Environmental Etiology of Polycythemia Vera, Essential Thrombocythemia and Primary Myelofibrosis: A Case-Control Study in Northeast Pennsylvania

Objectives The etiology of a rare category of myeloproliferative neoplasms (MPN), bone marrow diseases with an excess of blood cells, is currently unknown. An MPN cluster in Northeastern Pennsylvania allowed investigation of effects of environmental risk factors and to assess the potential for gene-environment interactions. Since no strong hypothesis could be advanced, we focused on known occupational and environmental carcinogens, especially those previously implicated in blood tumors, in our investigation (e.g. benzene, polycyclic aromatic hydrocarbons (PAH), aromatic & heterocyclic amines). The aims of this dissertation were to evaluate the associations between lifestyle and environmental risk factors for the most common myeloproliferative neoplasms (MPNs) (PV, ET, and PMF), with and without JAK2 V617FV617F. We also explore an interaction between known susceptibility genotypes for a subset of cases and controls and potential mutagenic chemical exposures, including PAHs. Methods This 2011 population based case-control study assessed residential, smoking and dietary history by telephone interview in Schuylkill, Luzerne and Carbon counties in Pennsylvania. Cases (n=55) were identified from the Pennsylvania cancer registry and a previous MPN study in Pennsylvania. Controls (n=473) were selected based on eligibility screening using random digit dialing. Blood samples for genotyping were collected from a subset of 31 cases and 292 controls. Results Cases were older (median age=71 vs. 61years) and more likely to be male (49% vs. 39%) compared to controls but otherwise demographically similar. We found no relationships between MPNs and smoking history, residential history, diet, and lifestyle behaviors with presumed exposure to aromatic and heterocyclic amines. After studying the main effects of 14 environmentally sensitive genes, we found that only the NAT2, CYP1A2, GSTA1, and GSTM3 variants were associated with an average of 3-to 5-fold increased odds of having an MPN. Conclusion While these results do not confirm a gene environment interaction effect for one specific chemical, the findings encourage further exploration of the interaction hypothesis with respect to NAT2, GST, and CYP gene biological pathway and chemical exposures. These same genes appear to be implicated in cases with the somatic mutation believed to be involved in the etiology of MPNs, especially PV. Although no association was found between exposures related to aromatic and heterocyclic amines and MPNs, our findings suggest that genotypes that modify the toxicity of these exposures may play a role in MPNs.Ph.D., Public Health -- Drexel University, 201

The Role of Genotypes That Modify the Toxicity of Chemical Mutagens in the Risk for Myeloproliferative Neoplasms

Background: The etiology of myeloproliferative neoplasms (MPN) (polycythemia vera; essential thrombocythemia; primary myelofibrosis) is unknown, however they are associated with a somatic mutation—JAK2 V617F—suggesting a potential role for environmental mutagens. Methods: We conducted a population-based case-control study in three rural Pennsylvania counties of persons born 1921–1968 and residing in the area between 2000–2008. Twenty seven MPN cases and 292 controls were recruited through random digit dialing. Subjects were genotyped and odds ratios estimated for a select set of polymorphisms in environmentally sensitive genes that might implicate specific environmental mutagens if found to be associated with a disease. Results: The presence of NAT2 slow acetylator genotype, and CYP1A2, GSTA1, and GSTM3 variants were associated with an average 3–5 fold increased risk. Conclusions: Exposures, such as to aromatic compounds, whose toxicity is modified by genotypes associated with outcome in our analysis may play a role in the environmental etiology of MPNs

A Multidisciplinary Investigation of a Polycythemia Vera Cancer Cluster of Unknown Origin

Cancer cluster investigations rarely receive significant public health resource allocations due to numerous inherent challenges and the limited success of past efforts. In 2008, a cluster of polycythemia vera, a rare blood cancer with unknown etiology, was identified in northeast Pennsylvania. A multidisciplinary group of federal and state agencies, academic institutions, and local healthcare providers subsequently developed a multifaceted research portfolio designed to better understand the cause of the cluster. This research agenda represents a unique and important opportunity to demonstrate that cancer cluster investigations can produce desirable public health and scientific outcomes when necessary resources are available

Decoding the massive genome of loblolly pine using haploid DNA and novel assembly strategies

