Table 4.
CVD deaths 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 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 deaths.
| Mediated effects |
|||||||
|---|---|---|---|---|---|---|---|
| CpG | Chr | Gene | Function | Location | Deaths attributable to a doubling of urinary As (95 % CI) (direct effect) | Deaths attributable to a doubling of urinary As through DNAm (95%CI) (indirect effect) | % deaths attributable to a doubling of urinary As explained by DNAm (95%CI) |
| cg05779585 | 8 | LOC286083 | Unknown function | Intergenic | 91.9 (−9.7, 193.3) | 52.9 (6.1, 120.4) | 36.5 (4.3, 109.0) |
| cg19693031 | 1 | TXNIP | Binding partner for redox signaling protein thioredoxin | 3’UTR | 70.7 (−35.4, 176.4) | 43.5 (18.1, 75.4) | 38.1 (9.9, 198.5) |
| cg06716655 | 1 | ADAR | RNA editing enzyme involved in innate immunity | Body | 88.9 (−16.1, 193.6) | 25.1 (7.2, 47.5) | 22 (3.2, 114.5) |
| cg17608381 | 6 | HLA-A | Central role in the immune system | Body | 91.9 (−14.2, 197.8) | 24.1 (6.5, 45.8) | 20.8 (2.8, 112.3) |
| cg22294740 | 19 | LINGO3 | Unknown function | 5’UTR | 89.9 (−14.6, 194.2) | 22.7 (1.4, 47.7) | 20.2 (−3.4, 108.3) |
| cg03362418 | 22 | TYMP * | Angiogenesis in vivo. Possible therapeutic target for CVD | Body | 93.4 (−11.1, 197.6) | 21.3 (4.6, 43.0) | 18.5 (1.6, 94.7) |
| cg11946459 | 6 | HLA-A | Central role in the immune system | Body | 98.2 (−6.2, 202.3) | 18.4 (3.6, 37.1) | 15.8 (1.2, 81.3) |
| cg21990700 | 12 | C1RL * | Complement protein in the endoplasmic reticulum | TSS200 | 92.3 (−11.9, 196.3) | 18.3 (5.7, 34.9) | 16.6 (2.6, 91.3) |
| cg06970472 | 4 | APBB2 * | Beta cell function and insulin secretion | Body | 99.2 (−4.6, 202.8) | 16.4 (5.0, 31.4) | 14.2 (2.8, 71.3) |
| cg03026982 | 11 | NAV2 * | Blood pressure regulation | Body | 101.4 (−3.2, 205.8) | 15.5 (1.9, 34.8) | 13.2 (0.3, 66.1) |
| cg05527044 | 2 | EGR4 | Transcription regulation | Intergenic | 101.3 (−2.2, 204.7) | 13.5 (0.6, 30.7) | 11.7 (−1.6, 60.6) |
| cg00451635 | 16 | EMP2 * | Endothelial cell migration and angiogenesis | TSS1500 | 106.8 (2.9, 210.4) | 9.9 (0.2, 24.2) | 8.5 (−1.0, 43.1) |
| cg27523527 | 1 | BARHL2 | Potential regulator of neural basic helix-loop-helix genes | Intergenic | 104.8 (0.9, 208.4) | 7.7 (0.1, 19.5) | 6.9 (−1.3, 37.8) |
| cg19301366 | 6 | HLA-DQB1 | Type 1 diabetes susceptibility | 3’UTR | 106.8 (3.2, 210.2) | 3.5 (0.04, 8.8) | 3.2 (−0.7, 18.6) |
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 mortality
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.