although statistical methodologies have advanced, in AE analyses, often the incidence proportion, the incidence density, or a non-parametric Kaplan-Meier estimator are used, which ignore either censoring or CEs. In an empirical study including randomized clinical trials from several sponsor organizations, these potential sources of bias are investigated. The main purpose is to compare the estimators that are typically used to quantify AE risk within trial arms to the non-parametric Aalen-Johansen estimator as the gold-standard for estimating cumulative AE probabilities. A follow-up paper will consider consequences when comparing safety between treatment groups. METHODS: Estimators are compared with descriptive statistics, graphical displays, and a more formal assessment using a random effects meta-analysis. The influence of different factors on the size of deviations from the gold-standard is investigated in a meta-regression. Comparisons are conducted at the maximum follow-up time and at earlier evaluation times. CEs definition does not only include death before AE but also end of follow-up for AEs due to events related to the disease course or safety of the treatment. RESULTS: Ten sponsor organizations provided 17 clinical trials including 186 types of investigated AEs. The one minus Kaplan-Meier estimator was on average about 1.2-fold larger than the Aalen-Johansen estimator and the probability transform of the incidence density ignoring CEs was even 2-fold larger. The average bias using the incidence proportion was less than 5%. Assuming constant hazards using incidence densities was hardly an issue provided that CEs were accounted for. The meta-regression showed that the bias depended mainly on the amount of censoring and on the amount of CEs. CONCLUSIONS: The choice of the estimator of the cumulative AE probability and the definition of CEs are crucial. We recommend using the Aalen-Johansen estimator with an appropriate definition of CEs whenever the risk for AEs is to be quantified and to change the guidelines accordingly.

Air Pollution and Polyclonal Elevation of Serum Free Light Chains: An Assessment of Adaptive Immune Responses in the Prospective Heinz Nixdorf Recall Study.

BACKGROUND: Residential exposure to air pollution (AP) has been shown to activate the immune system (IS). Although innate immune responses to AP have been studied extensively, investigations on the adaptive IS are scarce. OBJECTIVES: The aim of this study was to investigate the association between short- to long-term AP exposure and polyclonal free light chains (FLC) produced by plasma cells. METHODS: We used repeated data from three examinations (t0: 2000-2003; t1: 2006-2008; and t2: 2011-2015) of the population-based German Heinz Nixdorf Recall cohort of initially 4,814 participants (45-75 y old). Residential exposure to total and source-specific particulate matter (PM) with an aerodynamic diameter of 10 or 2.5µm (PM10 and PM2.5 respectively), nitrogen dioxide (NO2), and particle number concentrations (accumulation mode; PNAM) was estimated using a chemistry transport model with different time windows (1- to 365-d mean ± standard deviation) before blood draw. We applied linear mixed models with a random participant intercept to estimate associations between total, traffic- and industry-related AP exposures and log-transformed FLC, controlling for examination time, sociodemographic and lifestyle variables, estimated glomerular filtration rate and season. RESULTS: Analyzing 9,933 observations from 4,455 participants, we observed generally positive associations between AP exposures and FLC. We observed strongest associations with middle-term exposures, e.g., 3.0% increase in FLC (95% confidence interval: 1.8%, 4.3%) per interquartile range increase in 91-d mean of NO2 (14.1µg/m³). Across the different pollutants, NO2 showed strongest associations with FLC, followed by PM10 and PNAM. Effect estimates for traffic-related exposures were mostly higher compared with total exposures. Although NO2 and PNAM estimates remained stable upon adjustment for PM, PM estimates decreased considerably upon adjustment for NO2 and PNAM. DISCUSSION: Our results suggest that middle-term AP exposures in particular might be positively associated with activation of the adaptive IS. Traffic-related PM, PNAM, and NO2 showed strongest associations. https://doi.org/10.1289/EHP7164.

Associations between shift work and risk of colorectal cancer in two German cohort studies.

