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3. Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies.

Author

Imamura F., Fretts A.M., Marklund M., Ardisson Korat A.V., Yang W.-S., Lankinen M., Qureshi W., Helmer C., Chen T.-A., Virtanen J.K., Wong K., Bassett J.K., Murphy R., Tintle N., Yu C.I., Brouwer I.A., Chien K.-L., Chen Y.-Y., Wood A.C., del Gobbo L.C., Djousse L., Geleijnse J.M., Giles G.G., de Goede J., Gudnason V., Harris W.S., Hodge A., Hu F., Koulman A., Laakso M., Lind L., Lin H.-J., McKnight B., Rajaobelina K., Riserus U., Robinson J.G., Samieri C., Senn M., Siscovick D.S., Soedamah-Muthu S.S., Sotoodehnia N., Sun Q., Tsai M.Y., Tuomainen T.-P., Uusitupa M., Wagenknecht L.E., Wareham N.J., Wu J.H.Y., Micha R., Lemaitre R.N., Mozaffarian D., Forouhi N.G., Imamura F., Fretts A.M., Marklund M., Ardisson Korat A.V., Yang W.-S., Lankinen M., Qureshi W., Helmer C., Chen T.-A., Virtanen J.K., Wong K., Bassett J.K., Murphy R., Tintle N., Yu C.I., Brouwer I.A., Chien K.-L., Chen Y.-Y., Wood A.C., del Gobbo L.C., Djousse L., Geleijnse J.M., Giles G.G., de Goede J., Gudnason V., Harris W.S., Hodge A., Hu F., Koulman A., Laakso M., Lind L., Lin H.-J., McKnight B., Rajaobelina K., Riserus U., Robinson J.G., Samieri C., Senn M., Siscovick D.S., Soedamah-Muthu S.S., Sotoodehnia N., Sun Q., Tsai M.Y., Tuomainen T.-P., Uusitupa M., Wagenknecht L.E., Wareham N.J., Wu J.H.Y., Micha R., Lemaitre R.N., Mozaffarian D., and Forouhi N.G.

Abstract

Background De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). Methods and findings Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by impreci

Published
2021

4. N-3 fatty acid biomarkers and incident type 2 diabetes: An individual participant-level pooling project of 20 prospective cohort studies.

Author

Qian F., Ardisson Korat A.V., Imamura F., Marklund M., Tintle N., Virtanen J.K., Zhou X., Bassett J.K., Lai H., Hirakawa Y., Chien K.-L., Wood A.C., Lankinen M., Murphy R.A., Samieri C., Pertiwi K., de Mello V.D., Guan W., Forouhi N.G., Wareham N., Consortium I., Hu F.B., Riserus U., Lind L., Harris W.S., Shadyab A.H., Robinson J.G., Steffen L.M., Hodge A., Giles G.G., Ninomiya T., Uusitupa M., Tuomilehto J., Lindstrom J., Laakso M., Siscovick D.S., Helmer C., Geleijnse J.M., Wu J.H.Y., Fretts A., Lemaitre R.N., Micha R., Mozaffarian D., Sun Q., Qian F., Ardisson Korat A.V., Imamura F., Marklund M., Tintle N., Virtanen J.K., Zhou X., Bassett J.K., Lai H., Hirakawa Y., Chien K.-L., Wood A.C., Lankinen M., Murphy R.A., Samieri C., Pertiwi K., de Mello V.D., Guan W., Forouhi N.G., Wareham N., Consortium I., Hu F.B., Riserus U., Lind L., Harris W.S., Shadyab A.H., Robinson J.G., Steffen L.M., Hodge A., Giles G.G., Ninomiya T., Uusitupa M., Tuomilehto J., Lindstrom J., Laakso M., Siscovick D.S., Helmer C., Geleijnse J.M., Wu J.H.Y., Fretts A., Lemaitre R.N., Micha R., Mozaffarian D., and Sun Q.

Abstract

OBJECTIVE Prospective associations between n-3 fatty acid biomarkers and type 2 diabetes (T2D) risk are not consistent in individual studies. We aimed to summarize the prospective associations of biomarkers of a-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis. RESEARCH DESIGN AND METHODS For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance-weighted meta-analysis. RESULTS A total of 16,693 incident T2D cases were identified during follow-up (median follow-up ranging from 2.5 to 21.2 years). In pooled multivariable analysis, per interquintile range (difference between the 90th and 10th percentiles for each fatty acid), EPA, DPA, DHA, and their sum were associated with lower T2D incidence, with hazard ratios (HRs) and 95% CIs of 0.92 (0.87, 0.96), 0.79 (0.73, 0.85), 0.82 (0.76, 0.89), and 0.81 (0.75, 0.88), respectively (all P < 0.001). ALA was not associated with T2D (HR 0.97 [95% CI 0.92, 1.02]) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses. CONCLUSIONS Highercirculating biomarkers of seafood-derivedn-3 fattyacids, including EPA,DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk.Copyright © 2021 by the American Diabetes Association.

Published
2021

5. n-3 Fatty Acid Biomarkers and Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project of 20 Prospective Cohort Studies.

Author

Fretts A., Sun Q., Qian F., Ardisson Korat A.V., Imamura F., Marklund M., Tintle N., Mozaffarian D., Virtanen J.K., Zhou X., Bassett J.K., Lai H., Hirakawa Y., Chien K.-L., Wood A.C., Lankinen M., Murphy R.A., Samieri C., Micha R., Lemaitre R.N., Pertiwi K., de Mello V.D., Guan W., Forouhi N.G., Wareham N., Hu I.C.F.B., Riserus U., Lind L., Harris W.S., Shadyab A.H., Robinson J.G., Steffen L.M., Hodge A., Giles G.G., Ninomiya T., Uusitupa M., Tuomilehto J., Lindstrom J., Laakso M., Siscovick D.S., Helmer C., Geleijnse J.M., Wu J.H.Y., Fretts A., Sun Q., Qian F., Ardisson Korat A.V., Imamura F., Marklund M., Tintle N., Mozaffarian D., Virtanen J.K., Zhou X., Bassett J.K., Lai H., Hirakawa Y., Chien K.-L., Wood A.C., Lankinen M., Murphy R.A., Samieri C., Micha R., Lemaitre R.N., Pertiwi K., de Mello V.D., Guan W., Forouhi N.G., Wareham N., Hu I.C.F.B., Riserus U., Lind L., Harris W.S., Shadyab A.H., Robinson J.G., Steffen L.M., Hodge A., Giles G.G., Ninomiya T., Uusitupa M., Tuomilehto J., Lindstrom J., Laakso M., Siscovick D.S., Helmer C., Geleijnse J.M., and Wu J.H.Y.

Abstract

OBJECTIVE: Prospective associations between n-3 fatty acid biomarkers and type 2 diabetes (T2D) risk are not consistent in individual studies. We aimed to summarize the prospective associations of biomarkers of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an individual participant-level pooled analysis. RESEARCH DESIGN AND METHODS: For our analysis we incorporated data from a global consortium of 20 prospective studies from 14 countries. We included 65,147 participants who had blood measurements of ALA, EPA, DPA, or DHA and were free of diabetes at baseline. De novo harmonized analyses were performed in each cohort following a prespecified protocol, and cohort-specific associations were pooled using inverse variance-weighted meta-analysis. RESULT(S): A total of 16,693 incident T2D cases were identified during follow-up (median follow-up ranging from 2.5 to 21.2 years). In pooled multivariable analysis, per interquintile range (difference between the 90th and 10th percentiles for each fatty acid), EPA, DPA, DHA, and their sum were associated with lower T2D incidence, with hazard ratios (HRs) and 95% CIs of 0.92 (0.87, 0.96), 0.79 (0.73, 0.85), 0.82 (0.76, 0.89), and 0.81 (0.75, 0.88), respectively (all P < 0.001). ALA was not associated with T2D (HR 0.97 [95% CI 0.92, 1.02]) per interquintile range. Associations were robust across prespecified subgroups as well as in sensitivity analyses. CONCLUSION(S): Higher circulating biomarkers of seafood-derived n-3 fatty acids, including EPA, DPA, DHA, and their sum, were associated with lower risk of T2D in a global consortium of prospective studies. The biomarker of plant-derived ALA was not significantly associated with T2D risk.Copyright © 2021 by the American Diabetes Association.

