Background
Methods
Endometrial cancer study population
Identification of previously reported molecular risk factors for endometrial cancer
Exposure | GWAS | Sample size | Number of SNPs | R2 | F-statistic | Sex specificity |
---|---|---|---|---|---|---|
Adult BMI | Yengo et al. [41] | 681,275 | 507 | 0.078 | 57,847 | Combined |
LDL cholesterol | Willer et al. [33] | 188,577 | 81 | 0.182 | 15,002 | Combined |
HDL cholesterol | Willer et al. [33] | 188,577 | 89 | 0.055 | 10,978 | Combined |
Triglyceride | Willer et al. [33] | 188,577 | 55 | 0.052 | 9811 | Combined |
Total serum cholesterol | Willer et al. [33] | 188,577 | 88 | 0.063 | 12,696 | Combined |
Glucose | Neale et al. [35] | 361,194 | 109 | 0.036 | 11,776 | Female |
Fasting insulin (unadjusted for BMI) | Lagou et al. [42] | 98,210 | 14 | 0.005 | 523 | Combined |
Fasting insulin (adjusted for BMI) | Chen et al. [43] | 150,571 | 14 | 0.006 | 865 | Combined |
IGF-1 (cis and trans variants) | Sinnott-Armstrong et al. [36] | 358,072 | 413 | 0.036 | 13,367 | Combined |
IGF-1 (cis variants) | Larsson et al. [44] | 358,072 | 1 | 0.002 | 814 | Combined |
IL-6 | Georgakis et al. [37] | 204,402 | 7 | 0.004 | 911 | Combined |
Adiponectin (cis and trans variants) | Locke et al. [45] | 14,172 | 3 | 0.023 | 328 | Combined |
Adiponectin (cis variants) | Locke et al. [45] | 14,172 | 3 | 0.023 | 334 | Combined |
Leptin | Folkersen et al. [46] | 30,931 | 1 | 0.001 | 34 | Combined |
CRP (cis and trans variants) | Ligthart et al. [40] | 204,402 | 45 | 0.035 | 7414 | Combined |
CRP (cis variants) | C-Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC) [47] | 105,476 | 4 | 0.010 | 1030 | Combined |
Total testosterone | Ruth et al. [28] | 230,454 | 131 | 0.052 | 10,103 | Female |
Bioavailable testosterone | Ruth et al. [28] | 188,507 | 147 | 0.054 | 10,599 | Female |
SHBG | Ruth et al. [28] | 189,473 | 215 | 0.122 | 26,286 | Female |
Statistical analyses
Mediation analysis
Sample overlap sensitivity analyses
Results
Evaluating the effect of BMI on endometrial cancer risk
Outcome | Method | OR (95% CI) | P value |
---|---|---|---|
Overall endometrial cancer | IVW | 1.88 (1.69 to 2.09) | 3.87 × 10−31 |
Weighted median | 1.89 (1.58 to 2.26) | 5.18 × 10−12 | |
Weighted mode | 1.82 (1.35 to 2.44) | 9.88 × 10−5 | |
MR-Egger | 2.03 (1.54 to 2.67) | 8.41 × 10−7 | |
Endometrioid endometrial cancer | IVW | 1.89 (1.65 to 2.16) | 1.67 × 10−20 |
Weighted median | 1.99 (1.60 to 2.46) | 3.24 × 10−10 | |
Weighted mode | 1.96 (1.42 to 2.69) | 4.67 × 10−5 | |
MR-Egger | 2.15 (1.52 to 3.03) | 1.74 × 10−5 | |
Non-endometrioid endometrial cancer | IVW | 1.67 (1.19 to 2.35) | 3.03 × 10−3 |
Weighted median | 2.29 (1.24 to 4.22) | 8.24 × 10−3 | |
Weighted mode | 1.89 (0.77 to 4.63) | 1.63 × 10−1 | |
MR-Egger | 2.25 (0.99 to 5.07) | 5.28 × 10−2 |
Evaluating the effect of previously reported molecular risk factors on endometrial cancer risk
