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1. The impact of the COVID-19 pandemic on cardiovascular disease prevention and management

Author

Dale, Caroline E., Takhar, Rohan, Carragher, Raymond, Katsoulis, Michail, Torabi, Fatemeh, Duffield, Stephen, Kent, Seamus, Mueller, Tanja, Kurdi, Amanj, Le Anh, Thu Nguyen, McTaggart, Stuart, Abbasizanjani, Hoda, Hollings, Sam, Scourfield, Andrew, Lyons, Ronan A., Griffiths, Rowena, Lyons, Jane, Davies, Gareth, Harris, Daniel, Handy, Alex, Mizani, Mehrdad A., Tomlinson, Christopher, Thygesen, Johan H., Ashworth, Mark, Denaxas, Spiros, Banerjee, Amitava, Sterne, Jonathan A. C., Brown, Paul, Bullard, Ian, Priedon, Rouven, Mamas, Mamas A., Slee, Ann, Lorgelly, Paula, Pirmohamed, Munir, Khunti, Kamlesh, Morris, Andrew D., Sudlow, Cathie, Akbari, Ashley, Bennie, Marion, Sattar, Naveed, and Sofat, Reecha

Published
2023
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2. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Author

Kilpeläinen, Tuomas O, Carli, Jayne F Martin, Skowronski, Alicja A, Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F, Hedman, Åsa K, Drong, Alexander W, Hayes, James E, Zhao, Jinghua, Pers, Tune H, Schick, Ursula, Grarup, Niels, Kutalik, Zoltán, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikäinen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Del Greco M, Fabiola, Pasko, Dorota, Renström, Frida, Willems, Sara M, Mahajan, Anubha, Rose, Lynda M, Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E, Pérusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S, Ju Sung, Yun, Ramos, Yolande F, Amin, Najaf, Amuzu, Antoinette, Barroso, Inês, Bellis, Claire, Blangero, John, Buckley, Brendan M, Böhringer, Stefan, I Chen, Yii-Der, de Craen, Anton JN, Crosslin, David R, Dale, Caroline E, Dastani, Zari, Day, Felix R, Deelen, Joris, Delgado, Graciela E, Demirkan, Ayse, Finucane, Francis M, Ford, Ian, Garcia, Melissa E, Gieger, Christian, Gustafsson, Stefan, Hallmans, Göran, Hankinson, Susan E, Havulinna, Aki S, Herder, Christian, Hernandez, Dena, Hicks, Andrew A, Hunter, David J, Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S, Jørgensen, Marit E, Jørgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A, Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P, Myers, Richard H, Männistö, Satu, Nalls, Mike A, Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D, Rankinen, Tuomo, Rasmussen-Torvik, Laura J, Rathmann, Wolfgang, Rice, Treva K, Brent Richards, J, Ridker, Paul M, Sattar, Naveed, and Savage, David B

Subjects
Adipose Tissue, Animals, Mice, Leptin, RNA, Messenger, Tissue Culture Techniques, Gene Expression Regulation, Male, Genome-Wide Association Study, Gene Knockdown Techniques, RNA, Messenger
Abstract

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P

Published
2016

3. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.

Author

Holmes, Michael V, Dale, Caroline E, Zuccolo, Luisa, Silverwood, Richard J, Guo, Yiran, Ye, Zheng, Prieto-Merino, David, Dehghan, Abbas, Trompet, Stella, Wong, Andrew, Cavadino, Alana, Drogan, Dagmar, Padmanabhan, Sandosh, Li, Shanshan, Yesupriya, Ajay, Leusink, Maarten, Sundstrom, Johan, Hubacek, Jaroslav A, Pikhart, Hynek, Swerdlow, Daniel I, Panayiotou, Andrie G, Borinskaya, Svetlana A, Finan, Chris, Shah, Sonia, Kuchenbaecker, Karoline B, Shah, Tina, Engmann, Jorgen, Folkersen, Lasse, Eriksson, Per, Ricceri, Fulvio, Melander, Olle, Sacerdote, Carlotta, Gamble, Dale M, Rayaprolu, Sruti, Ross, Owen A, McLachlan, Stela, Vikhireva, Olga, Sluijs, Ivonne, Scott, Robert A, Adamkova, Vera, Flicker, Leon, Bockxmeer, Frank M van, Power, Christine, Marques-Vidal, Pedro, Meade, Tom, Marmot, Michael G, Ferro, Jose M, Paulos-Pinheiro, Sofia, Humphries, Steve E, Talmud, Philippa J, Mateo Leach, Irene, Verweij, Niek, Linneberg, Allan, Skaaby, Tea, Doevendans, Pieter A, Cramer, Maarten J, van der Harst, Pim, Klungel, Olaf H, Dowling, Nicole F, Dominiczak, Anna F, Kumari, Meena, Nicolaides, Andrew N, Weikert, Cornelia, Boeing, Heiner, Ebrahim, Shah, Gaunt, Tom R, Price, Jackie F, Lannfelt, Lars, Peasey, Anne, Kubinova, Ruzena, Pajak, Andrzej, Malyutina, Sofia, Voevoda, Mikhail I, Tamosiunas, Abdonas, Maitland-van der Zee, Anke H, Norman, Paul E, Hankey, Graeme J, Bergmann, Manuela M, Hofman, Albert, Franco, Oscar H, Cooper, Jackie, Palmen, Jutta, Spiering, Wilko, de Jong, Pim A, Kuh, Diana, Hardy, Rebecca, Uitterlinden, Andre G, Ikram, M Arfan, Ford, Ian, Hyppönen, Elina, Almeida, Osvaldo P, Wareham, Nicholas J, Khaw, Kay-Tee, Hamsten, Anders, Husemoen, Lise Lotte N, Tjønneland, Anne, Tolstrup, Janne S, Rimm, Eric, Beulens, Joline WJ, and Verschuren, WM Monique

Subjects
InterAct Consortium, Humans, Coronary Disease, Alcohol Dehydrogenase, Genetic Markers, Models, Statistical, Alcohol Drinking, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Male, Stroke, Mendelian Randomization Analysis, Biomarkers, General & Internal Medicine, Clinical Sciences, Public Health and Health Services
Abstract

ObjectiveTo use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.DesignMendelian randomisation meta-analysis of 56 epidemiological studies.Participants261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.Main outcome measuresOdds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.ResultsCarriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).ConclusionsIndividuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

Published
2014

5. The impact of the COVID-19 pandemic on cardiovascular disease prevention and management

Author

Dale, Caroline E, Takhar, Rohan, Carragher, Raymond, Katsoulis, Michail, Torabi, Fatemeh, Duffield, Stephen, Kent, Seamus, Mueller, Tanja, Kurdi, Amanj, Le Anh, Thu Nguyen, McTaggart, Stuart, Abbasizanjani, Hoda, Hollings, Sam, Scourfield, Andrew, Lyons, Ronan A, Griffiths, Rowena, Lyons, Jane, Davies, Gareth, Harris, Daniel, Handy, Alex, Mizani, Mehrdad A, Tomlinson, Christopher, Thygesen, Johan H, Ashworth, Mark, Denaxas, Spiros, Banerjee, Amitava, Sterne, Jonathan A C, Brown, Paul, Bullard, Ian, Priedon, Rouven, Mamas, Mamas A, Slee, Ann, Lorgelly, Paula, Pirmohamed, Munir, Khunti, Kamlesh, Morris, Andrew D, Sudlow, Cathie, Akbari, Ashley, Bennie, Marion, Sattar, Naveed, and Sofat, Reecha

Subjects
Cardiovascular Diseases - epidemiology - prevention & control - diagnosis, Pandemics - prevention & control, SDG 3 - Good Health and Well-being, Risk Factors, Hypertension - complications - drug therapy - epidemiology, COVID-19 - epidemiology, Humans, General Medicine, Diabetes Mellitus, Type 2 - complications - drug therapy - epidemiology, General Biochemistry, Genetics and Molecular Biology
Abstract

How the Coronavirus Disease 2019 (COVID-19) pandemic has affected prevention and management of cardiovascular disease (CVD) is not fully understood. In this study, we used medication data as a proxy for CVD management using routinely collected, de-identified, individual-level data comprising 1.32 billion records of community-dispensed CVD medications from England, Scotland and Wales between April 2018 and July 2021. Here we describe monthly counts of prevalent and incident medications dispensed, as well as percentage changes compared to the previous year, for several CVD-related indications, focusing on hypertension, hypercholesterolemia and diabetes. We observed a decline in the dispensing of antihypertensive medications between March 2020 and July 2021, with 491,306 fewer individuals initiating treatment than expected. This decline was predicted to result in 13,662 additional CVD events, including 2,281 cases of myocardial infarction and 3,474 cases of stroke, should individuals remain untreated over their lifecourse. Incident use of lipid-lowering medications decreased by 16,744 patients per month during the first half of 2021 as compared to 2019. By contrast, incident use of medications to treat type 2 diabetes mellitus, other than insulin, increased by approximately 623 patients per month for the same time period. In light of these results, methods to identify and treat individuals who have missed treatment for CVD risk factors and remain undiagnosed are urgently required to avoid large numbers of excess future CVD events, an indirect impact of the COVID-19 pandemic.

Published
2023

6. Association between alcohol and cardiovascular disease : Mendelian randomisation analysis based on individual participant data

Author

IMPROVE study group, The InterAct Consortium, Holmes, Michael V, Dale, Caroline E, Zuccolo, Luisa, Silverwood, Richard J, Guo, Yiran, Ye, Zheng, Prieto-Merino, David, Dehghan, Abbas, Trompet, Stella, Wong, Andrew, Cavadino, Alana, Drogan, Dagmar, Padmanabhan, Sandosh, Li, Shanshan, Yesupriya, Ajay, Leusink, Maarten, Sundstrom, Johan, Hubacek, Jaroslav A, Pikhart, Hynek, Swerdlow, Daniel I, Panayiotou, Andrie G, Borinskaya, Svetlana A, Finan, Chris, Shah, Sonia, Kuchenbaecker, Karoline B, Shah, Tina, Engmann, Jorgen, Folkersen, Lasse, Eriksson, Per, Ricceri, Fulvio, Melander, Olle, Sacerdote, Carlotta, Gamble, Dale M, Rayaprolu, Sruti, Ross, Owen A, McLachlan, Stela, Vikhireva, Olga, Sluijs, Ivonne, Scott, Robert A, Adamkova, Vera, Flicker, Leon, van Bockxmeer, Frank M, Power, Christine, Marques-Vidal, Pedro, Meade, Tom, Marmot, Michael G, Ferro, Jose M, Paulos-Pinheiro, Sofia, Humphries, Steve E, Talmud, Philippa J, Leach, Irene Mateo, Verweij, Niek, Linneberg, Allan, Skaaby, Tea, Doevendans, Pieter A, Cramer, Maarten J, van der Harst, Pim, Klungel, Olaf H, Dowling, Nicole F, Dominiczak, Anna F, Kumari, Meena, Nicolaides, Andrew N, Weikert, Cornelia, Boeing, Heiner, Ebrahim, Shah, Gaunt, Tom R, Price, Jackie F, Lannfelt, Lars, Peasey, Anne, Kubinova, Ruzena, Pajak, Andrzej, Malyutina, Sofia, Voevoda, Mikhail I, Tamosiunas, Abdonas, Maitland-vanderZee, Anke H, Norman, Paul E, Hankey, Graeme J, Bergmann, Manuela M, Hofman, Albert, Franco, Oscar H, Cooper, Jackie, Palmen, Jutta, Spiering, Wilko, de Jong, Pim A, Kuh, Diana, Hardy, Rebecca, Uitterlinden, Andre G, Ikram, M Arfan, Ford, Ian, Hyppönen, Elina, Almeida, Osvaldo P, Wareham, Nicholas J, Khaw, Kay-Tee, Hamsten, Anders, Husemoen, Lise Lotte N, Tjønneland, Anne, Tolstrup, Janne S, Rimm, Eric, Beulens, Joline W J, Verschuren, W M Monique, Onland-Moret, N Charlotte, Hofker, Marten H, Wannamethee, S Goya, Whincup, Peter H, Morris, Richard, Vicente, Astrid M, Watkins, Hugh, Farrall, Martin, Jukema, J Wouter, Meschia, James, Cupples, L Adrienne, Sharp, Stephen J, Fornage, Myriam, Kooperberg, Charles, LaCroix, Andrea Z, Dai, James Y, Lanktree, Matthew B, Siscovick, David S, Jorgenson, Eric, Spring, Bonnie, Coresh, Josef, Li, Yun R, Buxbaum, Sarah G, Schreiner, Pamela J, Curtis, R, Y Tsai, Michael, Patel, Sanjay R, Redline, Susan, Johnson, Andrew D, Hoogeveen, Ron C, Hakonarson, Hakon, Rotter, Jerome I, Boerwinkle, Eric, de Bakker, Paul I W, Kivimaki, Mika, Asselbergs, Folkert W, Sattar, Naveed, Lawlor, Debbie A, Whittaker, John, Smith, George Davey, Mukamal, Kenneth, Psaty, Bruce M, Wilson, James G, Lange, Leslie A, Hamidovic, Ajna, Hingorani, Aroon D, Nordestgaard, Børge G, Bobak, Martin, Leon, David A, Langenberg, Claudia, Palmer, Tom M, Reiner, Alex P, Keating, Brendan J, Dudbridge, Frank, and Casas, Juan P

Published
2014

9. The adverse impact of COVID-19 pandemic on cardiovascular disease prevention and management in England, Scotland and Wales: A population-scale analysis of trends in medication data

