Background
Methods
DHC cohort study
Participants
Data on covariates
Ethics statement
RCT
Participants
Study design
Blood sampling and storage
Ethics statement
Laboratory methods
DCH cohort study
RCT
Statistical methods
DCH cohort study
RCT
Results
DCH cohort study
Variable | Cases | Controls | IRRa (95 % CI) | ||
---|---|---|---|---|---|
n (%) | Median (5–95 %) | n (%) | Median (5–95 %) | ||
Women | 687 (100) | 687 (100) | |||
Age at inclusion, years | 57 (51–64) | 57 (51–64) | |||
School education | |||||
Short | 198 (29) | 257 (37) | 1.0 (ref.) | ||
Medium | 344 (50) | 316 (46) | 1.39 (1.07–1.79) | ||
Long | 145 (21) | 114 (17) | 1.59 (1.13–2.24) | ||
Body mass index, kg/m2 | 25 (20–34) | 25 (20–34) | 1.01 (0.96–1.07)b | ||
Nulliparous | 102 (15) | 78 (11) | 1.02 (0.64–1.60)c | ||
Number of births | 2 (1–4) | 2 (1–4) | 0.92 (0.79–1.06) | ||
Age at first birth, years | 23 (18–31) | 23 (18–32) | 1.07 (0.91–1.25)d | ||
Use of HRT, yearse | 6 (0.5–19) | 5 (0.5–20) | 1.00 (0.87–1.15)f | ||
Abstainers | 15 (2) | 22 (3) | 0.80 (0.40–1.61)g | ||
Alcohol intake, g/day | 11 (1–43) | 9 (1–40) | 1.12 (1.04–1.21)h | ||
NSAID usei | 286 (42) | 239 (35) | 1.33 (1.07–1.66) |
Associations with hormone levels
Genotype | n (%) | Estrone | P-valueb | Estrone sulphate | P-valueb | SHBG | P-valueb |
---|---|---|---|---|---|---|---|
n = 339 | ∆ (95 % CI)a | ∆ (95 % CI)a | ∆ (95 % CI)a | ||||
rs10519297 | |||||||
AA | 81 (24) | 0 (ref.) | 0 (ref.) | 0 (ref.) | |||
AG | 187 (55) | 8 (−4;21) | 0.35 | 10 (−1;21) | 0.05 | −5 (−14;6) | 0.66 |
GG | 71 (21) | 1 (−13;16) | 16 (3;31) | −2 (−14;11) | |||
AG + GG | 258 (56) | 6 (−6;18) | 0.34 | 12 (1;23) | 0.03 | −4 (−13;6) | 0.44 |
rs749292 | |||||||
GG | 101 (30) | 0 (ref.) | 0 (ref.) | 0 (ref.) | |||
AG | 169 (50) | −5 (−15;6) | 0.62 | −11 (−19;-2) | 0.007 | −3 (−12;7) | 0.07 |
AA | 69 (20) | −5 (−17;9) | −16 (−26;-6) | 11 (−2;26) | |||
AG + AA | 238 (70) | −5 (−14;5) | 0.33 | −12 (−20;-4) | 0.004 | 1 (−8;11) | 0.82 |
rs1062033 | |||||||
CC | 88 (26) | 0 (ref.) | 0 (ref.) | 0 (ref.) | |||
CG | 180 (53) | −2 (−13;10) | 0.53 | −10 (−19;-1) | 0.01 | −1 (−11;9) | 0.45 |
GG | 71 (21) | −7 (−20;6) | −16 (−26;-6) | 6 (−7;21) | |||