Exposure | Outcome | Method | OR (95% CI) | P value |
---|---|---|---|---|
LDL cholesterol | Overall endometrial cancer | IVW | 0.95 (0.87 to 1.04) | 3.05 × 10−1 |
Weighted median | 0.92 (0.82 to 1.03) | 1.31 × 10−1 | ||
Weighted mode | 0.91 (0.82 to 1.02) | 9.54 × 10−2 | ||
MR-Egger | 0.90 (0.79 to 1.03) | 1.35 × 10−1 | ||
Endometrioid endometrial cancer | IVW | 0.98 (0.89 to 1.08) | 6.70 × 10−1 | |
Weighted median | 0.96 (0.84 to 1.10) | 5.61 × 10−1 | ||
Weighted mode | 0.93 (0.83 to 1.06) | 2.79 × 10−1 | ||
MR-Egger | 0.93 (0.81 to 1.07) | 3.31 × 10−1 | ||
HDL cholesterol | Overall endometrial cancer | IVW | 1.09 (0.97 to 1.23) | 1.48 × 10−1 |
Weighted median | 1.10 (0.96 to 1.26) | 1.89 × 10−1 | ||
Weighted mode | 1.07 (0.94 to 1.23) | 3.11 × 10−1 | ||
MR-Egger | 1.08 (0.86 to 1.35) | 4.99 × 10−1 | ||
Endometrioid endometrial cancer | IVW | 1.04 (0.90 to 1.19) | 6.05 × 10−1 | |
Weighted median | 0.99 (0.84 to 1.16) | 8.76 × 10−1 | ||
Weighted mode | 1.03 (0.88 to 1.21) | 7.23 × 10−1 | ||
MR-Egger | 0.92 (0.71 to 1.20) | 5.61 × 10−1 | ||
Triglyceride | Overall endometrial cancer | IVW | 0.95 (0.84 to 1.06) | 3.55 × 10−1 |
Weighted median | 0.87 (0.75 to 1.01) | 7.75 × 10−2 | ||
Weighted mode | 0.91 (0.79 to 1.04) | 1.61 × 10−1 | ||
MR-Egger | 0.83 (0.69 to 1.00) | 6.03 × 10−2 | ||
Endometrioid endometrial cancer | IVW | 0.95 (0.83 to 1.09) | 4.65 × 10−1 | |
Weighted median | 0.92 (0.78 to 1.08) | 3.21 × 10−1 | ||
Weighted mode | 0.91 (0.77 to 1.08) | 2.87 × 10−1 | ||
MR-Egger | 0.87 (0.70 to 1.07) | 2.02 × 10−1 | ||
Total serum cholesterol | Overall endometrial cancer | IVW | 0.90 (0.81 to 1.00) | 4.01 × 10−2 |
Weighted median | 0.80 (0.71 to 0.90) | 2.08 × 10−4 | ||
Weighted mode | 0.82 (0.73 to 0.91) | 5.97 × 10−4 | ||
MR-Egger | 0.84 (0.71 to 0.98) | 3.09 × 10−2 | ||
Endometrioid endometrial cancer | IVW | 0.91 (0.82 to 1.02) | 9.31 × 10−2 | |
Weighted median | 0.81 (0.71 to 0.93) | 3.40 × 10−3 | ||
Weighted mode | 0.84 (0.74 to 0.97) | 1.64 × 10−2 | ||
MR-Egger | 0.86 (0.72 to 1.01) | 7.60 × 10−2 | ||
Glucose | Overall endometrial cancer | IVW | 0.95 (0.79 to 1.14) | 5.64 × 10−1 |
Weighted median | 0.97 (0.80 to 1.17) | 7.36 × 10−1 | ||
Weighted mode | 0.93 (0.78 to 1.11) | 4.47 × 10−1 | ||
MR-Egger | 0.99 (0.73 to 1.34) | 9.29 × 10−1 | ||
Endometrioid endometrial cancer | IVW | 0.90 (0.73 to 1.11) | 3.26 × 10−1 | |
Weighted median | 0.98 (0.77 to 1.23) | 8.31 × 10−1 | ||
Weighted mode | 0.98 (0.80 to 1.20) | 8.29 × 10−1 | ||
MR-Egger | 0.94 (0.67 to 1.33) | 7.39 × 10−1 | ||
Fasting insulin | Overall endometrial cancer | IVW | 3.93 (2.29 to 6.74) | 7.18 × 10−7 |
Weighted median | 3.49 (1.60 to 7.62) | 1.67 × 10−3 | ||
Weighted mode | 3.55 (0.85 to 14.78) | 1.06 × 10−1 | ||
MR-Egger | 8.28 (0.67 to 102.10) | 1.25 × 10−1 | ||
Endometrioid endometrial cancer | IVW | 4.64 (2.30 to 9.36) | 1.84 × 10−5 | |
