LINE-1 methylation in leukocyte DNA, interaction with phosphatidylethanolamine N-methyltransferase variants and bladder cancer risk

Amaral, André F.S.; Tajuddin, Salman Muhammad; Fernández, Agustín F.; Chanock, Stephen J.; Silverman, Debra T.; Tardón, Adonina; Carrato, Alfredo; García Closas, Montserrat; Jackson, Brian P.; Toraño, Estela; Márquez, Miriam; González Urdinguio, Rocío; García Closas, Reina; Rothman, Nathaniel; Kogevinas, Manolis; Real, Francisco X.; Fernández Fraga, Mario; Malats i Riera, Núria

doi:http://dx.doi.org/10.1038/bjc.2014.67

LINE-1 methylation in leukocyte DNA, interaction with phosphatidylethanolamine N-methyltransferase variants and bladder cancer risk

Citation

Tajuddin SM, Amaral AF, Fernández AF, Chanock S, Silverman DT, Tardón A et al. LINE-1 methylation in leukocyte DNA, interaction with phosphatidylethanolamine N-methyltransferase variants and bladder cancer risk. British Journal of Cancer. 2014;(110):2123-30. DOI: 10.1038/bjc.2014.67

Abstract

Background: Aberrant global DNA methylation is shown to increase cancer risk. LINE-1 has been proven a measure of global DNA methylation. The objectives of this study were to assess the association between LINE-1 methylation level and bladder cancer risk and to evaluate effect modification by environmental and genetic factors. Methods: Bisulphite-treated leukocyte DNA from 952 cases and 892 hospital controls was used to measure LINE-1 methylation level at four CpG sites by pyrosequencing. Logistic regression model was fitted to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Interactions between LINE-1 methylation levels and environmental and genetic factors were assessed. Results: The risk of bladder cancer followed a nonlinear association with LINE-1 methylation. Compared with subjects in the middle tertile, the adjusted OR for subjects in the lower and the higher tertiles were 1.26 (95% CI 0.99–1.60, P=0.06) and 1.33 (95% CI 1.05–1.69, P=0.02), respectively. This association significantly increased among individuals homozygous for the major allele of five single-nucleotide polymorphisms located in the phosphatidylethanolamine N-methyltransferase gene (corrected P-interaction<0.05). Conclusions: The findings from this large-scale study suggest that both low and high levels of global DNA methylation are associated with the risk of bladder cancer.