Author

Dale, Caroline E, primary, Takhar, Rohan, additional, Carragher, Ray, additional, Torabi, Fatemeh, additional, Katsoulis, Michalis, additional, Duffield, Stephen, additional, Kent, Seamus, additional, Mueller, Tanja, additional, Kurdi, Amanj, additional, McTaggart, Stuart, additional, Abbasizanjani, Hoda, additional, Hollings, Sam, additional, Scourfield, Andrew, additional, Lyons, Ronan, additional, Griffiths, Rowena, additional, Lyons, Jane, additional, Davies, Gareth, additional, Harris, Dan, additional, Handy, Alex, additional, Mizani, Mehrdad Alizadeh, additional, Tomlinson, Chris, additional, Ashworth, Mark, additional, Denaxas, Spiros, additional, Banerjee, Amitava, additional, Sterne, Jonathan, additional, Lovibond, Kate, additional, Brown, Paul, additional, Bullard, Ian, additional, Priedon, Rouven, additional, Mamas, Mamas A, additional, Slee, Ann, additional, Lorgelly, Paula, additional, Pirmohamed, Munir, additional, Khunti, Kamlesh, additional, Sattar, Naveed, additional, Morris, Andrew, additional, Sudlow, Cathie, additional, Akbari, Ashley, additional, Bennie, Marion, additional, and Sofat, Reecha, additional

Published
2022
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11. Mendelian randomization of blood lipids for coronary heart disease

Author

Holmes, Michael V., Asselbergs, Folkert W., Palmer, Tom M., Drenos, Fotios, Lanktree, Matthew B., Nelson, Christopher P., Dale, Caroline E., Padmanabhan, Sandosh, Finan, Chris, Swerdlow, Daniel I., Tragante, Vinicius, van Iperen, Erik P.A., Sivapalaratnam, Suthesh, Shah, Sonia, Elbers, Clara C., Shah, Tina, Engmann, Jorgen, Giambartolomei, Claudia, White, Jon, Zabaneh, Delilah, Sofat, Reecha, McLachlan, Stela, Doevendans, Pieter A., Balmforth, Anthony J., Hall, Alistair S., North, Kari E., Almoguera, Berta, Hoogeveen, Ron C., Cushman, Mary, Fornage, Myriam, Patel, Sanjay R., Redline, Susan, Siscovick, David S., Tsai, Michael Y., Karczewski, Konrad J., Hofker, Marten H., Verschuren, W. Monique, Bots, Michiel L., van der Schouw, Yvonne T., Melander, Olle, Dominiczak, Anna F., Morris, Richard, Ben-Shlomo, Yoav, Price, Jackie, Kumari, Meena, Baumert, Jens, Peters, Annette, Thorand, Barbara, Koenig, Wolfgang, Gaunt, Tom R., Humphries, Steve E., Clarke, Robert, Watkins, Hugh, Farrall, Martin, Wilson, James G., Rich, Stephen S., de Bakker, Paul I.W., Lange, Leslie A., Davey Smith, George, Reiner, Alex P., Talmud, Philippa J., Kivimäki, Mika, Lawlor, Debbie A., Dudbridge, Frank, Samani, Nilesh J., Keating, Brendan J., Hingorani, Aroon D., and Casas, Juan P.

Published
2015
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14. Alcohol consumption and cognitive performance: a Mendelian randomization study

Author

Kumari, Meena, Holmes, Michael V., Dale, Caroline E., Hubacek, Jaroslav A., Palmer, Tom M., Pikhart, Hynek, Peasey, Anne, Britton, Annie, Horvat, Pia, Kubinova, Ruzena, Malyutina, Sofia, Pajak, Andrzej, Tamosiunas, Abdonas, Shankar, Aparna, Singh-Manoux, Archana, Voevoda, Mikhail, Kivimaki, Mika, Hingorani, Aroon D., Marmot, Michael G., Casas, Juan P., and Bobak, Martin

Published
2014
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16. The relationship between sleep duration, cognition and dementia: a Mendelian randomization study

Author

Henry, Albert, Katsoulis, Michail, Masi, Stefano, Fatemifar, Ghazaleh, Denaxas, Spiros, Acosta, Dionisio, Garfield, Victoria, and Dale, Caroline E

Subjects
Adult, Male, cognition, Time Factors, Sleep duration, Mendelian Randomization Analysis, Middle Aged, United Kingdom, Alzheimer Disease, Memory, Mendelian Randomization, Reaction Time, Humans, Mendelian randomization, dementia, Cognitive Dysfunction, Dementia, Female, Sleep, Aged
Abstract

Background Short and long sleep duration have been linked with poorer cognitive outcomes, but it remains unclear whether these associations are causal. Methods We conducted the first Mendelian randomization (MR) study with 77 single-nucleotide polymorphisms (SNPs) for sleep duration using individual-participant data from the UK Biobank cohort (N = 395 803) and summary statistics from the International Genomics of Alzheimer’s Project (N cases/controls = 17 008/37 154) to investigate the potential impact of sleep duration on cognitive outcomes. Results Linear MR suggested that each additional hour/day of sleep was associated with 1% [95% confidence interval (CI) = 0–2%; P = 0.008] slower reaction time and 3% more errors in visual-memory test (95% CI = 0–6%; P = 0.05). There was little evidence to support associations of increased sleep duration with decline in visual memory [odds ratio (OR) per additional hour/day of sleep = 1.10 (95% CI = 0.76–1.57); P = 0.62], decline in reaction time [OR = 1.28 (95% CI = 0.49–3.35); P = 0.61], all-cause dementia [OR = 1.19 (95% CI = 0.65–2.19); P = 0.57] or Alzheimer’s disease risk [OR = 0.89 (95% CI = 0.67–1.18); P = 0.41]. Non-linear MR suggested that both short and long sleep duration were associated with poorer visual memory (P for non-linearity = 3.44e–9) and reaction time (P for non-linearity = 6.66e–16). Conclusions Linear increase in sleep duration has a small negative effect on reaction time and visual memory, but the true association might be non-linear, with evidence of associations for both short and long sleep duration. These findings suggest that sleep duration may represent a potential causal pathway for cognition.

Published
2019

17. Risk thresholds for alcohol consumption : combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Author

Wood, Angela M., Kaptoge, Stephen, Butterworth, Adam, Willeit, Peter, Warnakula, Samantha, Bolton, Thomas, Paige, Ellie, Paul, Dirk S., Sweeting, Michael, Burgess, Stephen, Bell, Steven, Astle, William, Stevens, David, Koulman, Albert, Selmer, Randi M., Verschuren, Monique, Sato, Shinichi, Njølstad, Inger, Woodward, Mark, Salomaa, Veikko, Nordestgaard, Børge G., Yeap, Bu B., Fletcher, Astrid, Melander, Olle, Kuller, Lewis H., Balkau, Beverley, Marmot, Michael, Koenig, Wolfgang, Casiglia, Edoardo, Cooper, Cyrus, Arndt, Volker, Franco, Oscar H., Wennberg, Patrik, Gallacher, John, de la Cámara, Agustín Gómez, Völzke, Henry, Dahm, Christina C., Dale, Caroline E., Bergmann, Manuela, Crespo, Carlos, van der Schouw, Yvonne T., Kaaks, Rudolf, Simons, Leon A., Lagiou, Pagona, Schoufour, Josje D., Boer, Jolanda M.A., Key, Timothy J., Rodriguez, Beatriz, Moreno-Iribas, Conchi, Grobbee, Diederick E., and Emerging Risk Factors Collaboration/EPIC-CVD/UK Biobank Alcohol Study Group

Subjects
Medicine(all)
Abstract

Background: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. Methods: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies. Findings: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively. Interpretation: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. Funding: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Published
2018

18. Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Author

Wood, Angela M, Kaptoge, Stephen, Butterworth, Adam S, Willeit, Peter, Warnakula, Samantha, Bolton, Thomas, Paige, Ellie, Paul, Dirk S, Sweeting, Michael, Burgess, Stephen, Bell, Steven, Tjønneland, Anne, Brenner, Hermann, Palmieri, Luigi, Dallongeville, Jean, Brunner, Eric J, Assmann, Gerd, Trevisan, Maurizio, Gillum, Richard F, Ford, Ian, Sattar, Naveed, Astle, William, Lazo, Mariana, Thompson, Simon G, Ferrari, Pietro, Leon, David A, Smith, George Davey, Peto, Richard, Jackson, Rod, Banks, Emily, Di Angelantonio, Emanuele, Danesh, John, Stevens, David, Butterworth, Adam, Koulman, Albert, Selmer, Randi M, Verschuren, Monique, Sato, Shinichi, Njølstad, Inger, Woodward, Mark, Veikko, Salomaa, Nordestgaard, Børge G, Yeap, Bu B, Flecther, Astrid, Melander, Olle, Kuller, Lewis H, Balkau, Beverley, Marmot, Michael, Koenig, Wolfgang, Casiglia, Edoardo, Cooper, Cyrus, Verschuren, W M Monique, Arndt, Volker, Franco, Oscar H, Wennberg, Patrik, Gallacher, John, Gómez de la Cámara, Agustín, Völzke, Henry, Dahm, Christina C, Dale, Caroline E, Bergmann, Manuela, Crespo, Carlos, van der Schouw, Yvonne T, Kaaks, Rudolf, Simons, Leon A, Lagiou, Pagona, Schoufour, Josje D, Boer, Jolanda M.A, Key, Timothy J, Rodriguez, Beatriz, Moreno-Iribas, Conchi, Davidson, Karina W, Taylor, James O, Sacerdote, Carlotta, Wallace, Robert B, Quiros, J. Ramon, Rimm, Eric B, Tumino, Rosario, Blazer III, Dan G, Linneberg, Allan, Daimon, Makoto, Panico, Salvatore, Howard, Barbara, Skeie, Guri, Salomaa, Veikko, Strandberg, Timo, Weiderpass, Elisabete, Nietert, Paul J, Psaty, Bruce M, Kromhout, Daan, Salamanca-Fernandez, Elena, Kiechl, Stefan, Krumholz, Harlan M, Grioni, Sara, Palli, Domenico, Huerta, José M, Price, Jackie, Sundström, Johan, Arriola, Larraitz, Arima, Hisatomi, Travis, Ruth C, Panagiotakos, Demosthenes B, Karakatsani, Anna, Trichopoulou, Antonia, Kühn, Tilman, Grobbee, Diederick E, Barrett-Connor, Elizabeth, van Schoor, Natasja, Boeing, Heiner, Overvad, Kim, Kauhanen, Jussi, Wareham, Nick, Langenberg, Claudia, Forouhi, Nita, Wennberg, Maria, Després, Jean-Pierre, Cushman, Mary, Cooper, Jackie A, Rodriguez, Carlos J, Sakurai, Masaru, Shaw, Jonathan E, Knuiman, Matthew, Fletcher, Astrid, Voortman, Trudy, Meisinger, Christa, Dallongeville, Jean-Pierre, Gillumn, Richard F, Ford, Ian Ford, Thompson, Simon, Davey Smith, George, de la Cámara, Agustín Gómez, Bergmann, Manuela M, Crespo, Carlos J, Boer, Jolanda M A, Quiros, J Ramon, Blazer, Dan G, Wood, Angela M, Kaptoge, Stephen, Butterworth, Adam S, Willeit, Peter, Warnakula, Samantha, Bolton, Thomas, Paige, Ellie, Paul, Dirk S, Sweeting, Michael, Burgess, Stephen, Bell, Steven, Tjønneland, Anne, Brenner, Hermann, Palmieri, Luigi, Dallongeville, Jean, Brunner, Eric J, Assmann, Gerd, Trevisan, Maurizio, Gillum, Richard F, Ford, Ian, Sattar, Naveed, Astle, William, Lazo, Mariana, Thompson, Simon G, Ferrari, Pietro, Leon, David A, Smith, George Davey, Peto, Richard, Jackson, Rod, Banks, Emily, Di Angelantonio, Emanuele, Danesh, John, Stevens, David, Butterworth, Adam, Koulman, Albert, Selmer, Randi M, Verschuren, Monique, Sato, Shinichi, Njølstad, Inger, Woodward, Mark, Veikko, Salomaa, Nordestgaard, Børge G, Yeap, Bu B, Flecther, Astrid, Melander, Olle, Kuller, Lewis H, Balkau, Beverley, Marmot, Michael, Koenig, Wolfgang, Casiglia, Edoardo, Cooper, Cyrus, Verschuren, W M Monique, Arndt, Volker, Franco, Oscar H, Wennberg, Patrik, Gallacher, John, Gómez de la Cámara, Agustín, Völzke, Henry, Dahm, Christina C, Dale, Caroline E, Bergmann, Manuela, Crespo, Carlos, van der Schouw, Yvonne T, Kaaks, Rudolf, Simons, Leon A, Lagiou, Pagona, Schoufour, Josje D, Boer, Jolanda M.A, Key, Timothy J, Rodriguez, Beatriz, Moreno-Iribas, Conchi, Davidson, Karina W, Taylor, James O, Sacerdote, Carlotta, Wallace, Robert B, Quiros, J. Ramon, Rimm, Eric B, Tumino, Rosario, Blazer III, Dan G, Linneberg, Allan, Daimon, Makoto, Panico, Salvatore, Howard, Barbara, Skeie, Guri, Salomaa, Veikko, Strandberg, Timo, Weiderpass, Elisabete, Nietert, Paul J, Psaty, Bruce M, Kromhout, Daan, Salamanca-Fernandez, Elena, Kiechl, Stefan, Krumholz, Harlan M, Grioni, Sara, Palli, Domenico, Huerta, José M, Price, Jackie, Sundström, Johan, Arriola, Larraitz, Arima, Hisatomi, Travis, Ruth C, Panagiotakos, Demosthenes B, Karakatsani, Anna, Trichopoulou, Antonia, Kühn, Tilman, Grobbee, Diederick E, Barrett-Connor, Elizabeth, van Schoor, Natasja, Boeing, Heiner, Overvad, Kim, Kauhanen, Jussi, Wareham, Nick, Langenberg, Claudia, Forouhi, Nita, Wennberg, Maria, Després, Jean-Pierre, Cushman, Mary, Cooper, Jackie A, Rodriguez, Carlos J, Sakurai, Masaru, Shaw, Jonathan E, Knuiman, Matthew, Fletcher, Astrid, Voortman, Trudy, Meisinger, Christa, Dallongeville, Jean-Pierre, Gillumn, Richard F, Ford, Ian Ford, Thompson, Simon, Davey Smith, George, de la Cámara, Agustín Gómez, Bergmann, Manuela M, Crespo, Carlos J, Boer, Jolanda M A, Quiros, J Ramon, and Blazer, Dan G

