Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)
Abstract
:1. Introduction
2. Materials and Methods
2.1. Research Design and Study Population
2.2. Assessment of Dietary Methyl-Group Donor Intake
2.3. Lifestyle Variables and Anthropometric Measurements
2.4. Outcome Assessment
2.5. Data Analysis
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Country | Study Participants | BC Cases | Age Range at Enrolment | Follow-Up | Person-Years | MGD Score | Dietary Folate Intake | Dietary Choline Intake | Dietary Betaine Intake | Dietary Methionine Intake |
---|---|---|---|---|---|---|---|---|---|---|
N | N | years | years a | unit b | µg/day b | mg/day b | mg/day b | g/day b | ||
Total | 318,686 | 13,320 | 19.9–98.5 | 14.1 (3.8) | 4,492,761 | −0.4 (−2.2; 1.7) | 327 (257; 415) | 264 (214; 323) | 112 (50; 174) | 1.41 (1.12; 1.76) |
Denmark | 28,720 | 1869 | 50.1–65.8 | 15.1 (3.9) | 432,423 | −1.4 (−2.9; 0.3) | 283 (235; 338) | 276 (219; 345) | 32 (20; 52) | 1.46 (1.18; 1.79) |
France | 67,403 | 3324 | 41.8–71.4 | 12.9 (3.4) | 869,372 | 1.5 (−0.4; 3.8) | 421 (344; 510) | 296 (242; 363) | 136 (88; 194) | 1.66 (1.33; 2.04) |
Germany | 27,379 | 817 | 19.9–70.1 | 10.4 (3.0) | 284,937 | −2.6 (−3.8; 1.2) | 302 (252; 360) | 208 (172; 251) | 17 (12; 24) | 1.30 (1.06; 1.58) |
Italy | 30,513 | 1211 | 29.1–77.8 | 14.3 (3.03) | 434,997 | 0.7 (−1.4; 3.1) | 340 (269; 431) | 244 (202; 292) | 168 (110; 249) | 1.67 (1.35; 2.03) |
The Netherlands | 26,912 | 1049 | 20.1–70.1 | 14.3 (3.4) | 384,249 | −0.5(−1.9; 0.9) | 304 (261; 352) | 256 (215; 301) | 146 (107; 189) | 1.31 (1.08; 1.55) |
Norway | 33,975 | 1201 | 40.9–55.9 | 13.3 (2.5) | 452,171 | −1.0 (−2.5; 0.5) | 230 (190; 275) | 255 (212; 303) | 135 (117; 207) | 1.33 (1.09; 1.61) |
Spain | 24,850 | 655 | 29.0–69.8 | 16.0 (2.9) | 398,837 | 0.2 (−1.4; 2.1) | 359 (292; 440) | 271 (224; 322) | 129 (86; 178) | 1.45 (1.19; 1.76) |
Sweden | 26,368 | 1314 | 29.2–73.6 | 16.8 (4.8) | 442,242 | −2.1 (−3.7; −0.4) | 256 (207; 312) | 227 (175; 288) | 49 (30; 79) | 1.35 (1.05; 1.67) |
UK General Population | 17,169 | 817 | 36.0–78.2 | 14.9 (4.0) | 255,137 | 0.1 (−1.5; 1.9) | 355 (293; 426) | 300 (251; 352) | 111 (71; 157) | 1.36 (1.13; 1.62) |
UK Health Conscious | 35,397 | 1063 | 20.0–98.5 | 15.2 (3.4) | 538,396 | −0.04 (−1.7; 1.9) | 388 (314; 476) | 285 (234; 341) | 130 (82; 182) | 1.09 (0.82; 1.40) |
Overall Breast Cancer Risk (N = 318,686) | Premenopausal Breast Cancer Risk (N = 110,678) | Postmenopausal Breast Cancer Risk (N = 145,212) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