Published
2021

6. Spatial priorities for conserving the most intact biodiverse forests within Central Africa

Author

Grantham, H.S., Shapiro, Aurélie C., Bonfils, D., Gond, Valéry, Goldman, E., Maisels, F., Plumptre, Andrew J., Rayden, T., Robinson, J.G., Strindberg, S., Stokes, A., Tulloch, A.I.T.T., Watson, J.E.M., Williams, L., Rickenbach, Olivia, Grantham, H.S., Shapiro, Aurélie C., Bonfils, D., Gond, Valéry, Goldman, E., Maisels, F., Plumptre, Andrew J., Rayden, T., Robinson, J.G., Strindberg, S., Stokes, A., Tulloch, A.I.T.T., Watson, J.E.M., Williams, L., and Rickenbach, Olivia

Abstract

The forests of Central Africa contain some of Earth's few remaining intact forests. These forests are increasingly threatened by infrastructure development, agriculture, and unsustainable extraction of natural resources (e.g. minerals, bushmeat, and timber), all of which is leading to deforestation and forest degradation, particularly defaunation, and hence causing declines in biodiversity and a significant increase in carbon emissions. Given the pervasive nature of these threats, the global importance of Central African forests for biodiversity conservation, and the limited resources for conservation and sustainable management, there is a need to identify where the most important areas are to orientate conservation efforts. We developed a novel approach for identifying spatial priorities where conservation efforts can maximize biodiversity benefits within Central Africa's most intact forest areas. We found that the Democratic Republic of Congo has the largest amount of priority areas in the region, containing more than half, followed by Gabon, the Republic of Congo and Cameroon. We compared our approach to one that solely prioritizes forest intactness and one that aims to achieve only biodiversity representation objectives. We found that when priorities are only based on forest intactness (without considering biodiversity representation), there are significantly fewer biodiversity benefits and vice versa. We therefore recommend multi-objective planning that includes biodiversity representation and forest intactness to ensure that both objectives are maximized. These results can inform various types of conservation strategies needed within the region, including land-use planning, jurisdictional REDD + initiatives, and performance related carbon payments, protected area expansion, community forest management, and forest concession plans.

