Table 3.
Incident CVD cases per 100,000 person-years for the doubling of urinary arsenic levels not attributable (direct effect) and attributable (indirect effect) to changes in DNA methylation (90th vs. 10th percentile) for each CpG site in separate models. The sum of the direct and indirect effect represents the total effect for a doubling of urinary arsenic in CVD incidence.
| Mediated effects |
|||||||
|---|---|---|---|---|---|---|---|
| CpG | Chr | Gene | Function | Location | Cases attributable to a doubling of urinary As (95% CI) (direct effect) | Cases attributable to a doubling of urinary As through DNAm (95% CI) (indirect effect) | % cases attributable to a doubling of urinary As explained by DNAm (95% CI) |
| cg19693031 | 1 | TXNIP | Binding partner for redox signaling protein thioredoxin | 3’UTR | 137.6 (−61.2, 335.9) | 95.7 (43.8, 158.8) | 41.0 (14.5, 183.0) |
| cg05779585 | 8 | LOC286083 | Unknown function | Intergenic | 200.2 (5.8, 394.2) | 69.2 (5.8, 161.2) | 25.7 (1.8, 83.6) |
| cg03497652 | 16 | ANKS3 | Vasopressin signaling in the kidney | Body | 181.7 (−14.4, 377.5) | 46.1 (12.9, 86.5) | 20.2 (3.8, 97.4) |
| cg01270753 | 9 | TGFBR1 * | Aortic disease and altered cardiovascular development | Intergenic | 200.3 (8.7, 391.4) | 43.9 (13.6, 82.9) | 18.0 (4.7, 70.6) |
| cg22294740 | 19 | LINGO3 | Unknown function | 5’UTR | 185.3 (−11.5, 381.9) | 43.3 (7.0, 8.4) | 18.9 (1.3, 92.4) |
| cg03362418 | 22 | TYMP * | Angiogenesis in vivo. Possible therapeutic target for CVD | Body | 190.3 (−3.8, 383.8) | 40.1 (9.1, 78.6) | 17.4 (2.8, 78.0) |
| cg23027596 | 9 | UBAC1 * | Glucose-induced insulin synthesis and secretion | TSS1500 | 186.3 (−6.0, 378.1) | 39.9 (11.1, 74.6) | 17.6 (3.5, 80.4) |
| cg17608381 | 6 | HLA-A | Central role in the immune system | Body | 196.3 (−0.4, 392.4) | 35.9 (5.5, 72.9) | 15.5 (1.1, 74.9) |
| cg09956442 | 19 | ARRDC2 | Unknown function | Intergenic | 195.2 (1.6, 388.4) | 35.3 (10.3, 67.9) | 15.3 (3.4, 68.2) |
| cg06668829 | 8 | EPPK1 * | Cytoskeletal linker protein involved in response to stress | TSS1500 | 203.4 (10.9, 395.5) | 33.2 (10.1, 63.8) | 14.0 (3.4, 60.5) |
| cg14827056 | 8 | EIF2C2 | RNA-mediated gene silencing | Body | 193.8 (−0.3, 387.5) | 31.0 (5.5, 63.8) | 13.8 (1.2, 67) |
| cg18032342 | 3 | NISCH | Cell growth and death in cardiac tissue | Body | 197.2 (3.3, 390.8) | 30.1 (2.2, 63.9) | 13.2 (−0.4, 61.5) |
| cg13092901 | 22 | TYMP * | Angiogenesis in vivo. Possible therapeutic target for CVD | TSS1500 | 200.1 (6.4, 393.3) | 30.3 (3.2, 62.7) | 13.1 (0.2, 59.4) |
| cg11946459 | 6 | HLA-A | Central role in the immune system | Body | 206.4 (11.6, 400.7) | 27.2 (1.9, 58.8) | 11.7 (−0.1, 55.5) |
| cg06970472 | 4 | APBB2 * | Beta cell function, insulin secretion | Body | 205.7 (13.7, 397.3) | 27.8 (7.7, 54.8) | 11.9 (2.6, 52.3) |
| cg06716655 | 1 | ADAR2 | RNA editing enzyme involved in innate immunity | Body | 203.3 (7.0, 399.2) | 25.7 (3.9, 56.5) | 11.2 (0.9, 55.7) |
| cg18618815 | 17 | COL1A1 * | Extracellular matrix. As-induced remodeling mice model | Body | 198.5 (3.1, 393.4) | 23.7 (4.8, 49.8) | 10.7 (1.2, 54.9) |
| cg01178924 | 13 | LMO7 | Development of muscle and heart tissues. Pancreatic cancer | Body | 208.7 (13.6, 403.4) | 23.7 (0.4, 54.7) | 10.2 (−0.8, 48.8) |
| cg01542019 | 19 | TECR | Sphingolipid synthesis and oxidoreductase activity | Body | 202.1 (7.7, 396.1) | 21.4 (2.3, 48.4) | 9.6 (0.2, 48.8) |
| cg02047803 | 5 | RELL2 | Apoptosis | Body | 206.3 (13.3, 398.8) | 18.7 (0.7, 45.6) | 8.3 (−0.3, 43.5) |
| cg16335098 | 6 | SMOC2 | Angiogenesis in tumor growth and myocardial ischemia | Intergenic | 219.2 (25.7, 412.2) | 13.1 (2.7, 26.9) | 5.7 (0.8, 25.4) |
Models adjusted for age, sex, smoking status, BMI, LDL cholesterol, study center (Arizona, Oklahoma or North and South Dakota), cell counts (CD8T, CD4T, NK, B cells and monocytes) and genetic PCs.
CpG sites selected by ISIS – Aenet as predictive of CVD incidence. Other CpG sites were originally identified as associated with arsenic exposure in Bozack et al. 2020.
To account for the withdrawal of one of the Tribal Nations, models were weighted with approximately 1/3 of weight for each center (33.0% AZ, 33.6% OK, 33.4% ND/SD) using inverse probability weighting.