BC Cases | Person Years | Multivariable Model a HR (95% CI) | BC cases | Person years | Multivariable Model b HR (95% CI) | BC Cases | Person Years | Multivariable Model b HR (95% CI) | Pinteraction b, c | |
MGD score | ||||||||||
Continuous (1 unit) | 13,320 | 4,492,760 | 1.00 (0.98–1.01) | 3314 | 1,592,971 | 0.99 (0.97–1.02) | 7002 | 2,015,866 | 1.00 (0.99–1.02) | 0.199b |
Q1: ≤ −2.58 | 2568 | 885,323 | 1 (Ref.) | 562 | 305,808 | 1 (Ref.) | 1429 | 410,789 | 1 (Ref.) | |
Q2: > −2.5–−1.00 | 2589 | 898,478 | 0.96 (0.91–1.02) | 608 | 305,208 | 1.03 (0.91–1.16) | 1421 | 420,851 | 0.98 (0.90–1.06) | |
Q3: > −1.00–0.39 | 2700 | 905,782 | 0.99 (0.93–1.06) | 680 | 320,068 | 1.06 (0.93–1.22) | 1448 | 410,339 | 1.03 (0.94–1.12) | |
Q4: > 0.39–2.31 | 2668 | 909,636 | 0.96 (0.89–1.04) | 702 | 329,377 | 1.05 (0.90–1.22) | 1352 | 400,920 | 0.98 (0.89–1.09) | |
Q5: > 2.31 | 2795 | 893,541 | 0.98 (0.89–1.08) | 762 | 332,509 | 1.05 (0.86–1.29) | 1352 | 372,967 | 1.05 (0.92–1.20) | 0.596c |
Ptrend | 0.857 | 0.675 | 0.449 | |||||||
Dietary folate (µg/day) | ||||||||||
Continuous (per 1 SD = 128 µg/day) | 13,320 | 4,492,760 | 1.01 (0.98–1.05) | 3314 | 1,592,971 | 1.02 (0.95–1.09) | 7002 | 2,015,866 | 1.02 (0.97–1.07) | 0.234 b |
Q1: ≤ 242 | 2724 | 903,078 | 1 (Ref.) | 568 | 275,216 | 1 (Ref.) | 1470 | 420,708 | 1 (Ref.) | |
Q2: > 242–298 | 2684 | 901223 | 0.97 (0.91–1.02) | 597 | 296,441 | 0.96 (0.85–1.09) | 1501 | 427,502 | 0.97 (0.90–1.05) | |
Q3: > 298–357 | 2569 | 899,889 | 0.93 (0.87–1.00) | 648 | 319,253 | 0.97 (0.85–1.11) | 1412 | 418,308 | 0.94 (0.86–1.03) | |
Q4: > 357–440 | 2683 | 896,336 | 0.98 (0.91–1.06) | 739 | 341,300 | 1.04 (0.89–1.21) | 1361 | 390,803 | 0.96 (0.86–1.06) | |
Q5: > 440 | 2660 | 892,233 | 0.98 (0.89–1.08) | 762 | 360,761 | 1.02 (0.84–1.23) | 1258 | 358,544 | 0.96 (0.84–1.10) | 0.665 c |
Ptrend | 0.999 | 0.609 | 0.618 | |||||||
Choline (mg/day) | ||||||||||
Continuous (per 1 SD = 90 mg/day) | 13,320 | 4,492,760 | 1.00 (0.98–1.03) | 3314 | 1,592,971 | 0.99 (0.94–1.05) | 7002 | 2,015,866 | 1.02 (0.98–1.05) | 0.088 b |
Q1: ≤ 202 | 2448 | 881,386 | 1 (Ref.) | 576 | 320,398 | 1 (Ref.) | 1297 | 392,442 | 1 (Ref.) | |
Q2: < 202–244 | 2626 | 893,846 | 1.01 (0.96–1.07) | 710 | 320,444 | 1.15 (1.02–1.29) | 1350 | 401,919 | 0.99 (0.92–1.08) | |
Q3: < 244–285 | 2554 | 904,412 | 0.96 (0.90–1.02) | 625 | 326,142 | 0.98 (0.86–1.11) | 1364 | 402,297 | 0.99 (0.91–1.08) | |
Q4: < 285–339 | 2716 | 909,864 | 0.98 (0.92–1.05) | 698 | 326,899 | 1.07 (0.93–1.23) | 1392 | 402,238 | 0.98 (0.90–1.08) | |