CG + GG | 251 (74) | −4 (−14;7) | 0.51 | −12 (−20;-3) | 0.007 | 1 (−9;11) | 0.88 |
rs10046 | |||||||
AA | 93 (27) | 0 (ref.) | 0 (ref.) | 0 (ref.) | |||
AG | 177 (52) | 2 (−9;15) | 0.58 | 4 (−5;15) | 0.26 | −1 (−10;10) | 0.94 |
GG | 69 (20) | −4 (−17;10) | 11 (−2;25) | −2 (−14;11) | |||
AG + GG | 246 (73) | 0 (−10;12) | 0.93 | 6 (−3;16) | 0.21 | −1 (−10;9) | 0.82 |
rs4646 | |||||||
CC | 186 (55) | 0 (ref.) | 0 (ref.) | 0 (ref.) | |||
CA | 133 (39) | 3 (−7;14) | 0.68 | 5 (−3;15) | 0.38 | −4 (−13;5) | 0.59 |
AA | 20 (6) | −6 (−23;16) | 10 (−8;31) | −5 (−21;15) | |||
CA + AA | 153 (45) | 2 (−8;12) | 0.73 | 6 (−3;15) | 0.18 | −4 (−13;4) | 0.30 |
rs6493487 | |||||||
AA | 203 (60) | 0 (ref.) | 0 (ref.) | 0 (ref.) | |||
GA | 127 (38) | −5 (−14;5) | 0.27 | 4 (−4;14) | 0.63 | −5 (−13;4) | 0.37 |
GG | 9 (3) | −19 (−40;9) | 0 (−23;29) | −14 (−34;13) | |||
GA + GG | 136 (41) | −6 (−15;4) | 0.23 | 4 (−4;13) | 0.36 | −5 (−13;3) | 0.22 |
rs2008691 | |||||||
AA | 220 (65) | 0 (ref.) | 0 (ref.) | 0 (ref.) | |||
GA | 109 (32) | 4 (−6;15) | 0.35 | 3 (−6;12) | 0.83 | 2 (−7;12) | 0.17 |
GG | 10 (3) | 21 (−9;60) | 0 (−21;28) | 27 (−1;64) | |||
GA + GG | 119 (35) | 5 (−4;16) | 0.29 | 2 (−6;12) | 0.57 | 4 (−5;14) | 0.37 |
rs3751591 | |||||||
TT | 241 (71) | 0 (ref.) | 0 (ref.) | 0 (ref.) | |||
TC | 90 (27) | 2 (−9;13) | 0.55 | 1 (−8;10) | 0.50 | 1 (−9;11) | 0.09 |
CC | 8 (2) | 19 (−13;63) | 18 (−10;54) | 38 (4;83) | |||
CC vs. TT + TC | 8 (2) | 18 (−14;62) | 0.29 | 17 (−10;53) | 0.24 | 37 (4;82) | 0.03 |
rs2445762 | |||||||
TT | 175 (52) | 0 (ref.) | 0 (ref.) | 0 (ref.) | |||
TC | 142 (42) | −3 (−12;7) | 0.71 | −1 (−9;8) | 0.71 | −3 (−19;16) | 0.53 |
CC | 22 (6) | −7 (−24;13) | −7 (−21;10) | −5 (−13;4) | |||
TC + CC | 164 (48) | −3 (−12;6) | 0.47 | −2 (−10;6) | 0.63 | −5 (−13;4) | 0.27 |
rs11070844 | |||||||
CC | 267 (79) | 0 (ref.) | 0 (ref.) | 0 (ref.) | |||
TC | 68 (20) | 17 (4;31) | 0.03 | 13 (2;25) | 0.04 | 6 (−5;18) | 0.20 |
TT | 4 (1) | 16 (−26;79) | 23 (−16;79) | 36 (−9;103) | |||
TC + TT | 72 (21) | 17 (4;31) | 0.009 | 14 (3;25) | 0.01 | 7 (−3;19) | 0.18 |
Genotype | n (%) | Estrone | P-valueb | Estrone sulphate | P-valueb | SHBG | P-valueb |
---|---|---|---|---|---|---|---|
n = 325 | ∆ (95 % CI)a | ∆ (95 % CI)a | ∆ (95 % CI)a | ||||