Abstract

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS:We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around o

Published
2018

19. Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Author

Public Health Epidemiologie, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 9, Wood, Angela M., Kaptoge, Stephen, Butterworth, Adam, Willeit, Peter, Warnakula, Samantha, Bolton, Thomas, Paige, Ellie, Paul, Dirk S., Sweeting, Michael, Burgess, Stephen, Bell, Steven, Astle, William, Stevens, David, Koulman, Albert, Selmer, Randi M., Verschuren, Monique, Sato, Shinichi, Njølstad, Inger, Woodward, Mark, Salomaa, Veikko, Nordestgaard, Børge G., Yeap, Bu B., Fletcher, Astrid, Melander, Olle, Kuller, Lewis H., Balkau, Beverley, Marmot, Michael, Koenig, Wolfgang, Casiglia, Edoardo, Cooper, Cyrus, Arndt, Volker, Franco, Oscar H., Wennberg, Patrik, Gallacher, John, de la Cámara, Agustín Gómez, Völzke, Henry, Dahm, Christina C., Dale, Caroline E., Bergmann, Manuela, Crespo, Carlos, van der Schouw, Yvonne T., Kaaks, Rudolf, Simons, Leon A., Lagiou, Pagona, Schoufour, Josje D., Boer, Jolanda M.A., Key, Timothy J., Rodriguez, Beatriz, Moreno-Iribas, Conchi, Grobbee, Diederick E., Emerging Risk Factors Collaboration/EPIC-CVD/UK Biobank Alcohol Study Group, Public Health Epidemiologie, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 9, Wood, Angela M., Kaptoge, Stephen, Butterworth, Adam, Willeit, Peter, Warnakula, Samantha, Bolton, Thomas, Paige, Ellie, Paul, Dirk S., Sweeting, Michael, Burgess, Stephen, Bell, Steven, Astle, William, Stevens, David, Koulman, Albert, Selmer, Randi M., Verschuren, Monique, Sato, Shinichi, Njølstad, Inger, Woodward, Mark, Salomaa, Veikko, Nordestgaard, Børge G., Yeap, Bu B., Fletcher, Astrid, Melander, Olle, Kuller, Lewis H., Balkau, Beverley, Marmot, Michael, Koenig, Wolfgang, Casiglia, Edoardo, Cooper, Cyrus, Arndt, Volker, Franco, Oscar H., Wennberg, Patrik, Gallacher, John, de la Cámara, Agustín Gómez, Völzke, Henry, Dahm, Christina C., Dale, Caroline E., Bergmann, Manuela, Crespo, Carlos, van der Schouw, Yvonne T., Kaaks, Rudolf, Simons, Leon A., Lagiou, Pagona, Schoufour, Josje D., Boer, Jolanda M.A., Key, Timothy J., Rodriguez, Beatriz, Moreno-Iribas, Conchi, Grobbee, Diederick E., and Emerging Risk Factors Collaboration/EPIC-CVD/UK Biobank Alcohol Study Group

Published
2018

20. Causal Associations of Adiposity and Body Fat Distribution With Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus: A Mendelian Randomization Analysis

Author

Dale, Caroline E, Fatemifar, Ghazaleh, Palmer, Tom M, White, Jon, Prieto-Merino, David, Zabaneh, Delilah, Engmann, Jorgen EL, Shah, Tina, Wong, Andrew, Warren, Helen R, McLachlan, Stela, Trompet, Stella, Moldovan, Max, Morris, Richard W, Sofat, Reecha, Kumari, Meena, Hyppönen, Elina, Jefferis, Barbara J, Gaunt, Tom R, Ben-Shlomo, Yoav, Zhou, Ang, Gentry-Maharaj, Aleksandra, Ryan, Andy, UCLEB Consortium, METASTROKE Consortium, Mutsert, Renée de, Noordam, Raymond, Caulfield, Mark J, Jukema, J Wouter, Worrall, Bradford B, Munroe, Patricia B, Menon, Usha, Power, Chris, Kuh, Diana, Lawlor, Debbie A, Humphries, Steve E, Mook-Kanamori, Dennis O, Sattar, Naveed, Kivimaki, Mika, Price, Jacqueline F, Davey Smith, George, Dudbridge, Frank, Hingorani, Aroon D, Holmes, Michael V, and Casas, Juan P

Abstract

BACKGROUND: The implications of different adiposity measures on cardiovascular disease etiology remain unclear. In this article, we quantify and contrast causal associations of central adiposity (waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) and general adiposity (body mass index [BMI]) with cardiometabolic disease. METHODS: Ninety-seven independent single-nucleotide polymorphisms for BMI and 49 single-nucleotide polymorphisms for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with coronary heart disease (CHD) data from CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics; combined total 66 842 cases), stroke from METASTROKE (12 389 ischemic stroke cases), type 2 diabetes mellitus from DIAGRAM (Diabetes Genetics Replication and Meta-analysis; 34 840 cases), and lipids from GLGC (Global Lipids Genetic Consortium; 213 500 participants) consortia. Primary outcomes were CHD, type 2 diabetes mellitus, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits. RESULTS: Each one standard deviation (SD) higher WHRadjBMI (1 SD≈0.08 U) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD, 1.48; 95% confidence interval [CI], 1.28-1.71), similar to findings for BMI (1 SD≈4.6 kg/m2; OR for CHD, 1.36; 95% CI, 1.22-1.52). Only WHRadjBMI increased risk of ischemic stroke (OR, 1.32; 95% CI, 1.03-1.70). For type 2 diabetes mellitus, both measures had large effects: OR, 1.82 (95% CI, 1.38-2.42) and OR, 1.98 (95% CI, 1.41-2.78) per 1 SD higher WHRadjBMI and BMI, respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95% CI, 9%-77% per 1 SD). CONCLUSIONS: Both general and central adiposity have causal effects on CHD and type 2 diabetes mellitus. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity.

Published
2017

21. Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Author

Wood, Angela M, primary, Kaptoge, Stephen, additional, Butterworth, Adam S, additional, Willeit, Peter, additional, Warnakula, Samantha, additional, Bolton, Thomas, additional, Paige, Ellie, additional, Paul, Dirk S, additional, Sweeting, Michael, additional, Burgess, Stephen, additional, Bell, Steven, additional, Astle, William, additional, Stevens, David, additional, Koulman, Albert, additional, Selmer, Randi M, additional, Verschuren, W M Monique, additional, Sato, Shinichi, additional, Njølstad, Inger, additional, Woodward, Mark, additional, Salomaa, Veikko, additional, Nordestgaard, Børge G, additional, Yeap, Bu B, additional, Fletcher, Astrid, additional, Melander, Olle, additional, Kuller, Lewis H, additional, Balkau, Beverley, additional, Marmot, Michael, additional, Koenig, Wolfgang, additional, Casiglia, Edoardo, additional, Cooper, Cyrus, additional, Arndt, Volker, additional, Franco, Oscar H, additional, Wennberg, Patrik, additional, Gallacher, John, additional, de la Cámara, Agustín Gómez, additional, Völzke, Henry, additional, Dahm, Christina C, additional, Dale, Caroline E, additional, Bergmann, Manuela M, additional, Crespo, Carlos J, additional, van der Schouw, Yvonne T, additional, Kaaks, Rudolf, additional, Simons, Leon A, additional, Lagiou, Pagona, additional, Schoufour, Josje D, additional, Boer, Jolanda M A, additional, Key, Timothy J, additional, Rodriguez, Beatriz, additional, Moreno-Iribas, Conchi, additional, Davidson, Karina W, additional, Taylor, James O, additional, Sacerdote, Carlotta, additional, Wallace, Robert B, additional, Quiros, J Ramon, additional, Tumino, Rosario, additional, Blazer, Dan G, additional, Linneberg, Allan, additional, Daimon, Makoto, additional, Panico, Salvatore, additional, Howard, Barbara, additional, Skeie, Guri, additional, Strandberg, Timo, additional, Weiderpass, Elisabete, additional, Nietert, Paul J, additional, Psaty, Bruce M, additional, Kromhout, Daan, additional, Salamanca-Fernandez, Elena, additional, Kiechl, Stefan, additional, Krumholz, Harlan M, additional, Grioni, Sara, additional, Palli, Domenico, additional, Huerta, José M, additional, Price, Jackie, additional, Sundström, Johan, additional, Arriola, Larraitz, additional, Arima, Hisatomi, additional, Travis, Ruth C, additional, Panagiotakos, Demosthenes B, additional, Karakatsani, Anna, additional, Trichopoulou, Antonia, additional, Kühn, Tilman, additional, Grobbee, Diederick E, additional, Barrett-Connor, Elizabeth, additional, van Schoor, Natasja, additional, Boeing, Heiner, additional, Overvad, Kim, additional, Kauhanen, Jussi, additional, Wareham, Nick, additional, Langenberg, Claudia, additional, Forouhi, Nita, additional, Wennberg, Maria, additional, Després, Jean-Pierre, additional, Cushman, Mary, additional, Cooper, Jackie A, additional, Rodriguez, Carlos J, additional, Sakurai, Masaru, additional, Shaw, Jonathan E, additional, Knuiman, Matthew, additional, Voortman, Trudy, additional, Meisinger, Christa, additional, Tjønneland, Anne, additional, Brenner, Hermann, additional, Palmieri, Luigi, additional, Dallongeville, Jean, additional, Brunner, Eric J, additional, Assmann, Gerd, additional, Trevisan, Maurizio, additional, Gillum, Richard F, additional, Ford, Ian, additional, Sattar, Naveed, additional, Lazo, Mariana, additional, Thompson, Simon G, additional, Ferrari, Pietro, additional, Leon, David A, additional, Smith, George Davey, additional, Peto, Richard, additional, Jackson, Rod, additional, Banks, Emily, additional, Di Angelantonio, Emanuele, additional, Danesh, John, additional, Wood, Angela M, additional, Butterworth, Adam, additional, Verschuren, Monique, additional, Veikko, Salomaa, additional, Flecther, Astrid, additional, Gómez de la Cámara, Agustín, additional, Bergmann, Manuela, additional, Crespo, Carlos, additional, Boer, Jolanda M.A, additional, Quiros, J. Ramon, additional, Rimm, Eric B, additional, Blazer III, Dan G, additional, Dallongeville, Jean-Pierre, additional, Gillumn, Richard F, additional, Ford, Ian Ford, additional, Thompson, Simon, additional, and Davey Smith, George, additional

Published
2018
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22. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Author

Kilpelainen, Tuomas O., Martin-Carli, Jayne Frances, Skowronski, Alicja Anna, Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F., Hedman, Asa K., Drong, Alexander W., Hayes, James E., Zhao, Jinghua, Pers, Tune H., Schick, Ursula, Grarup, Niels, Kutalik, Zolt��n, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytik��inen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian���an, Del Greco M, Fabiola, Pasko, Dorota, Renstr��m, Frida, Willems, Sara M., Mahajan, Anubha, Rose, Lynda M., Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E., P��russe, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S., Sung, Yun Ju, Ramos, Yolande F., Amin, Najaf, Amuzu, Antoinette, Barroso, In��s, Bellis, Claire, Blangero, John, Buckley, Brendan M., B��hringer, Stefan, Chen, Yii-Der I., de Craen, Anton J. N., Crosslin, David R., Dale, Caroline E., Dastani, Zari, Day, Felix R., Deelen, Joris, Delgado, Graciela E., Demirkan, Ayse, Finucane, Francis M., Ford, Ian, Garcia, Melissa E., Gieger, Christian, Gustafsson, Stefan, Hallmans, G��ran, Hankinson, Susan E., Havulinna, Aki S., Herder, Christian, Hernandez, Dena, Hicks, Andrew A., Hunter, David J., Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S., J��rgensen, Marit E., J��rgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A., Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P., Myers, Richard H., M��nnist��, Satu, Nalls, Mike A., Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rathmann, Wolfgang, Rice, Treva K., Richards, J. Brent, Ridker, Paul M., Sattar, Naveed, Savage, David B., S��derberg, Stefan, Timpson, Nicholas J., Vandenput, Liesbeth, van Heemst, Diana, Uh, Hae-Won, Vohl, Marie-Claude, Walker, Mark, Wichmann, Heinz-Erich, Wid��n, Elisabeth, Wood, Andrew R., Yao, Jie, Zeller, Tanja, Zhang, Yiying, Meulenbelt, Ingrid, Kloppenburg, Margreet, Astrup, Arne, S��rensen, Thorkild I. A., Sarzynski, Mark A., Rao, D. C., Jousilahti, Pekka, Vartiainen, Erkki, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andr�� G., Kajantie, Eero, Osmond, Clive, Palotie, Aarno, Eriksson, Johan G., Heli��vaara, Markku, Knekt, Paul B., Koskinen, Seppo, Jula, Antti, Perola, Markus, Huupponen, Risto K., Viikari, Jorma S., K��h��nen, Mika, Lehtim��ki, Terho, Raitakari, Olli T., Mellstr��m, Dan, Lorentzon, Mattias, Casas, Juan P., Bandinelli, Stefanie, M��rz, Winfried, Isaacs, Aaron, van Dijk, Ko W., van Duijn, Cornelia M., Harris, Tamara B., Bouchard, Claude, Allison, Matthew A., Chasman, Daniel I., Ohlsson, Claes, Lind, Lars, Scott, Robert A., Langenberg, Claudia, Wareham, Nicholas J., Ferrucci, Luigi, Frayling, Timothy M., Pramstaller, Peter P., Borecki, Ingrid B., Waterworth, Dawn M., Bergmann, Sven, Waeber, G��rard, and Vollenweider, Peter