The association between shift work and the risk of colorectal cancer (CRC) is still unclear. Therefore, we studied the associations between exposure to shift or night work and incident CRC in two German population-based cohort studies, the Heinz Nixdorf Recall Study (HNR) and the Study of Health in Pomerania (SHIP). Including up to 6,903 participants, we analyzed the cohorts pooled and individually. We estimated incidence rate ratios (IRRs) with adjusted log-linear Poisson regression models with the natural logarithm of person-years as offset and performed subgroup analyses by sex and tumor localization in HNR. The pooled analysis revealed no increased risks for men working in night shifts (IRR: 1.03, 95% CI: 0.62; 1.71). In male HNR participants, we found an increased risk estimate for cancer of the distal colon in shift workers (IRR: 1.60, 95% CI: 0.53; 4.87) and in shift workers who did not perform night work (IRR: 3.93, 95% CI: 0.98; 15.70), but not in night workers. In SHIP, we observed elevated CRC risk estimates for rotating shift work including night work (IRR: 1.45, 95% CI: 0.72; 2.92) and for long-term exposure (IRR: 1.79, 95% CI: 0.81; 3.92) for men. In conclusion, night-shift work was not associated with CRC, although an increased risk was suggested for rotating shift work including nights in SHIP. The heterogeneity of shift-work jobs and schedules and associated lifestyle factors should be taken into account to disentangle a possible relationship between shift work and the risk for CRC in future investigations.

Socioeconomic Position is Positively Associated with Monoclonal Gammopathy of Undetermined Significance in a Population-based Cohort Study.

Knowledge of social inequalities in monoclonal gammopathy of undetermined significance (MGUS) will contribute to understanding multiple myeloma (MM) etiology, as MGUS consistently precedes MM. The aim of the present study was to examine whether socioeconomic position (SEP) is associated with MGUS in a population-based cohort including information on potential MGUS risk factors. Overall, 4787 study participants aged 45-75 years with information on MGUS were included. SEP indicators (education, income) and potential risk factors (i.e., body mass index, diabetes, smoking, dietary factors) were assessed at baseline. Overall, 260 MGUS cases were detected at baseline and prospectively over a 10-year follow-up. In age-adjusted logistic regression models, a lower chance of having MGUS at baseline or developing MGUS during 10 years of follow-up was indicated for groups of low SEP with odds ratios (OR) of 0.39 (95% confidence interval [95%-CI] 0.19-0.76) for women and 0.48 (95% CI 0.10-1.16) for men in the lowest compared to the highest educational group. After additionally including potential mediating risk factors in the regression models, the estimated ORs changed only slightly in magnitude. Similar results were obtained for income. Current smoking and low fruit consumption were associated with MGUS independently of SEP in women, but not in men. The present study indicates a lower MGUS risk in lower SEP groups. Supporting evidence is given that smoking and diet play a role in the development of MGUS independently of SEP, while it has to be assumed that risk factors unknown to date are responsible for the observed social inequalities in MGUS.

Efficacy of the GMALL-B-ALL/NHL2002 protocol in Burkitt leukemia/lymphoma and aggressive non-Hodgkin-lymphomas with or without CNS involvement.

OBJECTIVES: The GMALL-B-ALL/NHL2002 protocol is effective in Burkitt lymphoma/leukemia (BL). Its role in other aggressive lymphomas and in patients with simultaneous central nervous system (CNS) and peripheral involvement is unclear. METHODS: This is a retrospective outcome analysis in 76 patients with BL (n = 26), B-lymphoblastic lymphoma (B-LBL; n = 3), diffuse large B-cell lymphoma (DLBCL; n = 31), mantle cell lymphoma (MCL; n = 6), transformed B-cell non-Hodgkin lymphomas (tB-NHL; n = 7), and T-cell NHL (T-NHL; n = 3) treated with the GMALL-B-ALL/NHL2002 protocol. RESULTS: 73.1% of scheduled chemotherapy cycles were administered. Treatment was discontinued in 38 patients (50.0%) due to progression (n = 14), toxicities (n = 11), scheduled treatment change (n = 6), and unknown reasons (n = 7). All BL/B-LBL patients were treated first-line, and at a median follow-up of 124.7 months, median progression-free survival was not reached. In DLBCL, median PFS was 68.4 months in first-line treated patients and 3.7 months in relapsed/refractory patients. CNS involvement was present in 10 non-BL/B-LBL cases and did not have a negative impact on survival in first-line treated patients but was fatal in all relapsed/refractory patients. CONCLUSION: This study confirmed the activity of the GMALL-B-ALL/NHL2002 protocol in BL/B-LBL. It was also effective in first-line treated non-BL/B-LBL lymphomas with and without simultaneous CNS-/peripheral involvement, but ineffective in relapsed/refractory disease.

