For gene-environment interactions, the environmental “signal” in this story represents the urinary “total nicotine equivalents”, a quantitative assay for cigarettes actually smoked (which is more reliable than the patient’s estimate of their smoking history). The genetic “response” in this story involves DNA methylation, (i.e., epigenetic markers in or near genes that might be relevant to cancer or toxicity).
The impact of tobacco exposure on health varies by race and ethnicity and is closely linked to internal nicotine dose, (a marker of carcinogen uptake). [Recall that genetic differences reflect alterations in DNA sequence, whereas epigenetic differences represent chromosomal changes independent of DNA-sequence variations. “Epigenetics” has been subdivided into DNA methylation, RNA interference, histone modifications, and chromatin remodeling.] The present study [see attached] focuses on changes in DNA methylation that might be attributed to the quantifiable amount of cigarette-smoke exposure.
DNA methylation is strongly responsive to smoking status and may mediate health effects, but studies of associations with internal dose are limited. Authors carried out a white-blood-cell epigenome-wide association study (EWAS) of DNA methylation [measured using the MethylationEPIC v1.0 BeadChip (EPIC) assay] and urinary total nicotine equivalents (TNEs; a measure of nicotine uptake) — in six racial and ethnic groups across three cohorts: the
Multiethnic Cohort Study (MEC), the Singapore Chinese Health Study (SCHS), and the Southern Community Cohort Study (SCCS).
The GEITP email blog topic on 9 May 2024 was about transcriptome-wide association studies (TWASs) in 49 tissues combined. This week’s GEITP email blog topic is about white-blood-cell epigenome-wide association study (EWAS) of DNA methylation.
Worldwide, cigarette smoking is a strong risk factor for lung cancer. Epidemiologic studies have shown that risk for smoking-related lung cancer differs by race and ethnicity, even after accounting for self-reported smoking history. This interindividual variation in risk may be attributed, in part, to racial and ethnic differences in smokers’ uptake of nicotine and carcinogens from each cigarette. It has previously been shown that urinary TNE levels per cigarette were higher among African-Americans and lower among Japanese-Americans, compared to European-Americans — consistent with their corresponding higher and lower smoking-related lung cancer risk, respectively, for these groups. However, authors found that TNE-uptake-levels-per-cigarette for Native-Hawaiians and Latinos (which are similar to that of European-Americans) were not consistent with their respective higher and lower smoking-related lung cancer risk.
Several previous EWASs of smoking have involved self-reported smoking status — with the largest study across
16 epidemiologic cohorts reporting differential methylation (between current and never smokers) for >2,600 cytosine-phosphate-guanine (CpG) sites in 1,405 genes, including AHRR (aryl hydrocarbon receptor repressor), F2RL3 (F2R-like thrombin or trypsin receptor-3), and GPR15 (G-protein-coupled receptor-15). Although most of these studies were conducted in populations of mainly European ancestry, more recent EWASs in racial and ethnic minorities have replicated many of the differentially methylated sites associated with smoking status in American Indians, African Americans, and Latinos. However, the authors feel that the generalizability of these studies is still limited — due to the lack of data for many other underrepresented populations.
Furthermore, self-reported smoking status may not fully capture the effect of smoking dose on DNA methylation.
To assess the effect of smoking dose, epigenetic studies have used other measures including biomarkers of smoking (i.e., cotinine and cadmium). However, these measurements are not entirely correlated with direction of disease risks (e.g., self-reported cigarettes per day), nor do they account for interindividual differences in nicotine uptake related to smoking behavior and nicotine metabolism (e.g., cotinine). Importantly, internal smoking dose as measured by urinary TNEs [the sum of major metabolites nicotine, cotinine, trans-3’-hydroxycotinine (3-HCOT), and their glucuronides and nicotine N-oxide] estimates 80%–90% of nicotine uptake and, thus, is the more reliable measure of dose.
In a previous EWAS of internal smoking dose in three racial and ethnic groups (Japanese Americans, Native Hawaiians, and European Americans; N = 612 individuals), it was found that increasing urinary nicotine equivalents
(sum of nicotine, cotinine, 3-HCOT, and their glucuronides) were associated with higher DNA methylation at eight CpG sites in Native Hawaiians, but NOT in European Americans or Japanese-Americans. Because this provided evidence of potential variation across race and ethnicity, authors felt that further investigation is needed to better explain the transethnic effects of smoking dose on the epigenome.
In the Multiethnic Cohort Study (N = 1,994), TNEs were associated with differential methylation at 408 CpG sites across >250 genomic regions (P <9.0 x 10–8). The top significant sites were associated with the genes AHRR (aryl hydrocarbon receptor repressor), F2RL3 (F2R-like thrombin or trypsin receptor 3), RARA (retinoic acid receptor-alpha), GPR15 (G-protein-coupled receptor-15), PRSS23 (serine protease-23), and 2q37.1 (nearest to NIDDM1; non-insulin-dependent diabetes mellitus, type 2) — all of which had decreasing methylation associated with increasing TNEs. Authors identified 45 novel CpG sites, of which 42 were unique to the EPIC array and eight annotated to genes not previously linked with smoking-related DNA methylation. The most significant signal in a novel gene was cg03748458 in MIR383;SGCZ (microRNA383). Fifty-one of the 408 discovery sites were validated in the Singapore Chinese Health Study (N = 340) and the Southern Community Cohort Study (N = 394) (Bonferroni corrected P <1.2 x 10–4). Significant heterogeneity by race and ethnicity was detected for CpG sites in MYO1G (myosin-1G located at Chr 7p13) and CYTH1 (cytohesin-1). In or near these two genes, TNEs were significantly associated between cigarettes per day and DNA methylation at 15 sites. Authors believe that their multiethnic study [see attached] highlights the trans-ethnic and ethnic-specific methylation associations with internal nicotine dose — as a strong predictor of smoking-related morbidities. DwN Am J Hum Genet 7 Mar 2024; 111: 456-472