Subjects
Leptin, Meta-analysis, Molecular biology, FOS: Biological sciences, digestive, oral, and skin physiology, Genetics, hormones, hormone substitutes, and hormone antagonists
Abstract

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P

Published
2016
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23. Replication and Characterization of Association between ABO SNPs and Red Blood Cell Traits by Meta-Analysis in Europeans

Author

McLachlan, Stela, Giambartolomei, Claudia, White, Jon, Charoen, Pimphen, Wong, Andrew, Finan, Chris, Engmann, Jorgen, Shah, Tina, Hersch, Micha, Podmore, Clara, Cavadino, Alana, Jefferis, Barbara J, Dale, Caroline E, Hypponen, Elina, Morris, Richard W, Casas, Juan P, Kumari, Meena, Ben-Shlomo, Yoav, Gaunt, Tom R, Drenos, Fotios, Langenberg, Claudia, Kuh, Diana, Kivimaki, Mika, Rueedi, Rico, Waeber, Gerard, Hingorani, Aroon D, Price, Jacqueline F, Walker, Ann P, UCLEB Consortium, White, Jon [0000-0003-2666-561X], Podmore, Clara [0000-0002-2452-8067], Walker, Ann P [0000-0002-8485-3494], and Apollo - University of Cambridge Repository

Subjects
DNA Replication, Erythrocytes, Quantitative Trait Loci, lcsh:R, lcsh:Medicine, Polymorphism, Single Nucleotide, ABO Blood-Group System, Europe, hemic and lymphatic diseases, Ethnicity, Humans, lcsh:Q, lcsh:Science, Genome-Wide Association Study
Abstract

Red blood cell (RBC) traits are routinely measured in clinical practice as important markers of health. Deviations from the physiological ranges are usually a sign of disease, although variation between healthy individuals also occurs, at least partly due to genetic factors. Recent large scale genetic studies identified loci associated with one or more of these traits; further characterization of known loci and identification of new loci is necessary to better understand their role in health and disease and to identify potential molecular mechanisms. We performed meta-analysis of Metabochip association results for six RBC traits-hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) and red blood cell count (RCC)-in 11 093 Europeans from seven studies of the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium. We identified 394 non-overlapping SNPs in five loci at genome-wide significance: 6p22.1-6p21.33 (with HFE among others), 6q23.2 (with HBS1L among others), 6q23.3 (contains no genes), 9q34.3 (only ABO gene) and 22q13.1 (with TMPRSS6 among others), replicating previous findings of association with RBC traits at these loci and extending them by imputation to 1000 Genomes. We further characterized associations between ABO SNPs and three traits: hemoglobin, hematocrit and red blood cell count, replicating them in an independent cohort. Conditional analyses indicated the independent association of each of these traits with ABO SNPs and a role for blood group O in mediating the association. The 15 most significant RBC-associated ABO SNPs were also associated with five cardiometabolic traits, with discordance in the direction of effect between groups of traits, suggesting that ABO may act through more than one mechanism to influence cardiometabolic risk.

Published
2016

24. Mendelian randomization of blood lipids for coronary heart disease

Author

Redline, Susan, Sofat, Reecha, Shah, Sonia, Sivapalaratnam, Suthesh, Swerdlow, Daniel I., White, Jon, North, Kari E., Patel, Sanjay R., Engmann, Jorgen, Holmes, Michael V., Fornage, Myriam, Elbers, Clara C., Almoguera, Berta, Lanktree, Matthew B., Padmanabhan, Sandosh, Shah, Tina, Cushman, Mary, Dale, Caroline E., Asselbergs, Folkert W., McLachlan, Stela, Palmer, Tom M., Nelson, Christopher P., Doevendans, Pieter A., Hoogeveen, Ron C., Giambartolomei, Claudia, Zabaneh, Delilah, Tragante, Vinicius, van Iperen, Erik P.A., Drenos, Fotios, Finan, Chris, Balmforth, Anthony J., and Hall, Alistair S.

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

AimsTo investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.Methods and resultsWe developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10−6); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).ConclusionThe genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

Published
2015
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25. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Author

University of Helsinki, Helsinki Collegium for Advanced Studies, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Hospital for Children and Adolescents, University of Helsinki, Clinicum, Kilpelainen, Tuomas O., Carli, Jayne F. Martin, Skowronski, Alicja A., Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F., Hedman, Asa K., Drong, Alexander W., Hayes, James E., Zhao, Jinghua, Pers, Tune H., Schick, Ursula, Grarup, Niels, Kutalik, Zoltan, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikainen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Del Greco M, Fabiola, Pasko, Dorota, Renstrom, Frida, Willems, Sara M., Mahajan, Anubha, Rose, Lynda M., Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E., Perusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S., Sung, Yun Ju, Ramos, Yolande F., Amin, Najaf, Amuzu, Antoinette, Barroso, Ines, Bellis, Claire, Blangero, John, Buckley, Brendan M., Boehringer, Stefan, Chen, Yii-Der I., de Craen, Anton J. N., Crosslin, David R., Dale, Caroline E., Dastani, Zari, Day, Felix R., Deelen, Joris, Delgado, Graciela E., Demirkan, Ayse, Finucane, Francis M., Ford, Ian, Garcia, Melissa E., Gieger, Christian, Gustafsson, Stefan, Hallmans, Goran, Hankinson, Susan E., Havulinna, Aki S., Herder, Christian, Hernandez, Dena, Hicks, Andrew A., Hunter, David J., Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S., Jorgensen, Marit E., Jorgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A., Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P., Myers, Richard H., Mannisto, Satu, Nalls, Mike A., Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rathmann, Wolfgang, Rice, Treva K., Richards, J. Brent, Ridker, Paul M., Sattar, Naveed, Savage, David B., Soderberg, Stefan, Timpson, Nicholas J., Vandenput, Liesbeth, van Heemst, Diana, Uh, Hae-Won, Vohl, Marie-Claude, Walker, Mark, Wichmann, Heinz-Erich, Widen, Elisabeth, Wood, Andrew R., Yao, Jie, Zeller, Tanja, Zhang, Yiying, Meulenbelt, Ingrid, Kloppenburg, Margreet, Astrup, Arne, Sorensen, Thorkild I. A., Sarzynski, Mark A., Rao, D. C., Jousilahti, Pekka, Vartiainen, Erkki, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G., Kajantie, Eero, Osmond, Clive, Palotie, Aarno, Eriksson, Johan G., Heliovaara, Markku, Knekt, Paul B., Koskinen, Seppo, Jula, Antti, Perola, Markus, Huupponen, Risto K., Viikari, Jorma S., Kahonen, Mika, Lehtimaki, Terho, Raitakari, Olli T., Mellstrom, Dan, Lorentzon, Mattias, Casas, Juan P., Bandinelli, Stefanie, Maerz, Winfried, Isaacs, Aaron, van Dijk, Ko W., van Duijn, Cornelia M., Harris, Tamara B., Bouchard, Claude, Allison, Matthew A., Chasman, Daniel I., Ohlsson, Claes, Lind, Lars, Scott, Robert A., Langenberg, Claudia, Wareham, Nicholas J., Ferrucci, Luigi, Frayling, Timothy M., Pramstaller, Peter P., Borecki, Ingrid B., Waterworth, Dawn M., Bergmann, Sven, Waeber, Gerard, Vollenweider, Peter, Vestergaard, Henrik, Hansen, Torben, Pedersen, Oluf, Hu, Frank B., Slagboom, P. Eline, Grallert, Harald, Spector, Tim D., Jukema, J. W., Klein, Robert J., Schadt, Erik E., Franks, Paul W., Lindgren, Cecilia M., Leibel, Rudolph L., Loos, Ruth J. F., University of Helsinki, Helsinki Collegium for Advanced Studies, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Hospital for Children and Adolescents, University of Helsinki, Clinicum, Kilpelainen, Tuomas O., Carli, Jayne F. Martin, Skowronski, Alicja A., Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F., Hedman, Asa K., Drong, Alexander W., Hayes, James E., Zhao, Jinghua, Pers, Tune H., Schick, Ursula, Grarup, Niels, Kutalik, Zoltan, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikainen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Del Greco M, Fabiola, Pasko, Dorota, Renstrom, Frida, Willems, Sara M., Mahajan, Anubha, Rose, Lynda M., Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E., Perusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S., Sung, Yun Ju, Ramos, Yolande F., Amin, Najaf, Amuzu, Antoinette, Barroso, Ines, Bellis, Claire, Blangero, John, Buckley, Brendan M., Boehringer, Stefan, Chen, Yii-Der I., de Craen, Anton J. N., Crosslin, David R., Dale, Caroline E., Dastani, Zari, Day, Felix R., Deelen, Joris, Delgado, Graciela E., Demirkan, Ayse, Finucane, Francis M., Ford, Ian, Garcia, Melissa E., Gieger, Christian, Gustafsson, Stefan, Hallmans, Goran, Hankinson, Susan E., Havulinna, Aki S., Herder, Christian, Hernandez, Dena, Hicks, Andrew A., Hunter, David J., Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S., Jorgensen, Marit E., Jorgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A., Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P., Myers, Richard H., Mannisto, Satu, Nalls, Mike A., Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rathmann, Wolfgang, Rice, Treva K., Richards, J. Brent, Ridker, Paul M., Sattar, Naveed, Savage, David B., Soderberg, Stefan, Timpson, Nicholas J., Vandenput, Liesbeth, van Heemst, Diana, Uh, Hae-Won, Vohl, Marie-Claude, Walker, Mark, Wichmann, Heinz-Erich, Widen, Elisabeth, Wood, Andrew R., Yao, Jie, Zeller, Tanja, Zhang, Yiying, Meulenbelt, Ingrid, Kloppenburg, Margreet, Astrup, Arne, Sorensen, Thorkild I. A., Sarzynski, Mark A., Rao, D. C., Jousilahti, Pekka, Vartiainen, Erkki, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G., Kajantie, Eero, Osmond, Clive, Palotie, Aarno, Eriksson, Johan G., Heliovaara, Markku, Knekt, Paul B., Koskinen, Seppo, Jula, Antti, Perola, Markus, Huupponen, Risto K., Viikari, Jorma S., Kahonen, Mika, Lehtimaki, Terho, Raitakari, Olli T., Mellstrom, Dan, Lorentzon, Mattias, Casas, Juan P., Bandinelli, Stefanie, Maerz, Winfried, Isaacs, Aaron, van Dijk, Ko W., van Duijn, Cornelia M., Harris, Tamara B., Bouchard, Claude, Allison, Matthew A., Chasman, Daniel I., Ohlsson, Claes, Lind, Lars, Scott, Robert A., Langenberg, Claudia, Wareham, Nicholas J., Ferrucci, Luigi, Frayling, Timothy M., Pramstaller, Peter P., Borecki, Ingrid B., Waterworth, Dawn M., Bergmann, Sven, Waeber, Gerard, Vollenweider, Peter, Vestergaard, Henrik, Hansen, Torben, Pedersen, Oluf, Hu, Frank B., Slagboom, P. Eline, Grallert, Harald, Spector, Tim D., Jukema, J. W., Klein, Robert J., Schadt, Erik E., Franks, Paul W., Lindgren, Cecilia M., Leibel, Rudolph L., and Loos, Ruth J. F.

Abstract

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P <10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P <5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

Published
2016

26. The burden of alcohol drinking on co-workers in the Australian workplace

Author

Dale, Caroline E. and Livingston, Michael J.

Subjects
Worker absenteeism -- Analysis, Australians -- Alcohol use, Drinking of alcoholic beverages -- Influence, Drinking of alcoholic beverages -- Social aspects, Work environment -- Influence, Health
Abstract

A secondary analysis of data obtained from 1677 Australian workers aged 18 years or older collected as part of a broader national study into the third-party harms of alcohol and computer-assisted telephone interviews were conducted to estimate the cost of the extra time worked by Australian workers due to their co-workersE alcohol drinking. The study findings for Australian workers who are significantly affected by other peopleEs alcohol drinking, at considerable cost highlighted the significant cost to the workplace of alcohol consumption, extended previous work which had focused only on alcohol-related absenteeism.

