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1. Vitamin B6 catabolism and lung cancer risk: results from the Lung Cancer Cohort Consortium (LC3)

Author

Zuo, H., Ueland, P.M., Midttun, Ø, Tell, G.S., Fanidi, A., Zheng, W., Shu, X., Xiang, Y., Wu, J., Prentice, R., Pettinger, M., Thomson, C.A., Giles, G.G., Hodge, A., Cai, Q., Blot, W.J., Johansson, M., Hultdin, J., Grankvist, K., Stevens, V.L., McCullough, M.L., Weinstein, S.J., Albanes, D., Ziegler, R.G., Freedman, N.D., Caporaso, N.E., Langhammer, A., Hveem, K., Næss, M., Buring, J.E., Lee, I., Gaziano, J.M., Severi, G., Zhang, X., Stampfer, M.J., Han, J., Zeleniuch-Jacquotte, A., Marchand, L.L., Yuan, J., Wang, R., Koh, W., Gao, Y., Ericson, U., Visvanathan, K., Jones, M.R., Relton, C., Brennan, P., and Ulvik, A.

Published
2019
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2. No association between circulating concentrations of vitamin D and risk of lung cancer: an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3)

Author

Muller, D.C., Hodge, A.M., Fanidi, A., Albanes, D., Mai, X.M., Shu, X.O., Weinstein, S.J., Larose, T.L., Zhang, X., Han, J., Stampfer, M.J., Smith-Warner, S.A., Ma, J., Gaziano, J.M., Sesso, H.D., Stevens, V.L., McCullough, M.L., Layne, T.M., Prentice, R., Pettinger, M., Thomson, C.A., Zheng, W., Gao, Y.T., Rothman, N., Xiang, Y.B., Cai, H., Wang, R., Yuan, J.M., Koh, W.P., Butler, L.M., Cai, Q., Blot, W.J., Wu, J., Ueland, P.M., Midttun, Ø., Langhammer, A., Hveem, K., Johansson, M., Hultdin, J., Grankvist, K., Arslan, A.A., Le Marchand, L., Severi, G., and Brennan, P.

Published
2018
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7. Is high vitamin B12 status a cause of lung cancer?

Author

Fanidi, A, Carreras-Torres, R, Larose, TL, Yuan, J-M, Stevens, VL, Weinstein, SJ, Albanes, D, Prentice, R, Pettinger, M, Cai, Q, Blot, WJ, Arslan, AA, Zeleniuch-Jacquotte, A, McCullough, ML, Le Marchand, L, Wilkens, LR, Haiman, CA, Zhang, X, Stampfer, MJ, Smith-Warner, SA, Giovannucci, E, Giles, GG, Hodge, AM, Severi, G, Johansson, M, Grankvist, K, Langhammer, A, Brumpton, BM, Wang, R, Gao, Y-T, Ericson, U, Bojesen, SE, Arnold, SM, Koh, W-P, Shu, X-O, Xiang, Y-B, Li, H, Zheng, W, Lan, Q, Visvanathan, K, Hoffman-Bolton, J, Ueland, PM, Midttun, O, Caporaso, NE, Purdue, M, Freedman, ND, Buring, JE, Lee, I-M, Sesso, HD, Gaziano, JM, Manjer, J, Relton, CL, Hung, RJ, Amos, C, Brennan, P, Fanidi, A, Carreras-Torres, R, Larose, TL, Yuan, J-M, Stevens, VL, Weinstein, SJ, Albanes, D, Prentice, R, Pettinger, M, Cai, Q, Blot, WJ, Arslan, AA, Zeleniuch-Jacquotte, A, McCullough, ML, Le Marchand, L, Wilkens, LR, Haiman, CA, Zhang, X, Stampfer, MJ, Smith-Warner, SA, Giovannucci, E, Giles, GG, Hodge, AM, Severi, G, Johansson, M, Grankvist, K, Langhammer, A, Brumpton, BM, Wang, R, Gao, Y-T, Ericson, U, Bojesen, SE, Arnold, SM, Koh, W-P, Shu, X-O, Xiang, Y-B, Li, H, Zheng, W, Lan, Q, Visvanathan, K, Hoffman-Bolton, J, Ueland, PM, Midttun, O, Caporaso, NE, Purdue, M, Freedman, ND, Buring, JE, Lee, I-M, Sesso, HD, Gaziano, JM, Manjer, J, Relton, CL, Hung, RJ, Amos, C, and Brennan, P

Abstract

Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre-diagnostic circulating vitamin B12 concentrations in a nested case-control study, complemented with a Mendelian randomization (MR) approach in an independent case-control sample. We used pre-diagnostic biomarker data from 5183 case-control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre-diagnostic blood samples from the nested case-control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12 ] = 1.15, 95% confidence interval (95%CI) = 1.06-1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD ] = 1.08, 95%CI = 1.00-1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.

Published
2019

8. Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)

