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Background: By-products are formed when disinfectants react with organic matter in source water. The most common class of disinfection byproducts, trihalomethanes (THMs), have been linked to bladder cancer. Several studies have shown exposure-response associations with THMs in drinking water and bladder cancer risk. Few epidemiologic studies have evaluated gene-environment interactions for total THMs (TTHMs) with known bladder cancer susceptibility variants. Objectives: In this study, we investigated the combined effect on bladder cancer risk contributed by TTHMs, bladder cancer susceptibility variants identified through genome-wide association studies, and variants in several candidate genes. Methods: We analyzed data from two large case-control studies--the New England Bladder Cancer Study (n/n = 989 cases/1,162 controls), a population-based study, and the Spanish Bladder Cancer Study (n/n = 706 cases/772 controls), a hospital-based study. Because of differences in exposure distributions and metrics, we estimated effects of THMs and genetic variants within each study separately using adjusted logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CI) with and without interaction terms, and then combined the results using meta-analysis. Results: Of the 16 loci showing strong evidence of association with bladder cancer, rs907611 at 11p15.5 [leukocyte- specific protein 1 (LSP1 region)] showed the strongest associations in the highest exposure category in each study, with evidence of interaction in both studies and in metaanalysis. In the highest exposure category, we observed OR= 1.66 (95% CI: 1.17, 2.34, p- trend = 0.005) for those with the rs907611-GG genotype and p-interaction = 0.02. No other genetic variants tested showed consistent evidence of interaction. Discussion: We found novel suggestive evidence for a multiplicative interaction between a putative bladder carcinogen, TTHMs, and genotypes of rs907611. Given the ubiquitous exposure to THMs, further work is needed to replicate and extend this finding and to understand potential molecular mechanisms. https://doi.org/10.1289/EHP9895, Introduction Worldwide, bladder cancer ranks as the ninth most common incident cancer and the 13th in mortality, with ~400,000 cases diagnosed each year. (1) Approximately 75% of incident cases occur [...]

DNA methylation plays a fundamental role in regulation of gene expression, genomic imprinting, X-chromosome inactivation, and repression of transposable elements (Jones and Liang 2009). Aberrant DNA methylation has been associated [...], BACKGROUND: Altered DNA methylation has been associated with various diseases. OBJECTIVE: We evaluated the association between levels of methylation in leukocyte DNA at long interspersed nuclear element 1 (LINE-1) and genetic and non-genetic characteristics of 892 control participants from the Spanish Bladder Cancer/EPICURO study. METHODS: We determined LINE-1 methylation levels by pyrosequencing. Individual data included demographics, smoking status, nutrient intake, toenail concentrations of 12 trace elements, xenobiotic metabolism gene variants, and 515 polymorphisms among 24 genes in the one-carbon metabolism pathway. To assess the association between LINE-1 methylation levels (percentage of methylated cytosines) and potential determinants, we estimated beta coefficients ([beta]s) by robust linear regression. RESULTS: Women had lower levels of LINE-1 methylation than men ([beta] = -0.7, p = 0.02). Persons who smoked blond tobacco showed lower methylation than nonsmokers ([beta] = -0.7, p = 0.03). Arsenic toenail concentration was inversely associated with LINE-1 methylation ([beta] = -3.6, p = 0.003). By contrast, iron ([beta] = 0.002, p = 0.009) and nickel ([beta] = 0.02, p = 0.004) were positively associated with LINE-1 methylation. Single nucleotide polymorphisms (SNPs) in DNMT3A (rs7581217per allele, [beta] = 0.3, p = 0.002), TCN2 (rs9606756-GG, [beta] = 1.9, p = 0.008; rs4820887-AA, [beta] = 4.0, p = 4.8 x [10.sup.-7]; rs9621049-TT, [beta] = 4.2, p = 4.7 x [10.sup.-9]), AS3MT (rs7085104-GG, [beta] = 0.7, p = 0.001), SLC19A1 (rs914238, TC vs. TT: |3 = 0.5 and CC vs. TT: [beta] = -0.3, global p = 0.0007) and MTHFS (rs1380642, CT vs. CC: [beta] = 0.3 and TT vs. CC; [beta] = -0.8, global p = 0.05) were associated with LINE-1 methylation. CONCLUSIONS: We identified several characteristics, environmental factors, and common genetic variants that predicted DNA methylation among study participants. KEY WORDS: DNA methylation, epigenetics, LINE-1, one-carbon metabolism gene variants, smoking, trace elements. Environ Health Perspect 121:650-656 (2013). http://dx.doi.org/10.1289/ehp.1206068 [Online 3 April 2013]