Published
2020

7. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author

Vries, P.S. (Paul) de, Brown, M.R., Bentley, A.R. (Amy), Sung, Y.J. (Yun J.), Winkler, T.W. (Thomas W.), Ntalla, I. (Ioanna), Schwander, K., Kraja, A. (Aldi), Guo, X. (Xiuqing), Franceschini, N. (Nora), Cheng, C.-Y. (Ching-Yu), Sim, X. (Xueling), Vojinović, D. (Dina), Huffman, J.E. (Jennifer E.), Musani, S.K. (Solomon K.), Li, C. (Changwei), Feitosa, M.F. (Mary Furlan), Richard, M.A. (Melissa A.), Noordam, R. (Raymond), Aschard, H. (Hugues), Bartz, T.M. (Traci M.), Bielak, L.F. (Lawrence F.), Deng, X. (Xuan), Dorajoo, R. (Rajkumar), Lohman, K.K. (Kurt K.), Manning, A.K. (Alisa), Rankinen, T. (Tuomo), Smith, A.V. (Albert), Tajuddin, S.M. (Salman M.), Evangelou, E. (Evangelos), Graff, M.J. (Maud J.L.), Alver, M. (Maris), Boissel, M. (Mathilde), Chai, J.F. (Jin Fang), Chen, X. (Xu), Divers, J. (Jasmin), Gandin, I. (Ilaria), Gao, C. (Chuan), Goel, A. (Anuj), Hagemeijer, Y. (Yanick), Harris, S.E. (Sarah), Hartwig, F.P. (Fernando P.), He, M. (Meian), Horimoto, A.R.V.R. (Andrea R V R), Hsu, F.-C. (Fang-Chi), Jackson, A.U. (Anne), Kasturiratne, A. (Anuradhani), Komulainen, P. (Pirjo), Kuhnel, B. (Brigitte), Laguzzi, F. (Federica), Lee, J.H. (Joseph H.), Luan, J. (Jian'an), Lyytikäinen, L.-P. (Leo-Pekka), Matoba, N. (Nana), Nolte, I.M. (Ilja), Pietzner, M. (Maik), Riaz, M. (Muhammad), Said, M.A. (M Abdullah), Scott, R.A. (Robert), Sofer, T. (Tamar), Stancáková, A. (Alena), Takeuchi, F. (Fumihiko), Tayo, B. (Bamidele), Most, P.J. (Peter) van der, Varga, T.V. (Tibor V.), Wang, Y. (Yajuan), Ware, E.B. (Erin B.), Wen, W. (Wanqing), Yanek, L.R. (Lisa), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Afaq, S. (Saima), Amin, N. (Najaf), Amini, M. (Marzyeh), Arking, D.E. (Dan), Aung, T. (Tin), Ballantyne, C. (Christie), Boerwinkle, E.A. (Eric), Broeckel, U. (Ulrich), Campbell, A. (Archie), Canouil, M. (Mickaël), Charumathi, S. (Sabanayagam), Chen, Y.D.I. (Yii-Der Ida), Connell, J. (John), Faire, U. (Ulf) de, de Las Fuentes, L. (Lisa), Mutsert, R. (Reneé) de, de Silva, H.J. (H Janaka), Ding, J. (Jingzhong), Dominiczak, A.F. (Anna F.), Duan, Q. (Qing), Eaton, C.B. (Charles B.), Eppinga, R.N. (Ruben N.), Faul, J.D. (Jessica D.), Fisher, V. (Virginia), Forrester, T. (Terrence), Franco, O.H. (Oscar), Friedlander, Y. (Yechiel), Ghanbari, M. (Mohsen), Giulianini, F. (Franco), Grabe, H.J. (Hans Jörgen), Grove, M.L. (Megan), Gu, C. (Charles), Harris, T.B. (Tamara), Heikkinen, S. (Sami), Heng, C.K. (Chew-Kiat), Hirata, M. (Makoto), Hixson, J.E. (James E.), Howard, B.V. (Barbara V.), Ikram, M.A. (Arfan), Jacobs, D.R. (David R.), Johnson, C. (Craig), Jonas, J.B., Kammerer, C.M. (Candace), Katsuya, T. (Tomohiro), Khor, C.C., Kilpeläinen, T.O. (Tuomas O.), Koh, W.-P. (Woon-Puay), Koistinen, H.A. (Heikki A.), Kolcic, I. (Ivana), Kooperberg, C. (Charles), Krieger, J.E. (José), Kritchevsky, S.B. (Steve B.), Kubo, M. (Michiaki), Kuusisto, J. (Johanna), Lakka, T.A. (Timo), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lemaitre, R.N. (Rozenn ), Li, Y. (Yize), Liang, J. (Jingjing), Liu, J. (Jianjun), Liu, K. (Kiang), Loh, M. (Marie), Louie, T. (Tin), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W.), McKenzie, C.A. (Colin A.), Meitinger, T. (Thomas), Metspalu, A. (Andres), Milaneschi, Y. (Yuri), Milani, L. (Lili), Mohlke, K.L. (Karen L.), Mosley, T.H. (Thomas H.), Mukamal, K. (Kenneth), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nelson, C.P. (Christopher P.), Sotoodehnia, N. (Nona), O´Connell, J.R., Palmer, N.D. (Nicholette), Pazoki, R. (Raha), Pedersen, N.L. (Nancy), Peters, A. (Annette), Peyser, P.A. (Patricia A.), Polasek, O. (Ozren), Poulter, N.R. (Neil), Raffel, L.J. (Leslie J.), Raitakari, O. (Olli), Reiner, A.P. (Alex P.), Rice, T.K. (Treva K.), Rich, S.S. (Stephen), Robino, A. (Antonietta), Robinson, J.G. (Jennifer), Rose, L.M. (Lynda M.), Rudan, I. (Igor), Schmidt, C.O. (Carsten O.), Schreiner, P.J. (Pamela), Scott, W.R. (William R.), Sever, P. (Peter), Shi, Y. (Yuan), Sidney, S. (Stephen), Sims, M. (Mario), Smith, B.H. (Blair), Smith, J.A. (Jennifer A), Snieder, H. (Harold), Starr, J.M. (John), Strauch, K. (Konstantin), Tan, N. (Nicholas), Taylor, K.D. (Kent), Teo, Y.Y. (Yik Ying), Tham, Y.C. (Yih Chung), Uitterlinden, A.G. (André), Heemst, D. (Diana) van, Vuckovic, D. (Dragana), Waldenberger, M. (Melanie), Wang, L. (Lihua), Wang, Y. (Yujie), Wang, Z. (Zhe), Wei, W.B. (Wen Bin), Williams, C. (Christine), Wilson, G. (Gregory), Wojczynski, M.K. (Mary ), Yao, J. (Jie), Yu, B. (Bing), Yu, C. (Caizheng), Yuan, J.-M. (Jian-Min), Zhao, W. (Wei), Zonderman, A.B., Becker, D.M. (Diane), Boehnke, M. (Michael), Bowden, D.W. (Donald W.), Chambers, J.C. (John C.), Deary, I.J. (Ian), Esko, T. (Tõnu), Farrall, M. (Martin), Franks, P.W. (Paul W.), Freedman, B.I. (Barry), Froguel, P. (Philippe), Gasparini, P. (Paolo), Gieger, C. (Christian), Horta, B.L. (Bernardo L.), Kamatani, Y. (Yoichiro), Kato, N. (Norihiro), Kooner, J.S. (Jaspal S.), Laakso, M. (Markku), Leander, K. (Karin), Lehtimäki, T. (Terho), Magnusson, P.K. (Patrik), Penninx, B.W.J.H. (Brenda), Pereira, A.C. (Alexandre C.), Rauramaa, R. (Rainer), Samani, N.J. (Nilesh), Scott, J. (James), Shu, X.-O. (Xiao-Ou), Harst, P. (Pim) van der, Wagenknecht, L.E. (Lynne), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Watkins, H. (Hugh), Weir, D.R. (David R.), Wickremasinghe, A.R. (Ananda R.), Zheng, W. (Wei), Elliott, P. (Paul), North, K.E. (Kari), Bouchard, C. (Claude), Evans, M.K. (Michele), Gudnason, V. (Vilmundur), Liu, C.-T. (Ching-Ti), Liu, Y. (YongMei), Psaty, B.M. (Bruce M.), Jarvelin, M.-R. (Marjo-Riitta), Dam, R.M. (Rob) van, Kardia, S.L.R. (Sharon), Dominiczak, A. (Anna), Rotimi, C. (Charles), Mook-Kanamori, D.O. (Dennis O.), Fornage, M. (Myriam), Kelly, T.N. (Tanika N.), Fox, E.R. (Ervin R.), Hayward, C. (Caroline), Duijn, C.M. (Cornelia) van, Tai, E.S. (Shyong), Wong, T.Y. (Tien Yin), Liu, J. (Jingmin), Rotter, J.I. (Jerome I.), Gauderman, W.J. (W James), Province, M.A. (Michael A.), Munroe, P. (Patricia), Rice, K. (Kenneth), Chasman, D.I. (Daniel), Cupples, L.A. (L Adrienne), Tobin, M.D. (Martin), Morrison, A.C. (Alanna), Vries, P.S. (Paul) de, Brown, M.R., Bentley, A.R. (Amy), Sung, Y.J. (Yun J.), Winkler, T.W. (Thomas W.), Ntalla, I. (Ioanna), Schwander, K., Kraja, A. (Aldi), Guo, X. (Xiuqing), Franceschini, N. (Nora), Cheng, C.-Y. (Ching-Yu), Sim, X. (Xueling), Vojinović, D. (Dina), Huffman, J.E. (Jennifer E.), Musani, S.K. (Solomon K.), Li, C. (Changwei), Feitosa, M.F. (Mary Furlan), Richard, M.A. (Melissa A.), Noordam, R. (Raymond), Aschard, H. (Hugues), Bartz, T.M. (Traci M.), Bielak, L.F. (Lawrence F.), Deng, X. (Xuan), Dorajoo, R. (Rajkumar), Lohman, K.K. (Kurt K.), Manning, A.K. (Alisa), Rankinen, T. (Tuomo), Smith, A.V. (Albert), Tajuddin, S.M. (Salman M.), Evangelou, E. (Evangelos), Graff, M.J. (Maud J.L.), Alver, M. (Maris), Boissel, M. (Mathilde), Chai, J.F. (Jin Fang), Chen, X. (Xu), Divers, J. (Jasmin), Gandin, I. (Ilaria), Gao, C. (Chuan), Goel, A. (Anuj), Hagemeijer, Y. (Yanick), Harris, S.E. (Sarah), Hartwig, F.P. (Fernando P.), He, M. (Meian), Horimoto, A.R.V.R. (Andrea R V R), Hsu, F.-C. (Fang-Chi), Jackson, A.U. (Anne), Kasturiratne, A. (Anuradhani), Komulainen, P. (Pirjo), Kuhnel, B. (Brigitte), Laguzzi, F. (Federica), Lee, J.H. (Joseph H.), Luan, J. (Jian'an), Lyytikäinen, L.-P. (Leo-Pekka), Matoba, N. (Nana), Nolte, I.M. (Ilja), Pietzner, M. (Maik), Riaz, M. (Muhammad), Said, M.A. (M Abdullah), Scott, R.A. (Robert), Sofer, T. (Tamar), Stancáková, A. (Alena), Takeuchi, F. (Fumihiko), Tayo, B. (Bamidele), Most, P.J. (Peter) van der, Varga, T.V. (Tibor V.), Wang, Y. (Yajuan), Ware, E.B. (Erin B.), Wen, W. (Wanqing), Yanek, L.R. (Lisa), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Afaq, S. (Saima), Amin, N. (Najaf), Amini, M. (Marzyeh), Arking, D.E. (Dan), Aung, T. (Tin), Ballantyne, C. (Christie), Boerwinkle, E.A. (Eric), Broeckel, U. (Ulrich), Campbell, A. (Archie), Canouil, M. (Mickaël), Charumathi, S. (Sabanayagam), Chen, Y.D.I. (Yii-Der Ida), Connell, J. (John), Faire, U. (Ulf) de, de Las Fuentes, L. (Lisa), Mutsert, R. (Reneé) de, de Silva, H.J. (H Janaka), Ding, J. (Jingzhong), Dominiczak, A.F. (Anna F.), Duan, Q. (Qing), Eaton, C.B. (Charles B.), Eppinga, R.N. (Ruben N.), Faul, J.D. (Jessica D.), Fisher, V. (Virginia), Forrester, T. (Terrence), Franco, O.H. (Oscar), Friedlander, Y. (Yechiel), Ghanbari, M. (Mohsen), Giulianini, F. (Franco), Grabe, H.J. (Hans Jörgen), Grove, M.L. (Megan), Gu, C. (Charles), Harris, T.B. (Tamara), Heikkinen, S. (Sami), Heng, C.K. (Chew-Kiat), Hirata, M. (Makoto), Hixson, J.E. (James E.), Howard, B.V. (Barbara V.), Ikram, M.A. (Arfan), Jacobs, D.R. (David R.), Johnson, C. (Craig), Jonas, J.B., Kammerer, C.M. (Candace), Katsuya, T. (Tomohiro), Khor, C.C., Kilpeläinen, T.O. (Tuomas O.), Koh, W.-P. (Woon-Puay), Koistinen, H.A. (Heikki A.), Kolcic, I. (Ivana), Kooperberg, C. (Charles), Krieger, J.E. (José), Kritchevsky, S.B. (Steve B.), Kubo, M. (Michiaki), Kuusisto, J. (Johanna), Lakka, T.A. (Timo), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lemaitre, R.N. (Rozenn ), Li, Y. (Yize), Liang, J. (Jingjing), Liu, J. (Jianjun), Liu, K. (Kiang), Loh, M. (Marie), Louie, T. (Tin), Mägi, R. (Reedik), Manichaikul, A.W. (Ani W.), McKenzie, C.A. (Colin A.), Meitinger, T. (Thomas), Metspalu, A. (Andres), Milaneschi, Y. (Yuri), Milani, L. (Lili), Mohlke, K.L. (Karen L.), Mosley, T.H. (Thomas H.), Mukamal, K. (Kenneth), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nelson, C.P. (Christopher P.), Sotoodehnia, N. (Nona), O´Connell, J.R., Palmer, N.D. (Nicholette), Pazoki, R. (Raha), Pedersen, N.L. (Nancy), Peters, A. (Annette), Peyser, P.A. (Patricia A.), Polasek, O. (Ozren), Poulter, N.R. (Neil), Raffel, L.J. (Leslie J.), Raitakari, O. (Olli), Reiner, A.P. (Alex P.), Rice, T.K. (Treva K.), Rich, S.S. (Stephen), Robino, A. (Antonietta), Robinson, J.G. (Jennifer), Rose, L.M. (Lynda M.), Rudan, I. (Igor), Schmidt, C.O. (Carsten O.), Schreiner, P.J. (Pamela), Scott, W.R. (William R.), Sever, P. (Peter), Shi, Y. (Yuan), Sidney, S. (Stephen), Sims, M. (Mario), Smith, B.H. (Blair), Smith, J.A. (Jennifer A), Snieder, H. (Harold), Starr, J.M. (John), Strauch, K. (Konstantin), Tan, N. (Nicholas), Taylor, K.D. (Kent), Teo, Y.Y. (Yik Ying), Tham, Y.C. (Yih Chung), Uitterlinden, A.G. (André), Heemst, D. (Diana) van, Vuckovic, D. (Dragana), Waldenberger, M. (Melanie), Wang, L. (Lihua), Wang, Y. (Yujie), Wang, Z. (Zhe), Wei, W.B. (Wen Bin), Williams, C. (Christine), Wilson, G. (Gregory), Wojczynski, M.K. (Mary ), Yao, J. (Jie), Yu, B. (Bing), Yu, C. (Caizheng), Yuan, J.-M. (Jian-Min), Zhao, W. (Wei), Zonderman, A.B., Becker, D.M. (Diane), Boehnke, M. (Michael), Bowden, D.W. (Donald W.), Chambers, J.C. (John C.), Deary, I.J. (Ian), Esko, T. (Tõnu), Farrall, M. (Martin), Franks, P.W. (Paul W.), Freedman, B.I. (Barry), Froguel, P. (Philippe), Gasparini, P. (Paolo), Gieger, C. (Christian), Horta, B.L. (Bernardo L.), Kamatani, Y. (Yoichiro), Kato, N. (Norihiro), Kooner, J.S. (Jaspal S.), Laakso, M. (Markku), Leander, K. (Karin), Lehtimäki, T. (Terho), Magnusson, P.K. (Patrik), Penninx, B.W.J.H. (Brenda), Pereira, A.C. (Alexandre C.), Rauramaa, R. (Rainer), Samani, N.J. (Nilesh), Scott, J. (James), Shu, X.-O. (Xiao-Ou), Harst, P. (Pim) van der, Wagenknecht, L.E. (Lynne), Wang, Y.X. (Ya Xing), Wareham, N.J. (Nick), Watkins, H. (Hugh), Weir, D.R. (David R.), Wickremasinghe, A.R. (Ananda R.), Zheng, W. (Wei), Elliott, P. (Paul), North, K.E. (Kari), Bouchard, C. (Claude), Evans, M.K. (Michele), Gudnason, V. (Vilmundur), Liu, C.-T. (Ching-Ti), Liu, Y. (YongMei), Psaty, B.M. (Bruce M.), Jarvelin, M.-R. (Marjo-Riitta), Dam, R.M. (Rob) van, Kardia, S.L.R. (Sharon), Dominiczak, A. (Anna), Rotimi, C. (Charles), Mook-Kanamori, D.O. (Dennis O.), Fornage, M. (Myriam), Kelly, T.N. (Tanika N.), Fox, E.R. (Ervin R.), Hayward, C. (Caroline), Duijn, C.M. (Cornelia) van, Tai, E.S. (Shyong), Wong, T.Y. (Tien Yin), Liu, J. (Jingmin), Rotter, J.I. (Jerome I.), Gauderman, W.J. (W James), Province, M.A. (Michael A.), Munroe, P. (Patricia), Rice, K. (Kenneth), Chasman, D.I. (Daniel), Cupples, L.A. (L Adrienne), Tobin, M.D. (Martin), and Morrison, A.C. (Alanna)