BACKGROUND: The size and complexity of conifer genomes has, until now, prevented full genome sequencing and assembly. The large research community and economic importance of loblolly pine, Pinus taeda L., made it an early candidate for reference sequence determination. RESULTS: We develop a novel strategy to sequence the genome of loblolly pine that combines unique aspects of pine reproductive biology and genome assembly methodology. We use a whole genome shotgun approach relying primarily on next generation sequence generated from a single haploid seed megagametophyte from a loblolly pine tree, 20-1010, that has been used in industrial forest tree breeding. The resulting sequence and assembly was used to generate a draft genome spanning 23.2 Gbp and containing 20.1 Gbp with an N50 scaffold size of 66.9 kbp, making it a significant improvement over available conifer genomes. The long scaffold lengths allow the annotation of 50,172 gene models with intron lengths averaging over 2.7 kbp and sometimes exceeding 100 kbp in length. Analysis of orthologous gene sets identifies gene families that may be unique to conifers. We further characterize and expand the existing repeat library based on the de novo analysis of the repetitive content, estimated to encompass 82% of the genome. CONCLUSIONS: In addition to its value as a resource for researchers and breeders, the loblolly pine genome sequence and assembly reported here demonstrates a novel approach to sequencing the large and complex genomes of this important group of plants that can now be widely applied

Meta-Analysis of Heterogeneity in the Effects of Wildfire Smoke Exposure on Respiratory Health in North America

Epidemiological studies consistently show an association between wildfire-related smoke exposure and adverse respiratory health. We conducted a systematic review of evidence in published literature pertaining to heterogeneity of respiratory effects from this exposure in North America. We calculated the within-study ratio of relative risks (RRR) and 95% confidence intervals (CI) to examine heterogeneity of effect by population subgroup, and then summarized the RRRs using meta-analysis. We found evidence of a greater effect of wildfire smoke on respiratory health among females relative to males for asthma (RRR: 1.035, 95% CI: 1.013, 1.057) and chronic obstructive pulmonary disease (RRR: 1.018, 95% CI: 1.003, 1.032). There was evidence of a lower relative risk for all respiratory outcomes among youth compared to adults (RRR: 0.976, 95% CI: 0.963, 0.989). We also found wildfire smoke effects stratified by income, race, education, health behaviors, access to care, housing occupancy, geographic region, and urban/rural status. However, data were insufficient to quantitatively evaluate effect modification by these characteristics. While we found evidence that certain demographic subgroups of the population are more susceptible to respiratory health outcomes from wildfire smoke, it is unclear whether this information can be used to inform policy aimed to reduce health impact of wildfires

South Philadelphia passive sampler and sensor study

<p>From June 2013 to March 2015, in total 41 passive sampler deployments of 2 wk duration each were conducted at 17 sites in South Philadelphia, PA, with results for benzene discussed here. Complementary time-resolved measurements with lower cost prototype fenceline sensors and an open-path ultraviolet differential optical absorption spectrometer were also conducted. Minimum passive sampler benzene concentrations for each sampling period ranged from 0.08 ppbv to 0.65 ppbv, with a mean of 0.25 ppbv, and were negatively correlated with ambient temperature (–0.01 ppbv/°C, <i>R</i>² = 0.68). Co-deployed duplicate passive sampler pairs (<i>N</i> = 609) demonstrated good precision with an average and maximum percent difference of 1.5% and 34%, respectively. A group of passive samplers located within 50 m of a refinery fenceline had a study mean benzene concentration of 1.22 ppbv, whereas a group of samplers located in communities >1 km distant from facilities had a mean of 0.29 ppbv. The difference in the means of these groups was statistically significant at the 95% confidence level (<i>p</i> < 0.001). A decreasing gradient in benzene concentrations moving away from the facilities was observed, as was a significant period-to-period variation. The highest recorded 2-wk average benzene concentration for the fenceline group was 3.11 ppbv. During this period, time-resolved data from the prototype sensors and the open-path spectrometer detected a benzene signal from the west on one day in particular, with the highest 5-min path-averaged benzene concentration measured at 24 ppbv.</p> <p><i>Implications</i>: Using a variation of EPA’s passive sampler refinery fenceline monitoring method, coupled with time-resolved measurements, a multiyear study in South Philadelphia informed benzene concentrations near facilities and in communities. The combination of measurement strategies can assist facilities in identification and mitigation of emissions from fugitive sources and improve information on air quality complex air sheds.</p

A Multidisciplinary Investigation of a Polycythemia Vera Cancer Cluster of Unknown Origin

Cancer cluster investigations rarely receive significant public health resource allocations due to numerous inherent challenges and the limited success of past efforts. In 2008, a cluster of polycythemia vera, a rare blood cancer with unknown etiology, was identified in northeast Pennsylvania. A multidisciplinary group of federal and state agencies, academic institutions, and local healthcare providers subsequently developed a multifaceted research portfolio designed to better understand the cause of the cluster. This research agenda represents a unique and important opportunity to demonstrate that cancer cluster investigations can produce desirable public health and scientific outcomes when necessary resources are available