Author

Huang, JY, Larose, TL, Luu, HN, Wang, R, Fanidi, A, Alcala, K, Stevens, VL, Weinstein, SJ, Albanes, D, Caporaso, NE, Purdue, MP, Ziegler, RG, Freedman, ND, Lan, Q, Prentice, RL, Pettinger, M, Thomson, CA, Cai, Q, Wu, J, Blot, WJ, Shu, X-O, Zheng, W, Arslan, AA, Zeleniuch-Jacquotte, A, Le Marchand, L, Wilkens, LR, Haiman, CA, Zhang, X, Stampfer, MJ, Giles, GG, Hodge, AM, Severi, G, Johansson, M, Grankvist, K, Langhammer, A, Hveem, K, Xiang, Y-B, Li, H-L, Gao, Y-T, Visvanathan, K, Ueland, PM, Midttun, O, Ulvi, A, Buring, JE, Lee, I-M, SeSS, HD, Gaziano, JM, Manjer, J, Relton, C, Koh, W-P, Brennan, P, Yuan, J-M, Han, J, Huang, JY, Larose, TL, Luu, HN, Wang, R, Fanidi, A, Alcala, K, Stevens, VL, Weinstein, SJ, Albanes, D, Caporaso, NE, Purdue, MP, Ziegler, RG, Freedman, ND, Lan, Q, Prentice, RL, Pettinger, M, Thomson, CA, Cai, Q, Wu, J, Blot, WJ, Shu, X-O, Zheng, W, Arslan, AA, Zeleniuch-Jacquotte, A, Le Marchand, L, Wilkens, LR, Haiman, CA, Zhang, X, Stampfer, MJ, Giles, GG, Hodge, AM, Severi, G, Johansson, M, Grankvist, K, Langhammer, A, Hveem, K, Xiang, Y-B, Li, H-L, Gao, Y-T, Visvanathan, K, Ueland, PM, Midttun, O, Ulvi, A, Buring, JE, Lee, I-M, SeSS, HD, Gaziano, JM, Manjer, J, Relton, C, Koh, W-P, Brennan, P, Yuan, J-M, and Han, J

Abstract

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

Published
2019

10. Circulating high sensitivity C reactive protein concentrations and lung cancer risk: a nested case-control study within the Lung Cancer Cohort Consortium

Author

Muller, D, Laros, TL, Hodge, A, Guida, F, Langhammer, A, Grankvist, K, Meyer, K, Cai, Q, Arslan, AA, Zeleniuch-Jacquotte, A, Albanes, D, Giles, GG, Sesso, HD, Lee, I-M, Gaziano, JM, Yuan, J-M, Hoffman Bolton, J, Buring, JE, Visvanathan, K, Le Marchand, L, Purdue, MP, Caporaso, NE, Midttun, Ø, Ueland, PM, Prentice, RL, Weinstein, SJ, Stevens, VL, Zheng, W, Blot, WJ, Shu, X-O, Zhang, X, Xiang, Y-B, Koh, W-P, Hveem, K, Thompson, CA, Pettinger, M, Engstrom, G, Brunnstrom, H, Milne, RL, Stampfer, M, Han, J, Johansson, M, Brennan, P, Severi, G, and Cancer Research UK

Subjects
Science & Technology, Medicine, General & Internal, VITAMIN STATUS, General & Internal Medicine, PRIMARY-CARE, cardiovascular diseases, METABOLISM, CRP, Life Sciences & Biomedicine, INFLAMMATION MARKERS, POINT
Abstract

Objectives To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type. Design Nested case-control study. Setting 20 population based cohort studies in Asia, Europe, Australia, and the United States. Participants 5299 patients with incident lung cancer, with individually incidence density matched controls. Exposure Circulating hsCRP concentrations in prediagnostic serum or plasma samples. Main outcome measure Incident lung cancer diagnosis. Results A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P

Published
2018

12. No association between circulating concentrations of vitamin D and risk of lung cancer : an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3)

Author

Muller, D. C., Hodge, A. M., Fanidi, A., Albanes, D., Mai, X. M., Shu, X. O., Weinstein, S. J., Larose, T. L., Zhang, X., Han, J., Stampfer, M. J., Smith-Warner, S. A., Ma, J., Gaziano, J. M., Sesso, H. D., Stevens, V. L., McCullough, M. L., Layne, T. M., Prentice, R., Pettinger, M., Thomson, C. A., Zheng, W., Gao, Y. T., Rothman, N., Xiang, Y. B., Cai, H., Wang, R., Yuan, J. M., Koh, W. P., Butler, L. M., Cai, Q., Blot, W. J., Wu, J., Ueland, P. M., Midttun, O., Langhammer, A., Hveem, K., Johansson, M., Hultdin, Johan, Grankvist, Kjell, Arslan, A. A., Le Marchand, L., Severi, G., Brennan, P., Muller, D. C., Hodge, A. M., Fanidi, A., Albanes, D., Mai, X. M., Shu, X. O., Weinstein, S. J., Larose, T. L., Zhang, X., Han, J., Stampfer, M. J., Smith-Warner, S. A., Ma, J., Gaziano, J. M., Sesso, H. D., Stevens, V. L., McCullough, M. L., Layne, T. M., Prentice, R., Pettinger, M., Thomson, C. A., Zheng, W., Gao, Y. T., Rothman, N., Xiang, Y. B., Cai, H., Wang, R., Yuan, J. M., Koh, W. P., Butler, L. M., Cai, Q., Blot, W. J., Wu, J., Ueland, P. M., Midttun, O., Langhammer, A., Hveem, K., Johansson, M., Hultdin, Johan, Grankvist, Kjell, Arslan, A. A., Le Marchand, L., Severi, G., and Brennan, P.

Abstract

Background: There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in prediagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3). Patients and methods: The study included 5313 lung cancer cases and 5313 controls. Blood samples for the cases were collected, on average, 5 years before lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in five categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 25(OH)D as both continuous and categorical variables. Results: Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% CI: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology. Conclusion: This study did not support an association between vitamin D concentrations and lung cancer risk.