Abstract

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

Published
2019
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8. Comparison of Cardiovascular Risk Factors for Coronary Heart Disease and Stroke Type in Women

Author

Leening, M.J.G. (Maarten), Cook, N.R. (Nancy), Franco, O.H. (Oscar), Manson, J.E. (JoAnn E), Lakshminarayan, K. (Kamakshi), LaMonte, M.J. (Michael J.), Leira, E.C. (Enrique C.), Robinson, J.G. (Jennifer), Ridker, P.M. (Paul), Paynter, N.P. (Nina), Leening, M.J.G. (Maarten), Cook, N.R. (Nancy), Franco, O.H. (Oscar), Manson, J.E. (JoAnn E), Lakshminarayan, K. (Kamakshi), LaMonte, M.J. (Michael J.), Leira, E.C. (Enrique C.), Robinson, J.G. (Jennifer), Ridker, P.M. (Paul), and Paynter, N.P. (Nina)

Abstract

Background Cardiovascular risk factors have differential effects on various manifestations of cardiovascular disease, but to date direct formal comparisons are scarce, have been conducted primarily in men, and include only traditional risk factors. Methods and Results Using data from the multi-ethnic Women's Health Initiative Observational Study, we used a case-cohort design to compare 1731 women with incident cardiovascular disease during follow-up to a cohort of 1914 women. The direction of effect of all 24 risk factors (including various apolipoproteins, hemoglobin A1c, high-sensitivity C-reactive protein, N-terminal pro-brain natriuretic peptide, and tissue plasminogen activator antigen) was concordant for coronary heart disease (CHD, defined as myocardial infarction and CHD death) and ischemic stroke; however, associations were generally stronger with CHD. Significant differences for multiple risk factors, including blood pressure, lipid levels, and measures of inflammation, were observed when comparing the effects on hemorrhagic stroke with those on ischemic outcomes. For instance, multivariable adjusted hazard ratios per standard deviation increase in non-high-density lipoprotein cholesterol were 1.16 (95% confidence interval, 1.06-1.28) for CHD, 0.97 (0.88-1.07) for ischemic stroke, and 0.76 (0.63-0.91) for hemorrhagic stroke ( P<0.05 for equal association). Model discrimination was better for models predicting CHD or ischemic stroke than for models predicting hemorrhagic stroke or a combined end point. Conclusions Cardiovascular risk factors have largely similar effects on incidence of CHD and ischemic stroke in women, although the magnitude of association varies. Determinants of ischemic and hemorrhagic stroke substantially differ, underscoring their distinct biology. Cardiovascular disease risk may be more accurately reflected when combined cardiovascular disease or cerebrovascular outcomes are broken down into different first manifestations, or when rest

Published
2018
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9. Coronary Artery Calcification (CAC) and Post‐Trial Cardiovascular Events and Mortality Within the Women's Health Initiative (WHI) Estrogen‐Alone Trial

Author

Poornima, Indu G., primary, Mackey, Rachel H., additional, Allison, Matthew A., additional, Manson, JoAnn E., additional, Carr, J. Jeffrey, additional, LaMonte, Michael J., additional, Chang, Yuefang, additional, Kuller, Lewis H., additional, Rossouw, J.E., additional, Ludlam, S., additional, Cochrane, B.B., additional, Hunt, J.R., additional, Lund, B., additional, Prentice, R., additional, O'Rourke, C., additional, Du, L., additional, Pillsbury, S., additional, Hightower, C., additional, Ellison, R., additional, Tan, J., additional, Wassertheil‐Smoller, S., additional, Magnani, M., additional, Noble, D.H., additional, Dellicarpini, T., additional, Bueche, M., additional, McGinnis, A.D., additional, Rybicki, F.J., additional, Assaf, A.R., additional, Sloane, G., additional, Phillips, L.S., additional, Butler, V., additional, Huber, M., additional, Vitali, J., additional, Hsia, J., additional, LeBrun, C., additional, Palm, R., additional, Embersit, D., additional, Whitlock, E., additional, Arnold, K., additional, Sidney, S., additional, Cantrell, V., additional, Kotchen, J.M., additional, Feltz, C., additional, Howard, B.V., additional, Thomas‐Geevarghese, A., additional, Boggs, G., additional, Jelinick, J.S., additional, Greenland, P., additional, Neuman, A., additional, Carlson‐Lund, G., additional, Giovanazzi, S.M., additional, Stefanick, M.L., additional, Swope, S., additional, Jackson, R., additional, Toussant, K., additional, Lewis, C.E., additional, Pierce, P., additional, Stallings, C., additional, Wactawski‐Wende, J., additional, Goel, S., additional, Laughlin, R., additional, Robbins, J., additional, Zaragoza, S., additional, Macias, D., additional, Belisle, D., additional, Nathan, L., additional, Voigt, B., additional, Goldin, J., additional, Woo, M., additional, Langer, R.D., additional, Lien, X., additional, Wright, C.M., additional, Gass, M., additional, Sheridan, S., additional, Robinson, J.G., additional, Feddersen, D., additional, Kelly‐Brake, K., additional, Carroll, J., additional, Ockene, J., additional, Churchill, L., additional, Lasser, N.L., additional, Miller, B., additional, Maldjian, P.D., additional, Pierre‐Louis, J., additional, Fishman, J., additional, O'Sullivan, M.J., additional, Fernandez, D., additional, Margolis, K.L., additional, Bjerk, C.L., additional, Truwit, C., additional, Hearity, J.A., additional, Hyslop, W.B., additional, Darroch, K., additional, Murphy, C., additional, Heiss, G., additional, Edmundowicz, D., additional, Ives, D., additional, Johnson, K.C., additional, Satterfield, S., additional, Connelly, S.A., additional, Jones, E.L., additional, Brzyski, R., additional, Nashawati, M.A., additional, Torchia, S., additional, Rodriguez, A., additional, Garza, R., additional, Nentwich, P., additional, Sarto, G.E., additional, Broderick, L., additional, Sweitzer, N.K., additional, Rossouw, Jacques, additional, Ludlam, Shari, additional, McGowan, Joan, additional, Ford, Leslie, additional, Geller, Nancy, additional, Anderson, Garnet, additional, Prentice, Ross, additional, LaCroix, Andrea, additional, Howard, Barbara V., additional, Jackson, Rebecca, additional, Thomson, Cynthia A., additional, Wactawski‐Wende, Jean, additional, Limacher, Marian, additional, Robinson, Jennifer, additional, Kuller, Lewis, additional, Shumaker, Sally, additional, and Brunner, Robert, additional

Published
2017
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11. Pharmacodynamic relationship between PCSK9, alirocumab, and LDL-C lowering in four phase 3 odyssey trials with/without statin background