rs10519297 | |||||||
AA | 74 (23) | 2 (−4;9) | 3 (−3;9) | −5 (−11;0) | |||
AG | 182 (56) | 3 (−1;6) | 0.82 | 3 (0;7) | 0.17 | −6 (−9;-3) | 0.23 |
GG | 69 (21) | 1 (−5;6) | 4 (0;9) | −3 (−7;2) | |||
AG + GG | 251 (77) | 2 (−1;5) | 0.54 | 4 (1;6) | 0.08 | −5 (−8;-2) | 0.27 |
rs749292 | |||||||
GG | 98 (30) | 3 (−2;7) | 4 (1;8) | −5 (−8;-1) | |||
AG | 165 (51) | 1 (−3;6) | 0.96 | 3 (0;7) | 0.38 | −6 (−9;-2) | 0.94 |
AA | 62 (19) | 2 (−5;10) | −1 (−7;6) | 0 (−7;6) | |||
AG + AA | 227 (70) | 1 (−2;5) | 0.85 | 3 (−1;6) | 0.15 | −5 (−8;-1) | 0.95 |
rs1062033 | |||||||
CC | 86 (26) | 1 (−3;6) | 4 (0;8) | −5 (−9;-1) | |||
CG | 175 (54) | 3 (−1;7) | 0.76 | 4 (0;7) | 0.11 | −5 (−8;-2) | 0.67 |
GG | 64 (20) | 1 (−6;8) | 1 (−4;7) | −4 (−9;2) | |||
CG + GG | 239 (74) | 2 (−1;6) | 0.45 | 3 (0;7) | 0.03 | −5 (−8;-2) | 0.90 |
rs10046 | |||||||
AA | 85 (26) | 3 (−3;10) | 4 (−2;10) | −7 (−12;-1) | |||
AG | 173 (53) | 2 (−1;7) | 0.89 | 3 (0;7) | 0.29 | −6 (−9;-3) | 0.06 |
GG | 67 (21) | 1 (−4;5) | 3 (0;8) | −3 (−7;1) | |||
AG + GG | 240 (74) | 2 (−1;5) | 0.64 | 3 (1;6) | 0.22 | −5 (−7;-2) | 0.24 |
rs4646 | |||||||
CC | 177 (54) | 3 (−2;7) | 4 (0;7) | −4 (−8;-1) | |||
CA | 129 (40) | 2 (−2;6) | 0.49 | 3 (0;7) | 0.30 | −5 (−8;-2) | 0.87 |
AA | 19 (6) | −6 (−18;7) | 6 (−5;19) | −8 (−18;4) | |||
CA + AA | 148 (46) | 1 (−2;5) | 0.41 | 3 (0;7) | 0.14 | −5 (−8;-2) | 0.59 |
rs6493487 | |||||||
AA | 192 (59) | 3 (−1;8) | 3 (−1;7) | −5 (−9;-1) | |||
GA | 125 (39) | 2 (−2;5) | 0.79 | 4 (1;8) | 0.64 | −5 (−8;-2) | 0.60 |
GG | 8 (2) | −1 (−11;11) | −1 (−10;9) | −5 (−14;5) | |||
GA + GG | 133 (41) | 1 (−2;5) | 0.79 | 4 (1;7) | 0.97 | −5 (−8;-2) | 0.33 |
rs2008691 | |||||||
AA | 210 | 2 (−2;6) | 5 (2;8) | −6 (−9;-3) | |||
(65) | |||||||
GA | 106 (32) | 2 (−2;6) | 0.67 | 1 (−2;5) | 0.03 | −4 (−8;0) | 0.41 |
GG | 9 (3) | 12 (−4;31) | 10 (−3;26) | 6 (−7;22) | |||
GA + GG | 115 (35) | 2 (−2;7) | 0.70 | 2 (−2;6) | 0.02 | −4 (−7;0) | 0.31 |
rs3751591 | |||||||
TT | 232 (72) | 2 (−1;6) | 4 (1;7) | −5 (−8;-2) | |||
TC | 85 (26) | 1 (−3;6) | 0.78 | 2 (−2;6) | 0.70 | −5 (−8;-1) | 0.90 |
CC | 8 (2) | 11 (−7;31) | 9 (−6;26) | 10 (−6;28) | |||
CC vs. TT + TC | 8 (2) | 11 (−7;31) | 0.81 | 9 (−6;26) | 0.74 | 10 (−6;28) | 0.86 |