Published
2010

27. Association between alcohol and cardiovascular disease:Mendelian randomisation analysis based on individual participant data

Author

Holmes, Michael V, Dale, Caroline E, Zuccolo, Luisa, Silverwood, Richard J, Guo, Yiran, Ye, Zheng, Prieto-Merino, David, Dehghan, Abbas, Trompet, Stella, Wong, Andrew, Cavadino, Alana, Drogan, Dagmar, Padmanabhan, Sandosh, Li, Shanshan, Yesupriya, Ajay, Leusink, Maarten, Sundstrom, Johan, Hubacek, Jaroslav A, Pikhart, Hynek, Swerdlow, Daniel I, Panayiotou, Andrie G, Borinskaya, Svetlana A, Finan, Chris, Shah, Sonia, Kuchenbaecker, Karoline B, Shah, Tina, Engmann, Jorgen, Folkersen, Lasse, Eriksson, Per, Ricceri, Fulvio, Melander, Olle, Sacerdote, Carlotta, Gamble, Dale M, Rayaprolu, Sruti, Ross, Owen A, McLachlan, Stela, Vikhireva, Olga, Sluijs, Ivonne, Scott, Robert A, Adamkova, Vera, Flicker, Leon, Bockxmeer, Frank M van, Power, Christine, Marques-Vidal, Pedro, Meade, Tom, Marmot, Michael G, Ferro, Jose M, Paulos-Pinheiro, Sofia, Humphries, Steve E, Tolstrup, Janne S, Center for Liver, Digestive and Metabolic Diseases (CLDM), Cardiovascular Centre (CVC), and Vascular Ageing Programme (VAP)

Subjects
Adult, Genetic Markers, Male, Alcohol Drinking, Genotype, Coronary Disease, VARIANTS, Polymorphism, Single Nucleotide, DEHYDROGENASE, DESIGN, DEPENDENCE, Humans, CORONARY-HEART-DISEASE, METAANALYSIS, Aged, Models, Statistical, MORTALITY, Alcohol Dehydrogenase, CONSUMPTION, Mendelian Randomization Analysis, Middle Aged, Stroke, RISK-FACTORS, Biological Markers, Female, HEALTH
Abstract

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

Published
2014

28. Mendelian randomization of blood lipids for coronary heart disease

Author

Holmes, Michael V., Asselbergs, Folkert W., Palmer, Tom M., Drenos, Fotios, Lanktree, Matthew B., Nelson, Christopher P., Dale, Caroline E., Padmanabhan, Sandosh, Finan, Chris, Swerdlow, Daniel I., Tragante, Vinicius, van Iperen, Erik P.A., Sivapalaratnam, Suthesh, Shah, Sonia, Elbers, Clara C., Shah, Tina, Engmann, Jorgen, Giambartolomei, Claudia, White, Jon, Zabaneh, Delilah, Sofat, Reecha, McLachlan, Stela, Doevendans, Pieter A., Balmforth, Anthony J., Hall, Alistair S., North, Kari E., Almoguera, Berta, Hoogeveen, Ron C., Cushman, Mary, Fornage, Myriam, Patel, Sanjay R., Redline, Susan, Siscovick, David S., Tsai, Michael Y., Karczewski, Konrad J., Hofker, Marten H., Verschuren, W. Monique, Bots, Michiel L., van der Schouw, Yvonne T., Melander, Olle, Dominiczak, Anna F., Morris, Richard, Ben-Shlomo, Yoav, Price, Jackie, Kumari, Meena, Baumert, Jens, Peters, Annette, Thorand, Barbara, Koenig, Wolfgang, Gaunt, Tom R., Humphries, Steve E., Clarke, Robert, Watkins, Hugh, Farrall, Martin, Wilson, James G., Rich, Stephen S., de Bakker, Paul I.W., Lange, Leslie A., Davey Smith, George, Reiner, Alex P., Talmud, Philippa J., Kivimäki, Mika, Lawlor, Debbie A., Dudbridge, Frank, Samani, Nilesh J., Keating, Brendan J., Hingorani, Aroon D., and Casas, Juan P.

Subjects
Male, Cardiac & Cardiovascular Systems, Genotype, Genotyping Techniques, Epidemiology, Coronary Artery Disease, Heart disease, 1102 Cardiovascular Medicine And Haematology, Polymorphism, Single Nucleotide, Risk Assessment, Gene Frequency, Clinical Research, GENETIC-VARIANTS, INSTRUMENTAL VARIABLES, Mendelian randomization, Humans, Cardiac and Cardiovascular Systems, CHOLESTEROL LEVELS, Aetiology, CARDIOVASCULAR EVENTS, METAANALYSIS, Triglycerides, Science & Technology, Cholesterol, HDL, VASCULAR-DISEASE, UCLEB consortium, Mendelian Randomization Analysis, Middle Aged, Heart Disease, Lipids, Mendelian Randomization, TRIALS, ATHEROSCLEROSIS, Cardiovascular System & Hematology, Case-Control Studies, Cardiovascular System & Cardiology, RISK-FACTORS, Female, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, HIGH-DENSITY-LIPOPROTEIN
Abstract

Aims To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. Methods and results We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10−6); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). Conclusion The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain. M.V.H. was funded by a UK Medical Research Council Population Health Scientist Fellowship (G0802432). F.W.A. is supported by UCL Hospitals NIHR Biomedical Research Centre. D.I.S. is supported by a Medical Research Council Doctoral Training Award and a grant from the Rosetrees Foundation. ME.K. is supported by the National Institute of Aging and the National Heart, Lung and Blood Institute (HL36310). S.E.H. and P.J.T. are supported by the British Heart Foundation (BHF RG 08/008, PG/07/133/24260), UK Medical Research Council, the US National Institutes of Health (grant NHLBI 33014) and Du Pont Pharma, Wilmington, USA. N.J.S. holds a Chair funded by the British Heart Foundation and is an NIHR Senior Investigator. MI.K. is supported by the National Institute of Aging, the Medical Research Council, the British Heart Foundation, and the National Heart, Lung and Blood Institute and the Academy of Finland. A.D.H. and J.P.C. are supported by the National Institute of Health Research University College London Hospitals Biomedical Research Centre. Funding to pay the Open Access publication charges for this article was provided by RCUK.

Published
2014

29. Mendelian randomization of blood lipids for coronary heart disease

Author

Cardiologie, Circulatory Health, Public Health Epidemiologie, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 5, Cardiovasculaire Epidemiologie, CMM Groep Kaaij, JC onderzoeksprogramma Methodologie, Cancer, Holmes, Michael V., Asselbergs, Folkert W., Palmer, Tom M., Drenos, Fotios, Lanktree, Matthew B., Nelson, Christopher P., Dale, Caroline E., Padmanabhan, Sandosh, Finan, Chris, Swerdlow, Daniel I., Tragante, Vinicius, Van Iperen, Erik P A, Sivapalaratnam, Suthesh, Shah, Sonia, Elbers, Clara C., Shah, Tina, Engmann, Jorgen, Giambartolomei, Claudia, White, Jon, Zabaneh, Delilah, Sofat, Reecha, McLachlan, Stela, Doevendans, Pieter A., Balmforth, Anthony J., Hall, Alistair S., North, Kari E., Almoguera, Berta, Hoogeveen, Ron C., Cushman, Mary, Fornage, Myriam, Patel, Sanjay R., Redline, Susan, Siscovick, David S., Tsai, Michael Y., Karczewski, Konrad J., Hofker, Marten H., Verschuren, W. Monique, Bots, Michiel L., Van Der Schouw, Yvonne T., Melander, Olle, Dominiczak, Anna F., Morris, Richard, Ben-Shlomo, Yoav, Price, Jackie, Kumari, Meena, Baumert, Jens, Peters, Annette, Thorand, Barbara, Koenig, Wolfgang, Gaunt, Tom R., Humphries, Steve E., Clarke, Robert, Watkins, Hugh, Farrall, Martin, Wilson, James G., Rich, Stephen S., De Bakker, Paul I W, Lange, Leslie A., Smith, George Davey, Reiner, Alex P., Talmud, Philippa J., Kivimäki, Mika, Lawlor, Debbie A., Dudbridge, Frank, Samani, Nilesh J., Keating, Brendan J., Hingorani, Aroon D., Casas, Juan P., Cardiologie, Circulatory Health, Public Health Epidemiologie, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 5, Cardiovasculaire Epidemiologie, CMM Groep Kaaij, JC onderzoeksprogramma Methodologie, Cancer, Holmes, Michael V., Asselbergs, Folkert W., Palmer, Tom M., Drenos, Fotios, Lanktree, Matthew B., Nelson, Christopher P., Dale, Caroline E., Padmanabhan, Sandosh, Finan, Chris, Swerdlow, Daniel I., Tragante, Vinicius, Van Iperen, Erik P A, Sivapalaratnam, Suthesh, Shah, Sonia, Elbers, Clara C., Shah, Tina, Engmann, Jorgen, Giambartolomei, Claudia, White, Jon, Zabaneh, Delilah, Sofat, Reecha, McLachlan, Stela, Doevendans, Pieter A., Balmforth, Anthony J., Hall, Alistair S., North, Kari E., Almoguera, Berta, Hoogeveen, Ron C., Cushman, Mary, Fornage, Myriam, Patel, Sanjay R., Redline, Susan, Siscovick, David S., Tsai, Michael Y., Karczewski, Konrad J., Hofker, Marten H., Verschuren, W. Monique, Bots, Michiel L., Van Der Schouw, Yvonne T., Melander, Olle, Dominiczak, Anna F., Morris, Richard, Ben-Shlomo, Yoav, Price, Jackie, Kumari, Meena, Baumert, Jens, Peters, Annette, Thorand, Barbara, Koenig, Wolfgang, Gaunt, Tom R., Humphries, Steve E., Clarke, Robert, Watkins, Hugh, Farrall, Martin, Wilson, James G., Rich, Stephen S., De Bakker, Paul I W, Lange, Leslie A., Smith, George Davey, Reiner, Alex P., Talmud, Philippa J., Kivimäki, Mika, Lawlor, Debbie A., Dudbridge, Frank, Samani, Nilesh J., Keating, Brendan J., Hingorani, Aroon D., and Casas, Juan P.

