摘要：AbstractBackgroundDNA methylation (DNAm) may contribute to processes that underlie associations between air pollution and poor health. Therefore, our objective was to evaluate associations between DNAm and ambient concentrations of particulate matter (PM) ≤2.5, ≤10, and 2.5–10 μm in diameter (PM2.5; PM10; PM2.5–10).MethodsWe conducted a methylome-wide association study among twelve cohort- and race/ethnicity-stratified subpopulations from the Women's Health Initiative and the Atherosclerosis Risk in Communities study (n = 8397; mean age: 61.5 years; 83% female; 45% African American; 9% Hispanic/Latino American). We averaged geocoded address-specific estimates of daily and monthly mean PM concentrations over 2, 7, 28, and 365 days and 1 and 12 months before exams at which we measured leukocyte DNAm in whole blood. We estimated subpopulation-specific, DNAm-PM associations at approximately 485,000 Cytosine-phosphate-Guanine (CpG) sites in multi-level, linear, mixed-effects models. We combined subpopulation- and site-specific estimates in fixed-effects, inverse variance-weighted meta-analyses, then for associations that exceeded methylome-wide significance and were not heterogeneous across subpopulations (P −7;PCochran's Q > 0.10), we characterized associations using publicly accessible genomic databases and attempted replication in the Cooperative Health Research in the Region of Augsburg (KORA) study.ResultsAnalyses identified significant DNAm-PM associations at three CpG sites. Twenty-eight-day mean PM10was positively associated with DNAm at cg19004594 (chromosome 20;MATN4;P = 3.33 × 10−8). One-month mean PM10and PM2.5–10were positively associated with DNAm at cg24102420 (chromosome 10;ARPP21;P = 5.84 × 10−8) and inversely associated with DNAm at cg12124767 (chromosome 7;CFTR;P = 9.86 × 10−8). The PM-sensitive CpG sites mapped to neurological, pulmonary, endocrine, and cardiovascular disease-related genes, but DNAm at those sites was not associated with gene expression in blood cells and did not replicate in KORA.ConclusionsAmbient PM concentrations were associated with DNAm at genomic regions potentially related to poor health among racially, ethnically and environmentally diverse populations of U.S. women and men. Further investigation is warranted to uncover mechanisms through which PM-induced epigenomic changes may cause disease.Highlights•DNA methylation (DNAm) may underlie processes linking air pollution and poor health•We conducted a methylome-wide association study of 8,397 women and men with estimates of PM2.5, PM10, and PM2.5-10•Mid-duration PM10and PM2.5-10were associated with methylation at three CpG sites, but associations did not replicate•The three PM-sensitive CpG sites mapped to neurological, pulmonary, endocrine, and cardiovascular-disease related genes
关键词：AbbreviationsAAAfrican American;AVannual visit;ARICAtherosclerosis Risk in Communities;AS311Ancillary Study 311;AQSUnited States Environmental Protection Agency Air Quality System;BAA23Broad Agency Award 23;CIconfidence interval;CpGCytosine-phosphate-Guanine;CTClinical Trial;DNAmdeoxyribonucleic acid methylation;CVDcardiovascular disease;EAEuropean American;eFORGEFunctional element Overlap analysis of Regions;EMPCEpigenetic Mechanisms of PM-Mediated CVD Risk;FDRfalse discovery rate;GTPGrady Trauma Project;GWASgenome-wide association study;HLAHispanic/Latino American;KORACooperative Health Research in the Region Augsburg study;LLSLong Life Study;LMMlinear mixed models;MESAMulti-Ethnic Study of Atherosclerosis;MICEmultiple imputation by chained equations;MWASmethylome-wide association study;NAAQSNational Ambient Air Quality Standards;OSObservational Study;PEprediction error;PM10PM < 10 μm in diameter;PM2.5PM < 2.5 μm in diameter;PM2.5–10PM > 2.5 and <10 μm in diameter;QQquantile-quantine;RMSSroot mean square standardized;SDstandard deviation;SEstandard error;SPEstandardized prediction error;WHIWomen's Health Initiative;Particulate matter;DNA methylation;Epigenetics;Air pollution;Epigenome-wide association study
