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Table 4 Ratio of hazard ratios and 95% confidence intervals for the interaction between 25(OH)D and methylation on the risk of breast cancer within 5 years of enrollment (1024 cases, 1270 from subcohort, including 46 additional casesa); CpGs with Fisher combined p values < 1 × 10−5 for subcohort combined with case comparison

From: Vitamin D, DNA methylation, and breast cancer

Rank

CpG

Gene/ Location

25(OH)D-methylation association, subcohort

25(OH)D-methylation association, cases

Fisher combined p value

HR (95% CI) for methylation-breast cancer association

RHRs (95% CI)c

Interaction p value

Cofficientb

p value

Cofficientb

p value

1

cg08092930

PPFIA1

−0.03

1.3 × 10−5

0.02

0.04

8.5 × 10−6*

1.01 (0.98–1.05)

1.15 (1.06–1.24)

6.3 × 10−4

2

cg23761815

SLC29A3

−0.02

5.1 × 10−7

− 0.01

0.03

2.7 × 10−7

1.13 (1.07–1.18)

1.22 (1.08–1.38)

0.002

3

cg13243168

SMARCD2

−0.02

2.9 × 10−7

− 7 × 10−4

0.87

4.0 × 10−6

1.05 (0.98–0.91)

1.29 (1.09–1.51)

0.002

4

cg15544721

PPP1R9A

−0.01

0.09

−0.03

6.4 × 10−6

8.8 × 10−6

0.98 (0.94–1.03)

0.87 (0.79–0.96)

0.008

5

cg11568290

5p15.1

−0.02

1.4 × 10−4

−0.01

0.004

7.7 × 10−6

1.15 (1.08–1.22)

1.23 (1.05–1.44)

0.009

6

cg19420720

P4HB

−0.01

0.002

0.02

2.3 × 10−4

8.1 × 10−6*

1.01 (0.94–1.08)

1.27 (1.06–1.52)

0.01

7

cg23839180

FAM49A

−0.02

0.05

−0.05

3.0 × 10−6

2.3 × 10−6

0.97 (0.94–1.03)

0.92 (0.86–0.98)

0.01

8

cg15320474d

UBD

0.02

2.8 × 10−6

− 0.01

0.16

7.0 × 10−6*

0.98 (0.83–1.04)

0.87 (0.77–0.99)

0.03

9

cg24350360d

EPHX1

−0.04

3.4 × 10−8

0.01

0.48

3.1 × 10−7*

1.02 (0.99–1.05)

1.08 (1.01–1.16)

0.04

10

cg22488164

PLBD1

−0.03

1.5 × 10−4

−0.03

5.0 × 10−4

1.3 × 10−6

1.06 (1.02–1.10)

0.93 (0.85–1.01)

0.07

11

cg10401362

DNAJB6

−0.02

1.0 × 10−6

−0.01

0.27

4.4 × 10−6

1.02 (0.97–1.07)

1.10 (0.98–1.24)

0.10

12

cg06177555

SPN

−0.02

9.8 × 10−8

−0.003

0.54

9.3 × 10−7

0.97 (0.91–1.03)

1.12 (0.98–1.28)

0.10

13

cg11277126

TRPC4AP

−0.02

7.7 × 10−5

−0.02

4.8 × 10−4

6.7 × 10−7

1.04 (0.98–1.11)

1.07 (0.92–1.24)

0.39

14

cg21527411

GLYAT

0.02

2.1 × 10−6

−0.01

0.30

9.6 × 10−6*

1.02 (0.97–1.07)

0.95 (0.83–1.08)

0.40

15

cg09914444

DMBX1

0.02

5.4 × 10−6

−0.01

0.08

6.9 × 10−6*

1.05 (1.01–1.10)

0.96 (0.87–1.06)

0.44

16

cg23999318

HIPK2

−0.02

2.8 × 10−4

−0.02

3.5 × 10−4

1.7 × 10−6

1.00 (0.94–1.05)

1.00 (0.88–1.14)

1.00

  1. CI confidence interval, HR hazard ratio, RHR ratio of hazard ratio
  2. aAfter excluding those with missing covariate information
  3. bEstimated change in methylation (logit(β)) per 10 ng/mL change in serum 25-hydroxyvitamin D (25(OH)D)
  4. cChange in the methylation-breast cancer association for being in the 4th quartile of 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
  5. dIntraclass correlation coefficient < 0.5
  6. *Effect estimate going in opposing direction for subcohort versus cases