Published
2015

30. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data

Author

Holmes, Michael V., Dale, Caroline E., Zuccolo, Luisa, Silverwood, Richard J., Guo, Yiran, Ye, Zheng, Prieto-Merino, David, Dehghan, Abbas, Trompet, Stella, Wong, Andrew, Cavadino, Alana, Drogan, Dagmar, Padmanabhan, Sandosh, Li, Shanshan, Yesupriya, Ajay, Leusink, Maarten, Sundstrom, Johan, Hubacek, Jaroslav A., Pikhart, Hynek, Swerdlow, Daniel I., Panayiotou, Andrie G., Borinskaya, Svetlana A., Finan, Chris, Shah, Sonia, Kuchenbaecker, Karoline B., Shah, Tina, Engmann, Jorgen, Folkersen, Lasse, Eriksson, Per, Ricceri, Fulvio, Melander, Olle, Sacerdote, Carlotta, Gamble, Dale M., Rayaprolu, Sruti, Ross, Owen A., McLachlan, Stela, Vikhireva, Olga, Sluijs, Ivonne, Scott, Robert A., Adamkova, Vera, Flicker, Leon, Van Bockxmeer, Frank M., Power, Christine, Marques-Vidal, Pedro, Meade, Tom, Marmot, Michael G., Ferro, Jose M., Paulos-Pinheiro, Sofia, Humphries, Steve E., Talmud, Philippa J., Leach, Irene Mateo, Verweij, Niek, Linneberg, Allan, Skaaby, Tea, Doevendans, Pieter A., Cramer, Maarten J., Van Der Harst, Pim, Klungel, Olaf H., Dowling, Nicole F., Dominiczak, Anna F., Kumari, Meena, Nicolaides, Andrew N., Weikert, Cornelia, Boeing, Heiner, Ebrahim, Shah, Gaunt, Tom R., Price, Jackie F., Lannfelt, Lars, Peasey, Anne, Kubinova, Ruzena, Pajak, Andrzej, Malyutina, Sofia, Voevoda, Mikhail I., Tamosiunas, Abdonas, Maitland-van Der Zee, Anke H., Norman, Paul E., Hankey, Graeme J., Bergmann, Manuela M., Hofman, Albert, Franco, Oscar H., Cooper, Jackie, Palmen, Jutta, Spiering, Wilko, De Jong, Pim A., Kuh, Diana, Hardy, Rebecca, Uitterlinden, Andre G., Ikram, M. Arfan, Ford, Ian, Hyppönen, Elina, Almeida, Osvaldo P., Wareham, Nicholas J., Khaw, Kay Tee, Hamsten, Anders, Husemoen, Lise Lotte N, Tjønneland, Anne, Tolstrup, Janne S., Rimm, Eric, Beulens, Joline W J, Verschuren, W. M Monique, Onland-Moret, N. Charlotte, Hofker, Marten H., Wannamethee, S. Goya, Whincup, Peter H., Morris, Richard, Vicente, Astrid M., Watkins, Hugh, Farrall, Martin, Jukema, J. Wouter, Meschia, James, Cupples, L. Adrienne, Sharp, Stephen J., Fornage, Myriam, Kooperberg, Charles, LaCroix, Andrea Z., Dai, James Y., Lanktree, Matthew B., Siscovick, David S., Jorgenson, Eric, Spring, Bonnie, Coresh, Josef, Li, Yun R., Buxbaum, Sarah G., Schreiner, Pamela J., Ellison, R. Curtis, Tsai, Michael Y., Patel, Sanjay R., Redline, Susan, Johnson, Andrew D., Hoogeveen, Ron C., Hakonarson, Hakon, Rotter, Jerome I., Boerwinkle, Eric, De Bakker, Paul I W, Kivimaki, Mika, Asselbergs, Folkert W., Sattar, Naveed, Lawlor, Debbie A., Whittaker, John, Smith, George Davey, Mukamal, Kenneth, Psaty, Bruce M., Wilson, James G., Lange, Leslie A., Hamidovic, Ajna, Nordestgaard, Børge G., Bobak, Martin, Leon, David A., Langenberg, Claudia, Palmer, Tom M., Reiner, Alex P., Keating, Brendan J., Dudbridge, Frank, Casas, Juan P., Holmes, Michael V., Dale, Caroline E., Zuccolo, Luisa, Silverwood, Richard J., Guo, Yiran, Ye, Zheng, Prieto-Merino, David, Dehghan, Abbas, Trompet, Stella, Wong, Andrew, Cavadino, Alana, Drogan, Dagmar, Padmanabhan, Sandosh, Li, Shanshan, Yesupriya, Ajay, Leusink, Maarten, Sundstrom, Johan, Hubacek, Jaroslav A., Pikhart, Hynek, Swerdlow, Daniel I., Panayiotou, Andrie G., Borinskaya, Svetlana A., Finan, Chris, Shah, Sonia, Kuchenbaecker, Karoline B., Shah, Tina, Engmann, Jorgen, Folkersen, Lasse, Eriksson, Per, Ricceri, Fulvio, Melander, Olle, Sacerdote, Carlotta, Gamble, Dale M., Rayaprolu, Sruti, Ross, Owen A., McLachlan, Stela, Vikhireva, Olga, Sluijs, Ivonne, Scott, Robert A., Adamkova, Vera, Flicker, Leon, Van Bockxmeer, Frank M., Power, Christine, Marques-Vidal, Pedro, Meade, Tom, Marmot, Michael G., Ferro, Jose M., Paulos-Pinheiro, Sofia, Humphries, Steve E., Talmud, Philippa J., Leach, Irene Mateo, Verweij, Niek, Linneberg, Allan, Skaaby, Tea, Doevendans, Pieter A., Cramer, Maarten J., Van Der Harst, Pim, Klungel, Olaf H., Dowling, Nicole F., Dominiczak, Anna F., Kumari, Meena, Nicolaides, Andrew N., Weikert, Cornelia, Boeing, Heiner, Ebrahim, Shah, Gaunt, Tom R., Price, Jackie F., Lannfelt, Lars, Peasey, Anne, Kubinova, Ruzena, Pajak, Andrzej, Malyutina, Sofia, Voevoda, Mikhail I., Tamosiunas, Abdonas, Maitland-van Der Zee, Anke H., Norman, Paul E., Hankey, Graeme J., Bergmann, Manuela M., Hofman, Albert, Franco, Oscar H., Cooper, Jackie, Palmen, Jutta, Spiering, Wilko, De Jong, Pim A., Kuh, Diana, Hardy, Rebecca, Uitterlinden, Andre G., Ikram, M. Arfan, Ford, Ian, Hyppönen, Elina, Almeida, Osvaldo P., Wareham, Nicholas J., Khaw, Kay Tee, Hamsten, Anders, Husemoen, Lise Lotte N, Tjønneland, Anne, Tolstrup, Janne S., Rimm, Eric, Beulens, Joline W J, Verschuren, W. M Monique, Onland-Moret, N. Charlotte, Hofker, Marten H., Wannamethee, S. Goya, Whincup, Peter H., Morris, Richard, Vicente, Astrid M., Watkins, Hugh, Farrall, Martin, Jukema, J. Wouter, Meschia, James, Cupples, L. Adrienne, Sharp, Stephen J., Fornage, Myriam, Kooperberg, Charles, LaCroix, Andrea Z., Dai, James Y., Lanktree, Matthew B., Siscovick, David S., Jorgenson, Eric, Spring, Bonnie, Coresh, Josef, Li, Yun R., Buxbaum, Sarah G., Schreiner, Pamela J., Ellison, R. Curtis, Tsai, Michael Y., Patel, Sanjay R., Redline, Susan, Johnson, Andrew D., Hoogeveen, Ron C., Hakonarson, Hakon, Rotter, Jerome I., Boerwinkle, Eric, De Bakker, Paul I W, Kivimaki, Mika, Asselbergs, Folkert W., Sattar, Naveed, Lawlor, Debbie A., Whittaker, John, Smith, George Davey, Mukamal, Kenneth, Psaty, Bruce M., Wilson, James G., Lange, Leslie A., Hamidovic, Ajna, Nordestgaard, Børge G., Bobak, Martin, Leon, David A., Langenberg, Claudia, Palmer, Tom M., Reiner, Alex P., Keating, Brendan J., Dudbridge, Frank, and Casas, Juan P.

Abstract

Objective: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. Design: Mendelian randomisation meta-analysis of 56 epidemiological studies. Participants: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. Main outcome measures: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. Results: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m2). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). Conclusions: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular

Published
2014

31. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data

Author

Sub Pharmacotherapy, Theoretical, Pharmacoepidemiology and Clinical Pharmacology, Holmes, Michael V., Dale, Caroline E., Zuccolo, Luisa, Silverwood, Richard J., Guo, Yiran, Ye, Zheng, Prieto-Merino, David, Dehghan, Abbas, Trompet, Stella, Wong, Andrew, Cavadino, Alana, Drogan, Dagmar, Padmanabhan, Sandosh, Li, Shanshan, Yesupriya, Ajay, Leusink, Maarten, Sundstrom, Johan, Hubacek, Jaroslav A., Pikhart, Hynek, Swerdlow, Daniel I., Panayiotou, Andrie G., Borinskaya, Svetlana A., Finan, Chris, Shah, Sonia, Kuchenbaecker, Karoline B., Shah, Tina, Engmann, Jorgen, Folkersen, Lasse, Eriksson, Per, Ricceri, Fulvio, Melander, Olle, Sacerdote, Carlotta, Gamble, Dale M., Rayaprolu, Sruti, Ross, Owen A., McLachlan, Stela, Vikhireva, Olga, Sluijs, Ivonne, Scott, Robert A., Adamkova, Vera, Flicker, Leon, Van Bockxmeer, Frank M., Power, Christine, Marques-Vidal, Pedro, Meade, Tom, Marmot, Michael G., Ferro, Jose M., Paulos-Pinheiro, Sofia, Humphries, Steve E., Talmud, Philippa J., Leach, Irene Mateo, Verweij, Niek, Linneberg, Allan, Skaaby, Tea, Doevendans, Pieter A., Cramer, Maarten J., Van Der Harst, Pim, Klungel, Olaf H., Dowling, Nicole F., Dominiczak, Anna F., Kumari, Meena, Nicolaides, Andrew N., Weikert, Cornelia, Boeing, Heiner, Ebrahim, Shah, Gaunt, Tom R., Price, Jackie F., Lannfelt, Lars, Peasey, Anne, Kubinova, Ruzena, Pajak, Andrzej, Malyutina, Sofia, Voevoda, Mikhail I., Tamosiunas, Abdonas, Maitland-van Der Zee, Anke H., Norman, Paul E., Hankey, Graeme J., Bergmann, Manuela M., Hofman, Albert, Franco, Oscar H., Cooper, Jackie, Palmen, Jutta, Spiering, Wilko, De Jong, Pim A., Kuh, Diana, Hardy, Rebecca, Uitterlinden, Andre G., Ikram, M. Arfan, Ford, Ian, Hyppönen, Elina, Almeida, Osvaldo P., Wareham, Nicholas J., Khaw, Kay Tee, Hamsten, Anders, Husemoen, Lise Lotte N, Tjønneland, Anne, Tolstrup, Janne S., Rimm, Eric, Beulens, Joline W J, Verschuren, W. M Monique, Onland-Moret, N. Charlotte, Hofker, Marten H., Wannamethee, S. Goya, Whincup, Peter H., Morris, Richard, Vicente, Astrid M., Watkins, Hugh, Farrall, Martin, Jukema, J. Wouter, Meschia, James, Cupples, L. Adrienne, Sharp, Stephen J., Fornage, Myriam, Kooperberg, Charles, LaCroix, Andrea Z., Dai, James Y., Lanktree, Matthew B., Siscovick, David S., Jorgenson, Eric, Spring, Bonnie, Coresh, Josef, Li, Yun R., Buxbaum, Sarah G., Schreiner, Pamela J., Ellison, R. Curtis, Tsai, Michael Y., Patel, Sanjay R., Redline, Susan, Johnson, Andrew D., Hoogeveen, Ron C., Hakonarson, Hakon, Rotter, Jerome I., Boerwinkle, Eric, De Bakker, Paul I W, Kivimaki, Mika, Asselbergs, Folkert W., Sattar, Naveed, Lawlor, Debbie A., Whittaker, John, Smith, George Davey, Mukamal, Kenneth, Psaty, Bruce M., Wilson, James G., Lange, Leslie A., Hamidovic, Ajna, Nordestgaard, Børge G., Bobak, Martin, Leon, David A., Langenberg, Claudia, Palmer, Tom M., Reiner, Alex P., Keating, Brendan J., Dudbridge, Frank, Casas, Juan P., Sub Pharmacotherapy, Theoretical, Pharmacoepidemiology and Clinical Pharmacology, Holmes, Michael V., Dale, Caroline E., Zuccolo, Luisa, Silverwood, Richard J., Guo, Yiran, Ye, Zheng, Prieto-Merino, David, Dehghan, Abbas, Trompet, Stella, Wong, Andrew, Cavadino, Alana, Drogan, Dagmar, Padmanabhan, Sandosh, Li, Shanshan, Yesupriya, Ajay, Leusink, Maarten, Sundstrom, Johan, Hubacek, Jaroslav A., Pikhart, Hynek, Swerdlow, Daniel I., Panayiotou, Andrie G., Borinskaya, Svetlana A., Finan, Chris, Shah, Sonia, Kuchenbaecker, Karoline B., Shah, Tina, Engmann, Jorgen, Folkersen, Lasse, Eriksson, Per, Ricceri, Fulvio, Melander, Olle, Sacerdote, Carlotta, Gamble, Dale M., Rayaprolu, Sruti, Ross, Owen A., McLachlan, Stela, Vikhireva, Olga, Sluijs, Ivonne, Scott, Robert A., Adamkova, Vera, Flicker, Leon, Van Bockxmeer, Frank M., Power, Christine, Marques-Vidal, Pedro, Meade, Tom, Marmot, Michael G., Ferro, Jose M., Paulos-Pinheiro, Sofia, Humphries, Steve E., Talmud, Philippa J., Leach, Irene Mateo, Verweij, Niek, Linneberg, Allan, Skaaby, Tea, Doevendans, Pieter A., Cramer, Maarten J., Van Der Harst, Pim, Klungel, Olaf H., Dowling, Nicole F., Dominiczak, Anna F., Kumari, Meena, Nicolaides, Andrew N., Weikert, Cornelia, Boeing, Heiner, Ebrahim, Shah, Gaunt, Tom R., Price, Jackie F., Lannfelt, Lars, Peasey, Anne, Kubinova, Ruzena, Pajak, Andrzej, Malyutina, Sofia, Voevoda, Mikhail I., Tamosiunas, Abdonas, Maitland-van Der Zee, Anke H., Norman, Paul E., Hankey, Graeme J., Bergmann, Manuela M., Hofman, Albert, Franco, Oscar H., Cooper, Jackie, Palmen, Jutta, Spiering, Wilko, De Jong, Pim A., Kuh, Diana, Hardy, Rebecca, Uitterlinden, Andre G., Ikram, M. Arfan, Ford, Ian, Hyppönen, Elina, Almeida, Osvaldo P., Wareham, Nicholas J., Khaw, Kay Tee, Hamsten, Anders, Husemoen, Lise Lotte N, Tjønneland, Anne, Tolstrup, Janne S., Rimm, Eric, Beulens, Joline W J, Verschuren, W. M Monique, Onland-Moret, N. Charlotte, Hofker, Marten H., Wannamethee, S. Goya, Whincup, Peter H., Morris, Richard, Vicente, Astrid M., Watkins, Hugh, Farrall, Martin, Jukema, J. Wouter, Meschia, James, Cupples, L. Adrienne, Sharp, Stephen J., Fornage, Myriam, Kooperberg, Charles, LaCroix, Andrea Z., Dai, James Y., Lanktree, Matthew B., Siscovick, David S., Jorgenson, Eric, Spring, Bonnie, Coresh, Josef, Li, Yun R., Buxbaum, Sarah G., Schreiner, Pamela J., Ellison, R. Curtis, Tsai, Michael Y., Patel, Sanjay R., Redline, Susan, Johnson, Andrew D., Hoogeveen, Ron C., Hakonarson, Hakon, Rotter, Jerome I., Boerwinkle, Eric, De Bakker, Paul I W, Kivimaki, Mika, Asselbergs, Folkert W., Sattar, Naveed, Lawlor, Debbie A., Whittaker, John, Smith, George Davey, Mukamal, Kenneth, Psaty, Bruce M., Wilson, James G., Lange, Leslie A., Hamidovic, Ajna, Nordestgaard, Børge G., Bobak, Martin, Leon, David A., Langenberg, Claudia, Palmer, Tom M., Reiner, Alex P., Keating, Brendan J., Dudbridge, Frank, and Casas, Juan P.