Q5: > 339 | 2976 | 903,251 | 1.00 (0.93–1.08) | 705 | 299,087 | 1.13 (0.96–1.33) | 1599 | 416,970 | 1.03 (0.93–1.14) | 0.110 c |
Ptrend | 0.995 | 0.307 | 0.580 | |||||||
Betaine (mg/day) | ||||||||||
Continuous (per 1 SD = 88 mg/day) | 13,320 | 4,492,760 | 0.99 (0.96–1.02) | 3314 | 1,592,971 | 0.99 (0.94–1.04) | 7002 | 2,015,866 | 0.99 (0.96–1.03) | 0.303 b |
Q1: ≤ 39 | 2783 | 840,795 | 1 (Ref.) | 488 | 233,239 | 1 (Ref.) | 1776 | 455,887 | 1 (Ref.) | |
Q2: < 39–88 | 2816 | 936,529 | 0.97 (0.91–1.03) | 617 | 302,013 | 0.99 (0.85–1.16) | 1559 | 448,325 | 0.95 (0.88–1.03) | |
Q3: < 88–132 | 2659 | 906,530 | 1.00 (0.94–1.08) | 655 | 322,004 | 0.94 (0.80–1.12) | 1352 | 392,397 | 1.02 (0.93–1.12) | |
Q4: < 132–193 | 2642 | 909,235 | 1.01 (0.94–1.09) | 808 | 360,323 | 1.04 (0.88–1.23) | 1248 | 382,114 | 0.99 (0.89–1.09) | |
Q5: > 193 | 2420 | 899,670 | 0.97 (0.89–1.05) | 746 | 375,393 | 0.93 (0.78–1.12) | 1067 | 337,143 | 0.98 (0.88–1.09) | 0.269 c |
Ptrend | 0.741 | 0.513 | 0.985 | |||||||
Methionine (g/day) | ||||||||||
Continuous (per 1 g/day) | 13,320 | 449,2760 | 0.97 (0.92–1.02) | 3314 | 1,592,971 | 0.95 (0.85–1.06) | 7002 | 2,015,866 | 0.99 (0.92–1.06) | 0.199 b |
Q1: ≤ 1.06 | 2282 | 910,975 | 1 (Ref.) | 661 | 396,925 | 1 (Ref.) | 1168 | 363,005 | 1 (Ref.) | |
Q2: < 1.06–1.30 | 2591 | 896,369 | 1.02 (0.96–1.08) | 630 | 317,619 | 0.99 (0.89–1.12) | 1362 | 410,524 | 0.99 (0.92–1.08) | |
Q3: < 1.30–1.54 | 2731 | 899,018 | 1.03 (0.96–1.09) | 646 | 302,725 | 1.00 (0.89–1.13) | 1497 | 419,107 | 1.05 (0.97–1.14) | |
Q4: < 1.54–1.85 | 2815 | 898,204 | 1.01 (0.95–1.08) | 673 | 291,694 | 1.01 (0.88–1.15) | 1520 | 421,103 | 1.04 (0.95–1.13) | |
Q5: > 1.85 | 2901 | 888,193 | 0.99 (0.91–1.07) | 704 | 284,007 | 0.98 (0.84–1.15) | 1455 | 402,128 | 1.00 (0.90–1.11) | 0.596 c |
Ptrend | 0.572 | 0.889 | 0.896 |
Low Alcohol Intake (<2 Drinks/Week) (N = 157,363) | Moderate Alcohol Intake (2–12 Drinks/Week) (N = 124,578) | High Alcohol Intake (>12 Drinks/Week) (N = 36,745) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
BC Cases | Person Years | Multivariable Model a HR (95% CI) | BC Cases | Person Years | Multivariable Model a HR (95% CI) | BC Cases | Person Years | Multivariable Model a HR (95% CI) | Pinteraction b, c | |
MGD score | ||||||||||
Continuous (1 unit) | 5882 | 2,241,059 | 0.99 (0.97–1.01) | 5448 | 1,748,126 | 1.00 (0.98–1.02) | 1990 | 503,575 | 1.00 (0.97–1.03) | 0.049 b |
Q1: ≤ −2.58 | 1324 | 504,409 | 1 (Ref.) | 963 | 307,475 | 1 (Ref.) | 281 | 73,439 | 1 (Ref.) | |
