Introduction
Materials and methods
Study subjects
SNP selection and genotyping
SNP | Chr. (Cytoband) | Position | Associated genes | GWAS study | Allelesa | Call Rate (%) |
P
b
| MAFc | MAFd | Case (%) | Control (%) |
P
e
|
---|---|---|---|---|---|---|---|---|---|---|---|---|
rs13387042
| 2q35 | 217614077 | TNP1, IGFBP5, IGFBP2 | Stacey, 2007 (12) Thomas, 2009 (13) | G > A | 98.65 | 0.41 | 0.11 | 0.12 | 1.39/25.87/72.74 | 1.01/21.08/77.91 | 0.039 |
rs4973768
| 3p24.1 | 27391017 | SLC4A7 | Ahmed, 2009 (8) | C > T | 97.58 | 0.91 | 0.17 | 0.19 | 3.05/35.05/61.90 | 3.63/31.52/64.85 | 0.265 |
rs2307032
| 3p24.1 | 27407999 | SLC4A7 | Ahmed, 2009 (8) | C > T | 97.92 | 0.08 | 0.41 | 0.40 | 18.58/50.64/30.78 | 17.61/45.23/37.16 | 0.017 |
rs16886165
| 5p11.2 | 56058840 | MAP3K1 | Thomas, 2009 (13) | T > G | 96.34 | 0.65 | 0.31 | 0.34 | 12.10/46.98/40.93 | 11.49/45.98/42.53 | 0.781 |
rs889312
| 5q11.2 | 56067641 | MAP3K1 | Easton, 2007 (9) | C > A | 98.31 | 0.23 | 0.50 | 0.48 | 21.55/50.41/28.04 | 22.03/52.09/25.88 | 0.595 |
rs4415084
| 5p12 | 44698272 | Unknown | Stacey, 2008 (12) Thomas,2009 (13) | A > G | 96.12 | 0.03 | 0.46 | 0.43 | 19.95/44.56/35.84 | 20.41/45.64/33.94 | 0.798 |
rs10941679
| 5p12 | 44742255 | MRPS30 | Stacey, 2008 (12) Thomas,2009 (13) | G > A | 97.19 | 0.95 | 0.57 | 0.50 | 24.23/49.29/26.48 | 24.83/50.23/24.94 | 0.768 |
rs2180341
| 6q22.33 | 127642323 | ECHDC1, RNF146 | Gold, 2008 (10) | A > G | 97.30 | 0.49 | 0.22 | 0.26 | 6.35/43.88/49.76 | 7.50/37.95/54.55 | 0.040 |
rs2046210
| 6q25.1 | 151990059 | ESR1, C6orf97 | Zheng, 2009 (14) | G > A | 98.48 | 0.50 | 0.35 | 0.34 | 18.35/47.97/33.68 | 12.36/44.16/43.48 | 1.26 × 10-5 |
rs13281615
| 8q24.21 | 128424800 | Unknown | Easton, 2007 (9) | A > G | 97.98 | 0.59 | 0.57 | 0.49 | 23.56/52.40/24.03 | 24.63/49.04/26.32 | 0.353 |
rs1562430
| 8q24.21 | 128457034 | Unknown | Thomas 2009 (13) | T > C | 98.82 | 0.11 | 0.20 | 0.18 | 2.75/27.38/69.87 | 2.49/31.33/66.18 | 0.191 |
rs2981582
| 10q26.13 | 123342307 | FGFR2 | Easton, 2007 (9) | C > T | 99.44 | 0.94 | 0.33 | 0.31 | 12.61/45.87/41.51 | 9.82/43.3/46.88 | 0.037 |
rs3817198
| 11p15.5 | 1865582 | LSP1 | Easton, 2007 (9) | T > C | 98.82 | 0.88 | 0.09 | 0.12 | 2.41/23.79/73.79 | 1.58/21.53/76.89 | 0.213 |
rs12443621
| 16q12.1 | 51105538 | TNRC9 | Easton, 2007 (9) | G > A | 99.10 | 0.34 | 0.39 | 0.45 | 18.23/48.17/33.60 | 19.10/51.12/29.78 | 0.227 |
