Genetic variants, PM2.5 exposure level and global DNA methylation level: A multi-center population-based study in Chinese.

Global DNA methylation levels can be determined by environmental and genetic factors. There are emerging evidences that methylation status can be modified as exposed to environmental factors such as PM2.5, but the genetic determinants are still largely unknown. To explore whether genetic variants contribute to global DNA methylation levels with consideration of environmental exposures, we systematically evaluated the association between genetic variants and global DNA methylation levels in 301 subjects from three cities in southern, central and northern China with different PM2.5 exposure levels (Zhuhai, Wuhan and Tianjin, respectively). Personal 24-h PM2.5 exposure levels and global DNA methylation levels for each subject were evaluated. Using Illumina Human Exome BeadChip, 241,305 SNVs was genotyped and assessed for their association with global DNA methylation levels. We found that after adjusting for age, gender, PM2.5 exposure level, pack-years of smoking and BMI, 14 SNVs were consistently associated with global DNA methylation levels with pooled P≤1.00×10-4 after meta-analysis of three cohorts, in which 8 SNVs together with age were independent factors modifying global DNA methylation levels. Joint analysis of these identified SNVs showed a significant allele-dosage association between the number of variants and global DNA methylation levels (P=1.82×10-23). In particular, we detected a significant multiplicative interaction between rs4344916 on chromosome 2p22.3 and PM2.5 exposure on global DNA methylation level (P=0.0095). Our findings indicate that genetic variants alone or in combination with PM2.5 play an important role in modifying individual global DNA methylation levels.