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UBC Theses and Dissertations

Interactions between cytochrome P450 genetic polymorphisms and plasma organochlorines in non-Hodgkin lymphoma Dhalla, Anar


Following World War II, the production of chlorine-containing organic molecules known as organochlorines (OCs) became commonplace. Although heightened regulation has since occurred in Canada, OCs continue to pose health and environmental concerns due to their persistence and ongoing use elsewhere. To date, the largest study assessing the association between plasma OCs and non-Hodgkin lymphoma (NHL) was conducted in British Columbia (BC) between 2000 and 2004. Eight hundred twenty-eight newly diagnosed NHL cases were ascertained from the BC Cancer Registry and 848 population controls were randomly obtained from the BC Ministry of Health Client Registry. Significant associations were observed between NHL and 14 individual organochlorines. Because the effects of OCs on NHL may be modified by an individual’s genetic makeup, gene-environment (GxE) interactions between OCs and cytochrome P450 (CYP) genes were examined here, using data from the subset of participants of European ethnic origin (“Europeans”) in the BC study. CYPs were chosen because they are involved in the metabolism of chemicals, including some OCs. First, the effects of the OCs were re-evaluated in Europeans only, as this was the analytic group in subsequent genetic analyses. Significant trends were noted for polychlorinated biphenyls (PCBs) 153, 180, 187, summed PCBs (total, dioxin-like, non-dioxin-like), beta-hexachlorocyclohexane (β-HCCH), hexachlorobenzene (HCB), mirex, trans-nonachlor, and oxychlordane. Significance was maintained after controlling for multiple testing for PCB-187, total summed PCBs, β-HCCH, HCB, trans-nonachlor, and oxychlordane. No significant trends were found for PCB-28, 99, 105, 118, 138, 156, 170, 183, cis-nonachlor, p, p’-DDT, or p, p’-DDE. Secondly, 129 single nucleotide polymorphisms (SNPs) in 18 CYP genes were selected for study. Significant trends were noted for rs743572 (CYP17A1) and rs1322179 (CYP2C19). Significance was not maintained after controlling for multiple testing. Two SNPs, rs9332197 and rs10509679 (CYP2C9), in the same gene cluster as CYP2C19 were of borderline non-significance. A significant GxE interaction was found between rs743572 and mirex, even after controlling for multiple testing. The increased risk of NHL conferred by higher mirex levels is lessened in minor allele homozygotes of rs743572. As CYP17A1 is involved in steroid metabolism, these results suggest the involvement of hormonal modulation in NHL risk.

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