Published
2018
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13. Impaired functional vitamin B6 status is associated with increased risk of lung cancer

Author

Theofylaktopoulou, D, Midttun, O, Ueland, PM, Meyer, K, Fanidi, A, Zheng, W, Shu, X-O, Xiang, Y-B, Prentice, R, Pettinger, M, Thomson, CA, Giles, GG, Hodge, A, Cai, Q, Blot, WJ, Wu, J, Johansson, M, Hultdin, J, Grankvist, K, Stevens, VL, McCullough, MM, Weinstein, SJ, Albanes, D, Ziegler, R, Freedman, ND, Langhammer, A, Hveem, K, Naess, M, Sesso, HD, Gaziano, JM, Buring, JE, Lee, I-M, Severi, G, Zhang, X, Stampfer, MJ, Han, J, Smith-Warner, SA, Zeleniuch-Jacquotte, A, Le Marchand, L, Yuan, J-M, Wang, R, Butler, LM, Koh, W-P, Gao, Y-T, Rothman, N, Ericson, U, Sonestedt, E, Visvanathan, K, Jones, MR, Relton, C, Brennan, P, Ulvik, A, Theofylaktopoulou, D, Midttun, O, Ueland, PM, Meyer, K, Fanidi, A, Zheng, W, Shu, X-O, Xiang, Y-B, Prentice, R, Pettinger, M, Thomson, CA, Giles, GG, Hodge, A, Cai, Q, Blot, WJ, Wu, J, Johansson, M, Hultdin, J, Grankvist, K, Stevens, VL, McCullough, MM, Weinstein, SJ, Albanes, D, Ziegler, R, Freedman, ND, Langhammer, A, Hveem, K, Naess, M, Sesso, HD, Gaziano, JM, Buring, JE, Lee, I-M, Severi, G, Zhang, X, Stampfer, MJ, Han, J, Smith-Warner, SA, Zeleniuch-Jacquotte, A, Le Marchand, L, Yuan, J-M, Wang, R, Butler, LM, Koh, W-P, Gao, Y-T, Rothman, N, Ericson, U, Sonestedt, E, Visvanathan, K, Jones, MR, Relton, C, Brennan, P, and Ulvik, A

Abstract

Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5'-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3-hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case-control study consisting of 5,364 matched case-control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR4thvs.1st ) was 1.25 (95% confidence interval, 1.10-1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status.

Published
2018

14. Anticholinergic medication use and falls in postmenopausal women: Findings from the women's health initiative cohort study

Author

Marcum, ZA, Wirtz, HS, Pettinger, M, Lacroix, AZ, Carnahan, R, Cauley, JA, Bea, JW, Gray, SL, Marcum, ZA, Wirtz, HS, Pettinger, M, Lacroix, AZ, Carnahan, R, Cauley, JA, Bea, JW, and Gray, SL

Abstract

Background: Results from studies assessing the association between anticholinergic use and falls are mixed, and prior studies are limited in their ability to control for important potential confounders. Thus, we sought to examine the association between anticholinergic medication use, including over-the-counter medications, and recurrent falls in community-dwelling older women. Methods: We analyzed data from a prospective cohort study of women aged 65 to 79 years from the Women's Health Initiative Observational Study and Clinical Trials. Women were recruited between 1993 and 1998, and analyses included 61,451 women with complete information. Medications with moderate or strong anticholinergic effects were ascertained directly from drug containers during face-to-face interviews. The main outcome measure was recurrent falls (≥2 falls in previous year), which was determined from self-report within 1.5 years subsequent to the medication assessment. Results: At baseline, 11.3 % were using an anticholinergic medication, of which antihistamines (commonly available over-the-counter) were the most common medication class (received by 45.2 % of individuals on anticholinergic medication). Using multivariable GEE models and controlling for potential confounders, the adjusted odds ratio for anticholinergic medication use was 1.51 (95 % CI, 1.43-1.60) for recurrent falls. Participants using multiple anticholinergic medications had a 100 % increase in likelihood of recurrent falls (adjusted odds ratio 2.00, 95 % CI 1.73-2.32). Results were robust to sensitivity analysis. Conclusions: Anticholinergic medication use was associated with increased risk for recurrent falls. Our findings reinforce judicious use of anticholinergic medications in older women. Public health efforts should emphasize educating older women regarding the risk of using over-the-counter anticholinergics, such as first-generation antihistamines.

Published
2016

15. Loci influencing blood pressure identified using a cardiovascular gene-centric array (vol 22, pg 1663, 2013)

Author

Ganesh, SK, Tragante, V, Guo, W, Guo, YR, Lanktree, MB, Smith, EN, Johnson, T, Castillo, BA, Barnard, J, Baumert, J, Chang, YPC, Elbers, CC, Farrall, M, Fischer, ME, Franceschini, N, Gaunt, TR, Gho, JMIH, Gieger, C, Gong, Y, Isaacs, Aaron, Kleber, ME, Leach, IM, McDonough, CW, Meijs, MFL, Mellander, O, Molony, CM, Nolte, IM (Ilja), Padmanabhan, S, Price, TS, Rajagopalan, R, Shaffer, J, Shah, S, Shen, HQ, Soranzo, N, van der Most, PJ, Van Iperen, EPA, van Setten, J, Vonk, JM, Zhang, Lei, Beitelshees, AL, Berenson, GS, Bhatt, DL, Boer, JMA, Boerwinkle, E, Burkley, B, Burt, A, Chakravarti, A, Chen, W, Cooper-DeHoff, RM, Curtis, SP, Dreisbach, A, Duggan, D, Ehret, GB, Fabsitz, RR, Fornage, M, Fox, E, Furlong, CE, Gansevoort, RT, Hofker, MH, Hovingh, GK, Kirkland, SA, Kottke-Marchant, K, Kutlar, A, Lacroix, AZ, Langaee, TY, Li, YR, Lin, HH, Liu, K, Maiwald, S, Malik, R, Murugesan, G, Newton-Cheh, C, OConnell, JR, Onland-Moret, NC, Ouwehand, WH, Palmas, W, Penninx, BW, Pepine, CJ, Pettinger, M, Polak, JF, Ramachandran, VS, Ranchalis, J, Redline, S, Ridker, PM, Rose, LM, Scharnag, H, Schork, NJ, Shimbo, D, Shuldiner, AR, Srinivasan, SR (Sathanur), Stolk, RP (Ronald), Taylor, HA, Thorand, B, Trip, MD, Duijn, Cornelia, Verschuren, WM, Wijmenga, C, Winkelmann, BR, Wyatt, S, Young, JH, Boehm, BO, Caulfield, MJ, Chasman, DI, Davidson, KW, Doevendans, PA, FitzGerald, GA, Gums, JG, Hakonarson, H, Hillege, HL, Illig, T, Jarvik, GP, Johnson, JA, Kastelein, JJP, Koenig, W, Marz, W, Mitchell, BD, Murray, SS, Oldehinkel, AJ (A.), Rader, DJ, Reilly, MP, Reiner, AP, Schadt, EE, Silverstein, RL, Snieder, H, Stanton, AV, Uitterlinden, André, van der Harst, P, van der Schouw, YT, Samani, NJ, Johnson, AD, Munroe, PB, de Bakker, PIW, Zhu, XF, Levy, D, Keating, BJ, Asselbergs, FW, Epidemiology, Public Health, Clinical Genetics, Immunology, Child and Adolescent Psychiatry / Psychology, and Internal Medicine