Author

Robinson, J.G., primary, Farnier, M., additional, Kastelein, J.J., additional, Roth, E.M., additional, Taskinen, M.R., additional, Colhoun, H.M., additional, Brunet, A., additional, DiCioccio, A.T., additional, Lecorps, G., additional, Pordy, R., additional, Baccara-Dinet, M.T., additional, and Cannon, C.P., additional

Published
2016
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14. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis

Author

Swerdlow, D.I., Holmes, M.V., Kuchenbaecker, K.B., Engmann, J.E.L., Shah, T., Sofat, R., Guo, Y.R., Chung, C., Peasey, A., Ster, R.P., Mooijaart, S.P., Ireland, H.A., Leusink, M., Langenberg, C., Li, K., Palmen, J., Howard, P., Cooper, J.A., Drenos, F., Hardy, J., Nalls, M.A., Li, Y.R., Lowe, G., Stewart, M., Bielinski, S.J., Peto, J., Timpson, N.J., Gallacher, J., Dunlop, M., Houlston, R., Tomlinson, I., Tzoulaki, I., Luan, J., Boer, J.M.A., Forouhi, N.G., Onland-Moret, N.C., Schouw, Y.T. van der, Schnabel, R.B., Hubacek, J.A., Kubinova, R., Baceviciene, M., Tamosiunas, A., Pajak, A., Topor-Madry, R., Malyutina, S.A., Baldassarre, D., Sennblad, B., Tremoli, E., Faire, U. de, Ferrucci, L., Bandenelli, S., Tanaka, T., Meschia, J.F., Singleton, A., Navis, G., Leach, I.M., Bakker, S.J.L., Gansevoort, R.T., Ford, I., Epstein, S.E., Burnett, M.S., Devaney, J.M., Jukema, J.W., Westendorp, R.G.J., Borst, G.J. de, Graaf, Y. van der, Jong, P.A. de, Maitland-van der Zee, A.H., Klungel, O.H., Boer, A. de, Doevendans, P.A., Stephens, J.W., Eaton, C.B., Robinson, J.G., Manson, J.E., Fowkes, F.G.R., Frayling, T.M., Price, J.F., Whincup, P.H., Morris, R.W., Lawlor, D.A., Smith, G.D., Ben-Shlomo, Y., Redline, S., Lange, L.A., Kumari, M., Wareham, N.J., Verschuren, W.M.M., Benjamin, E.J., Whittaker, J.C., Hamsten, A., Dudbridge, F., Delaney, J.A.C., Wong, A., Kuh, D., Hardy, R., Castillo, B.A., Connolly, J.J., Harst, P. van der, Brunner, E.J., Marmot, M.G., Wassel, C.L., Humphries, S.E., Talmud, P.J., Kivimaki, M., Asselbergs, F.W., Voevoda, M., Bobak, M., Pikhart, H., Wilson, J.G., Hakonarson, H., Reiner, A.P., Keating, B.J., Sattar, N., Hingorani, A.D., Casas, J.P., and Interleukin-6 Receptor Mendelian R

Abstract

BACKGROUND: A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. METHODS: Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. FINDINGS: In 40 studies including up to 133,449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34-10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31-9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25,458 coronary heart disease cases and 100,740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93-0·97, p=1·53×10(-5)). INTERPRETATION: On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses. FUNDING: UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.

Published
2012

15. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial

Author

Robinson, J.G., Nedergaard, B.S., Rogers, W.J., Fialkow, J., Neutel, J.M., Ramstad, D., Somaratne, R., Legg, J.C., Nelson, P., Scott, R., Wasserman, S.M., Weiss, R., Graaf, J. de, et al., Robinson, J.G., Nedergaard, B.S., Rogers, W.J., Fialkow, J., Neutel, J.M., Ramstad, D., Somaratne, R., Legg, J.C., Nelson, P., Scott, R., Wasserman, S.M., Weiss, R., Graaf, J. de, and et al.

Abstract

Item does not contain fulltext, IMPORTANCE: In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy. OBJECTIVE: To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin. DESIGN, SETTING, AND PATIENTS: Phase 3, 12-week, randomized, double-blind, placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries. INTERVENTIONS: Patients (n = 2067) were randomized to 1 of 24 treatment groups in 2 steps. Patients were initially randomized to a daily, moderate-intensity (atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]) or high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) statin. After a 4-week lipid-stabilization period, patients (n = 1899) were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients only) when added to statin therapies. MAIN OUTCOMES AND MEASURES: Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12. RESULTS: Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95% CI, 65% to 84%) (every 2 weeks) and by 63% (95% CI, 54% to 71%) to 75% (95% CI, 67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL t

Published
2014

16. Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

Author

Lange, L.A. (Leslie), Hu, Y. (Youna), Zhang, H. (He), Xue, C. (Chenyi), Schmidt, E.M. (Ellen), Tang, Z.-Z. (Zheng-Zheng), Bizon, C. (Chris), Lange, E.M. (Ethan), Smith, A.V. (Davey), Turner, E.H. (Emily), Jun, Y. (Yang), Kang, H.M. (Hyun Min), Peloso, G.M. (Gina), Auer, P. (Paul), Li, K.-P. (Kuo-Ping), Flannick, J. (Jason), Zhang, J. (Ji), Fuchsberger, C. (Christian), Gaulton, K. (Kyle), Lindgren, C.M. (Cecilia), Locke, A. (Adam), Manning, A.K. (Alisa), Sim, X. (Xueling), Rivas, M.A. (Manuel), Holmen, O.L. (Oddgeir), Gottesman, R.F. (Rebecca), Lu, Y. (Yingchang), Ruderfer, D. (Douglas), Stahl, E.A. (Eli), Duan, Q. (Qing), Li, Y. (Yun), Durda, P. (Peter), Jiao, S. (Shuo), Isaacs, A.J. (Aaron), Hofman, A. (Albert), Bis, J.C. (Joshua), Correa, D.D., Griswold, M.D. (Michael), Jakobsdottir, M. (Margret), Schreiner, P.J. (Pamela), Feitosa, M.F. (Mary Furlan), Zhang, Q. (Qunyuan), Huffman, J.E. (Jennifer), Crosby, S., Wassel, C.L. (Christina), Do, R. (Ron), Franceschini, N. (Nora), Martin, L.W. (Lisa), Robinson, J.G. (Jennifer), Assimes, T.L. (Themistocles), Crosslin, D.R. (David), Rosenthal, E.A. (Elisabeth), Tsai, M.Y. (Michael), Rieder, M. (Mark), Farlow, D.N. (Deborah), Folsom, A.R. (Aaron), Lumley, T. (Thomas), Fox, E.R. (Ervin), Carlson, C.S. (Christopher), Peters, U. (Ulrike), Jackson, R.D. (Rebecca), Duijn, C.M. (Cornelia) van, Uitterlinden, A.G. (André), Levy, D. (Daniel), Rotter, J.I. (Jerome), Taylor, H.A. (Herman), Gudnason, V. (Vilmundur), Siscovick, D.S. (David), Fornage, M. (Myriam), Borecki, I.B. (Ingrid), Hayward, C. (Caroline), Rudan, I. (Igor), Chen, Y.E. (Y. Eugene), Bottinger, E.P. (Erwin), Loos, R.J.F. (Ruth), Sætrom, P. (Pål), Hveem, K. (Kristian), Boehnke, M. (Michael), Groop, L. (Leif), McCarthy, M.I. (Mark), Meitinger, T. (Thomas), Ballantyne, C. (Christie), Gabriel, S.B. (Stacey), O'Donnell, C.J. (Christopher), Post, W.S. (Wendy S.), North, K.E. (Kari), Reiner, A. (Alexander), Boerwinkle, E.A. (Eric), Psaty, B.M. (Bruce), Altshuler, D. (David), Kathiresan, S. (Sekar), Lin, D.Y. (Dan), Jarvik, G.P. (Gail), Cupples, L.A. (Adrienne), Kooperberg, C. (Charles), Wilson, J.G. (James), Nickerson, D.A. (Deborah), Abecasis, G.R. (Gonçalo), Rich, S.S. (Stephen), Tracy, R.P. (Russell), Willer, C.J. (Cristen), Lange, L.A. (Leslie), Hu, Y. (Youna), Zhang, H. (He), Xue, C. (Chenyi), Schmidt, E.M. (Ellen), Tang, Z.-Z. (Zheng-Zheng), Bizon, C. (Chris), Lange, E.M. (Ethan), Smith, A.V. (Davey), Turner, E.H. (Emily), Jun, Y. (Yang), Kang, H.M. (Hyun Min), Peloso, G.M. (Gina), Auer, P. (Paul), Li, K.-P. (Kuo-Ping), Flannick, J. (Jason), Zhang, J. (Ji), Fuchsberger, C. (Christian), Gaulton, K. (Kyle), Lindgren, C.M. (Cecilia), Locke, A. (Adam), Manning, A.K. (Alisa), Sim, X. (Xueling), Rivas, M.A. (Manuel), Holmen, O.L. (Oddgeir), Gottesman, R.F. (Rebecca), Lu, Y. (Yingchang), Ruderfer, D. (Douglas), Stahl, E.A. (Eli), Duan, Q. (Qing), Li, Y. (Yun), Durda, P. (Peter), Jiao, S. (Shuo), Isaacs, A.J. (Aaron), Hofman, A. (Albert), Bis, J.C. (Joshua), Correa, D.D., Griswold, M.D. (Michael), Jakobsdottir, M. (Margret), Schreiner, P.J. (Pamela), Feitosa, M.F. (Mary Furlan), Zhang, Q. (Qunyuan), Huffman, J.E. (Jennifer), Crosby, S., Wassel, C.L. (Christina), Do, R. (Ron), Franceschini, N. (Nora), Martin, L.W. (Lisa), Robinson, J.G. (Jennifer), Assimes, T.L. (Themistocles), Crosslin, D.R. (David), Rosenthal, E.A. (Elisabeth), Tsai, M.Y. (Michael), Rieder, M. (Mark), Farlow, D.N. (Deborah), Folsom, A.R. (Aaron), Lumley, T. (Thomas), Fox, E.R. (Ervin), Carlson, C.S. (Christopher), Peters, U. (Ulrike), Jackson, R.D. (Rebecca), Duijn, C.M. (Cornelia) van, Uitterlinden, A.G. (André), Levy, D. (Daniel), Rotter, J.I. (Jerome), Taylor, H.A. (Herman), Gudnason, V. (Vilmundur), Siscovick, D.S. (David), Fornage, M. (Myriam), Borecki, I.B. (Ingrid), Hayward, C. (Caroline), Rudan, I. (Igor), Chen, Y.E. (Y. Eugene), Bottinger, E.P. (Erwin), Loos, R.J.F. (Ruth), Sætrom, P. (Pål), Hveem, K. (Kristian), Boehnke, M. (Michael), Groop, L. (Leif), McCarthy, M.I. (Mark), Meitinger, T. (Thomas), Ballantyne, C. (Christie), Gabriel, S.B. (Stacey), O'Donnell, C.J. (Christopher), Post, W.S. (Wendy S.), North, K.E. (Kari), Reiner, A. (Alexander), Boerwinkle, E.A. (Eric), Psaty, B.M. (Bruce), Altshuler, D. (David), Kathiresan, S. (Sekar), Lin, D.Y. (Dan), Jarvik, G.P. (Gail), Cupples, L.A. (Adrienne), Kooperberg, C. (Charles), Wilson, J.G. (James), Nickerson, D.A. (Deborah), Abecasis, G.R. (Gonçalo), Rich, S.S. (Stephen), Tracy, R.P. (Russell), and Willer, C.J. (Cristen)