rs6504950
| 17q23.2 | 50411470 | COX11 | Ahmed, 2009 (8) | G > A | 98.71 | 0.84 | 0.10 | 0.09 | 0.35/14.14/85.52 | 0.78/15.92/83.30 | 0.264 |
Statistical analyses
Results
Variables | Testing Set, TS (n= 1,778) | Validation Set, VS (n= 1,881) | TS + VS (n= 3,659) | ||||
---|---|---|---|---|---|---|---|
Cases (n= 878) | Controls (n= 900) | Cases (n= 914) | Controls (n= 967) | Cases (n= 1,792) | Controls (n= 1,867) | P-value | |
Age, yr (Mean ± SD)
| 51.29 ± 11.38 | 51.47 ± 11.67 | 50.11 ± 11.36 | 48.64 ± 12.28 | 50.69 ± 11.38 | 50.01 ± 12.07 | 0.08 |
Age group, yr (%)
| 0.06 | ||||||
< 50
| 425 (48.41) | 463 (51.44) | 467 (51.09) | 526 (54.40) | 896 (49.78) | 989 (52.97) | |
≥ 50
| 453 (51.59) | 437 (48.56) | 447 (48.91) | 441 (45.60) | 900 (50.22) | 878 (47.03) | |
Age at menarche, yr (Mean ± SD)
| 15.26 ± 1.83 | 15.85 ± 1.89 | 15.19 ± 1.94 | 16.23 ± 1.81 | 15.22 ± 1.89 | 16.05 ± 1.86 | < 0.001 |
Age at menarche group, yr (%)
| < 0.001 | ||||||
< 15 (Early menarche)
| 331 (38.40) | 227 (25.33) | 357 (39.98) | 169 (17.57) | 688 (39.20) | 396 (21.31) | |
15 to 17 (Normal menarche)
| 325 (37.70) | 352 (39.29) | 333 (37.29) | 376 (39.09) | 658 (37.49) | 728 (39.18) | |
≥ 17 (Late menarche)
| 206 (23.90) | 317 (35.38) | 203 (22.73) | 417 (43.35) | 409 (23.30) | 734 (39.50) | |
Age at first live birth, yr (Mean ± SD)
| 25.62 ± 3.39 | 24.90 ± 3.35 | 25.51 ± 3.06 | 24.17 ± 2.51 | 25.56 ± 3.22 | 24.52 ± 2.99 | < 0.001d |
Age at first live birth group, yr (%)
a
| < 0.001 | ||||||
< 25 (Early birth)
| 305 (34.74) | 398 (44.27) | 312 (34.36) | 527 (54.67) | 617 (34.55) | 925 (49.65) | |
≥ 25
a
(Late birth)
| 573 (65.26) | 501 (55.73) | 596 (65.64) | 437 (45.33) | 1,169 (65.45) | 938 (50.35) | |
Age at menopause, yr. (Mean ± SD)
b
| 49.15 ± 4.09 | 48.90 ± 4.43 | 48.71 ± 4.63 | 49.42 ± 4.04 | 48.93 ± 4.37 | 49.16 ± 4.25 | 0.27 |
Menopausal status (%)
b
| 0.02 | ||||||
Premenopausal
| 416 (47.38) | 437 (48.56) | 434 (47.48) | 529 (54.71) | 850 (47.43) | 966 (51.74) | |
Postmenopausal
| 444 (50.57) | 448 (49.78) | 463 (50.66) | 428 (44.26) | 907 (50.61) | 876 (46.92) | |
Estrogen receptor (ER) (%)
c
| |||||||
Positive | 369 (42.03) | 434 (47.48) | 803 (44.81) | ||||
Negative
| 321 (36.56) | 322 (35.23) | 643 (35.88) | ||||
Progesterone receptor (PR) (%)
c
| |||||||
Positive
| 396 (45.10) | 414 (45.30) | 810 (45.20) | ||||