Published
2013

16. Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals

Author

Guo, Y., Lanktree, M. B., Taylor, K. C., Hakonarson, H., Lange, L. A., Keating, B. J., Fairfax, B. P., Elbers, C. C., Barnard, J., Farrall, M., Padmanabhan, S., Baumert, J., Castillo, B. A., Gaunt, T. R., Gong, Y., Rajagopalan, R., Romaine, S. P., Kumari, M., Rafelt, S., Smith, E. N., Li, Y. R., Sivapalaratnam, S., van Iperen, E. P., Speliotes, E. K., Toskala, E., Zhang, L., Ochs-Balcom, H. M., Bhangale, T. R., Chandrupatla, H. R., Drenos, F., Gieger, C., Gupta, J., Johnson, T., Kleber, M. E., Makino, S., Mangino, M., Meng, Y., Nelson, C. P., Pankow, J. S., Pankratz, N., Price, T. S., Shaffer, J., Shen, H., Tischfield, S., Tomaszewski, M., Atwood, L. D., Bailey, K. M., Balasubramanyam, A., Baldwin, C. T., Basart, H., Bauer, F., Behr, E. R., Beitelshees, A. L., Berenson, G. S., Beresford, S. A., Bezzina, C. R., Bhatt, D. L., Boer, J. M., Braund, P. S., Burke, G. L., Burkley, B., Carty, C., Chen, W., Clarke, R., Cooper-DeHoff, R. M., Curtis, S. P., de Bakker, P. I., de Jong, J. S., Delles, C., Dominiczak, A. F., Duggan, D., Feldman, H. I., Furlong, C. E., Gorski, M. M., Gums, J. G., Hardwick, R., Hastie, C., Heid, I. M., Huang, G.-H., Huggins, G. S., Humphries, S. E., Kirkland, S. A., Kivimaki, M., Klein, R., Klein, B. E., Knowler, W. C., Kottke-Marchant, K., LaCroix, A. Z., Langaee, T. Y., Li, M., Lyon, H. N., Maiwald, S., Marshall, J. K., Mehta, A., Meijs, M. F., Melander, O., Meyer, N., Mitra, N., Molony, C. M., Morrow, D. A., Murugesan, G., Newhouse, S. J., Nieto, J. F., Onland-Moret, N. C., Ouwehand, W. H., Palmen, J., Pepine, C. J., Ranchalis, J., Rosas, S. E., Rosenthal, E. A., Scharnagl, H., Schork, N. J., Schreiner, P. J., Shah, T., Shashaty, M., Shimbo, D., Srinivasan, S. R., Thomas, F., Tobin, M. D., Tsai, M. Y., Verschuren, W. M. M., Wagenknecht, L. E., Winkelmann, B. R., Young, T., Yusuf, S., Zafarmand, M. H., Zmuda, J. M., Zwinderman, A. H., Anand, S. S., Balmforth, A. J., Boehm, B. O., Boerwinkle, E., Burton, P. R., Cappola, T. P., Casas, J. P., Caulfield, M. J., Christiani, D. C., Christie, J., Cruickshanks, K. J., Davey-Smith, G., Davidson, K. W., Day, I. N., Doevendans, P. A., Dorn, G. W., FitzGerald, G. A., Hall, A. S., Hingorani, A. D., Hirschhorn, J. N., Hofker, M. H., Hovingh, K. G., Illig, T., Jamshidi, Y., Jarvik, G. P., Johnson, J. A., Kanetsky, P. A., Kastelein, J. J., Koenig, W., Lawlor, D. A., Marz, W., McCaffery, J., Mega, J. L., Mitchell, B. D., Murray, S. S., O'Connell, J. R., Patel, S. R., Peters, A., Pettinger, M., Rader, D. J., Redline, S., Reilly, M. P., Sabatine, M. S., Schadt, E. E., Shuldiner, A. R., Silverstein, R. L., Spector, T. D., Taylor, H. A., Thorand, B., Trip, M. D., Watkins, H., Wichmann, H.- E., Fox, C. S., Grant, S. F., Peter, I., Talmud, P. J., Munroe, P. B., Wilson, J. G., Knight, J. C., Samani, N. J., Hegele, R. A., Asselbergs, F. W., Monda, K. L., van der Schouw, Y. T., Demerath, E. W., Wijmenga, C., Timpson, N. J., Reiner, A. P., North, K. E., Papanicolaou, G. J., Lange , L. A., Keating , B. J., Vascular Medicine, Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Other departments, Amsterdam Cardiovascular Sciences, Cardiology, Other Research, and Public and occupational health

Subjects
Population, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Body Mass Index, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, SH2B1, Genotype, Ethnicity, Genetics, Humans, education, Molecular Biology, Gene, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, Association Studies Articles, General Medicine, Melanocortin 4 receptor, 030217 neurology & neurosurgery
Abstract

