Aristolochic acid exposure in Romania and implications for renal cell carcinoma

Background: Aristolochic acid (AA) is a nephrotoxicant associated with AA nephropathy (AAN) and upper urothelial tract cancer (UUTC). Whole-genome sequences of 14 Romanian cases of renal cell carcinoma (RCC) recently exhibited mutational signatures consistent with AA exposure, although RCC had not been previously linked with AAN and AA exposure was previously reported only in localised rural areas. Methods: We performed mass spectrometric measurements of the aristolactam (AL) DNA adduct 7-(deoxyadenosin-N6-yl) aristolactam I (dA-AL-I) in nontumour renal tissues of the 14 Romanian RCC cases and 15 cases from 3 other countries. Results: We detected dA-AL-I in the 14 Romanian cases at levels ranging from 0.7 to 27 adducts per 108 DNA bases, in line with levels reported in Asian and Balkan populations exposed through herbal remedies or food contamination. The 15 cases from other countries were negative. Interpretation: Although the source of exposure is uncertain and likely different in AAN regions than elsewhere, our results demonstrate that AA exposure in Romania exists outside localised AAN regions and provide further evidence implicating AA in RCC

Sex specific associations in genome wide association analysis of renal cell carcinoma.

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC

Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.

BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13). CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk

Unternehmensstrategien und Verbraucherverhalten unter marktbasierter Nachhaltigkeitspolitik

This dissertation studies different approaches to sustainability regulation. The author evaluates the effectiveness of several policy measures in achieving their objective and discusses potential unintended side-effects. Both depend on strategic firm behavior and consumer sensitivity. Chapter II considers the impact of fuel taxes on the fuel efficiency of new automobiles. The results rely on exhaustive consumer-level data of French automobile purchases; the author estimates the parameters of automobile demand using a nested logit model accounting for heterogeneity of consumer groups. The estimated parameters are used to predict the impact of two hypothetical changes in fuel taxes. The results show that new vehicle purchases react very little to changes in fuel tax and the impact of the examined fuel tax policies is economically small. Chapter III studies the strategic interactions between two sustainability labels competing for firms to offer their products: it shows why the industry has an interest to introduce its own label. The results rely on a model of oligopolistic firms offering several horizontally (between firms) and vertically (between label qualities) differentiated products. These firms interact with two labeling organizations that pursue different objectives: a for-profit label and an industry standard maximizing joint firm profit. The results show that the industry benefits from introducing an industry standard that reduces competition by segmenting the market; by contrast, a social planner maximizes consumer welfare and total social welfare by maximizing the number of labeled goods. Horizontal differentiation plays a key role for the final market outcome. Chapter IV measures the magnitude of fixed transaction costs in European emissions trading. Transaction costs are defined in a broad sense as monetary and non-monetary frictions from certificate trading of firms. The results rely on plant-level administrative data from European emissions trading; the author estimates the distribution of fixed transaction costs arising from the use of ``normal'' European certificates, on the one hand, and international offset certificates, on the other hand. The results show that for most firms, the bulk of transaction costs stems from market participation in general rather than from the use of international certificates. The magnitude of transaction costs is such that a fifth of all firms does not participate in profitable offset trading. Chapter V studies whether European emissions trading has led to a displacement of European carbon emissions to other parts of the world (``carbon leakage''), both via relocation and via loss of market shares to foreign competitors. A literature survey reveals different approaches to identify carbon leakage empirically. This chapter's results rely on a combination of sector-level trade data and plant-level data from European emissions trading; using various ways of defining both outcome and stringency of environmental policy, the author finds no evidence of carbon leakage.Diese Dissertation untersucht unterschiedliche Ansätze zur Nachhaltigkeitsregulierung. Die Autorin bewertet die Wirksamkeit von Politikmaßnahmen sowie potenzielle unbeabsichtigte Nebenwirkungen. Beide hängen vom strategischen Verhalten von Unternehmen sowie der Sensitivität der Verbraucher ab. Kapitel II betrachtet die Auswirkung von Treibstoffsteuern auf die Kraftstoffeffizienz von neuen Automobilen. Die Ergebnisse beruhen auf Verbraucherdaten über französischen Automobilkäufe; die Autorin schätzt die Parameter der Automobilnachfrage mit einem Nested Logit Modell, das die Heterogenität von Verbrauchergruppen berücksichtigt. Die geschätzten Parameter werden verwendet, um die Auswirkung von zwei hypothetischen Änderungen der Treibstoffsteuer zu berechnen. Die Ergebnisse zeigen, dass neue Fahrzeugkäufe sehr wenig auf Änderungen der Treibstoffsteuer reagieren und die Auswirkungen der untersuchten Steuerreformen wirtschaftlich vernachlässigbar sind. Kapitel III untersucht die strategischen Interaktionen zwischen zwei Nachhaltigkeitslabels im Kaffeemarkt: es zeigt, warum die Röstereibranche ein Interesse daran hat, ihr eigenes Label einzuführen. Die Ergebnisse beruhen auf einem Modell mit Firmen im Oligopol, die mehrere horizontal (zwischen Firmen) und vertikal (zwischen Labelqualitäten) differenzierte Produkte anbieten. Diese Unternehmen interagieren mit zwei Labelorganisationen, die unterschiedliche Ziele verfolgen: ein profitorientierter Lizensierer und ein Industriestandard, der den gemeinsamen Unternehmensgewinn maximiert. Die Ergebnisse zeigen, dass ein Industriestandard immer versucht, den Wettbewerb durch Segmentierung des Marktes zu reduzieren. Im Gegensatz dazu maximiert ein sozialer Planer die gesamtgesellschaftliche Wohlfahrt durch die Maximierung der Zahl der gelabelten Produkte. Die horizontale Differenzierung spielt eine entscheidende Rolle für das Marktergebnis. Kapitel IV misst Transaktionskosten im europäischen Emissionshandel. Transaktionskosten werden hier im weiten Sinne als monetäre und nicht monetäre Aufwände von Firmen im Zertifikatshandel definiert. Die Ergebnisse beruhen auf administrativen Daten des europäischen Emissionshandels; die Autorin schätzt die Verteilung der fixen Transaktionskosten, die sich aus der Verwendung von "normalen" europäischen Zertifikaten einerseits und internationalen Offsetzertifikaten andererseits ergeben. Die Ergebnisse zeigen, dass für die meisten Unternehmen der Großteil der Transaktionskosten von der Marktbeteiligung im Allgemeinen und nicht von der Verwendung internationaler Offsetzertifikate stammt. Die Größenordnung der Transaktionskosten ist so, dass ein Fünftel aller Firmen nicht am gewinnbringenden Offsethandel teilnimmt. Kapitel V untersucht, ob der europäische Emissionshandel zu einer Verschiebung der europäischen CO2-Emissionen in andere Teile der Welt geführt hat ("carbon leakage"), sowohl durch Verlagerung der Produktion als auch durch Verlust von Marktanteilen an ausländische Wettbewerber. Eine Literaturrecherche zeigt verschiedene Ansätze zur Identifizierung von carbon leakage in den Daten. Die Ergebnisse dieses Kapitels beruhen auf einer Kombination von Handelsdaten und Daten aus dem europäischen Emissionshandel; mit verschiedenen Definitionen der Ergebnisvariablen sowie der Emissionskosten, findet die Autorin keine Hinweise auf carbon leakage