Negative
| 294 (33.49) | 340 (37.20) | 634 (35.38) |
Genotype | Testing Set, TS. (n= 1,779) | Validation Set, VS. (n= 1,881) | Adjusted OR (95% CI)a |
P
a
| Adjusted OR (95% CI)b |
P
b
| Adjusted OR (95% CI)c |
P
c
| ||
---|---|---|---|---|---|---|---|---|---|---|
Case (%) (n= 878) | Control (%) (n= 900) | Cases (%) (n= 914) | Controls (%) (n= 967) | |||||||
2q35: rs13387042
| ||||||||||
GG
| 627 (72.74) | 695 (77.91) | 712 (78.33) | 773 (80.60) | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
GA
| 223 (25.87) | 188 (21.08) | 181 (19.91) | 178 (18.56) |
1.29 (1.03 to 1.63)
| 0.030 | 1.21 (0.93 to 1.56) | 0.155 |
1.23 (1.04 to 1.46)
| 0.018 |
AA
| 12 (1.39) | 9 (1.01) | 16 (1.76) | 8 (0.83) | 1.46 (0.60 to 3.54) | 0.407 |
2.56 (1.03 to 6.38)
| 0.044 |
1.95 (1.04 to 3.66)
| 0.037 |
GA/AA
| 235 (27.26) | 197 (22.09) | 197 (21.67) | 186 (19.40) |
1.30 (1.04 to 1.63)
| 0.023 | 1.27 (0.99 to 1.63) | 0.064 |
1.26 (1.07 to 1.49)
| 0.006 |
A allelic trend (Additive model)
|
1.30 (1.05 to 1.62)
| 0.017 | 1.21 (0.97 to 1.51) | 0.085 |
1.25 (1.07 to 1.46)
| 0.004 | ||||
3q24.1: rs2307032
| ||||||||||
CC
| 265 (30.78) | 327 (37.16) | 288 (31.58) | 326 (34.42) | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
CT
| 436 (50.64) | 398 (45.23) | 429 (47.04) | 464 (49.00) |
1.31 (1.05 to 1.63)
| 0.016 | 1.09 (0.87 to 1.37) | 0.459 |
1.20 (1.02 to 1.40)
| 0.027 |
TT
| 160 (18.58) | 155 (17.61) | 195 (21.38) | 157 (16.58) | 1.27 (0.95 to 1.69) | 0.105 |
1.43 (1.06 to 1.91)
| 0.018 |
1.36 (1.11 to 1.66)
| 0.003 |
CT/TT
| 596 (69.22) | 553 (62.84) | 624 (68.42) | 621 (65.58) |
1.30 (1.06 to 1.60)
| 0.014 | 1.18 (0.95 to 1.46) | 0.138 |
1.24 (1.07 to 1.44)
| 0.005 |
T allelic trend (Additive model)
| 1.11 (0.97 to 1.27) | 0.122 |
1.17 (1.02 to 1.34)
| 0.025 |
1.14 (1.04 to 1.26)
| 0.006 | ||||
6q22.33: rs2180341
| ||||||||||
AA
| 423 (49.76) | 480 (54.55) | 479 (52.64) | 541 (56.53) | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
AG
| 373 (43.88) | 334 (37.95) | 380 (41.76) | 350 (36.57) |
1.29 (1.05 to 1.59)
| 0.016 |
1.26 (1.02 to 1.56)
| 0.033 |
1.28 (1.10 to 1.48)
| 0.001 |
GG
| 54 (6.35) | 66 (7.50) | 51 (5.60) | 66 (6.90) | 0.96 (0.64 to 1.43) | 0.847 | 0.87 (0.57 to 1.32) | 0.505 | 0.93 (0.70 to 1.24) | 0.614 |
AG/GG
| 427 (50.24) | 400 (45.45) | 431 (47.36) | 416 (43.47) |
1.24 (1.01 to 1.51)
| 0.036 | 1.20 (0.97 to 1.47) | 0.086 |