Light chain monoclonal gammopathy of undetermined significance is characterized by a high disappearance rate and low risk of progression on longitudinal analysis.

We determined the 10-year progression rate of light chain monoclonal gammopathy of undetermined significance (LCMGUS) and investigated potential associations with cancer utilizing the German population-based Heinz Nixdorf Recall Study. The Heinz Nixdorf Recall Study comprises 4814 men and women aged 45-75 years. Serum samples from baseline (2000-2003) and five-year (2006-2008) and 10-year (2011-2015) follow-up examinations were screened for monoclonal free light chains (FLC). LCMGUS was defined as abnormal FLC ratio, increase of involved FLC with complete loss of immunoglobulin heavy chain, and absence of a history of lymphoproliferative disease (LPD). Seventy-five individuals with LCMGUS were identified across all three evaluation time points (median age 64 years; 43 (57%) male; FLCR > 1.65 65 (87%); FLCR ≤ 0.65 10 (13%)). After a median observation time of 11.5 years, none of the LCMGUS cases had progressed to overt LPD; in particular, we did not observe incident light chain multiple myeloma. On serial analysis 17/31 (55%), LCMGUS could not be confirmed and disappearance of the monoclonal protein was associated with low concentrations of the involved FLC. Individuals with LCMGUS had a 1.5-fold increased risk of cancer but did not show differences in overall survival or renal function as compared to individuals with normal FLC. In conclusion, LCMGUS represents a relatively benign condition with a high disappearance rate of the monoclonal protein on longitudinal analysis and normal overall survival at least in the population-based setting.

Occupational Exposure to Manganese and Fine Motor Skills in Elderly Men: Results from the Heinz Nixdorf Recall Study.

OBJECTIVES: Exposure to manganese (Mn) may cause movement disorders, but less is known whether the effects persist after the termination of exposure. This study investigated the association between former exposure to Mn and fine motor deficits in elderly men from an industrial area with steel production. METHODS: Data on the occupational history and fine motor tests were obtained from the second follow-up of the prospective Heinz Nixdorf Recall Study (2011-2014). The study population included 1232 men (median age 68 years). Mn in blood (MnB) was determined in archived samples (2000-2003). The association between Mn exposure (working as welder or in other at-risk occupations, cumulative exposure to inhalable Mn, MnB) with various motor functions (errors in line tracing, steadiness, or aiming and tapping hits) was investigated with Poisson and logistic regression, adjusted for iron status and other covariates. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated for substantially impaired dexterity (errors >90th percentile, tapping hits <10th percentile). RESULTS: The median of cumulative exposure to inhalable Mn was 58 µg m-3 years in 322 men who ever worked in at-risk occupations. Although we observed a partly better motor performance of exposed workers at group level, we found fewer tapping hits in men with cumulative Mn exposure >184.8 µg m-3 years (OR 2.15, 95% CI 1.17-3.94). MnB ≥ 15 µg l-1, serum ferritin ≥ 400 µg l-1, and gamma-glutamyl transferase ≥74 U l-1 were associated with a greater number of errors in line tracing. CONCLUSIONS: We found evidence that exposure to inhalable Mn may carry a risk for dexterity deficits. Whether these deficits can be exclusively attributed to Mn remains to be elucidated, as airborne Mn is strongly correlated with iron in metal fumes, and high ferritin was also associated with errors in line tracing. Furthermore, hand training effects must be taken into account when testing for fine motor skills.

Is long-term particulate matter and nitrogen dioxide air pollution associated with incident monoclonal gammopathy of undetermined significance (MGUS)? An analysis of the Heinz Nixdorf Recall study.