rs2445762 | |||||||
TT | 166 (51) | 2 (−1;6) | 3 (0;6) | −4 (−7;-1) | |||
TC | 139 (43) | 1 (−3;6) | 0.94 | 5 (1;9) | 0.19 | −6 (−10;-2) | 0.72 |
CC | 20 (6) | 3 (−9;16) | −2 (−11;8) | −8 (−17;2) | |||
TC + CC | 159 (49) | 1 (−3;6) | 1.00 | 4 (0;8) | 0.17 | −6 (−10;-3) | 0.61 |
rs11070844 | |||||||
CC | 255 (78) | 1 (−2;5) | 3 (0;6) | −4 (−7;-1) | |||
TC | 66 (21) | 5 (−1;11) | 0.73 | 7 (1;12) | 0.92 | −7 (−12;-3) | 0.06 |
TT | 4 (1) | 4 (−20;37) | 15 (−9;45) | 11 (−13;42) | |||
TC + TT | 70 (22) | 5 (−1;11) | 0.42 | 7 (2;12) | 0.74 | −7 (−12;-2) | 0.03 |
Associations with BC risk
ncases (%) | ncontrol (%) | IRRa (95 % CI) | IRRb (95 % CI) | P-valuec | |
---|---|---|---|---|---|
(n = 687) | (n = 687) | ||||
rs10519297 | |||||
AA | 170 (25) | 174 (25) | 1.00 (ref.) | 1.00 (ref.) | |
AG | 341 (50) | 361 (53) | 0.98 (0.76–1.27) | 0.94 (0.72–1.23) | 0.15 |
GG | 176 (25) | 152 (22) | 1.23 (0.90–1.68) | 1.25 (0.91–1.72) | |
AG + GG | 511 (75) | 513 (54) | 1.05 (0.82–1.34) | 1.03 (0.80–1.32) | 0.83 |
rs749292 | |||||
GG | 216 (31) | 203 (30) | 1.00 (ref.) | 1.00 (ref.) | |
AG | 332 (48) | 352 (51) | 0.89 (0.69–1.14) | 0.89 (0.69–1.16) | 0.62 |
AA | 139 (20) | 132 (19) | 0.97 (0.71–1.33) | 0.99 (0.72–1.37) | |
AG + AA | 471 (68) | 484 (70) | 0.91 (0.72–1.15) | 0.92 (0.72–1.17) | 0.50 |
rs1062033 | |||||
CC | 203 (30) | 186 (27) | 1.00 (ref.) | 1.00 (ref.) | |
CG | 333 (48) | 354 (52) | 0.85 (0.66–1.10) | 0.85 (0.65–1.11) | 0.46 |
GG | 151 (22) | 147 (21) | 0.92 (0.67–1.25) | 0.94 (0.68–1.28) | |
CG + GG | 484 (70) | 501 (73) | 0.87 (0.68–1.11) | 0.88 (0.68–1.12) | 0.30 |
rs10046 | |||||
AA | 182 (27) | 188 (28) | 1.00 (ref.) | 1.00 (ref.) | |
AG | 346 (50) | 353 (51) | 1.02 (0.79–1.31) | 0.97 (0.75–1.26) | 0.52 |
GG | 159 (23) | 146 (21) | 1.16 (0.85–1.57) | 1.15 (0.84–1.57) | |
AG + GG | 505 (73) | 499 (72) | 1.06 (0.84–1.34) | 1.02 (0.80–1.31) | 0.86 |
rs4646 | |||||
CC | 372 (54) | 371 (54) | 1.00 (ref.) | 1.00 (ref.) | |
CA | 265 (39) | 262 (38) | 1.00 (0.80–1.25) | 0.97 (0.77–1.21) | 0.95 |
AA | 50 (7) | 54 (8) | 0.96 (0.63–1.45) | 1.00 (0.65–1.53) | |
CA + AA | 315 (46) | 316 (46) | 0.99 (0.81–1.22) | 0.97 (0.78–1.20) | 0.78 |