Recent genetic association studies have made progress in uncovering components of the genetic architecture of the body mass index (BMI). We used the ITMAT-Broad-Candidate Gene Association Resource (CARe) (IBC) array comprising up to 49 320 single nucleotide polymorphisms (SNPs) across ~2100 metabolic and cardiovascular-related loci to genotype up to 108 912 individuals of European ancestry (EA), African-Americans, Hispanics and East Asians, from 46 studies, to provide additional insight into SNPs underpinning BMI. We used a five-phase study design: Phase I focused on meta-analysis of EA studies providing individual level genotype data; Phase II performed a replication of cohorts providing summary level EA data; Phase III meta-analyzed results from the first two phases; associated SNPs from Phase III were used for replication in Phase IV; finally in Phase V, a multi-ethnic meta-analysis of all samples from four ethnicities was performed. At an array-wide significance (P < 2.40E-06), we identify novel BMI associations in loci translocase of outer mitochondrial membrane 40 homolog (yeast) - apolipoprotein E - apolipoprotein C-I (TOMM40-APOE-APOC1) (rs2075650, P = 2.95E-10), sterol regulatory element binding transcription factor 2 (SREBF2, rs5996074, P = 9.43E-07) and neurotrophic tyrosine kinase, receptor, type 2 [NTRK2, a brain-derived neurotrophic factor (BDNF) receptor gene, rs1211166, P = 1.04E-06] in the Phase IV meta-analysis. Of 10 loci with previous evidence for BMI association represented on the IBC array, eight were replicated, with the remaining two showing nominal significance. Conditional analyses revealed two independent BMI-associated signals in BDNF and melanocortin 4 receptor (MC4R) regions. Of the 11 array-wide significant SNPs, three are associated with gene expression levels in both primary B-cells and monocytes; with rs4788099 in SH2B adaptor protein 1 (SH2B1) notably being associated with the expression of multiple genes in cis. These multi-ethnic meta-analyses expand our knowledge of BMI genetics.

Published
2013

17. Erratum: Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci (American Journal of Human Genetics (2012) 90 (410-425))

Author

Saxena, R, Elbers, CC, Guo, Y, Peter, I, Gaunt, TR, Mega, JL, Lanktree, MB, Tare, A, Castillo, BA, Li, YR, Johnson, T, Bruinenberg, M, Gilbert-Diamond, D, Rajagopalan, R, Voight, BF, Balasubramanyam, A, Barnard, J, Bauer, F, Baumert, J, Bhangale, T, Böhm, BO, Braund, PS, Burton, PR, Chandrupatla, HR, Clarke, R, Cooper-Dehoff, RM, Crook, ED, Davey-Smith, G, Day, IN, De Boer, A, De Groot, MCH, Drenos, F, Ferguson, J, Fox, CS, Furlong, CE, Gibson, Q, Gieger, C, Gilhuijs-Pederson, LA, Glessner, JT, Goel, A, Gong, Y, Grant, SFA, Grobbee, DE, Hastie, C, Humphries, SE, Kim, CE, Kivimaki, M, Kleber, M, Meisinger, C, Kumari, M, Langaee, TY, Lawlor, DA, Li, M, Lobmeyer, MT, Maitland-Van Der Zee, A-H, Meijs, MFL, Molony, CM, Morrow, DA, Murugesan, G, Musani, SK, Nelson, CP, Newhouse, SJ, O'Connell, JR, Padmanabhan, S, Palmen, J, Patel, SR, Pepine, CJ, Pettinger, M, Price, TS, Rafelt, S, Ranchalis, J, Rasheed, A, Rosenthal, E, Ruczinski, I, Shah, S, Shen, H, Silbernagel, G, Smith, EN, Spijkerman, AWM, Stanton, A, Steffes, MW, Thorand, B, Trip, M, Van Der Harst, P, Van Der A, DL, Van Iperen, EPA, Van Setten, J, Van Vliet-Ostaptchouk, JV, Verweij, N, Wolffenbuttel, BHR, Young, T, Hadi Zafarmand, M, Zmuda, JM, Boehnke, M, Altshuler, D, McCarthy, M, Linda Kao, WH, Pankow, JS, Cappola, TP, Sever, P, Poulter, N, Caulfield, M, Dominiczak, A, Shields, DC, Bhatt, DL, Zhang, L, Curtis, SP, Danesh, J, Casas, JP, Van Der Schouw, YT, Onland-Moret, NC, Doevendans, PA, Dorn II, GW, Farrall, M, Fitzgerald, GA, Robert Hegele, AH, Hingorani, AD, Hofker, MH, Huggins, GS, Illig, T, Jarvik, GP, Johnson, JA, Klungel, OH, Knowler, WC, Koenig, W, März, W, Meigs, JB, Melander, O, Munroe, PB, Mitchell, BD, Bielinski, SJ, Rader, DJ, Reilly, MP, Rich, SS, Rotter, JI, Saleheen, D, Samani, NJ, Schadt, EE, Shuldiner, AR, Silverstein, R, Kottke-Marchant, K, Talmud, PJ, Watkins, H, Asselbergs, FW, De Bakker, PIW, McCaffery, J, Wijmenga, C, Sabatine, MS, Wilson, JG, Reiner, A, Bowden, DW, Hakonarson, H, Siscovick, DS, and Keating, BJ

