Integrative methylation profiling uncovers IL10RB hypomethylation as a mediator between environmental heavy metal exposure and lung cancer risk

Residents living in areas exposed to environmental hazards, such as abandoned mines and refineries, are hypothesized to exhibit distinct omics profiles compared with those in unaffected regions. In this article, we aimed to identify the differentially methylated regions (DMRs) affected by these hazards using Forensic Research via Omics Markers in Environmental Health Vulnerable Areas (FROM) cohort. We then evaluated the potential effects of these DMRs on 23 human diseases by using data from the Korean Genome and Epidemiology Study (KoGES) cohort, which included 79,294 participants. We conducted a DMR analysis using reduced representation bisulfite sequencing on peripheral blood mononuclear cells samples, and employed the Meet-in-the-Middle analysis to identify biomarkers that enable more precise and biologically meaningful interpretation with the forensic research via FROM cohort, and significant findings were further validated with one-sample Mendelian Randomization (MR) method. To explore relationships between these biomarkers and 23 diseases, the two-sample MR approach within the KoGES cohort was conducted. Our findings indicate that long-term exposure to heavy metals in environmentally vulnerable areas alters methylation patterns, potentially affecting disease risk. Notably, a DMR in the IL10RB gene region was identified, where hypomethylation was associated with the development of lung cancer (P = 1.92 × 10^-3, β = -1.7830). This study highlights the potential epigenetic impact of environmental exposures and underscores the importance of uncovering biomarkers linking exposure to disease outcome.