Q2: > −2.58–−1.00 | 1175 | 459,463 | 0.92 (0.85–1.01) | 1039 | 349,334 | 0.95 (0.86–1.04) | 375 | 89,680 | 1.12 (0.95–1.32) | |
Q3: > −1.00–0.39 | 1154 | 450,289 | 0.91 (0.82–1.00) | 1134 | 362,348 | 1.00 (0.91–1.11) | 412 | 93,145 | 1.20 (1.01–1.44) | |
Q4: > 0.39–2.31 | 1127 | 433,205 | 0.90 (0.81–1.01) | 1151 | 369,993 | 1.00 (0.89–1.12) | 390 | 106,439 | 1.02 (0.83–1.24) | |
Q5: > 2.31 | 1102 | 393,694 | 0.90 (0.78–1.04) | 1161 | 358,976 | 1.02 (0.87–1.19) | 532 | 140,871 | 1.10 (0.86–1.41) | 0.025 c |
Ptrend | 0.210 | 0.586 | 0.867 | |||||||
Dietary folate (µg/day) | ||||||||||
Continuous (per 1 SD = 128 µg/day) | 5882 | 2,241,059 | 0.96 (0.91–1.02) | 5448 | 1,748,126 | 1.03 (0.97–1.09) | 1990 | 503,575 | 1.10 (1.00–1.20) | 0.063 b |
Q1: ≤ 242 | 1438 | 533,297 | 1 (Ref.) | 975 | 298,193 | 1 (Ref.) | 311 | 71,589 | 1 (Ref.) | |
Q2: > 242–298 | 1211 | 458,111 | 0.93 (0.86–1.02) | 1076 | 350,013 | 0.98 (0.89–1.08) | 397 | 93,099 | 1.02 (0.87–1.19) | |
Q3: > 298–357 | 1067 | 431,110 | 0.85 (0.77–0.94) | 1113 | 366,994 | 1.02 (0.92–1.13) | 389 | 101,785 | 0.95 (0.80–1.13) | |
Q4: > 357–440 | 1101 | 417,655 | 0.89 (0.79–0.99) | 1152 | 368,818 | 1.09 (0.97–1.23) | 430 | 109,863 | 1.00 (0.82–1.22) | |
Q5: > 440 | 1065 | 400,886 | 0.85 (0.74–0.98) | 1132 | 364,109 | 1.12 (0.96–1.31) | 463 | 127,239 | 1.00 (0.78–1.29) | 0.231 c |
Ptrend | 0.052 | 0.059 | 0.998 | |||||||
Dietary choline (mg/day) | ||||||||||
Continuous (per 1 SD = 90 mg/day) | 5882 | 2,241,059 | 0.99 (0.95–1.02) | 5448 | 174,8126 | 1.01 (0.97–1.05) | 1990 | 503,575 | 1.01 (0.95–1.07) | 0.064 b |
Q1: ≤ 202 | 1365 | 535,685 | 1 (Ref.) | 858 | 284,036 | 1 (Ref.) | 225 | 61,666 | 1 (Ref.) | |
Q2: < 202–244 | 1226 | 471,093 | 0.97 (0.90–1.06) | 1055 | 337,077 | 1.03 (0.94–1.13) | 345 | 85,676 | 1.12 (0.94–1.33) | |
Q3: < 244–285 | 1136 | 444,750 | 0.94 (0.86–1.03) | 1038 | 359,764 | 0.94 (0.85–1.03) | 380 | 99,898 | 1.06 (0.89–1.27) | |
Q4: < 285–339 | 1106 | 418,570 | 0.94 (0.85–1.04) | 1171 | 378,671 | 0.98 (0.88–1.09) | 439 | 112,623 | 1.09 (0.91–1.31) | |
Q5: > 339 | 1049 | 370,961 | 0.92 (0.82–1.04) | 1326 | 388,578 | 1.04 (0.92–1.17) | 601 | 143,712 | 1.13 (0.93–1.38) | 0.292 c |
Ptrend | 0.177 | 0.577 | 0.344 | |||||||
Dietary betaine (mg/day) | ||||||||||
Continuous (per 1 SD = 88 mg /day) | 5882 | 2,241,059 | 1.01 (0.97–1.04) | 5448 | 1,748,126 | 0.96 (0.92–1.00) | 1990 | 503,575 | 1.02 (0.95–1.08) | 0.037 b |
Q1: ≤ 39 | 1089 | 378,757 | 1 (Ref.) | 1254 | 359,896 | 1 (Ref.) | 440 | 102,142 | 1 (Ref.) | |
Q2: < 39–88 | 1160 | 464,885 | 0.93 (0.85–1.03) | 1240 | 373,502 | 0.96 (0.87–1.05) | 416 | 98,141 | 1.06 (0.91–1.24) | |