Published
2012

18. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci

Author

Tragante, V. (Vinicius), Barnes, M.J. (Michael), Ganesh, S.K. (Santhi), Lanktree, M.B. (Matthew), Guo, W. (Weixiang), Franceschini, N. (Nora), Smith, A.V. (Davey), Johnson, T. (Toby), Holmes, M.V. (Michael), Padmanabhan, S. (Sandosh), Karczewski, K.J. (Konrad), Almoguera, B. (Berta), Barnard, J. (John), Baumert, J. (Jens), Chang, Y.-P.C. (Yen-Pei), Elbers, C.C. (Clara), Farrall, M. (Martin), Fischer, M.E. (Mary), Gaunt, T.R. (Tom), Gho, J.M.I.H. (Johannes), Gieger, C. (Christian), Goel, A. (Anuj), Gong, Y. (Yeming), Isaacs, A.J. (Aaron), Kleber, M.E. (Marcus), Leach, I.M. (Irene Mateo), McDonough, C.W. (Caitrin), Meijs, M.F.L. (Matthijs), Melander, O. (Olle), Nelson, C.P. (Christopher P.), Nolte, I.M. (Ilja), Pankratz, V.S. (Shane), Price, T.S. (Thomas), Shaffer, J. (Jonathan), Shah, S. (Sonia), Tomaszewski, M. (Maciej), Most, P.J. (Peter) van der, Iperen, E.P.A. (Erik) van, Vonk, J.M. (Judith), Witkowska, H.E. (Ewa), Wong, C.O.L. (Caroline), Zhang, L. (Lingling), Beitelshees, A.L. (Amber), Berenson, G. (Gerald), Bhatt, D.L. (Deepak), Brown, M.J. (Morris), Burt, A.D. (Alastair), Cooper-Dehoff, R.M. (Rhonda), Connell, J. (John), Cruickshanks, K.J. (Karen), Curtis, S.P. (Sean), Davey-Smith, G. (George), Delles, C. (Christian), Gansevoort, R.T. (Ron), Guo, X. (Xiuqing), Haiqing, S. (Shen), Hastie, C.E. (Claire), Hofker, M.A. (Marten), Hovingh, G.K. (Kees), Kim, D.S. (Daniel), Kirkland, S.A. (Susan), Klein, B.E.K. (Barbara), Li, Y.R. (Yun), Maiwald, R. (Robert), Newton-Cheh, C. (Christopher), O'Brien, E. (Eoin), Onland-Moret, N.C. (Charlotte), Palmas, W. (Walter), Parsa, A. (Afshin), Penninx, B.W.J.H. (Brenda), Pettinger, M. (Mary), Vasan, R.S. (Ramachandran Srini), Ranchalis, J.E. (Jane), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Sever, P. (Peter), Shimbo, D. (Daichi), Steele, L. (Linda), Stolk, R.P. (Ronald), Thorand, B. (Barbara), Trip, M.D. (Mieke), Duijn, C.M. (Cornelia) van, Verschuren, W.M.M. (W. M. Monique), Wijmenga, C. (Cisca), Wyatt, S. (Sally), Young, J.C. (J. C.), Zwinderman, A.H. (Ailko), Bezzina, C.R. (Connie), Boerwinkle, E.A. (Eric), Casas, J.P. (Juan), Caulfield, M. (Mark), Chakravarti, A. (Aravinda), Chasman, D.I. (Daniel), Davidson, K.W. (Karina), Doevendans, P.A. (Pieter), Dominiczak, A. (Anna), Fitzgerald, G.A. (Garret), Gums, J.G. (John), Fornage, M. (Myriam), Hakonarson, H. (Hakon), Halder, H. (Han) van, Hillege, H.L. (Hans), Illig, T. (Thomas), Jarvik, G.P. (Gail), Johnson, J.A. (Jennifer ), Kastelein, J.J.P. (John), Koenig, W. (Wolfgang), Kumari, M. (Meena), März, W. (Winfried), Murray, S.S. (Sarah), O'Connell, J.R. (Jeffery), Oldehinkel, A.J. (Albertine), Pankow, J.S. (James), Rader, D.J. (Daniel), Redline, S. (Susan), Reilly, M.P. (Muredach), Schadt, E.E. (Eric), Kottke-Marchant, K. (Kandice), Snieder, H. (Harold), Snyder, M. (Michael), Stanton, A. (Alice), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Harst, P. (Pim) van der, Schouw, Y.T. (Yvonne) van der, Samani, N.J. (Nilesh), Watkins, H. (Hugh), Johnson, A.D. (Andrew), Reiner, A.P. (Alex), Zhu, X. (Xiaofeng), Bakker, P.I.W. (Paul) de, Levy, D. (Daniel), Asselbergs, F.W. (Folkert), Munroe, P. (Patricia), Keating, J. (John), Tragante, V. (Vinicius), Barnes, M.J. (Michael), Ganesh, S.K. (Santhi), Lanktree, M.B. (Matthew), Guo, W. (Weixiang), Franceschini, N. (Nora), Smith, A.V. (Davey), Johnson, T. (Toby), Holmes, M.V. (Michael), Padmanabhan, S. (Sandosh), Karczewski, K.J. (Konrad), Almoguera, B. (Berta), Barnard, J. (John), Baumert, J. (Jens), Chang, Y.-P.C. (Yen-Pei), Elbers, C.C. (Clara), Farrall, M. (Martin), Fischer, M.E. (Mary), Gaunt, T.R. (Tom), Gho, J.M.I.H. (Johannes), Gieger, C. (Christian), Goel, A. (Anuj), Gong, Y. (Yeming), Isaacs, A.J. (Aaron), Kleber, M.E. (Marcus), Leach, I.M. (Irene Mateo), McDonough, C.W. (Caitrin), Meijs, M.F.L. (Matthijs), Melander, O. (Olle), Nelson, C.P. (Christopher P.), Nolte, I.M. (Ilja), Pankratz, V.S. (Shane), Price, T.S. (Thomas), Shaffer, J. (Jonathan), Shah, S. (Sonia), Tomaszewski, M. (Maciej), Most, P.J. (Peter) van der, Iperen, E.P.A. (Erik) van, Vonk, J.M. (Judith), Witkowska, H.E. (Ewa), Wong, C.O.L. (Caroline), Zhang, L. (Lingling), Beitelshees, A.L. (Amber), Berenson, G. (Gerald), Bhatt, D.L. (Deepak), Brown, M.J. (Morris), Burt, A.D. (Alastair), Cooper-Dehoff, R.M. (Rhonda), Connell, J. (John), Cruickshanks, K.J. (Karen), Curtis, S.P. (Sean), Davey-Smith, G. (George), Delles, C. (Christian), Gansevoort, R.T. (Ron), Guo, X. (Xiuqing), Haiqing, S. (Shen), Hastie, C.E. (Claire), Hofker, M.A. (Marten), Hovingh, G.K. (Kees), Kim, D.S. (Daniel), Kirkland, S.A. (Susan), Klein, B.E.K. (Barbara), Li, Y.R. (Yun), Maiwald, R. (Robert), Newton-Cheh, C. (Christopher), O'Brien, E. (Eoin), Onland-Moret, N.C. (Charlotte), Palmas, W. (Walter), Parsa, A. (Afshin), Penninx, B.W.J.H. (Brenda), Pettinger, M. (Mary), Vasan, R.S. (Ramachandran Srini), Ranchalis, J.E. (Jane), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Sever, P. (Peter), Shimbo, D. (Daichi), Steele, L. (Linda), Stolk, R.P. (Ronald), Thorand, B. (Barbara), Trip, M.D. (Mieke), Duijn, C.M. (Cornelia) van, Verschuren, W.M.M. (W. M. Monique), Wijmenga, C. (Cisca), Wyatt, S. (Sally), Young, J.C. (J. C.), Zwinderman, A.H. (Ailko), Bezzina, C.R. (Connie), Boerwinkle, E.A. (Eric), Casas, J.P. (Juan), Caulfield, M. (Mark), Chakravarti, A. (Aravinda), Chasman, D.I. (Daniel), Davidson, K.W. (Karina), Doevendans, P.A. (Pieter), Dominiczak, A. (Anna), Fitzgerald, G.A. (Garret), Gums, J.G. (John), Fornage, M. (Myriam), Hakonarson, H. (Hakon), Halder, H. (Han) van, Hillege, H.L. (Hans), Illig, T. (Thomas), Jarvik, G.P. (Gail), Johnson, J.A. (Jennifer ), Kastelein, J.J.P. (John), Koenig, W. (Wolfgang), Kumari, M. (Meena), März, W. (Winfried), Murray, S.S. (Sarah), O'Connell, J.R. (Jeffery), Oldehinkel, A.J. (Albertine), Pankow, J.S. (James), Rader, D.J. (Daniel), Redline, S. (Susan), Reilly, M.P. (Muredach), Schadt, E.E. (Eric), Kottke-Marchant, K. (Kandice), Snieder, H. (Harold), Snyder, M. (Michael), Stanton, A. (Alice), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Harst, P. (Pim) van der, Schouw, Y.T. (Yvonne) van der, Samani, N.J. (Nilesh), Watkins, H. (Hugh), Johnson, A.D. (Andrew), Reiner, A.P. (Alex), Zhu, X. (Xiaofeng), Bakker, P.I.W. (Paul) de, Levy, D. (Daniel), Asselbergs, F.W. (Folkert), Munroe, P. (Patricia), and Keating, J. (John)