Published
2014

32. Alcohol consumption and cognitive performance:a Mendelian randomization study

Author

Kumari, Meena, Holmes, Michael V., Dale, Caroline E., Hubacek, Jaroslav A., Palmer, Tom M., Pikhart, Hynek, Peasey, Anne, Britton, Annie, Horvat, Pia, Kubinova, Ruzena, Malyutina, Sofia, Pajak, Andrzej, Tamosiunas, Abdonas, Shankar, Aparna, Singh-Manoux, Archana, Voevoda, Mikhail, Kivimaki, Mika, Hingorani, Aroon D., Marmot, Michael G., Casas, Juan P., Bobak, Martin, Kumari, Meena, Holmes, Michael V., Dale, Caroline E., Hubacek, Jaroslav A., Palmer, Tom M., Pikhart, Hynek, Peasey, Anne, Britton, Annie, Horvat, Pia, Kubinova, Ruzena, Malyutina, Sofia, Pajak, Andrzej, Tamosiunas, Abdonas, Shankar, Aparna, Singh-Manoux, Archana, Voevoda, Mikhail, Kivimaki, Mika, Hingorani, Aroon D., Marmot, Michael G., Casas, Juan P., and Bobak, Martin

Abstract

AIMS: To use Mendelian randomization to assess whether alcohol intake was causally associated with cognitive function. DESIGN: Mendelian randomization using a genetic variant related to alcohol intake (ADH1B rs1229984) was used to obtain unbiased estimates of the association between alcohol intake and cognitive performance. SETTING: Europe. PARTICIPANTS: More than 34 000 adults. MEASUREMENTS: Any versus no alcohol intake and units of intake in the previous week was measured by questionnaire. Cognitive function was assessed in terms of immediate and delayed word recall, verbal fluency and processing speed. FINDINGS: Having consumed any versus no alcohol was associated with higher scores by 0.17 standard deviations (SD) [95% confidence interval (CI) = 0.15, 0.20] for immediate recall, 0.17 SD (95% CI = 0.14, 0.19) for delayed recall, 0.17 SD (95% CI = 0.14, 0.19) for verbal fluency and 0.12 SD (95% CI = 0.09, 0.15) for processing speed. The minor allele of rs1229984 was associated with reduced odds of consuming any alcohol (odds ratio = 0.87; 95% CI = 0.80, 0.95; P = 0.001; R(2) = 0.1%; F-statistic = 47). In Mendelian randomization analysis, the minor allele was not associated with any cognitive test score, and instrumental variable analysis suggested no causal association between alcohol consumption and cognition: -0.74 SD (95% CI = -1.88, 0.41) for immediate recall, -1.09 SD (95% CI = -2.38, 0.21) for delayed recall, -0.63 SD (95% CI = -1.78, 0.53) for verbal fluency and -0.16 SD (95% CI = -1.29, 0.97) for processing speed. CONCLUSIONS: The Mendelian randomization analysis did not provide strong evidence of a causal association between alcohol consumption and cognitive ability.

Published
2014

33. Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study:application to alcohol and cardiovascular traits

Author

Silverwood, Richard J., Holmes, Michael V., Dale, Caroline E., Lawlor, Debbie A., Whittaker, John C., Smith, George Davey, Leon, David A., Palmer, Tom, Keating, Brendan J., Zuccolo, Luisa, Casas, Juan P., Dudbridge, Frank, Alcohol-ADH1B Consortium, Silverwood, Richard J., Holmes, Michael V., Dale, Caroline E., Lawlor, Debbie A., Whittaker, John C., Smith, George Davey, Leon, David A., Palmer, Tom, Keating, Brendan J., Zuccolo, Luisa, Casas, Juan P., Dudbridge, Frank, and Alcohol-ADH1B Consortium

Abstract

BACKGROUND: Mendelian randomization studies have so far restricted attention to linear associations relating the genetic instrument to the exposure, and the exposure to the outcome. In some cases, however, observational data suggest a non-linear association between exposure and outcome. For example, alcohol consumption is consistently reported as having a U-shaped association with cardiovascular events. In principle, Mendelian randomization could address concerns that the apparent protective effect of light-to-moderate drinking might reflect 'sick-quitters' and confounding. METHODS: The Alcohol-ADH1B Consortium was established to study the causal effects of alcohol consumption on cardiovascular events and biomarkers, using the single nucleotide polymorphism rs1229984 in ADH1B as a genetic instrument. To assess non-linear causal effects in this study, we propose a novel method based on estimating local average treatment effects for discrete levels of the exposure range, then testing for a linear trend in those effects. Our method requires an assumption that the instrument has the same effect on exposure in all individuals. We conduct simulations examining the robustness of the method to violations of this assumption, and apply the method to the Alcohol-ADH1B Consortium data. RESULTS: Our method gave a conservative test for non-linearity under realistic violations of the key assumption. We found evidence for a non-linear causal effect of alcohol intake on several cardiovascular traits. CONCLUSIONS: We believe our method is useful for inferring departure from linearity when only a binary instrument is available. We estimated non-linear causal effects of alcohol intake which could not have been estimated through standard instrumental variable approaches.

Published
2014

34. Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis:the CARTA consortium

Author

Taylor, Amy E, Fluharty, Meg E, Bjørngaard, Johan H, Gabrielsen, Maiken Elvestad, Skorpen, Frank, Marioni, Riccardo E, Campbell, Archie, Engmann, Jorgen, Mirza, Saira Saeed, Loukola, Anu, Laatikainen, Tiina, Partonen, Timo, Kaakinen, Marika, Ducci, Francesca, Cavadino, Alana, Husemoen, Lise Lotte N, Ahluwalia, Tarun Veer Singh, Jacobsen, Rikke Kart, Skaaby, Tea, Ebstrup, Jeanette Frost, Mortensen, Erik Lykke, Minica, Camelia C, Vink, Jacqueline M, Willemsen, Gonneke, Marques-Vidal, Pedro, Dale, Caroline E, Amuzu, Antoinette, Lennon, Lucy T, Lahti, Jari, Palotie, Aarno, Räikkönen, Katri, Wong, Andrew, Paternoster, Lavinia, Wong, Angelita Pui-Yee, Horwood, L John, Murphy, Michael, Johnstone, Elaine C, Kennedy, Martin A, Pausova, Zdenka, Paus, Tomáš, Ben-Shlomo, Yoav, Nohr, Ellen A, Kuh, Diana, Kivimaki, Mika, Eriksson, Johan G, Morris, Richard W, Casas, Juan P, Preisig, Martin, Boomsma, Dorret I, Linneberg, Allan, Power, Chris, Hyppönen, Elina, Veijola, Juha, Jarvelin, Marjo-Riitta, Korhonen, Tellervo, Tiemeier, Henning, Kumari, Meena, Porteous, David J, Hayward, Caroline, Romundstad, Pål R, Smith, George Davey, Munafò, Marcus R, Taylor, Amy E, Fluharty, Meg E, Bjørngaard, Johan H, Gabrielsen, Maiken Elvestad, Skorpen, Frank, Marioni, Riccardo E, Campbell, Archie, Engmann, Jorgen, Mirza, Saira Saeed, Loukola, Anu, Laatikainen, Tiina, Partonen, Timo, Kaakinen, Marika, Ducci, Francesca, Cavadino, Alana, Husemoen, Lise Lotte N, Ahluwalia, Tarun Veer Singh, Jacobsen, Rikke Kart, Skaaby, Tea, Ebstrup, Jeanette Frost, Mortensen, Erik Lykke, Minica, Camelia C, Vink, Jacqueline M, Willemsen, Gonneke, Marques-Vidal, Pedro, Dale, Caroline E, Amuzu, Antoinette, Lennon, Lucy T, Lahti, Jari, Palotie, Aarno, Räikkönen, Katri, Wong, Andrew, Paternoster, Lavinia, Wong, Angelita Pui-Yee, Horwood, L John, Murphy, Michael, Johnstone, Elaine C, Kennedy, Martin A, Pausova, Zdenka, Paus, Tomáš, Ben-Shlomo, Yoav, Nohr, Ellen A, Kuh, Diana, Kivimaki, Mika, Eriksson, Johan G, Morris, Richard W, Casas, Juan P, Preisig, Martin, Boomsma, Dorret I, Linneberg, Allan, Power, Chris, Hyppönen, Elina, Veijola, Juha, Jarvelin, Marjo-Riitta, Korhonen, Tellervo, Tiemeier, Henning, Kumari, Meena, Porteous, David J, Hayward, Caroline, Romundstad, Pål R, Smith, George Davey, and Munafò, Marcus R

Abstract

OBJECTIVES: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach.DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress.PARTICIPANTS: Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA).PRIMARY OUTCOME MEASURES: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis.RESULTS: The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers.CONCLUSIONS: Findings from Mendelian randomisation analyses do not support a causal role of

Published
2014

35. Causal Associations of Adiposity and Body Fat Distribution with Coronary Heart Disease, Stroke Subtypes and Type 2 Diabetes: A Mendelian Randomization Analysis.

Author

Dale, Caroline E., Fatemifar, Ghazaleh, Palmer, Tom M., White, Jon, Prieto-Merino, David, Zabaneh, Delilah, Engmann, Jorgen E. L., Shah, Tina, Wong, Andrew, Warren, Helen R., McLachlan, Stela, Trompet, Stella, Moldovan, Max, Morris, Richard W., Sofat, Reecha, Kumari, Meena, Hyppönen, Elina, Jefferis, Barbara J., Gaunt, Tom R., and Ben-Shlomo, Yoav

Subjects
*OBESITY, *FAT, *SINGLE nucleotide polymorphisms, *BODY mass index, *CORONARY disease, *META-analysis
Abstract

Background -Implications of different adiposity measures on cardiovascular disease aetiology remain unclear. In this paper we quantify and contrast causal associations of central adiposity (waist:hip ratio adjusted for BMI (WHRadjBMI)) and general adiposity (body mass index (BMI)) with cardiometabolic disease. Methods -97 independent single nucleotide polymorphisms (SNPs) for BMI and 49 SNPs for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with CHD data from CARDIoGRAMplusC4D (combined total 66,842 cases), stroke from METASTROKE (12,389 ischaemic stroke cases), type 2 diabetes (T2D) from DIAGRAM (34,840 cases), and lipids from GLGC (213,500 participants) consortia. Primary outcomes were CHD, T2D, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits. Results -Each one standard deviation (SD) higher WHRadjBMI (1SD~0.08 units) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD: 1.48; 95%CI: 1.28-1.71), similar to findings for BMI (1SD~4.6kg/m2; OR for CHD: 1.36; 95%CI: 1.22-1.52). Only WHRadjBMI increased risk of ischaemic stroke (OR 1.32; 95%CI 1.03-1.70). For T2D, both measures had large effects: OR 1.82 (95%CI 1.38-2.42) and OR 1.98 (95%CI 1.41-2.78) per 1SD higher WHRadjBMI and BMI respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycaemic traits, interleukin-6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95%CI: 9%-77% per 1SD). Conclusions -Both general and central adiposity have causal effects on CHD and T2D. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity. [ABSTRACT FROM AUTHOR]

Published
2017
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37. Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium

Author

Taylor, Amy E, primary, Fluharty, Meg E, additional, Bjørngaard, Johan H, additional, Gabrielsen, Maiken Elvestad, additional, Skorpen, Frank, additional, Marioni, Riccardo E, additional, Campbell, Archie, additional, Engmann, Jorgen, additional, Mirza, Saira Saeed, additional, Loukola, Anu, additional, Laatikainen, Tiina, additional, Partonen, Timo, additional, Kaakinen, Marika, additional, Ducci, Francesca, additional, Cavadino, Alana, additional, Husemoen, Lise Lotte N, additional, Ahluwalia, Tarunveer Singh, additional, Jacobsen, Rikke Kart, additional, Skaaby, Tea, additional, Ebstrup, Jeanette Frost, additional, Mortensen, Erik Lykke, additional, Minica, Camelia C, additional, Vink, Jacqueline M, additional, Willemsen, Gonneke, additional, Marques-Vidal, Pedro, additional, Dale, Caroline E, additional, Amuzu, Antoinette, additional, Lennon, Lucy T, additional, Lahti, Jari, additional, Palotie, Aarno, additional, Räikkönen, Katri, additional, Wong, Andrew, additional, Paternoster, Lavinia, additional, Wong, Angelita Pui-Yee, additional, Horwood, L John, additional, Murphy, Michael, additional, Johnstone, Elaine C, additional, Kennedy, Martin A, additional, Pausova, Zdenka, additional, Paus, Tomáš, additional, Ben-Shlomo, Yoav, additional, Nohr, Ellen A, additional, Kuh, Diana, additional, Kivimaki, Mika, additional, Eriksson, Johan G, additional, Morris, Richard W, additional, Casas, Juan P, additional, Preisig, Martin, additional, Boomsma, Dorret I, additional, Linneberg, Allan, additional, Power, Chris, additional, Hyppönen, Elina, additional, Veijola, Juha, additional, Jarvelin, Marjo-Riitta, additional, Korhonen, Tellervo, additional, Tiemeier, Henning, additional, Kumari, Meena, additional, Porteous, David J, additional, Hayward, Caroline, additional, Romundstad, Pål R, additional, Smith, George Davey, additional, and Munafò, Marcus R, additional

