title: LINE-1 methylation in granulocyte DNA and trihalomethane exposure is associated with bladder cancer risk.
abstract: DNA methylation changes contribute to bladder carcinogenesis. Trihalomethanes (THM), a class of disinfection by-products, are associated with increased urothelial bladder cancer (UBC) risk. THM exposure in animal models produces DNA hypomethylation. We evaluated the relationship of LINE-1 5-methylcytosine levels (LINE-1%5mC) as outcome of long-term THM exposure among controls and as an effect modifier in the association between THM exposure and UBC risk. We used a case-control study of UBC conducted in Spain. We obtained personal lifetime residential THM levels and measured LINE-1%5mC by pyrosequencing in granulocyte DNA from blood samples in 548 incident cases and 559 hospital controls. Two LINE-1%5mC clusters (above and below 64%) were identified through unsupervised hierarchical cluster analysis. The association between THM levels and LINE-1%5mC was evaluated with β regression analyses and logistic regression was used to estimate odds ratios (OR) adjusting for covariables. LINE-1%5mC change between percentiles 75(th) and 25(th) of THM levels was 1.8% (95% confidence interval (CI): 0.1, 3.4%) among controls. THM levels above vs. below the median (26 μg/L) were associated with increased UBC risk, OR = 1.86 (95% CI: 1.25, 2.75), overall and among subjects with low levels of LINE-1%5mC (n = 975), OR = 2.14 (95% CI: 1.39, 3.30), but not associated with UBC risk among subjects' high levels of LINE-1%5mC (n = 162), interaction P = 0.03. Results suggest a positive association between LINE-1%5mC and THM levels among controls, and LINE-1%5mC status may modify the association between UBC risk and THM exposure. Because reverse causation and chance cannot be ruled out, confirmation studies are warranted.
authors.affiliation: a Centre for Research in Environmental Epidemiology (CREAL) ; Barcelona , Spain.
authors.forename: Lucas A
authors.initials: LA
authors.lastname: Salas
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Villanueva
authors.forename: Salman M
authors.initials: SM
authors.lastname: Tajuddin
authors.forename: André F S
authors.initials: AF
authors.lastname: Amaral
authors.forename: Agustín F
authors.initials: AF
authors.lastname: Fernandez
authors.forename: Lee E
authors.initials: LE
authors.lastname: Moore
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.forename: Adonina
authors.initials: A
authors.lastname: Tardón
authors.forename: Consol
authors.initials: C
authors.lastname: Serra
authors.forename: Reina
authors.initials: R
authors.lastname: García-Closas
authors.forename: Xavier
authors.initials: X
authors.lastname: Basagaña
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Debra T
authors.initials: DT
authors.lastname: Silverman
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Cantor
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
mesh_terms: D044503:5-Methylcytosine / Q000097:blood; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D016000:Cluster Analysis; D019175:DNA Methylation; D004781:Environmental Exposure / Q000009:adverse effects / Q000032:analysis; D005260:Female; D006098:Granulocytes / Q000502:physiology*; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013030:Spain; D022882:Trihalomethanes / Q000032:analysis / Q000633:toxicity*; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000235:genetics; D055815:Young Adult
chemical_list: D022882:Trihalomethanes; D044503:5-Methylcytosine
keywords: %5mC; 95%, confidence intervals; DBP, Disinfection by-products; DNA methylation; LINE-1; LINE-1, Long Interspersed Element 1; OR, Odds ratio; Percentage of 5-methylcytosine, 95%, CI; SBC/EPICURO, Spanish Bladder Cancer/EPICURO Study; THM, Trihalomethanes; UBC, Urothelial bladder cancer; epigenetic repression; long interspersed nucleotide elements; trihalomethanes; urinary bladder cancer; y, years