Abstract

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previousl

Published
2014
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17. Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks

Author

Peloso, G.M. (Gina), Auer, P. (Paul), Bis, J.C. (Joshua), Voorman, J.M. (Jeanine), Morrison, A.C. (Alanna), Stitziel, N.O. (Nathan), Brody, J.A. (Jennifer A.), Khetarpal, S.A. (Sumeet), Crosby, S., Fornage, M. (Myriam), Isaacs, A.J. (Aaron), Jakobsdottir, M. (Margret), Feitosa, M.F. (Mary Furlan), Davies, G. (Gail), Huffman, J.E. (Jennifer), Manichaikul, A. (Ani), Davis, B. (Brian), Lohman, K. (Kurt), Joon, A.Y. (Aron), Smith, A.V. (Davey), Grove, M.L. (Megan), Zanoni, P. (Paolo), Redon, V. (Valeska), Demissie, S. (Serkalem), Lawson, K. (Kim), Peters, U. (Ulrike), Carlson, C.S. (Christopher), Jackson, R.D. (Rebecca), Ryckman, K.K. (Kelli), MacKey, R.H. (Rachel), Robinson, J.G. (Jennifer), Siscovick, D.S. (David), Schreiner, P.J. (Pamela), Mychaleckyj, J.C. (Josyf), Pankow, J.S. (James), Hofman, A. (Albert), Uitterlinden, A.G. (André), Harris, T.B. (Tamara), Taylor, K.D. (Kent), Stafford, M., Reynolds, L.M. (Lindsay), Marioni, R.E. (Riccardo), Dehghan, A. (Abbas), Franco, O.H. (Oscar), Patel, A.P. (Aniruddh), Lu, Y. (Yingchang), Hindy, G. (George), Gottesman, R.F. (Rebecca), Bottinger, E.P. (Erwin), Melander, O. (Olle), Orho-Melander, M. (Marju), Loos, R.J.F. (Ruth), Duga, S. (Stefano), Merlini, P.A. (Piera), Farrall, M. (Martin), Goel, A. (Anuj), Asselta, R. (Rosanna), Girelli, D. (Domenico), Martinelli, N. (Nicola), Shah, S.H. (Svati), Kraus, T. (Thomas), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), McPherson, R. (Ruth), Watkins, H. (Hugh), Ardissino, D. (Diego), Zhang, Q. (Qunyuan), Wang, J. (Judy), Tsai, M.Y. (Michael), Taylor, H.A. (Herman), Correa, D.D., Griswold, M.D. (Michael), Lange, L.A. (Leslie), Starr, J.M. (John), Rudan, I. (Igor), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Ordovas, J.M. (Jose), Levy, D. (Daniel), Chen, Y.-D.I. (Y.-D. Ida), Reiner, A. (Alexander), Hayward, C. (Caroline), Polasek, O. (Ozren), Deary, I.J. (Ian), Borecki, I.B. (Ingrid), Liu, Y. (YongMei), Gudnason, V. (Vilmundur), Wilson, J.G. (James), Duijn, C.M. (Cornelia) van, Kooperberg, C. (Charles), Rich, S.S. (Stephen), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), O'Donnell, C.J. (Christopher), Rice, K.M. (Kenneth), Boerwinkle, E.A. (Eric), Kathiresan, S. (Sekar), Cupples, L.A. (Adrienne), Li, M. (Mingyao), Peloso, G.M. (Gina), Auer, P. (Paul), Bis, J.C. (Joshua), Voorman, J.M. (Jeanine), Morrison, A.C. (Alanna), Stitziel, N.O. (Nathan), Brody, J.A. (Jennifer A.), Khetarpal, S.A. (Sumeet), Crosby, S., Fornage, M. (Myriam), Isaacs, A.J. (Aaron), Jakobsdottir, M. (Margret), Feitosa, M.F. (Mary Furlan), Davies, G. (Gail), Huffman, J.E. (Jennifer), Manichaikul, A. (Ani), Davis, B. (Brian), Lohman, K. (Kurt), Joon, A.Y. (Aron), Smith, A.V. (Davey), Grove, M.L. (Megan), Zanoni, P. (Paolo), Redon, V. (Valeska), Demissie, S. (Serkalem), Lawson, K. (Kim), Peters, U. (Ulrike), Carlson, C.S. (Christopher), Jackson, R.D. (Rebecca), Ryckman, K.K. (Kelli), MacKey, R.H. (Rachel), Robinson, J.G. (Jennifer), Siscovick, D.S. (David), Schreiner, P.J. (Pamela), Mychaleckyj, J.C. (Josyf), Pankow, J.S. (James), Hofman, A. (Albert), Uitterlinden, A.G. (André), Harris, T.B. (Tamara), Taylor, K.D. (Kent), Stafford, M., Reynolds, L.M. (Lindsay), Marioni, R.E. (Riccardo), Dehghan, A. (Abbas), Franco, O.H. (Oscar), Patel, A.P. (Aniruddh), Lu, Y. (Yingchang), Hindy, G. (George), Gottesman, R.F. (Rebecca), Bottinger, E.P. (Erwin), Melander, O. (Olle), Orho-Melander, M. (Marju), Loos, R.J.F. (Ruth), Duga, S. (Stefano), Merlini, P.A. (Piera), Farrall, M. (Martin), Goel, A. (Anuj), Asselta, R. (Rosanna), Girelli, D. (Domenico), Martinelli, N. (Nicola), Shah, S.H. (Svati), Kraus, T. (Thomas), Rader, D.J. (Daniel), Reilly, M.P. (Muredach), McPherson, R. (Ruth), Watkins, H. (Hugh), Ardissino, D. (Diego), Zhang, Q. (Qunyuan), Wang, J. (Judy), Tsai, M.Y. (Michael), Taylor, H.A. (Herman), Correa, D.D., Griswold, M.D. (Michael), Lange, L.A. (Leslie), Starr, J.M. (John), Rudan, I. (Igor), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Ordovas, J.M. (Jose), Levy, D. (Daniel), Chen, Y.-D.I. (Y.-D. Ida), Reiner, A. (Alexander), Hayward, C. (Caroline), Polasek, O. (Ozren), Deary, I.J. (Ian), Borecki, I.B. (Ingrid), Liu, Y. (YongMei), Gudnason, V. (Vilmundur), Wilson, J.G. (James), Duijn, C.M. (Cornelia) van, Kooperberg, C. (Charles), Rich, S.S. (Stephen), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), O'Donnell, C.J. (Christopher), Rice, K.M. (Kenneth), Boerwinkle, E.A. (Eric), Kathiresan, S. (Sekar), Cupples, L.A. (Adrienne), and Li, M. (Mingyao)

Abstract

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121-], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Published
2014
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19. Efficacy and safety of dalcetrapib in type 2 diabetes mellitus and/or metabolic syndrome patients, at high cardiovascular disease risk.