Weighted median | 3.93 (1.56 to 9.93) | 3.80 × 10−3 | ||
Weighted mode | 3.28 (0.69 to 15.62) | 1.61 × 10−1 | ||
MR-Egger | 21.59 (0.78 to 593.93) | 9.66 × 10−2 | ||
IGF-1 (cis and trans variants) | Overall endometrial cancer | IVW | 0.93 (0.85 to 1.06) | 2.60 × 10−1 |
Weighted median | 1.01 (0.85 to 1.20) | 8.96 × 10−1 | ||
Weighted mode | 1.22 (0.89 to 1.67) | 2.28 × 10−1 | ||
MR-Egger | 1.17 (0.85 to 1.60) | 3.49 × 10−1 | ||
Endometrioid endometrial cancer | IVW | 0.89 (0.77 to 1.03) | 1.12 × 10−1 | |
Weighted median | 1.03 (0.84 to 1.25) | 8.06 × 10−1 | ||
Weighted mode | 1.32 (0.92 to 1.90) | 1.30 × 10−1 | ||
MR-Egger | 1.22 (0.85 to 1.76) | 2.75 × 10−1 | ||
IGF-1 (cis variants) | Overall endometrial cancer | Wald ratio | 1.20 (0.79 to 1.82) | 3.92 × 10−1 |
Endometrioid endometrial cancer | Wald ratio | 1.40 (0.85 to 2.28) | 1.84 × 10−1 | |
IL-6 (scaled to natural log transformed mg/L change in CRP) | Overall endometrial cancer | IVW | 0.90 (0.66 to 1.21) | 4.80 × 10−1 |
Endometrioid endometrial cancer | IVW | 0.86 (0.60 to 1.23) | 4.01 × 10−1 | |
Adiponectin (cis and trans variants) | Overall endometrial cancer | IVW | 0.92 (0.79 to 1.08) | 3.17 × 10−1 |
Endometrioid endometrial cancer | IVW | 0.94 (0.78 to 1.13) | 4.99 × 10−1 | |
Adiponectin (cis variants) | Overall endometrial cancer | IVW | 0.95 (0.83 to 1.08) | 3.94 × 10−1 |
Endometrioid endometrial cancer | IVW | 1.00 (0.86 to 1.16) | 9.92 × 10−1 | |
Leptin | Overall endometrial cancer | Wald Ratio | 1.03 (0.68 to 1.54) | 8.96 × 10−1 |
Endometrioid endometrial cancer | Wald Ratio | 0.88 (0.54 to 1.42) | 5.99 × 10−1 | |
CRP (cis and trans variants) | Overall endometrial cancer | IVW | 1.07 (0.94 to 1.22) | 3.03 × 10−1 |
Weighted median | 0.97 (0.84 to 1.12) | 6.76 × 10−1 | ||
Weighted mode | 1.02 (0.91 to 1.14) | 7.80 × 10−1 | ||
MR-Egger | 0.96 (0.80 to 1.16) | 6.99 × 10−1 | ||
Endometrioid endometrial cancer | IVW | 1.12 (0.96 to 1.30) | 1.39 × 10−1 | |
Weighted median | 1.03 (0.87 to 1.23) | 6.92 × 10−1 | ||
Weighted mode | 1.04 (0.90 to 1.20) | 6.34 × 10−1 | ||
MR-Egger | 0.97 (0.78 to 1.20) | 7.69 × 10−1 | ||
CRP (cis variants) | Overall endometrial cancer | IVW | 0.98 (0.85 to 1.13) | 7.52 × 10−1 |
Endometrioid endometrial cancer | IVW | 0.98 (0.83 to 1.16) | 8.02 × 10−1 | |
Total testosterone | Overall endometrial cancer | IVW | 1.64 (1.43 to 1.88) | 1.71 × 10−12 |
Weighted median | 1.67 (1.39 to 2.01) | 3.95 × 10−8 | ||
Weighted mode | 1.74 (1.38 to 2.20) | 8.33 × 10−6 | ||
MR-Egger | 1.81 (1.38 to 2.38) | 4.17 × 10−5 | ||
Endometrioid endometrial cancer | IVW | 1.60 (1.36 to 1.87) | 8.70 × 10−9 | |
Weighted median | 1.81 (1.45 to 2.26) | 2.05 × 10−7 | ||
Weighted mode | 1.88 (1.42 to 2.48) | 2.34 × 10−5 | ||
MR-Egger | 1.74 (1.26 to 2.41) | 1.02 × 10−3 | ||
Bioavailable testosterone | Overall endometrial cancer | IVW | 1.46 (1.29 to 1.65) | 3.48 × 10−9 |
