Table 2.
Interacting effects of 25(OH)D and methylation at CpG sites in vitamin D-related genes on the 5-year risk of breast cancer (1024 cases, 1270 from subcohort, including 46 additional casesa): ratio of hazard ratios and 95% confidence intervals for CpGs with statistically significant interactions (p < 0.05)
| Rank | CpG site | Gene / location type | HR (95% CI) for methylation-breast cancer association | HR (95% CI) for methylation-breast cancer association, if 25(OH)D ≤ 38.0 ng/mL | HR (95% CI) for methylation-breast cancer association, if 25(OH)D > 38.0 ng/mL | Ratio of Hazard Ratios (95% CI)b | Interaction p value |
|---|---|---|---|---|---|---|---|
| 1 | cg21201924 | RXRA / body | 1.00 (0.96–1.04) | 0.97 (0.93–1.01) | 1.18 (1.08–1.29) | 1.22 (1.10–1.34) | 7.0 × 10−5 |
| 2 | cg13786567 | RXRA / body | 1.01 (0.94–1.08) | 0.94 (0.87–1.02) | 1.34 (1.12–1.60) | 1.42 (1.17–1.73) | 4.0 × 10−4 |
| 3 | cg02127980 | RXRA / body | 1.00 (0.94–1.06) | 0.95 (0.88–1.01) | 1.22 (1.07–1.38) | 1.29 (1.11–1.49) | 7.0 × 10−4 |
| 4 | cg12978433 | CYP24A1 / 1st exon | 1.01 (0.98–1.04) | 1.04 (1.00–1.07) | 0.93 (0.88–0.98) | 0.90 (0.84–0.96) | 9.0 × 10−4 |
| 5 | cg14154547c | RXRA / body | 0.96 (0.90–1.03) | 0.91 (0.84–0.98) | 1.17 (1.01–1.36) | 1.29 (1.09–1.53) | 0.003 |
| 6 | cg18956481c | CYP24A1 / 5´ UTR | 0.99 (0.97–1.02) | 1.01 (0.99–1.04) | 0.93 (0.88–0.98) | 0.92 (0.86–0.98) | 0.006 |
| 7 | cg13510651c | RXRA / body | 0.99 (0.93–1.06) | 0.95 (0.88–1.02) | 1.18 (1.03–1.35) | 1.24 (1.06–1.45) | 0.007 |
| 8 | cg14236758 | RXRA / body | 1.00 (0.94–1.06) | 0.96 (0.90–1.03) | 1.19 (1.03–1.37) | 1.23 (1.05–1.44) | 0.01 |
| 9 | cg09253762 | CYP27B1 / TSS1500 | 0.99 (0.95–1.04) | 0.96 (0.91–1.01) | 1.12 (1.01–1.24) | 1.16 (1.04–1.31) | 0.01 |
| 10 | cg18482822c | DHCR7 / body | 1.02 (0.97–1.06) | 0.99 (0.93–1.04) | 1.13 (1.02–1.24) | 1.14 (1.02–1.27) | 0.02 |
| 11 | cg05072492c | NADSYN1 / TSS1500 | 1.01 (0.96–1.06) | 0.97 (0.92–1.03) | 1.11 (1.00–1.24) | 1.15 (1.01–1.29) | 0.03 |
| 12 | cg11035813c | DHCR7 / TSS1500 | 1.02 (0.98–1.07) | 1.00 (0.95–1.05) | 1.13 (1.02–1.24) | 1.13 (1.01–1.26) | 0.03 |
| 13 | cg14854850 | VDR / 3´ UTR | 0.99 (0.94–1.03) | 1.02 (0.97–1.07) | 0.90 (0.82–0.99) | 0.89 (0.79–0.99) | 0.03 |
| 14 | cg25588697c | DHCR7 / body | 1.01 (0.95–1.08) | 0.96 (0.89–1.05) | 1.14 (1.00–1.30) | 1.18 (1.01–1.38) | 0.04 |
| 15 | cg10592901 | VDR / body | 1.04 (1.01–1.07) | 1.06 (1.03–1.10) | 0.98 (0.92–1.05) | 0.92 (0.86–1.00) | 0.04 |
| 16 | cg12474705c | NADSYN1 / body | 0.96 (0.92–1.01) | 0.99 (0.94–1.05) | 0.88 (0.80–0.98) | 0.89 (0.79–1.00) | 0.04 |
| 17 | cg16984335c | CYP27B1 / body | 1.00 (0.96–1.04) | 1.02 (0.97–1.06) | 0.92 (0.83–1.00) | 0.90 (0.81–1.00) | 0.05 |
| 18 | cg13941235 | RXRA / body | 1.00 (0.97–1.02) | 0.98 (0.95–1.01) | 1.04 (0.99–1.10) | 1.06 (1.00–1.13) | 0.05 |
CI confidence interval, HR hazard ratio, TSS1500 within 1500 basepairs upstream of the transcription start site, UTR Untranslated region
aAfter excluding those with missing covariate information
bChange in the methylation-breast cancer association for being in the 4th quartile of 25-hydroxyvitamin D (25(OH)D) (≥ 38.0 ng/mL) versus the first three (< 38.0 ng/mL)—a value > 1.00 indicates that the estimated HR for the methylation-breast cancer association is higher among those with higher 25(OH)D levels; similarly, an RHR < 1.00 indicates that the estimated HR for the methylation-breast cancer association is higher among those with lower 25(OH)D levels
cIntraclass correlation coefficient < 0.5