Background
Methods
Study subjects
Cancer-specific case-control genome-wide association studies (GWASs)
UK Biobank cohort data
Two-sample MR analysis and sensitivity analysis of cancer-specific GWAS
Instrumental variable (IV) selection
Summary statistic-based method
GRS-based method
Sensitivity analysis
Validation in the UK Biobank cohort
Circulating vitamin E based GRS analysis
One-sample MR analysis for dietary vitamin E intake
Sensitivity analysis
Results
Power analysis and genetic effect estimation
Cancer type | Sample size (N = 602,435) | F-statistics | Minimum detectable ORa | |
---|---|---|---|---|
Cases (N = 297,699) | Controls (N = 304,736) | |||
Bladder cancer | 5930 | 5468 | 198.12 | 0.67/1.49 |
Breast cancer | 122,977 | 105,974 | 3960.48 | 0.91/1.09 |
Colorectal cancer | 24,476 | 23,073 | 823.31 | 0.82/1.22 |
Esophagus cancer | 2268 | 1865 | 72.48 | 0.53/1.97 |
Lung cancer | 29,266 | 56,450 | 1483.37 | 0.85/1.16 |
Oral and pharynx cancer | 4950 | 2907 | 136.88 | 0.63/1.70 |
Ovarian cancer | 22,406 | 40,941 | 1096.52 | 0.83/1.19 |
Pancreatic cancer | 4970 | 3532 | 148.03 | 0.64/1.63 |
Prostate cancer | 79,148 | 61,106 | 2426.55 | 0.89/1.12 |
Kidney cancer | 1308 | 3420 | 82.77 | 0.44/1.81 |
Causal association between circulating vitamin E and cancer risk
Sensitivity analysis for causal estimation across each cancer
Corrected trait | Bladder cancer | Breast cancer | ||||
---|---|---|---|---|---|---|
Betaa | 95% CIa | Pa | Betaa | 95% CIa | Pa | |
E70-E90 metabolic disorders | 3.03 | 0.69, 5.37 | 0.011 | −0.18 | −0.73, 0.36 | 0.507 |
E78 disorders of lipoprotein metabolism and other lipidemias | 2.96 | 0.91, 5.01 | 4.70×10-3 | −0.23 | −0.70, 0.25 | 0.349 |
Eosinophill count | 2.61 | 1.15, 4.07 | 4.53×10-4 | −0.36 | −0.71, −0.01 | 0.043 |
Eosinophill percentage | 2.34 | 1.02, 3.66 | 5.28×10-4 | −0.37 | −0.69, −0.05 | 0.022 |
High cholesterol | 2.99 | 1.16, 4.83 | 1.38×10-3 | −0.28 | −0.71, 0.15 | 0.204 |
High light scatter reticulocyte count | 3.07 | 1.26, 4.89 | 8.93×10-4 | −0.30 | −0.73, 0.13 | 0.165 |
High light scatter reticulocyte percentage | 2.94 | 1.22, 4.65 | 7.85×10-4 | −0.31 | −0.71, 0.10 | 0.137 |
I20-I25 ischemic heart diseases | 1.58 | −0.15, 3.32 | 0.073 | −0.26 | −0.66, 0.15 | 0.211 |
I25 chronic ischemic heart disease | 1.62 | −0.28, 3.51 | 0.095 | −0.23 | −0.67, 0.21 | 0.308 |
Lymphocyte count | 1.29 | −0.15, 2.74 | 0.080 | −0.34 | −0.67, −0.01 | 0.046 |
Mean corpuscular hemoglobin | 1.13 | −0.70, 2.95 | 0.225 | −0.28 | −0.70, 0.15 | 0.202 |
Mean corpuscular hemoglobin concentration | 2.67 | 1.17, 4.17 | 4.67×10-4 | −0.35 | −0.71, 0.01 | 0.057 |
Mean corpuscular volume | 2.83 | 0.34, 5.32 | 0.026 | −0.15 | −0.73, 0.43 | 0.607 |
Mean platelet (thrombocyte) volume | 2.66 | 1.05, 4.27 | 1.18×10-3 | −0.29 | −0.67, 0.08 | 0.126 |
Mean reticulocyte volume | 3.09 | 1.19, 4.98 | 1.42×10-3 | −0.28 | −0.72, 0.17 | 0.223 |
Mean sphered cell volume | 3.14 | 1.04, 5.23 | 3.29×10-3 | −0.24 | −0.72, 0.25 | 0.341 |
Monocyte count | 1.81 | 0.60, 3.02 | 3.40×10-3 | −0.38 | −0.67, −0.10 | 0.008 |