BACKGROUND: Exposure to air pollution activates the innate immune system and influences the adaptive immune system in experimental settings. We investigated the association of residential long-term exposure to particulate matter (PM) and NO2 air pollution with monoclonal gammopathy of undetermined significance (MGUS) as a marker of adaptive immune system activation. METHODS: We used data from the baseline (2000-2003), 5-year (2006-2008) and 10-year (2011-2015) follow-up examinations of the German Heinz Nixdorf Recall cohort study of 4814 participants (45-75years). Residential exposure to PM size fractions and NO2 was estimated by land-use regression (ESCAPE-LUR, annual mean 2008/2009) and dispersion chemistry transport models (EURAD-CTM, 3-year mean at baseline). We used logistic regression to estimate the effects of air pollutants on incident MGUS, adjusting for age, sex, education, smoking status, physical activity, and BMI. As a non-linear approach, we looked at quartiles (2-4) of the air pollutants in comparison to quartile 1. RESULTS: Of the 3949 participants with complete data, 100 developed MGUS during the 10-year follow-up. In the main model, only PMcoarse was associated with incident MGUS (OR per IQR (1.9µg/m3): 1.32, 95% CI 1.04-1.67). We further found positive associations between PM size fractions estimated by ESCAPE-LUR and incident MGUS by quartiles of exposure (OR Q4 vs Q1: PM2.5 2.03 (1.08-3.80); PM10 1.97 (1.05-3.67); PMcoarse 1.98 (1.09-3.60)). CONCLUSIONS: Our results indicate that an association between long-term exposure to PM and MGUS may exist. Further epidemiologic studies are needed to corroborate this possible link.

Shift work and the incidence of prostate cancer: a 10-year follow-up of a German population-based cohort study.

Objectives We investigated the association of shift and night work with the incidence of prostate cancer using data of the population-based prospective Heinz Nixdorf Recall Study from the highly industrialized Ruhr area in Germany. Methods Participants of the baseline survey were recruited between 2000-2003. A follow-up survey including, a detailed interview on shift and night work, was conducted from 2011-2014. We included 1757 men who did not report a history of prostate cancer at baseline. We assessed shift- and night-work exposure up to time of the baseline interview. Incident prostate cancers were recorded from baseline through September 2014. We calculated hazard ratios (HR) of shift- and night-work exposure using Cox proportional hazards regression with age at event as timescale, adjusting for smoking status, family history of prostate cancer, education (≤13, 14-17, ≥18 years), and equivalent income (low, medium, high). Results We observed a twofold increased HR for prostate cancer among shift and night workers. Ever employment in shift work was associated with HR 2.29, 95% confidence interval (CI) 1.43-3.67 and night work with HR 2.27, 95% CI 1.42-3.64. HR increased steadily with duration of employment in shift or night work. Stratifying analyses by preferred midpoint of sleep, yielded strongly elevated HR among subjects with early sleep preference, although these analyses were limited by small number of cases. Conclusions We identified increased risks for prostate cancer among men with employment in shift or night work. HR were strongly elevated among long-term employed shift workers and men with early preferred midpoint of sleep.

Prolongation of the QTc interval in HIV-infected individuals compared to the general population.

OBJECTIVES: Prolonged QT interval is associated with arrhythmias and sudden death. An increased prevalence of QT interval prolongation in human immunodeficiency virus-infected (HIV) subjects was previously described. The impact of different medications and HIV infection itself on the QT interval is rarely investigated in large HIV+ cohorts. METHODS: We compared QT interval measurement in 496 HIV(+) patients of the HIV-HEART study (HIVH) and 992 sex- and age-matched controls of the population-based German Heinz Nixdorf Recall study (HNR). QT corrected for heart rate (QTc) >440 ms in male and >460 ms in female was considered pathological. We analysed the impact of HIV status and HIV medication on QTc prolongation in the HIVH subjects. RESULTS: We observed longer QTc in HIVH subjects compared with HNR controls: 424.1 ms ± 23.3 vs. 411.3 ± 15.3 ms for male and 435.5 ms ± 19.6 vs. 416.4 ms ± 17.3 for female subjects (p < 0.0001 for both sexes). Adjusting for QT prolonging medication the mean differences in QTc between the two studies remained significant with 12.6 ms (95% CI 10.5-14.8; p value <0.0001) for male and 19.3 ms (95% CI 14.5-24.2; p value <0.0001) for female subjects. Prolongation of QTc was pathologic in 22.8 vs. 3.9% of HIV(+) and non-infected males and in 12.1 vs. 1.8% of the females [OR of 7.9 (5.0-12.6) and OR of 6.7 (1.8-24.2), respectively]. Smoking behaviour was an independent factor to lengthen QTc in HIV(+) patients. Diabetes mellitus was not a risk factor itself, but might be associated with medication which was associated with LQT. We could not observe any influence of the HIV status, ART, or any co-medication on the QTc. CONCLUSIONS: Our study showed that HIV(+) patients had significantly longer QTc intervals compared to the general population. The number of patients with pathologic QTc prolongation was significantly increased in HIV(+) population.

