Sex-Specific Differential DNA Methylation Related to Cigarette Smoking in African Americans Open Access

Li, Weiyan (2013)

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Tobacco smoking is a leading cause of mortality and morbidity worldwide. Differential susceptibility to tobacco smoking by sex has been observed in lung cancer patients. However, how tobacco smoking exerts its harmful health effect, especially how it may affect two sexes differently, has not been well understood. DNA methylation is one major mechanism of gene expression regulation that can be modified by environmental exposures such as cigarette smoking. Previous studies have reported smoking-related changes in DNA methylation with a loci-specific resolution. However, little investigation was done on sex-specific effect of smoking on DNA methylation on autosomal sites, and X chromosome sites were routinely excluded in epigenome-wide association studies (EWAS) due to analytical difficulties. In our study, we aim to examine sex-specific effect of tobacco smoking on DNA methylation across the entire epigenome. After adjusting for age, top 5 principal components, relatedness and multiple testing we did not detect any statistically significant sexXsmoking interaction throughout autosomal CpG sites. For X chromosomal analysis, we did not detect any CpG sites that was significantly associated with current or ever smoking status after stratification by sex. However, we detected site cg12857957 located in LZTFL2 (leucine zipper transcription factor-like 1) on chromosome 3 with marginal significance in terms of sexXcurrent smoking status interaction (p value=4.74×10-6). Although further validation is needed, our results suggest that there may be a sex-specific effect of smoking related DNA methylation changes, which may partially explain the differences in susceptibility to tobacco exposure between males and females.

Table of Contents



Tobacco use associated adverse health outcomes...4

Tobacco use associated epigenetic modifications...4


Study population...8

DNA Methylation Data...8

Statistical Analysis...10


Sex-specific effect of smoking on autosomal DNAm sites...12

Sex-specific effect of smoking on X chromosome DNAm sites...15


Strengths and limitations...18

Future directions...21




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