Author

Stalenhoef, A.F.H., Davidson, M.H., Robinson, J.G., Burgess, T., Duttlinger-Maddux, R., Kallend, D., Goldberg, A.C., Bays, H., Stalenhoef, A.F.H., Davidson, M.H., Robinson, J.G., Burgess, T., Duttlinger-Maddux, R., Kallend, D., Goldberg, A.C., and Bays, H.

Abstract

1 januari 2012, Item does not contain fulltext, AIMS: Mixed dyslipidaemia, characterized by low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of triglycerides, is common in patients with type 2 diabetes mellitus (T2DM) and/or metabolic syndrome. Dalcetrapib effectively increases HDL-C levels by modulating cholesteryl ester transfer protein (CETP) activity. The aim of this analysis was to investigate the lipid modifying efficacy and safety of dalcetrapib in patients with T2DM and/or metabolic syndrome. METHODS: Post hoc analysis of dalcetrapib therapy in five placebo-controlled, Phase II trials (4-48 weeks of duration) involving T2DM and/or metabolic syndrome, in dyslipidaemic patients with coronary heart disease (CHD) or CHD risk equivalent. RESULTS: Both in patients with and without T2DM and/or metabolic syndrome, dalcetrapib decreased CETP activity by 26-58% and increased HDL-C levels by 23-34%, depending on dose and duration of treatment. Dalcetrapib did not significantly affect low-density lipoprotein cholesterol (LDL-C) or apolipoprotein B levels. Treatment with dalcetrapib was generally well tolerated with a similar number of adverse events reported between patient groups and between those receiving dalcetrapib compared with placebo. CONCLUSIONS: Dalcetrapib similarly decreased CETP activity and increased HDL-C levels in patients with and without T2DM or metabolic syndrome; the ongoing Phase III dal-OUTCOMES study will help to determine if dalcetrapib's improvement in lipid levels also reduces cardiovascular morbidity and mortality.

Published
2012

20. A collaboratively-derived science-policy research agenda

Author

Sutherland, W.J., Bellingan, L., Bellingham, J.R., Blackstock, J.J., Bloomfield, R.M., Bravo, M., Cadman, V.M., Cleevely, D.D., Clements, A., Cohen, A.S., Cope, D.R., Daemmrich, A.A., Devecchi, C., Anadon, L.D., Denegri, S., Doubleday, R., Dusic, N.R., Evans, R.J., Feng, W.Y., Godfray, H.C.J., Harris, P., Hartley, S.E., Hester, A.J., Holmes, J., Hughes, A., Hulme, M., Irwin, C., Jennings, R.C., Kass, G.S., Littlejohns, P., Marteau, T.M., McKee, G., Millstone, E.P., Nuttall, W.J., Owens, S., Parker, M.M., Pearson, S., Petts, J., Ploszek, R., Pullin, A.S., Reid, G., Richards, K.S., Robinson, J.G., Shaxson, L., Sierra, L., Smith, B.G., Spiegelhalter, D.J., Stilgoe, J., Stirling, A., Tyler, C.P., Winickoff, D.E., Zimmern, R.L., Sutherland, W.J., Bellingan, L., Bellingham, J.R., Blackstock, J.J., Bloomfield, R.M., Bravo, M., Cadman, V.M., Cleevely, D.D., Clements, A., Cohen, A.S., Cope, D.R., Daemmrich, A.A., Devecchi, C., Anadon, L.D., Denegri, S., Doubleday, R., Dusic, N.R., Evans, R.J., Feng, W.Y., Godfray, H.C.J., Harris, P., Hartley, S.E., Hester, A.J., Holmes, J., Hughes, A., Hulme, M., Irwin, C., Jennings, R.C., Kass, G.S., Littlejohns, P., Marteau, T.M., McKee, G., Millstone, E.P., Nuttall, W.J., Owens, S., Parker, M.M., Pearson, S., Petts, J., Ploszek, R., Pullin, A.S., Reid, G., Richards, K.S., Robinson, J.G., Shaxson, L., Sierra, L., Smith, B.G., Spiegelhalter, D.J., Stilgoe, J., Stirling, A., Tyler, C.P., Winickoff, D.E., and Zimmern, R.L.

Abstract

The need for policy makers to understand science and for scientists to understand policy processes is widely recognised. However, the science-policy relationship is sometimes difficult and occasionally dysfunctional; it is also increasingly visible, because it must deal with contentious issues, or itself becomes a matter of public controversy, or both. We suggest that identifying key unanswered questions on the relationship between science and policy will catalyse and focus research in this field. To identify these questions, a collaborative procedure was employed with 52 participants selected to cover a wide range of experience in both science and policy, including people from government, non-governmental organisations, academia and industry. These participants consulted with colleagues and submitted 239 questions. An initial round of voting was followed by a workshop in which 40 of the most important questions were identified by further discussion and voting. The resulting list includes questions about the effectiveness of science-based decision-making structures; the nature and legitimacy of expertise; the consequences of changes such as increasing transparency; choices among different sources of evidence; the implications of new means of characterising and representing uncertainties; and ways in which policy and political processes affect what counts as authoritative evidence. We expect this exercise to identify important theoretical questions and to help improve the mutual understanding and effectiveness of those working at the interface of science and policy.

Published
2012

21. Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: A genome-wide association study of 13,372 participants

Author

Deo, R., primary, Nalls, M.A., additional, Avery, C.L., additional, Smith, J.G., additional, Evans, D.S., additional, Keller, M.F., additional, Butler, A.M., additional, Buxbaum, S.G., additional, Li, G., additional, Miguel Quibrera, P., additional, Smith, E.N., additional, Tanaka, T., additional, Akylbekova, E.L., additional, Alonso, A., additional, Arking, D.E., additional, Benjamin, E.J., additional, Berenson, G.S., additional, Bis, J.C., additional, Chen, L.Y., additional, Chen, W., additional, Cummings, S.R., additional, Ellinor, P.T., additional, Evans, M.K., additional, Ferrucci, L., additional, Fox, E.R., additional, Heckbert, S.R., additional, Heiss, G., additional, Hsueh, W.C., additional, Kerr, K.F., additional, Limacher, M.C., additional, Liu, Y., additional, Lubitz, S.A., additional, Magnani, J.W., additional, Mehra, R., additional, Marcus, G.M., additional, Murray, S.S., additional, Newman, A.B., additional, Njajou, O., additional, North, K.E., additional, Paltoo, D.N., additional, Psaty, B.M., additional, Redline, S.S., additional, Reiner, A.P., additional, Robinson, J.G., additional, Rotter, J.I., additional, Samdarshi, T.E., additional, Schnabel, R.B., additional, Schork, N.J., additional, Singleton, A.B., additional, Siscovick, D., additional, Soliman, E.Z., additional, Sotoodehnia, N., additional, Srinivasan, S.R., additional, Taylor, H.A., additional, Trevisan, M., additional, Zhang, Z., additional, Zonderman, A.B., additional, Newton-Cheh, C., additional, and Whitsel, E.A., additional

Published
2013
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22. Matrilineage and allelic sorting within an expanding population

Author

Valderrama, X., Robinson, J.G., and Melnick, D.J.

Subjects
Matrilineal kinship -- Social aspects, Anthropology/archeology/folklore
Abstract

Genetic analyses, demographic data, and climatic indices were used to examine kin and group structure of wedge-capped capuchin monkeys, Cebus olivaceus, in the Venezuelan llanos. One large and one small group were followed for 23 and 7 years, respectively. Variables included rates of birth, death, male and female individual transfer, and group fission and fusion. Capuchins in both groups and across the region were genotyped at autosomal microsatellite loci, and sequenced at a 485-base pair segment of the mitochondrial control region. The large group's birth rate and matrilineal infant death rate were influenced by annual fluctuation in rainfall levels, which in turn were signalled in part by ENSO cycles. Some low-ranking matrilines went extinct and others fissioned from the group. Of eight initial matrilines in 1977, only the three highest-ranking persisted in 1999. Unique alleles in the group were lost with each matriline. Thus, matrilineage loss and allelic erosion were nonrandom with respect to female rank. Multiple group fissions followed El Nino events. In 1999, members of two matrilines from the large group fused with the small group, introducing new microsatellite alleles. The new females also assumed higher ranks than natal females. Based on the empirical evidence above, matrilineage sorting in the small group likely will remove natal members and unique alleles, and replace them with those of the new females. Across the region, depauperate mitochondrial variability and deficient heterozygosity in autosomal genotypes revealed a recent population expansion. Supported by NSF 9908455, NSF DBI 9602234, and the Wildlife Conservation Society.