The distribution of blood concentrations of lead (Pb), cadmium (Cd), chromium (Cr) and manganese (Mn) in residents of the German Ruhr area and its potential association with occupational exposure in metal industry and/or other risk factors.

OBJECTIVE: This study investigated the metal distribution in blood samples from the general population and the risk of having high metal concentration for metal workers. METHODS: Metal concentrations were determined in archived blood samples from 1411 men and 1410 women (median age 59 and 57 years, respectively) collected at baseline (2000-2003) of the prospective Heinz Nixdorf Recall Study. Retrospective information on working in metal industry was obtained from previous follow-up survey (2011-2014). Odds ratios (ORs) with 95% confidence intervals (CI) of having a metal concentration >90th percentile (P90) for working in metal industry were calculated using logistic regression with adjustment for covariates. RESULTS: More men than women worked in metal industry (57 vs. 3 at baseline). Male metal workers had increased blood lead (Pb) (OR: 2.86; 95% CI: 1.38-5.91) and manganese (Mn) (OR: 2.92; 95% CI: 1.46-5.81). Smoking (≥30 cigarettes/day) strongly influenced cadmium (Cd) in blood (OR: 168; 95% CI: 55-510). Women had higher Mn (8.92µg/L) and Cd (0.36µg/L) concentrations than men (Mn: 8.11µg/L; Cd: 0.29µg/L). Blood Pb in women (29.2µg/L) was lower than in men (33.2µg/L). None of the studied risk factors was significantly associated with chromium and nickel concentrations above their 90th percentiles. CONCLUSIONS: In this population-based cohort we found evidence that working in metal industry was predictive for having elevated blood Pb and Mn concentrations. However, the 95th percentiles of all investigated metals were not significantly influenced by metal-related occupations. The present study is supportive for gender-specific reference values to limit occupational exposure to Mn and Pb. The strong influence of smoking on blood Cd hinders establishing reference values.

Hypoxia Inducible Factor-2 Alpha and Prolinhydroxylase 2 Polymorphisms in Patients with Acute Respiratory Distress Syndrome (ARDS).

Hypoxia-inducible-factor-2α (HIF-2α) and HIF-2 degrading prolyl-hydroxylases (PHD) are key regulators of adaptive hypoxic responses i.e., in acute respiratory distress syndrome (ARDS). Specifically, functionally active genetic variants of HIF-2α (single nucleotide polymorphism (SNP) [ch2:46441523(hg18)]) and PHD2 (C/T; SNP rs516651 and T/C; SNP rs480902) are associated with improved adaptation to hypoxia i.e., in high-altitude residents. However, little is known about these SNPs' prevalence in Caucasians and impact on ARDS-outcome. Thus, we tested the hypotheses that in Caucasian ARDS patients SNPs in HIF-2α or PHD2 genes are (1) common, and (2) independent risk factors for 30-day mortality. After ethics-committee approval, 272 ARDS patients were prospectively included, genotyped for PHD2 (Taqman SNP Genotyping Assay) and HIF-2α-polymorphism (restriction digest + agarose-gel visualization), and genotype dependent 30-day mortality was analyzed using Kaplan-Meier-plots and multivariate Cox-regression analyses. Frequencies were 99.62% for homozygous HIF-2α CC-carriers (CG: 0.38%; GG: 0%), 2.3% for homozygous PHD2 SNP rs516651 TT-carriers (CT: 18.9%; CC: 78.8%), and 3.7% for homozygous PHD2 SNP rs480902 TT-carriers (CT: 43.9%; CC: 52.4%). PHD2 rs516651 TT-genotype in ARDS was independently associated with a 3.34 times greater mortality risk (OR 3.34, CI 1.09-10.22; p = 0.034) within 30-days, whereas the other SNPs had no significant impact (p = ns). The homozygous HIF-2α GG-genotype was not present in our Caucasian ARDS cohort; however PHD2 SNPs exist in Caucasians, and PHD2 rs516651 TT-genotype was associated with an increased 30-day mortality suggesting a relevance for adaptive responses in ARDS.

