Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study

Abstract

BACKGROUND: The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals. OBJECTIVES: We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles. We also evaluated the implication of findings to relevant methylation pathways and the potential contribution of Cd exposure from smoking to explain the association between smoking and site-specific DNAm. METHODS: We conducted an epigenome-wide association study of urine Cd and self-reported smoking (current and former vs. never, and cumulative smoking dose) with blood DNAm in 790,026 CpGs (methylation sites) measured with the Illumina Infinium Human MethylationEPIC (Illumina Inc.) platform in 2,325 adults 45-74 years of age who participated in the Strong Heart Study in 1989-1991. In a mediation analysis, we estimated the amount of change in DNAm associated with smoking that can be independently attributed to increases in urine Cd concentrations from smoking. We also conducted enrichment analyses and in silico protein-protein interaction networks to explore the biological relevance of the findings. RESULTS: At a false discovery rate (FDR)-corrected level of 0.05, we found 6 differentially methylated positions (DMPs) for Cd; 288 and 17, respectively, for current and former smoking status; and 77 for cigarette pack-years. Enrichment analyses of these DMPs displayed enrichment of 58 and 6 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene sets, respectively, including biological pathways for cancer and cardiovascular disease. In in silico protein-to-protein networks, we observed key proteins in DNAm pathways directly and indirectly connected to Cd-and smoking-DMPs. Among DMPs that were significant for both Cd and current smoking (annotated to PRSS23, AHRR, F2RL3, RARA, and 2q37.1), we found statistically significant contributions of Cd to smoking-related DNAm. CONCLUSIONS: Beyond replicating well-known smoking epigenetic signatures, we found novel DMPs related to smoking. Moreover, increases in smoking-related Cd exposure were associated with differential DNAm. Our integrative analysis supports a biological link for Cd and smoking-associated health effects, including the possibility that Cd is partly responsible for smoking toxicity through epigenetic changes.

Review of cadmium exposure and smoking‐independent effects on atherosclerotic cardiovascular disease in the general population

“…Women with high levels of B‐Cd (>5μg/L vs. <5μg/L) showed a clear indication of oxidative stress in terms of increased plasma levels of malondialdehyde [68]. In a population study, U‐Cd was associated with the same and other markers of oxidative stress [69]. Hence, these data support an association between Cd exposure and oxidation of LDL cholesterol.…”

Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects

“…Replication was pursued in two independent samples, the first included 2325 American Indian participants from the Strong Heart Study [ 28 ], and the second included 1100 African-American participants in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. A recent study in the SHS sample by Domingo-Relloso et al [ 9 ] analyzed EPIC array profiles of whole blood samples for smoke exposure in connection with cadmium levels in urine and also identified novel smoking-DMPs. In addition to the distinct ancestry, this cohort also has a higher proportion of smokers, and furthermore one of the leading causes of death for American Indians is CVD, for which smoking is a risk factor.…”

Dissecting the Epigenomic Differences between Smoking and Nicotine Dependence in a Veteran Cohort

“…We detected three DMS in the PRSS23 gene (cg14391737, cg00475490 and cg11660018), which encodes a member of the trypsin family of serine proteases. Methylation changes in PRSS23 gene was recently associated with cadmium and smoking exposure in a EWAS study of the Strong Heart Study (38).…”

“…An additional ND-specific DMS was located in the ANPEP gene. ANPEP is a diabetes risk gene (48), which was recently identified as SSassociated in a EWAS examining the effects of cadmium and smoking in the Strong Heart Study cohort in blood tissue (38). SLC29A1 mediates uptake of nucleosides and is not correlated to smoking in EWAS.…”