Abstract

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10-7) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.

Published
2014
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19. The Variability of Stable Water Isotopes in an Alpine ice-core over the last 1000 Years

Author

Bohleber, Pascal, Jahn, F., Pettinger, M., Eisen, Olaf, Wagenbach, D., Bohleber, Pascal, Jahn, F., Pettinger, M., Eisen, Olaf, and Wagenbach, D.

Abstract

Water isotopes( del18O or del D) preserved in high Alpine glaciers may provide temperatureproxy records complementary to those of polar ice cores, including a potentialextension of the 250a instrumental temperature series available for the Greater AlpineRegion. To minimize the influence of glacio-meteorological noise, which challengethe reconstruction of long-term temperature changes from Alpine ice core sites, amulti-core array established at Colle Gnifetti (Monte Rosa, 4450m a.s.l.) was supplementedby a new ice core to bedrock, specifically dedicated to the millennial timescale.The 62m core is shown to offer an outstanding small annual snow accumulation rate(11 cm water i.e. up to a factor of 2-4 lower than at previous cores), an accordinglyincreased distance of the 1000a horizon to bedrock at around 16 m and an approximately2m bottom section possibly older than 10.000a.Main features of the new del18O-record are discussed over last 1000a in view of constraintsarising from the implementable time resolution, dating uncertainties (up to+ 80a), the varying isotope/temperature relationship and the glaciological up streameffects. Overall, over last 250a common isotope variability is seen among the differentcores (though considerably differing by their depositional regime), with a fairlygood correspondence to the instrumental time series. Beyond that period, there is noclear sign of a LIA related cooling, but two striking periods of relative warm isotopetemperature around 1400 (+- 50a) and 900 (+- 100a) AD , with the latter, possiblyassociated with the medieval warming phenomenon.

Published
2008

23. Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study

Author

Prentice, R. L., primary, Pettinger, M. B., additional, Jackson, R. D., additional, Wactawski-Wende, J., additional, LaCroix, A. Z., additional, Anderson, G. L., additional, Chlebowski, R. T., additional, Manson, J. E., additional, Van Horn, L., additional, Vitolins, M. Z., additional, Datta, M., additional, LeBlanc, E. S., additional, Cauley, J. A., additional, and Rossouw, J. E., additional

Published
2012
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24. The Influence of Health and Lifestyle Characteristics on the Relation of Serum 25-Hydroxyvitamin D With Risk of Colorectal and Breast Cancer in Postmenopausal Women

Author

Neuhouser, M. L., primary, Manson, J. E., additional, Millen, A., additional, Pettinger, M., additional, Margolis, K., additional, Jacobs, E. T., additional, Shikany, J. M., additional, Vitolins, M., additional, Adams-Campbell, L., additional, Liu, S., additional, LeBlanc, E., additional, Johnson, K. C., additional, and Wactawski-Wende, J., additional