rs6493487 | |||||
AA | 407 (59) | 430 (62) | 1.00 (ref.) | 1.00 (ref.) | |
GA | 245 (36) | 218 (32) | 1.23 (0.98–1.55) | 1.24 (0.98–1.58) | 0.16 |
GG | 35 (5) | 39 (6) | 0.96 (0.60–1.54) | 0.88 (0.54–1.44) | |
GA + GG | 280 (40) | 257 (38) | 1.19 (0.95–1.48) | 1.18 (0.94–1.48) | 0.16 |
rs2008691 | |||||
AA | 479 (70) | 470 (68) | 1.00 (ref.) | 1.00 (ref.) | |
GA | 179 (26) | 198 (29) | 0.88 (0.69–1.11) | 0.88 (0.69–1.12) | 0.25 |
GG | 29 (4) | 19 (3) | 1.43 (0.80–2.57) | 1.45 (0.80–2.64) | |
GA + GG | 208 (30) | 217 (32) | 0.93 (0.74–1.17) | 0.93 (0.74–1.18) | 0.57 |
rs3751591 | |||||
TT | 479 (70) | 498 (72) | 1.00 (ref.) | 1.00 (ref.) | |
TC | 182 (26) | 176 (26) | 1.07 (0.84–1.36) | 1.07 (0.83–1.37) | 0.60 |
CC | 26 (4) | 13 (2) | 2.13 (1.04–4.39) | 2.12 (1.02–4.43) | 0.04 |
TC + CC | 208 (30) | 189 (28) | 1.13 (0.89–1.42) | 1.13 (0.89–1.44) | 0.31 |
CC vs. TT + TCd | 26 (4) | 13 (2) | 2.09 (1.02–4.29) | 2.09 (1.00–4.34) | 0.05 |
rs2445762 | |||||
TT | 359 (52) | 365 (53) | 1.00 (ref.) | 1.00 (ref.) | |
TC | 278 (40) | 276 (40) | 1.02 (0.81–1.27) | 1.04 (0.83–1.31) | 0.74 |
CC | 50 (8) | 46 (7) | 1.10 (0.72–1.69) | 1.19 (0.76–1.85) | |
TC + CC | 328 (48) | 322 (47) | 1.03 (0.83–1.27) | 1.06 (0.85–1.32) | 0.61 |
rs11070844 | |||||
CC | 552 (80) | 556 (81) | 1.00 (ref.) | 1.00 (ref.) | |
TC | 129 (19) | 125 (18) | 1.06 (0.801–1.39) | 1.06 (0.80–1.40) | 0.88 |
TT | 6 (1) | 6 (1) | 1.01 (0.33–3.13) | 0.86 (0.27–2.73) | |
TC + TT | 135 (20) | 131 (19) | 1.06 (0.81–1.38) | 1.05 (0.80–1.38) | 0.73 |
RCT
Characteristic | PPARγ2 Pro12 (n = 18) | PPARγ2
12Ala (n = 7) | P-valuesd | ||
Median | Range | Median | Range | ||
Agea, years | 58.5 | (49–70) | 55 | (47–67) | 0.28 |
Weight, kg | 64.1 | (50.1–86.5) | 59.8 | (57.2–68.4) | 0.27 |
BMI, kg/m2 | 23.5 | (19.1–26.9) | 22.4 | (19.4–24.5) | 0.14 |
Years since last menses | 5.5 | (1–25) | 6 | (3–16) | 0.46 |
Alcohol intake/week | 6.5 | (1–15) | 6 | (3.5–14) | 0.70 |
Characteristic | PPARγ2 Pro12 (n = 18) | PPARγ2
12Ala (n = 7) | |||
No. | % | No. | % | ||
Menopause type | |||||
Naturalb | 17 | 94.4 | 6 | 85.7 | |
Hysterectomyc | 1 | 6.6 | 1 | 14.3 | |
Smoking status | |||||
Never | 10 | 55.6 | 5 | 71.4 | |
Former | 8 | 44.4 | 2 | 28.6 |