Table 3.
Association between instrumental genetic variables for vigorous physical activity, assessed in two ways, and risk of breast cancer
| Accelerometer-measured activity over 425 milligravities, per fraction of time, using one SNP a | Self-reported vigorous physical activity (≥ 3 vs. 0 days/week) | |||||
|---|---|---|---|---|---|---|
|
| ||||||
| Full instrument (five SNPs) | Excluding one pleiotropic SNP for outcome with detected pleiotropy b | |||||
|
|
||||||
| Type of breast cancer | N cases (vs. 54,452 controls) | Odds ratios (95% CI) c | Odds ratios (95% CI) c | P for heterogeneity d | Odds ratios (95% CI) c | P for heterogeneity d |
|
| ||||||
| Invasive cancers | ||||||
|
| ||||||
| All invasive | 69,838 | 0.63 (0.32–1.22) | 0.83 (0.69–1.01) | 0.650 | -- | |
| Pre/perimenopausal | e 23,999 | 0.80 (0.25–2.58) | 0.62 (0.45–0.87) | 0.788 | -- | |
| Postmenopausal | f 45,839 | 0.53 (0.24–1.21) | 0.95 (0.75–1.19) | 0.630 | -- | |
|
| ||||||
| By receptor status | ||||||
|
| ||||||
| ER+ | 46,528 | 0.74 (0.35–1.55) | 0.86 (0.70–1.07) | 0.917 | -- | |
| ER− | 11,246 | 0.58 (0.17–1.94) | 0.86 (0.61–1.21) | 0.418 | -- | |
| PR+ | 34,891 | 0.68 (0.30–1.54) | 0.77 (0.61–0.98) | 0.544 | -- | |
| PR− | 16,432 | 0.56 (0.19–1.59) | 0.95 (0.70–1.28) | 0.948 | -- | |
| HER2+ | 6,945 | 0.31 (0.07–1.39) | 0.83 (0.53–1.31) | 0.327 | -- | |
| HER2- | 33,214 | 1.01 (0.44–2.31) | 0.86 (0.68–1.10) | 0.550 | -- | |
|
| ||||||
| Combined hormone receptor- and/or HER2-defined subtypes | ||||||
|
| ||||||
| ER+ or PR+; HER2+ | 4,816 | 0.41 (0.07–2.35) | 1.00 (0.58–1.70) | 0.321 | -- | |
| ER+ or PR+; HER2− | 27,874 | 0.84 (0.35–2.02) | 0.82 (0.64–1.06) | 0.560 | -- | |
| ER−; PR−; HER2+ | 1,974 | 0.21 (0.02–2.87) | 0.57 (0.27–1.20) | 0.727 | -- | |
| ER−; PR−; HER2− | 4,964 | 2.16 (0.39–12.1) | 1.30 (0.79–2.12) | 0.593 | -- | |
| ER− and PR− (all) | 9,215 | 0.78 (0.21–2.91) | 0.95 (0.66–1.39) | 0.559 | -- | |
|
| ||||||
| By morphology | ||||||
|
| ||||||
| Ductal | 42,223 | 0.62 (0.29–1.32) | 0.81 (0.65–1.00) | 0.932 | -- | |
| Lobular | 8,795 | 0.60 (0.15–2.45) | 0.78 (0.53–1.17) | 0.809 | -- | |
|
| ||||||
| By stage at diagnosis | ||||||
|
| ||||||
| Stage I | 17,583 | 0.47 (0.16–1.36) | 0.88 (0.65–1.19) | 0.598 | -- | |
| Stage II | 15,992 | 0.66 (0.21–2.07) | 0.82 (0.59–1.14) | 0.788 | -- | |
| Stage III/IV | 4,553 | 0.41 (0.06–2.63) | 0.75 (0.44–1.27) | 0.910 | -- | |
|
| ||||||
| By tumour grade | ||||||
|
| ||||||
| Grade 1/2 | 34,647 | 0.54 (0.24–1.22) | 0.84 (0.66–1.06) | 0.640 | -- | |
| Grade 3 | 16,432 | 0.51 (0.18–1.46) | 0.99 (0.73–1.33) | 0.557 | -- | |
|
| ||||||
| In situ cancers | ||||||
|
| ||||||
| All in situ | 6,667 | 0.47 (0.11–2.09) | 0.94 (0.43–2.08) | 0.007 | 1.30 (0.72–2.34) | 0.189 |
| Ductal carcinoma in situ | 3,510 | 0.65 (0.09–4.72) | 0.85 (0.42–1.69) | 0.204 | -- | |
Abbreviations: CI, confidence interval; ER+/−, oestrogen receptor positive/negative; GWAS, genome wide association study; HER2+/−, human epidermal growth factor receptor 2 positive/negative; PR+/−, progesterone receptor positive/negative; SNP, single nucleotide polymorphism.
This SNP is a missense mutation in the gene PML, which plays a role in tumour suppression and is associated with height. PML is not expressed in breast tissue, but highly expressed in adipose tissue, suggesting that inverse (protective) associations observed do not derive from direct oncosuppression.
Excluding one outlying SNP identified by MR-PRESSO: rs2764261 (for analyses modelling the association with in situ tumours)
Causal odds ratios were estimated by inverse-variance weighted Mendelian randomization, using SNPs identified in a GWAS of physical activity by Klimentidis et al (10)
p-value associated with the heterogeneity test statistic (Cochran’s Q statistic) measuring heterogeneity of causal effects between SNPs
vs pre/perimenopausal controls (n=17,686), assigned using age (<50 years) if menopause status was unknown
vs postmenopausal controls (n=36,766), assigned using age (≥50 years) if menopause status was unknown
-- No outlying SNPs were identified by MR-PRESSO.