Published
2012
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28. Conjugated Equine Estrogens and Breast Cancer Risk in the Women's Health Initiative Clinical Trial and Observational Study

Author

Prentice, R. L., primary, Chlebowski, R. T., additional, Stefanick, M. L., additional, Manson, J. E., additional, Langer, R. D., additional, Pettinger, M., additional, Hendrix, S. L., additional, Hubbell, F. A., additional, Kooperberg, C., additional, Kuller, L. H., additional, Lane, D. S., additional, McTiernan, A., additional, O'Sullivan, M. J., additional, Rossouw, J. E., additional, and Anderson, G. L., additional

Published
2008
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29. Estrogen Plus Progestin Therapy and Breast Cancer in Recently Postmenopausal Women

Author

Prentice, R. L., primary, Chlebowski, R. T., additional, Stefanick, M. L., additional, Manson, J. E., additional, Pettinger, M., additional, Hendrix, S. L., additional, Hubbell, F. A., additional, Kooperberg, C., additional, Kuller, L. H., additional, Lane, D. S., additional, McTiernan, A., additional, Jo O'Sullivan, M., additional, Rossouw, J. E., additional, and Anderson, G. L., additional

Published
2008
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30. Low-Fat Dietary Pattern and Cancer Incidence in the Women's Health Initiative Dietary Modification Randomized Controlled Trial

Author

Prentice, R. L., primary, Thomson, C. A., additional, Caan, B., additional, Hubbell, F. A., additional, Anderson, G. L., additional, Beresford, S. A. A., additional, Pettinger, M., additional, Lane, D. S., additional, Lessin, L., additional, Yasmeen, S., additional, Singh, B., additional, Khandekar, J., additional, Shikany, J. M., additional, Satterfield, S., additional, and Chlebowski, R. T., additional

Published
2007
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31. Lack of a relation between vitamin and mineral antioxidants and bone mineral density: results from the Women's Health Initiative

Author

Wolf, R.L., Cauley, J.A., and Pettinger, M.

Subjects
Women -- Health aspects, Antioxidants -- Nutritional aspects, Health, Nutritional aspects
Abstract

BACKGROUND: Antioxidant defenses are one possible mechanism for decreasing oxidative damage and its potentially negative effects on age-related bone mass. OBJECTIVE: This study cross-sectionally examined whether higher dietary intakes, total [...]

Published
2005

48. Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women's Health Initiative Clinical Trial.

Author

Prentice RL, Langer R, Stefanick ML, Howard BV, Pettinger M, Anderson G, Barad D, Curb JD, Kotchen J, Kuller L, Limacher M, Wactawski-Wende J, and Women's Health Initiative Investigators

Abstract

Observational research on postmenopausal hormone therapy suggests a 40-50% reduction in coronary heart disease incidence among women using these preparations. In contrast, the Women's Health Initiative clinical trial of estrogen plus progestin found an elevated incidence over a 5.6-year intervention period through July 7, 2002. Toward explaining this discrepancy, the authors analyzed data from this trial, which included 16,608 postmenopausal women aged 50-79 years, and corresponding data from 53,054 women in the Women's Health Initiative observational study, 33% of whom were estrogen-plus-progestin users at baseline. Estrogen-plus-progestin hazard ratio estimates for coronary heart disease, stroke, and venous thromboembolism in the observational study were 39-48% lower than those in the clinical trial following age adjustment. However, hazard ratios tended to decrease with increasing time from initiation of estrogen-plus-progestin use, and observational study hazard ratio estimates are heavily weighted by longer-term use while clinical trial hazard ratio estimates reflect shorter-term use. Following control for time from estrogen-plus-progestin initiation and confounding, hazard ratio estimates were rather similar for the two cohorts, although there was evidence of some remaining difference for stroke. These analyses have implications for both the design and the analysis of observational studies. [ABSTRACT FROM AUTHOR]

Published
2005
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49. Lack of a relation between vitamin and mineral antioxidants and bone mineral density: results from the Women's Health Initiative.

Author

Wolf RL, Cauley JA, Pettinger M, Jackson R, Lacroix A, Leboff MS, Lewis CE, Nevitt MC, Simon JA, Stone KL, and Wactawski-Wende J

Abstract

BACKGROUND: Antioxidant defenses are one possible mechanism for decreasing oxidative damage and its potentially negative effects on age-related bone mass. OBJECTIVE: This study cross-sectionally examined whether higher dietary intakes, total intakes, and serum concentrations of antioxidants may be associated with higher bone mineral density (BMD). DESIGN: Total hip (and subregions), spine, and total-body BMDs were measured in 11 068 women aged 50-79 y enrolled in the Women's Health Initiative Observational Study and Clinical Trial at 3 clinics. Antioxidant intakes from diet (vitamin A, retinol, beta-carotene, vitamin C, vitamin E, and selenium) were estimated by using a self-reported food-frequency questionnaire. Antioxidants from supplements were estimated with an interviewer-administered questionnaire. A random subset (n = 379) had serum concentrations of retinol, carotenoids, and tocopherols measured. RESULTS: After adjustment for important BMD-related covariates, increasing intakes of antioxidants were not independently associated with BMD. A significant interaction effect was observed between intake of total vitamin C (lower three-fourths compared with highest one-fourth) and use of hormone therapy (HT) (P < 0.01). The beneficial effect of current HT use on femoral neck BMD appeared to be greater in women with higher concentrations of total vitamin C. This interaction was also significant for total-body (P < 0.045), spine (P = 0.03), and total-hip BMDs (P = 0.029). CONCLUSIONS: Our results do not support independent associations between dietary intake, total intake, or serum concentrations of antioxidants and BMD in women participating in the Women's Health Initiative. The extent to which HT use may interact with vitamin C intake and BMD warrants further exploration. Copyright © 2005 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Published
2005

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