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