1.22 (1.06 to 1.40)
| 0.006 |
G allelic trend (Additive model)
| 1.10 (0.94 to 1.29) | 0.222 | 1.06 (0.90 to 1.24) | 0.496 | 1.08 (0.97 to 1.20) | 0.174 | ||||
6q25.1: rs2046210
| ||||||||||
GG
| 290 (33.68) | 387 (43.48) | 292 (32.19) | 380 (39.58) | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
GA
| 413 (47.97) | 393 (44.16) | 460 (50.72) | 443 (46.15) |
1.46 (1.17 to 1.81)
| 6.31 × 10to 4 |
1.38 (1.10 to 1.73)
| 4.81 × 10-3 |
1.43 (1.23 to 1.67)
| 5.12 × 10-6 |
AA
| 158 (18.35) | 110 (12.36) | 155 (17.09) | 137 (14.27) |
2.05 (1.52 to 2.76)
| 2.95 × 10-6 |
1.54 (1.13 to 2.09)
| 5.76 × 10-3 |
1.79 (1.45 to 2.22)
| 7.13 × 10-8 |
GA/AA
| 571 (66.32) | 503 (56.52) | 615 (67.81) | 580 (60.42) |
1.59 (1.29 to 1.94)
| 8.52 × 10-6 |
1.42 (1.15 to 1.76)
| 1.27 × 10-3 |
1.51 (1.31 to 1.75)
| 2.40 × 10-8 |
A allelic trend (Additive model)
|
1.41 (1.22 to 1.62)
| 1.54E-06 |
1.24 (1.08 to 1.43)
| 2.27E-03 |
1.33 (1.20 to 1.46)
| 1.92E-08 | ||||
10q26.13: rs2981582
| ||||||||||
CC
| 362 (41.51) | 420 (46.88) | 370 (41.29) | 464 (48.95) | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
CT
| 400 (45.87) | 388 (43.30) | 420 (46.88) | 408 (43.04) |
1.25 (1.01 to 1.53)
| 3.85 × 10-2 | 1.20 (0.97 to 1.49) | 9.84 × 10-2 |
1.24 (1.07 to 1.44)
| 4.40 × 10-3 |
TT
| 110 (12.61) | 88 (9.82) | 106 (11.83) | 76 (8.02) |
1.49 (1.07 to 2.08)
| 1.76 × 10-2 |
1.82 (1.27 to 2.62)
| 1.19 × 10-3 |
1.65 (1.29 to 2.10)
| 5.75 × 10-5 |
CT/TT
| 510 (58.49) | 476 (53.13) | 526 (58.71) | 484 (51.05) |
1.29 (1.06 to 1.57)
| 1.15 × 10-2 |
1.29 (1.05 to 1.59)
| 9.84 × 10-2 |
1.31 (1.14 to 1.50)
| 1.96 × 10-4 |
T allelic trend (Additive model)
|
1.23 (1.07 to 1.42)
| 0.005 |
1.30 (1.12-1.51)
| 0.0005 |
1.27 (1.15 to 1.41)
| 4.89E-06 |
Risk models | TS + VS sets | Adjusted ORc (95% CI) |
P
c
| Pfor trendc | |
---|---|---|---|---|---|
Cases (%) | Controls (%) | ||||
Counts of risk alleles
a
| |||||
0 to 1
| 187 (11.08) | 295 (16.70) | 1.00 (ref.) | ||
2
| 327 (19.37) | 408 (23.10) | 1.25 (0.98 to 1.60) | 7.04E-02 | |
3
| 472 (27.96) | 503 (28.48) |
1.48 (1.18 to 1.87)
| 8.04E-04 | |
4
| 404 (23.93) | 351 (19.88) |
1.85 (1.45 to 2.35)
| 6.03E-07 | |
5
| 201 (11.91) | 152 (8.61) |
2.09 (1.56 to 2.79)
| 6.76E-07 | |
≥ 6
| 97 (5.75) | 57 (3.23) |
2.67 (1.81 to 3.93)
| 6.40E-07 | 2.27E-12 |
Counts of risk factors
b
| |||||
0 to 2