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

Socioeconomic Status Interacts with the Genetic Effect of a Chromosome 9p21.3 Common Variant to Influence Coronary Artery Calcification and Incident Coronary Events in the Heinz Nixdorf Recall Study (Risk Factors, Evaluation of Coronary Calcium, and Lifestyle).

BACKGROUND: Genetic variants of a locus within the chromosome 9p21.3 region are consistently associated with coronary artery disease and coronary artery calcification (CAC). The aim of this study was to examine whether a 9p21.3 common variant interacts with socioeconomic status (SES) to influence CAC and incident coronary events in a population-based cohort. METHODS AND RESULTS: 9p21.3 single nucleotide polymorphism rs2891168 was genotyped in 4116 participants of the Heinz Nixdorf Recall study. SES indicators (education and income) and CAC were assessed at baseline. Incident coronary events were ascertained over a median follow-up of 9.3 years. Multiple regression models were fitted to estimate genetic effects on loge(CAC+1) and incident coronary events. Genetic effects were highest in the lower income tertile with a 53.1% (95% confidence interval, 30.6%-79.6%; P=1.8×10 -7) increase in CAC and a hazard ratio of 1.44 (95% confidence interval, 1.01-2.07; P=0.049) for incident coronary events per additional risk allele. After including genotype×SES interaction terms in the regression models, genotype×income interactions were observed for CAC (exp[ßg×income]=0.85 [95% confidence interval, 0.74-0.98; Pg×income=0.02] per 1000€/mo increase and additional risk allele) and for incident coronary events (hazard ratiog×income=0.69 [95% confidence interval, 0.48-0.98; Pg×income=0.04] per 1000€/mo increase and additional risk allele). No interaction was observed using education as SES indicator. CONCLUSIONS: A 9p21.3 common variant seems to interact with SES to influence CAC and incident coronary events in a population-based cohort. This supports the hypothesis that better material, psychosocial, and lifestyle conditions enable higher SES groups to reduce the expression of their genetic susceptibility to coronary artery disease.

Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci.

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10-9) with opposing effects between CLL (P = 1.97 × 10-8) and HL (P = 3.31 × 10-3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10-12) was associated with increased CLL and HL risk (P = 4.68 × 10-12), and reduced MM risk (P = 1.12 × 10-2), and Gly70 in HLA-DQB1 (P = 3.15 × 10-10) showed opposing effects between CLL (P = 3.52 × 10-3) and HL (P = 3.41 × 10-9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.

Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: A report from the German reference center.

BACKGROUND: Survivors of heritable retinoblastoma carry a high risk to develop second cancers. Eye-preserving radiotherapy raises this risk, while the impact of chemotherapy remains less defined. PROCEDURE: This population-based study characterizes the impact of all treatment modalities on second cancers incidence and type after retinoblastoma treatment in Germany. Data on second cancer incidence in 648 patients with heritable retinoblastoma treated between 1940 and 2008 at the German national reference center for retinoblastoma were analyzed to identify associations with treatment. RESULTS: The cumulative incidence ratio (per 1,000 person years) of second cancers was 8.6 (95% confidence interval 7.0-10.4). Second cancer incidence was influenced by type of retinoblastoma treatment but not by the year of diagnosis or by sex. Radiotherapy and systemic chemotherapy increased the incidence of second cancers (by 3.0- and 1.8-fold, respectively). While radiotherapy was specifically associated with second cancers arising within the periorbital region in the previously irradiated field, chemotherapy was the strongest risk factor for second cancers in other localizations. Soft tissue sarcomas and osteosarcomas were the most prevalent second cancers (standardized incidence ratio 179.35 compared to the German population). CONCLUSIONS: Second cancers remain a major concern in heritable retinoblastoma survivors. Consistent with previous reports, radiotherapy increased second cancer incidence and influenced type and localization. However, chemotherapy was the strongest risk factor for second malignancies outside the periorbital region. Our results provide screening priorities during life-long oncological follow-up based on the curative therapy the patient has received and emphasize the need for less-detrimental therapies for children with heritable retinoblastoma.