Monocyte percentage | 1.47 | 0.19, 2.74 | 0.025 | −0.38 | −0.67, −0.08 | 0.012 |
Platelet count | 2.74 | 1.14, 4.34 | 7.81×10-4 | −0.31 | −0.69, 0.07 | 0.109 |
Platelet crit | 2.71 | 1.17, 4.25 | 5.70×10-4 | −0.33 | −0.69, 0.04 | 0.080 |
Platelet distribution width | 2.81 | 1.18, 4.43 | 7.21×10-4 | −0.31 | −0.70, 0.07 | 0.112 |
Red blood cell (erythrocyte) distribution width | 2.51 | 1.09, 3.94 | 5.43×10-4 | −0.34 | −0.67, 0.00 | 0.051 |
Reticulocyte count | 3.15 | 1.25, 5.05 | 1.17×10-3 | −0.29 | −0.74, 0.16 | 0.207 |
Reticulocyte percentage | 3.01 | 1.23, 4.79 | 9.32×10-4 | −0.30 | −0.72, 0.12 | 0.164 |
Validation in the UK Biobank cohort
Cancer type | Cases | Methoda | HRb | 95% CIb | Pb | Corrected Pc |
---|---|---|---|---|---|---|
Bladder cancer | 526 | Circulating vitamin E-based GRS | 0.86 | 0.05, 14.64 | 0.918 | 0.983 |
One-sample weighted GRS | 0.70 | 0.28, 1.75 | 0.444 | 0.989 | ||
One-sample unweighted GRS | 0.75 | 0.29, 1.93 | 0.551 | 0.988 | ||
Breast cancer | 4350 | Circulating vitamin E-based GRS | 2.30 | 0.86, 6.14 | 0.096 | 0.337 |
One-sample weighted GRS | 1.06 | 0.82, 1.36 | 0.674 | 0.989 | ||
One-sample unweighted GRS | 1.06 | 0.82, 1.38 | 0.664 | 0.988 | ||
Colorectal cancer | 2621 | Circulating vitamin E-based GRS | 0.43 | 0.12, 1.54 | 0.194 | 0.400 |
One-sample weighted GRS | 1.19 | 0.79, 1.80 | 0.404 | 0.989 | ||
One-sample unweighted GRS | 1.22 | 0.80, 1.87 | 0.348 | 0.988 | ||
Esophagus cancer | 460 | Circulating vitamin E-based GRS | 14.06 | 0.72, 275.16 | 0.082 | 0.337 |
One-sample weighted GRS | 1.01 | 0.38, 2.69 | 0.989 | 0.989 | ||
One-sample unweighted GRS | 0.99 | 0.36, 2.72 | 0.988 | 0.988 | ||
Lung cancer | 1700 | Circulating vitamin E-based GRS | 0.79 | 0.16, 3.89 | 0.772 | 0.983 |
One-sample weighted GRS | 1.17 | 0.70, 1.96 | 0.542 | 0.989 | ||
One-sample unweighted GRS | 1.16 | 0.69, 1.97 | 0.573 | 0.988 | ||
Oral and pharynx cancer | 458 | Circulating vitamin E-based GRS | 1.03 | 0.05, 21.74 | 0.983 | 0.983 |
One-sample weighted GRS | 0.93 | 0.35, 2.50 | 0.891 | 0.989 | ||
One-sample unweighted GRS | 0.87 | 0.32, 2.39 | 0.792 | 0.988 | ||
Ovarian cancer | 437 | Circulating vitamin E-based GRS | 2.09 | 0.09, 47.08 | 0.644 | 0.983 |
One-sample weighted GRS | 0.87 | 0.39, 1.92 | 0.724 | 0.989 | ||
One-sample unweighted GRS | 0.86 | 0.38, 1.96 | 0.722 | 0.988 | ||
Pancreatic cancer | 506 | Circulating vitamin E-based GRS | 1.08 | 0.06, 20.08 | 0.960 | 0.983 |
One-sample weighted GRS | 0.94 | 0.37, 2.41 | 0.898 | 0.989 | ||
One-sample unweighted GRS | 0.96 | 0.37, 2.52 | 0.934 | 0.988 | ||
Prostate cancer | 4882 | Circulating vitamin E-based GRS | 0.54 | 0.21, 1.39 | 0.200 | 0.400 |
One-sample weighted GRS | 0.93 | 0.72, 1.19 | 0.572 | 0.989 | ||
One-sample unweighted GRS | 0.97 | 0.75, 1.26 | 0.840 | 0.988 | ||
Kidney cancer | 649 | Circulating vitamin E-based GRS | 0.11 | 0.01, 1.54 | 0.101 | 0.337 |
One-sample weighted GRS | 0.68 | 0.30, 1.57 | 0.370 | 0.989 | ||
One-sample unweighted GRS | 0.73 | 0.31, 1.70 | 0.466 | 0.988 |