Schenk, Maryjean

Abstract Background Previous epidemiologic findings suggest an association between exposure to trichloroethylene (TCE), a chlorinated solvent primarily used for vapor degreasing of metal parts, and non-Hodgkin lymphoma (NHL). Objectives We investigated the association between occupational TCE exposure and NHL within a population-based case–control study using detailed exposure assessment methods. Methods Cases (n = 1,189; 76% participation rate) and controls (n = 982; 52% participation rate) provided information on their occupational histories and, for selected occupations, on possible workplace exposure to TCE using job-specific interview modules. An industrial hygienist assessed potential TCE exposure based on this information and a review of the TCE industrial hygiene literature. We computed odds ratios (ORs) and 95% confidence intervals (CIs) relating NHL and different metrics of estimated TCE exposure, categorized using tertiles among exposed controls, with unexposed subjects as the reference group. Results We observed associations with NHL for the highest tertiles of estimated average weekly exposure (23 exposed cases; OR = 2.5; 95% CI, 1.1–6.1) and cumulative exposure (24 exposed cases; OR = 2.3; 95% CI, 1.0–5.0) to TCE. Tests for trend with these metrics surpassed or approached statistical significance (p-value for trend = 0.02 and 0.08, respectively); however, we did not observe dose–response relationships across the exposure levels. Overall, neither duration nor intensity of exposure was associated with NHL, although we observed an association with the lowest tertile of exposure duration (OR = 2.1; 95% CI, 1.0–4.7). Conclusions Our findings offer additional support for an association between high levels of exposure to TCE and increased risk of NHL. However, we cannot rule out the possibility of confounding from other chlorinated solvents used for vapor degreasing and note that our exposure assessment methods have not been validated.

Abstract Caspases play a critical role in regulation of apoptosis, cell differentiation, inflammation, and innate immunity, and several are mutated or have altered expression in non-Hodgkin lymphoma (NHL). To study the impact of genetic variation in caspases on NHL risk, we analyzed tag single nucleotide polymorphisms (SNPs) in 12 caspase and related genes in 3 population-based case-control studies (1946 cases and 1808 controls). Gene-based analysis, adjusting for the number of tagSNPs genotyped in each gene, showed significant associations for CASP8, CASP9, and CASP1. SNP-based analysis showed that CASP8 rs6736233 (odds ratio (OR) CG = 1.21; ORCC = 2.13; P trend = .011); CASP9 rs4661636 (ORCT = 0.89; ORTT = 0.77; P trend = .011); and CASP1 rs1785882 (ORAT = 1.12; ORAA = 1.30; P trend = .0054) were significantly associated with NHL risk and consistent across studies. It is noteworthy that genetic variants in CASP8 were associated with risk of all major NHL subtypes. Our findings suggest that genetic variation in caspases may play an important role in lymphomagenesis.

AbstractUnderstanding patterns of etiologic commonality and heterogeneity for non-Hodgkin lymphomas may illuminate lymphomagenesis. We present the first systematic comparison of risks by lymphoma subtype for a broad range of putative risk factors in a population-based case-control study, including diffuse large B-cell (DLBCL; N = 416), follicular (N = 318), and marginal zone lymphomas (N = 106), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; N = 133). We required at least 2 of 3 analyses to support differences in risk: (1) polytomous logistic regression, (2) homogeneity tests, or (3) dichotomous logistic regression, analyzing all 7 possible pairwise comparisons among the subtypes, corresponding to various groupings by clinical behavior, genetic features, and differentiation. Late birth order and high body mass index (≥ 35) kg/m2) increased risk for DLBCL alone. Autoimmune conditions increased risk for marginal zone lymphoma alone. The tumor necrosis factor G-308A polymorphism (rs1800629) increased risks for both DLBCL and marginal zone lymphoma. Exposure to certain dietary heterocyclic amines from meat consumption increased risk for CLL/SLL alone. We observed no significant risk factors for follicular lymphoma alone. These data clearly support both etiologic commonality and heterogeneity for lymphoma subtypes, suggesting that immune dysfunction is of greater etiologic importance for DLBCL and marginal zone lymphoma than for CLL/SLL and follicular lymphoma.

AbstractWe previously reported a lower risk of non-Hodgkin lymphoma (NHL) associated with high consumption of vitamin B6 and methionine, dietary determinants of one-carbon metabolism. Evidence has linked genetic variants involved in one-carbon metabolism to NHL. We investigated 30 polymorphisms in 18 genes for their main effect on NHL among 1141 incident cases and 949 population-based controls and examined gene-nutrient interactions in a subgroup of 386 cases and 319 controls who provided detailed food-frequency information. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for age, sex, and race. We observed a decreased risk of NHL overall with BHMT Ex8+453A>T and increased risk with CBS Ex13+41C>T, FPGS Ex15-263T>C, and SHMT1 Ex12+138C>T and Ex12+236C>T. Furthermore, significant gene-nutrient interactions limited the protective association comparing high versus low vitamin B6 to FPGS Ex15-263T>C CC (OR = 0.22; 95% CI = 0.10-0.52), MTHFS IVS2-1411T>G TT/TG (OR = 0.54; 95% CI = 0.36-0.81), and MTR Ex26-20A>G AA (OR = 0.55; 95% CI = 0.35-0.86) genotypes, and the protective association of methionine to FTHFD Ex10-40G>T GG (OR = 0.63; 95% CI = 0.44-0.91), MTHFR Ex8-62A>C CC (OR = 0.13; 95% CI = 0.04-0.39), and MTRR Ex5+136T>C TT (OR = 0.67; 95% CI = 0.47-0.97) genotypes. Warranting replication, our finding of gene-nutrient interactions in one-carbon metabolism supports their etiologic involvement in lymphomagenesis.