Q3: < 88–132 | 1264 | 474,910 | 1.01 (0.91–1.13) | 1031 | 342,637 | 0.92 (0.83–1.03) | 364 | 88,983 | 1.19 (0.99–1.44) | |
Q4: < 132–193 | 1194 | 447,685 | 1.03 (0.92–1.15) | 1040 | 353,835 | 0.94 (0.83–1.05) | 408 | 107,715 | 1.13 (0.93–1.38) | |
Q5: > 193 | 1175 | 474,821 | 0.98 (0.87–1.10) | 883 | 318,255 | 0.89 (0.79–1.02) | 362 | 106,593 | 1.12 (0.90–1.39) | 0.221 c |
Ptrend | 0.741 | 0.126 | 0.497 | |||||||
Dietary methionine (g/day) | ||||||||||
Continuous (per 1 g/day) | 5882 | 2,241,059 | 0.95 (0.88–1.02) | 5448 | 1,748,126 | 1.02 (0.94–1.10) | 1990 | 503,575 | 0.88 (0.77–1.00) | 0.018 b |
Q1: ≤ 1.06 | 1175 | 510,519 | 1 (Ref.) | 826 | 321,954 | 1 (Ref.) | 281 | 78,502 | 1 (Ref.) | |
Q2: < 1.06–1.30 | 1230 | 469,493 | 1.05 (0.96–1.14) | 1033 | 339,137 | 1.01 (0.92–1.11) | 328 | 87,739 | 0.94 (0.80–1.11) | |
Q3: < 1.30–1.54 | 1220 | 451,112 | 1.03 (0.95–1.13) | 1093 | 353,461 | 0.99 (0.89–1.09) | 418 | 94,445 | 1.09 (0.92–1.28) | |
Q4: < 1.54–1.85 | 1140 | 423,892 | 0.99 (0.90–1.09) | 1226 | 367,949 | 1.02 (0.9–1.14) | 449 | 106,363 | 1.02 (0.86–1.22) | |
Q5: > 1.85 | 1117 | 386,043 | 0.98 (0.87–1.10) | 1270 | 365,624 | 1.03 (0.91–1.16) | 514 | 136,526 | 0.87 (0.71–1.07) | 0.023 c |
Ptrend | 0.460 | 0.581 | 0.200 |
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Van Puyvelde, H.; Papadimitriou, N.; Clasen, J.; Muller, D.; Biessy, C.; Ferrari, P.; Halkjær, J.; Overvad, K.; Tjønneland, A.; Fortner, R.T.; et al. Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Nutrients 2021, 13, 1843. https://doi.org/10.3390/nu13061843
Van Puyvelde H, Papadimitriou N, Clasen J, Muller D, Biessy C, Ferrari P, Halkjær J, Overvad K, Tjønneland A, Fortner RT, et al. Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Nutrients. 2021; 13(6):1843. https://doi.org/10.3390/nu13061843
Chicago/Turabian StyleVan Puyvelde, Heleen, Nikos Papadimitriou, Joanna Clasen, David Muller, Carine Biessy, Pietro Ferrari, Jytte Halkjær, Kim Overvad, Anne Tjønneland, Renée T. Fortner, and et al. 2021. "Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)" Nutrients 13, no. 6: 1843. https://doi.org/10.3390/nu13061843
APA StyleVan Puyvelde, H., Papadimitriou, N., Clasen, J., Muller, D., Biessy, C., Ferrari, P., Halkjær, J., Overvad, K., Tjønneland, A., Fortner, R. T., Katzke, V., Schulze, M. B., Chiodini, P., Masala, G., Pala, V., Sacerdote, C., Tumino, R., Bakker, M. F., Agudo, A., ... Huybrechts, I. (2021). Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Nutrients, 13(6), 1843. https://doi.org/10.3390/nu13061843