Weighted median | 1.47 (1.20 to 1.82) | 2.46 × 10−4 | ||
Weighted mode | 1.51 (1.19 to 1.93) | 1.16 × 10−3 | ||
MR-Egger | 1.90 (1.46 to 2.47) | 5.63 × 10−6 | ||
Endometrioid endometrial cancer | IVW | 1.46 (1.26 to 1.69) | 3.08 × 10−7 | |
Weighted median | 1.42 (1.14 to 1.76) | 1.97 × 10−3 | ||
Weighted mode | 1.60 (1.20 to 2.13) | 1.59 × 10−3 | ||
MR-Egger | 1.79 (1.31 to 2.43) | 3.08 × 10−7 | ||
SHBG | Overall endometrial cancer | IVW | 0.71 (0.59 to 0.85) | 2.07 × 10−4 |
Weighted median | 0.64 (0.48 to 0.86) | 2.54 × 10−3 | ||
Weighted mode | 0.69 (0.53 to 0.89) | 4.97 × 10−3 | ||
MR-Egger | 0.62 (0.46 to 0.84) | 2.52 × 10−3 | ||
Endometrioid endometrial cancer | IVW | 0.65 (0.54 to 0.80) | 3.31 × 10−5 | |
Weighted median | 0.60 (0.43 to 0.86) | 4.90 × 10−3 | ||
Weighted mode | 0.58 (0.40 to 0.82) | 2.50 × 10−3 | ||
MR-Egger | 0.61 (0.44 to 0.84) | 3.33 × 10−3 |
Evaluating the effect of BMI on previously reported molecular risk factors
Outcome | Method | Effect estimate (95% CI) | P value |
---|---|---|---|
Total serum cholesterol | IVW | − 0.03 (− 0.06 to 0.01) | 1.22 × 10−1 |
Weighted median | − 0.06 (− 0.11 to − 0.01) | 2.98 × 10−2 | |
Weighted mode | − 0.08 (− 0.15 to 0.00) | 4.46 × 10−2 | |
MR-Egger | − 0.08 (− 0.16 to 0.00) | 3.89 × 10−2 | |
Fasting insulin | IVW | 0.17 (0.15 to 0.19) | 1.51 × 10−74 |
Weighted median | 0.18 (0.15 to 0.21) | 8.51 × 10−31 | |
Weighted mode | 0.18 (0.12 to 0.24) | 1.88 × 10−9 | |
MR-Egger | 0.20 (0.16 to 0.25) | 1.30 × 10−16 | |
Total testosterone | IVW | 0.08 (0.05 to 0.11) | 9.04 × 10−10 |
Weighted median | 0.06 (0.03 to 0.09) | 4.95 × 10−4 | |
Weighted mode | − 0.01 (− 0.08 to 0.07) | 8.60 × 10−1 | |
MR-Egger | 0.02 (− 0.05 to 0.09) | 5.23 × 10−1 | |
Bioavailable testosterone | IVW | 0.26 (0.23 to 0.29) | 9.97 × 10−68 |
Weighted median | 0.24 (0.20 to 0.28) | 1.72 × 10−38 | |
Weighted mode | 0.09 (0.01 to 0.17) | 2.41 × 10−2 | |
MR-Egger | 0.16 (0.08 to 0.24) | 4.36 × 10−5 | |
SHBG | IVW | − 0.17 (− 0.19 to − 0.16) | 4.86 × 10−125 |
Weighted median | − 0.16 (− 0.18 to − 0.15) | 8.85 × 10−77 | |
Weighted mode | − 0.15 (− 0.18 to − 0.12) | 8.43 × 10−20 | |
MR-Egger | − 0.13 (− 0.17 to − 0.09) | 3.11 × 10−11 |
Mendelian randomization mediation analysis
Mediator | Outcome | Direct effect of BMI on outcome | Indirect effect of mediator on outcome | % mediated (95% CI) | P value |
---|---|---|---|---|---|
Fasting insulin | Overall Endometrial Cancer | 1.75 | 1.07 | 11% (1 to 21%) | 2.89 × 10−2 |
Endometrioid Endometrial Cancer | 1.72 | 1.11 | 16% (3 to 28%) | 1.24 × 10−2 | |
Bioavailable testosterone | Overall Endometrial Cancer | 1.70 | 1.11 | 15% (10 to 20%) | 1.43 × 10−8 |
Endometrioid Endometrial Cancer | 1.72 | 1.11 | 15% (9 to 22%) | 2.15 × 10−6 | |
SHBG | Overall Endometrial Cancer | 1.80 | 1.04 | 7% (1 to 12%) | 1.81 × 10−2 |
Endometrioid Endometrial Cancer | 1.86 | 1.02 | 2% (− 9 to 14%) | 6.87 × 10−1 |