| 109 (6.61) | 277 (15.79) | 1.00 (ref.) | ||
3
| 203 (12.31) | 344 (19.61) |
1.54 (1.16 to 2.04)
| 3.08E-03 | |
4
| 335 (20.32) | 386 (22.01) |
2.28 (1.75 to 2.99)
| 1.54E-09 | |
5
| 346 (20.98) | 377 (21.49) |
2.47 (1.89 to 3.23)
| 4.11E-11 | |
6
| 338 (20.50) | 219 (12.49) |
4.19 (3.15 to 5.56)
| 4.07E-23 | |
≥ 7
| 318 (19.28) | 151 (8.61) |
5.61 (4.16 to 7.56)
| 1.03E-29 | 3.76E-40 |
Genetic risk score
a
| |||||
0 (< Q25)
| 349 (20.68) | 487 (27.58) | 1.00 (ref.) | ||
1(Q25 to Q50)
| 406 (24.05) | 499 (28.26) | 1.21 (0.99 to 1.48) | 6.96E-02 | |
2 (Q50 to Q75)
| 436 (25.83) | 405 (22.93) |
1.57 (1.28 to 1.93)
| 1.74E-05 | |
3 (≥ Q75)
| 497 (29.44) | 375 (21.23) |
1.91 (1.56 to 2.35)
| 5.60E-10 | 2.02E-11 |
Genetic & clinical risk score
b
| |||||
0 (< Q25)
| 167 (10.13) | 437 (24.91) | 1.00 (ref.) | ||
1 (Q25 to Q50)
| 332 (20.13) | 442 (25.20) |
2.01 (1.60 to 2.53)
| 2.68E-09 | |
2 (Q50 to Q75)
| 406 (24.62) | 438 (24.97) |
2.55 (2.03 to 3.20)
| 6.66E-16 | |
3 (≥ Q75)
| 744 (45.12) | 437 (24.91) |
4.73 (3.80 to 5.88)
| 2.38E-44 | 2.27E-47 |
Groups | Case (%) | Controls (%) | Relative risk | Absolute risk | ||
---|---|---|---|---|---|---|
Median (SD) | Min to Max | Median (SD) | Min to Max | |||
Counts of risk alleles
a
| ||||||
0 to 1
| 187 (11.08) | 295 (16.70) | 0.51 (0.05) | 0.45 to 0.59 | 0.03 (0.003) | 0.03 to 0.03 |
2
| 327 (19.37) | 408 (23.10) | 0.65 (0.06) | 0.53 to 0.77 | 0.04 (0.003) | 0.03 to 0.04 |
3
| 472 (27.96) | 503 (28.48) | 0.81 (0.08) | 0.61 to 0.97 | 0.05 (0.005) | 0.04 to 0.06 |
4
| 404 (23.93) | 351 (19.88) | 0.96 (0.11) | 0.69 to 1.23 | 0.06 (0.006) | 0.04 to 0.07 |
5
| 201 (11.91) | 152 (8.61) | 1.16 (0.12) | 0.87 to 1.53 | 0.07 (0.007) | 0.05 to 0.09 |
≥ 6
| 97 (5.75) | 57 (3.23) | 1.45 (0.21) | 1.10 to 2.36 | 0.08 (0.012) | 0.06 to 0.14 |
Counts of risk factors
b
| ||||||
0 to 2
| 109 (6.61) | 277 (15.79) | 0.61 (0.20) | 0.35 to 1.14 | 0.04 (0.01) | 0.02 to 0.07 |
3 | 203 (12.31) | 344 (19.61) | 0.91 (0.33) | 0.47 to 2.00 | 0.05 (0.02) | 0.03 to 0.12 |
4
| 335 (20.32) | 386 (22.01)c | 1.22 (0.47) | 0.53 to 2.62 | 0.07 (0.03) | 0.03 to 0.15 |
5
| 346 (20.98) | 377 (21.49) | 1.78 (0.65) | 0.67 to 3.43 | 0.10 (0.04) | 0.04 to 0.20 |
6
| 338 (20.50) | 219 (12.49) | 2.44 (0.82) | 0.88 to 4.33 | 0.14 (0.05) | 0.05 to 0.25 |
≥ 7
| 318 (19.28) | 151 (8.61) | 3.92 (1.24) | 1.11 to 7.78 | 0.23 (0.07) | 0.06 to 0.45 |