Published
2003

23. Coronary Artery Calcification (CAC) and Post‐Trial Cardiovascular Events and Mortality Within the Women's Health Initiative (WHI) Estrogen‐Alone Trial

Author

Poornima, Indu G., Mackey, Rachel H., Allison, Matthew A., Manson, JoAnn E., Carr, J. Jeffrey, LaMonte, Michael J., Chang, Yuefang, Kuller, Lewis H., Rossouw, J.E., Ludlam, S., Cochrane, B.B., Hunt, J.R., Lund, B., Prentice, R., O'Rourke, C., Du, L., Pillsbury, S., Hightower, C., Ellison, R., Tan, J., Wassertheil‐Smoller, S., Magnani, M., Noble, D.H., Dellicarpini, T., Bueche, M., McGinnis, A.D., Rybicki, F.J., Assaf, A.R., Sloane, G., Phillips, L.S., Butler, V., Huber, M., Vitali, J., Hsia, J., LeBrun, C., Palm, R., Embersit, D., Whitlock, E., Arnold, K., Sidney, S., Cantrell, V., Kotchen, J.M., Feltz, C., Howard, B.V., Thomas‐Geevarghese, A., Boggs, G., Jelinick, J.S., Greenland, P., Neuman, A., Carlson‐Lund, G., Giovanazzi, S.M., Stefanick, M.L., Swope, S., Jackson, R., Toussant, K., Lewis, C.E., Pierce, P., Stallings, C., Wactawski‐Wende, J., Goel, S., Laughlin, R., Robbins, J., Zaragoza, S., Macias, D., Belisle, D., Nathan, L., Voigt, B., Goldin, J., Woo, M., Langer, R.D., Lien, X., Wright, C.M., Gass, M., Sheridan, S., Robinson, J.G., Feddersen, D., Kelly‐Brake, K., Carroll, J., Ockene, J., Churchill, L., Lasser, N.L., Miller, B., Maldjian, P.D., Pierre‐Louis, J., Fishman, J., O'Sullivan, M.J., Fernandez, D., Margolis, K.L., Bjerk, C.L., Truwit, C., Hearity, J.A., Hyslop, W.B., Darroch, K., Murphy, C., Heiss, G., Edmundowicz, D., Ives, D., Johnson, K.C., Satterfield, S., Connelly, S.A., Jones, E.L., Brzyski, R., Nashawati, M.A., Torchia, S., Rodriguez, A., Garza, R., Nentwich, P., Sarto, G.E., Broderick, L., Sweitzer, N.K., Rossouw, Jacques, Ludlam, Shari, McGowan, Joan, Ford, Leslie, Geller, Nancy, Anderson, Garnet, Prentice, Ross, LaCroix, Andrea, Howard, Barbara V., Jackson, Rebecca, Thomson, Cynthia A., Wactawski‐Wende, Jean, Limacher, Marian, Robinson, Jennifer, Kuller, Lewis, Shumaker, Sally, and Brunner, Robert

Subjects
cardiovascular disease, coronary artery calcification, hormonal therapy, mortality, women, Cardiovascular Disease, Women, Mortality/Survival, Computerized Tomography (CT), Risk Factors
Abstract

Background: Among women aged 50 to 59 years at baseline in the Women's Health Initiative (WHI) Estrogen‐Alone (E‐Alone) trial, randomization to conjugated equine estrogen‐alone versus placebo was associated with lower risk of myocardial infarction and mortality, and, in an ancillary study, the WHI‐CACS (WHI Coronary Artery Calcification Study) with lower CAC, measured by cardiac computed tomography ≈8.7 years after baseline randomization. We hypothesized that higher CAC would be related to post‐trial coronary heart disease (CHD), cardiovascular disease (CVD), and total mortality, independent of baseline randomization or risk factors. Methods and Results: WHI‐CACS participants (n=1020) were followed ≈8 years from computed tomography scan in 2005 (mean age=64.4) through 2013 for incident CHD (myocardial infarction and fatal CHD, n=17), CVD (n=69), and total mortality (n=55). Incident CHD and CVD analyses excluded women with CVD before scan (n=89). Women with CAC=0 (n=54%) had very low age‐adjusted rates/1000 person‐years of CHD (0.91), CVD (5.56), and mortality (3.45). In comparison, rates were ≈2‐fold higher for women with any CAC (>0). Associations were not modified by baseline randomization to conjugated equine estrogen–alone versus placebo. Adjusted for baseline randomization and risk factors, the hazard ratio (95% confidence interval) for CAC >100 (19%) was 4.06 (2.11, 7.80) for CVD and 2.70 (1.26, 5.79) for mortality. Conclusions: Among a subset of postmenopausal women aged 50 to 59 years at baseline in the WHI E‐Alone Trial, CAC at mean age of 64 years was strongly related to incident CHD, CVD, and to total mortality over ≈8 years, independent of baseline randomization to conjugated equine estrogen–alone versus placebo or CVD risk factors. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00000611.

Published
2017
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35. Physiological Responses of Lake Trout to Stress: Effects of Water Hardness and Genotype

Author

McDonald, D.G. and Robinson, J.G.

Abstract

AbstractWe evaluated stress due to net confinement among three genetically isolated strains of juvenile lake trout Salvelinus namaycushin relation to water hardness. Changes in plasma cortisol, glucose, sodium, and chloride were used as the stress indicators. In lake trout acclimated and then confined for 8 h in hard water, plasma glucose and cortisol increased significantly (by three- and sixfold, respectively), reaching a plateau by 4 h, while plasma Na+and Cl–significantly decreased by about 7%. Fish transferred from hard water to soft water and then confined exhibited significantly greater changes in blood chemistry than did fish confined in hard water. This soft-water effect on the stress response disappeared if fish were first acclimated to soft water, but full soft-water acclimation may take at least 2 months. Comparisons of blood chemistry among three different strains of lake trout (Lake Manitou, Killala Lake, and Slate Island) revealed significant differences in their responses to confinement stress. These findings have important implications for two fish culture issues: The choice of whether to rear stocks in soft-water versus hard-water hatcheries, and the selection of stocks for stress resistance.

Published
1993
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41. Book reviews.

Author

Robinson, J.G.

Subjects
EXPENDABLE Future, The (Book)
Abstract

Reviews the book `The Expendable Future: U.S. Politics and the Protection of Biological Diversity,' by Richard Tobin.

Published
1992

42. Treatment effect of alirocumab according to age group, smoking status, and hypertension: Pooled analysis from 10 randomized ODYSSEY studies

Author

Jennifer G. Robinson, Frederick J. Raal, Maurizio Averna, Keith C. Ferdinand, Michel Farnier, R. Scott Wright, L. Veronica Lee, Andrei C. Sposito, Danielle M. Lerch, Raul D. Santos, Michael J. Louie, Alexia Letierce, Jaakko Tuomilehto, Francisco Antonio Helfenstein Fonseca, Eliano Pio Navarese, Raal F.J., Tuomilehto J., Sposito A.C., Fonseca F.A., Averna M., Farnier M., Santos R.D., Ferdinand K.C., Wright R.S., Navarese E.P., Lerch D.M., Louie M.J., Lee L.V., Letierce A., and Robinson J.G.

Subjects
medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Hypercholesterolemia, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Placebo, law.invention, PCSK9, 03 medical and health sciences, Age, 0302 clinical medicine, Randomized controlled trial, Ezetimibe, Risk Factors, law, Internal medicine, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Adverse effect, Aged, Alirocumab, Nutrition and Dietetics, business.industry, Smoking, Age Factors, Cholesterol, LDL, Middle Aged, medicine.disease, Cholesterol, Treatment Outcome, Concomitant, Hypertension, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

Background: Age, smoking, hypercholesterolemia, and hypertension are major risk factors for atherosclerotic cardiovascular disease. Objective: We examined whether the effects of alirocumab on low-density lipoprotein cholesterol (LDL-C) differed according to age, hypertension, or smoking status. Methods: Data were pooled from 10 Phase 3 ODYSSEY randomized trials (24–104 weeks’ duration) in 4983 people with heterozygous familial hypercholesterolemia (FH) or non–familial hypercholesterolemia (3188 on alirocumab, 1795 on control [620 on ezetimibe and 1175 on placebo]). Most participants received concomitant maximum tolerated statin therapy. In 8 trials, the alirocumab dose was increased from 75 mg every 2 weeks (Q2W) to 150 mg Q2W at Week 12 if predefined risk-based LDL-C goals were not achieved at Week 8 (≥70 mg/dL in very high cardiovascular risk; ≥100 mg/dL in moderate or high cardiovascular risk). Two trials compared alirocumab 150 mg Q2W vs placebo. The efficacy and safety of alirocumab were assessed post hoc in subgroups stratified by age (

Published
2019

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