Associations between former exposure to manganese and olfaction in an elderly population: Results from the Heinz Nixdorf Recall Study.

Occupational exposure to manganese (Mn) has been associated with impairments in olfaction and motor functions, but it has yet to be determined if such effects persist upon cessation of exposure. The objective of this study was to evaluate the influence of former occupational Mn exposure on olfaction within the framework of a prospective cohort study among an elderly German population. Information on job tasks with recognized Mn exposure and data on odor identification assessed with Sniffin' sticks was collected during the second follow-up of the Heinz Nixdorf Recall Study. The study population consisted of 1385 men aged 55-86 years, 354 of whom ever worked in jobs with potential Mn exposure (median 58.3µg/m3 years, interquartile range 19.0-185µg/m3 years). Multiple exposure measures, including job tasks, cumulative Mn exposure, and Mn determined in blood samples (MnB) archived at baseline, were used to estimate effects of Mn on olfaction. Having ever worked as welder was associated with better olfaction compared to other blue-collar workers without Mn exposure. Blue-collar workers identified less odors in comparison to white-collar workers. Concentrations of previous Mn exposure >185µg/m3 years or MnB ≥15µg/L were not associated with impaired olfaction. In addition to a strong age effect, participants with lower occupational qualification identified less odors. We found no relevant association of former Mn exposure at relatively low levels with impaired olfaction. Possible neurotoxic Mn effects may not be persistent after cessation.

Hypoxia inducible factor-1 alpha and prolinhydroxlase 2 polymorphisms in patients with severe sepsis: a prospective observational trial.

BACKGROUND: Hypoxia-inducible-factor-1α (HIF-1α) and HIF-1 degrading prolyl-hydroxylases (PHD) are key regulators of the hypoxic-inflammatory response. Functionally active genetic variants in the HIF-1α (C/T; Single Nucleotide Polymorphism (SNP) rs11549465) and the PHD2 gene (EGLN1; C/T; SNP rs516651 and T/C; SNP rs480902) are associated with altered HIF-1α mRNA nuclear translocation and an altered adaptation to hypoxia. Furthermore, the HIF system is important in surviving inflammatory disorders and sepsis. Thus, we tested the hypotheses, that SNPs in the HIF-1α or PHD2 genes are (1) common in Caucasians, with 2) the HIF-1α genetic variant being associated with an altered HIF-1α mRNA expression; and 3) independent risk factors for 30-day mortality in severe sepsis. METHODS: After ethics approval, 128 septic patients (Caucasian descent) were included prospectively within 24 h after first diagnosing sepsis. Patients characteristics and severity of illness (simplified acute physiology score II), genotypes (Taqman assay), and their influence on leukocyte HIF-1α-mRNA-expression (Real-Time PCR) and 30-day mortality were determined. RESULTS: Frequencies were 0.8 % for homozygous HIF-1α TT-carriers (CT 17.6 %; CC 81.6 %), 2.5 % for homozygous PHD2 SNP rs516651 TT-allele carriers (CT 17.5 % and CC 80 %), and 9.4 % for homozygous PHD2 SNP rs480902 TT-allele carriers (CT 34.4 % and CC 56.3 %). While HIF-1α T-allele carriers had a borderline decrease in HIF-1α-mRNA-expression (p = 0.06) neither HIF-1α nor PHD2 SNPs were (independent) risk factors for 30-day mortality. CONCLUSIONS: Genetic variants in HIF-1α and PHD2 genes exist in Caucasians but do not appear to alter 30-day mortality in sepsis.