Published
2014
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38. Alcohol consumption and cognitive performance: a M endelian randomization study

Author

Kumari, Meena, primary, Holmes, Michael V., additional, Dale, Caroline E., additional, Hubacek, Jaroslav A., additional, Palmer, Tom M., additional, Pikhart, Hynek, additional, Peasey, Anne, additional, Britton, Annie, additional, Horvat, Pia, additional, Kubinova, Ruzena, additional, Malyutina, Sofia, additional, Pajak, Andrzej, additional, Tamosiunas, Abdonas, additional, Shankar, Aparna, additional, Singh‐Manoux, Archana, additional, Voevoda, Mikhail, additional, Kivimaki, Mika, additional, Hingorani, Aroon D., additional, Marmot, Michael G., additional, Casas, Juan P., additional, and Bobak, Martin, additional

Published
2014
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39. Replication and Characterization of Association between ABO SNPs and Red Blood Cell Traits by Meta-Analysis in Europeans

Author

McLachlan, Stela, Giambartolomei, Claudia, White, Jon, Charoen, Pimphen, Wong, Andrew, Finan, Chris, Engmann, Jorgen, Shah, Tina, Hersch, Micha, Podmore, Clara, Cavadino, Alana, Jefferis, Barbara J, Dale, Caroline E, Hypponen, Elina, Morris, Richard W, Casas, Juan P, Kumari, Meena, Ben-Shlomo, Yoav, Gaunt, Tom R, Drenos, Fotios, Langenberg, Claudia, Kuh, Diana, Kivimaki, Mika, Rueedi, Rico, Waeber, Gerard, Hingorani, Aroon D, Price, Jacqueline F, Walker, Ann P, and UCLEB Consortium

Subjects
DNA Replication, Europe, Erythrocytes, hemic and lymphatic diseases, Quantitative Trait Loci, Ethnicity, Humans, Polymorphism, Single Nucleotide, 3. Good health, ABO Blood-Group System, Genome-Wide Association Study
Abstract

Red blood cell (RBC) traits are routinely measured in clinical practice as important markers of health. Deviations from the physiological ranges are usually a sign of disease, although variation between healthy individuals also occurs, at least partly due to genetic factors. Recent large scale genetic studies identified loci associated with one or more of these traits; further characterization of known loci and identification of new loci is necessary to better understand their role in health and disease and to identify potential molecular mechanisms. We performed meta-analysis of Metabochip association results for six RBC traits-hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) and red blood cell count (RCC)-in 11 093 Europeans from seven studies of the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium. We identified 394 non-overlapping SNPs in five loci at genome-wide significance: 6p22.1-6p21.33 (with HFE among others), 6q23.2 (with HBS1L among others), 6q23.3 (contains no genes), 9q34.3 (only ABO gene) and 22q13.1 (with TMPRSS6 among others), replicating previous findings of association with RBC traits at these loci and extending them by imputation to 1000 Genomes. We further characterized associations between ABO SNPs and three traits: hemoglobin, hematocrit and red blood cell count, replicating them in an independent cohort. Conditional analyses indicated the independent association of each of these traits with ABO SNPs and a role for blood group O in mediating the association. The 15 most significant RBC-associated ABO SNPs were also associated with five cardiometabolic traits, with discordance in the direction of effect between groups of traits, suggesting that ABO may act through more than one mechanism to influence cardiometabolic risk.

40. Association between alcohol and cardiovascular disease

Author

Holmes, Michael V., Dale, Caroline E., Luisa Zuccolo, Silverwood, Richard J., Yiran Guo, Zheng Ye, David Prieto-Merino, Abbas Dehghan, Stella Trompet, Andrew Wong, Alana Cavadino, Dagmar Drogan, Sandosh Padmanabhan, Shanshan Li, Ajay Yesupriya, Maarten Leusink, Johan Sundstrom, Hubacek, Jaroslav A., Hynek Pikhart, Swerdlow, Daniel I., Panayiotou, Andrie G., Borinskaya, Svetlana A., Chris Finan, Sonia Shah, Kuchenbaecker, Karoline B., Tina Shah, Jorgen Engmann, Lasse Folkersen, Per Eriksson, Fulvio Ricceri, Olle Melander, Carlotta Sacerdote, Gamble, Dale M., Sruti Rayaprolu, Ross, Owen A., Stela McLachlan, Olga Vikhireva, Ivonne Sluijs, Scott, Robert A., Vera Adamkova, Leon Flicker, Bockxmeer, Frank M., Christine Power, Pedro Marques-Vidal, Tom Meade, Marmot, Michael G., Ferro, Jose M., Sofia Paulos-Pinheiro, Humphries, Steve E., Talmud, Philippa J., Irene Mateo Leach, Niek Verweij, Allan Linneberg, Tea Skaaby, Doevendans, Pieter A., Cramer, Maarten J., Pim van der Harst, Klungel, Olaf H., Dowling, Nicole F., Dominiczak, Anna F., Meena Kumari, Nicolaides, Andrew N., Cornelia Weikert, Heiner Boeing, Shah Ebrahim, Tom Gaunt, Price, Jackie F., Lars Lannfelt, Anne Peasey, Ruzena Kubinova, Andrzej Pajak, Sofia Malyutina, Voevoda, Mikhail I., Abdonas Tamosiunas, Maitland-Van Zee, Anke H., Norman, Paul E., Hankey, Graeme J., Bergmann, Manuela M., Albert Hofman, Franco, Oscar H., Jackie Cooper, Jutta Palmen, Wilko Spiering, Jong, Pim A., Diana Kuh, Rebecca Hardy, Uitterlinden, Andre G., Arfan Ikram, M., Ian Ford, Elina Hyppönen, Almeida, Osvaldo P., Wareham, Nicholas J., Kay-Tee Khaw, Anders Hamsten, Husemoen, Lise Lotte N., Anne Tjønneland, Tolstrup, Janne S., Eric Rimm, Beulens, Joline W. J., Monique Verschuren, W. M., Charlotte Onland-Moret, N., Hofker, Marten H., Goya Wannamethee, S., Whincup, Peter H., Richard Morris, Vicente, Astrid M., Hugh Watkins, Martin Farrall, Wouter Jukema, J., James Meschia, Adrienne Cupples, L., Sharp, Stephen J., Myriam Fornage, Charles Kooperberg, Lacroix, Andrea Z., Dai, James Y., Lanktree, Matthew B., Siscovick, David S., Eric Jorgenson, Bonnie Spring, Josef Coresh, Li, Yun R., Buxbaum, Sarah G., Schreiner, Pamela J., Curtis Ellison, R., Tsai, Michael Y., Patel, Sanjay R., Susan Redline, Johnson, Andrew D., Hoogeveen, Ron C., Hakon Hakonarson, Rotter, Jerome I., Eric Boerwinkle, Bakker, Paul I. W., Mika Kivimaki, Asselbergs, Folkert W., Naveed Sattar, Debbie Lawlor, John Whittaker, George Davey Smith, Kenneth Mukamal, Psaty, Bruce M., Wilson, James G., Lange, Leslie A., Ajna Hamidovic, Hingorani, Aroon D., Nordestgaard, Børge G., Martin Bobak, Leon, David A., Claudia Langenberg, Palmer, Tom M., Reiner, Alex P., Keating, Brendan J., Frank Dudbridge, Casas, Juan P., and InterAct Consortium

41. Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Author

Wood, Angela M., Kaptoge, Stephen, Butterworth, Adam S., Willeit, Peter, Warnakula, Samantha, Bolton, Thomas, Paige, Ellie, Paul, Dirk S., Sweeting, Michael, Burgess, Stephen, Bell, Steven, Astle, William, Stevens, David, Koulman, Albert, Selmer, Randi, Verschuren, W. M. Monique, Sato, Shinichi, Njølstad, Inger, Woodward, Mark, Salomaa, Veikko, Nordestgaard, Børge G., Yeap, Bu B., Fletcher, Astrid, Melander, Olle, Kuller, Lewis H., Balkau, Beverley, Marmot, Michael, Koenig, Wolfgang, Casiglia, Edoardo, Cooper, Cyrus, Arndt, Volker, Franco, Oscar H., Wennberg, Patrik, Gallacher, John, Gómez De La Cámara, Agustín, Völzke, Henry, Dahm, Christina C., Dale, Caroline E., Bergmann, Manuela M., Crespo, Carlos J., Van Der Schouw, Yvonne T., Kaaks, Rudolf, Simons, Leon A., Lagiou, Pagona, Schoufour, Josje D., Boer, Jolanda M. A., Key, Timothy J., Rodriguez, Beatriz, Moreno-Iribas, Conchi, Davidson, Karina W., Taylor, James O., Sacerdote, Carlotta, Wallace, Robert B., Quiros, J. Ramon, Tumino, Rosario, Blazer II, Dan G., Linneberg, Allan, Daimon, Makoto, Panico, Salvatore, Howard, Barbara, Skeie, Guri, Strandberg, Timo, Weiderpass, Elisabete, Nietert, Paul J., Psaty, Bruce M., Kromhout, Daan, Salamanca-Fernandez, Elena, Kiechl, Stefan, Krumholz, Harlan M., Grioni, Sara, Palli, Domenico, Huerta, José M., Price, Jackie F., Sundström, Johan, Arriola, Larraitz, Arima, Hisatomi, Travis, Ruth C., Panagiotakos, Demosthenes B., Karakatsani, Anna, Trichopoulou, Antonia, Kühn, Tilman, Grobbee, Diederick E., Barrett-Connor, Elizabeth, Van Schoor, Natasja, Boeing, Heiner, Overvad, Kim, Kauhanen, Jussi, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita, Wennberg, Maria, Després, Jean-Pierre, Cushman, Mary, Cooper, Jackie A, Rodriguez, Carlos J., Sakurai, Masaru, Shaw, Jonathan E., Knuiman, Matthew W., Voortman, Trudy, Meisinger, Christa, Tjønneland, Anne, Brenner, Hermann, Palmieri, Luigi, Dallongeville, Jean, Brunner, Eric J., Assmann, Gerd, Trevisan, Maurizio, Gillum, Richard F., Ford, Ian, Sattar, Naveed, Lazo, Mariana, Thompson, Simon G., Ferrari, Pietro, Leon, David A., Davey-Smith, George, Peto, Richard, Jackson, Rod, Banks, Emily, Di Angelantonio, Emanuele, Danesh, John, and Emerging Risk Factors Collaboration/EPIC-CVD/UK Biobank Alcohol Study Group

Subjects
Cardiovascular system--Diseases, Drinking of alcoholic beverages, Mortality, Diseases--Risk factors, 3. Good health
Abstract

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.

44. Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Author

Angela M Wood, Stephen Kaptoge, Adam S Butterworth, Peter Willeit, Samantha Warnakula, Thomas Bolton, Ellie Paige, Dirk S Paul, Michael Sweeting, Stephen Burgess, Steven Bell, William Astle, David Stevens, Albert Koulman, Randi M Selmer, W M Monique Verschuren, Shinichi Sato, Inger Njølstad, Mark Woodward, Veikko Salomaa, Børge G Nordestgaard, Bu B Yeap, Astrid Fletcher, Olle Melander, Lewis H Kuller, Beverley Balkau, Michael Marmot, Wolfgang Koenig, Edoardo Casiglia, Cyrus Cooper, Volker Arndt, Oscar H Franco, Patrik Wennberg, John Gallacher, Agustín Gómez de la Cámara, Henry Völzke, Christina C Dahm, Caroline E Dale, Manuela M Bergmann, Carlos J Crespo, Yvonne T van der Schouw, Rudolf Kaaks, Leon A Simons, Pagona Lagiou, Josje D Schoufour, Jolanda M A Boer, Timothy J Key, Beatriz Rodriguez, Conchi Moreno-Iribas, Karina W Davidson, James O Taylor, Carlotta Sacerdote, Robert B Wallace, J Ramon Quiros, Rosario Tumino, Dan G Blazer, Allan Linneberg, Makoto Daimon, Salvatore Panico, Barbara Howard, Guri Skeie, Timo Strandberg, Elisabete Weiderpass, Paul J Nietert, Bruce M Psaty, Daan Kromhout, Elena Salamanca-Fernandez, Stefan Kiechl, Harlan M Krumholz, Sara Grioni, Domenico Palli, José M Huerta, Jackie Price, Johan Sundström, Larraitz Arriola, Hisatomi Arima, Ruth C Travis, Demosthenes B Panagiotakos, Anna Karakatsani, Antonia Trichopoulou, Tilman Kühn, Diederick E Grobbee, Elizabeth Barrett-Connor, Natasja van Schoor, Heiner Boeing, Kim Overvad, Jussi Kauhanen, Nick Wareham, Claudia Langenberg, Nita Forouhi, Maria Wennberg, Jean-Pierre Després, Mary Cushman, Jackie A Cooper, Carlos J Rodriguez, Masaru Sakurai, Jonathan E Shaw, Matthew Knuiman, Trudy Voortman, Christa Meisinger, Anne Tjønneland, Hermann Brenner, Luigi Palmieri, Jean Dallongeville, Eric J Brunner, Gerd Assmann, Maurizio Trevisan, Richard F Gillum, Ian Ford, Naveed Sattar, Mariana Lazo, Simon G Thompson, Pietro Ferrari, David A Leon, George Davey Smith, Richard Peto, Rod Jackson, Emily Banks, Emanuele Di Angelantonio, John Danesh, Adam Butterworth, Monique Verschuren, Salomaa Veikko, Astrid Flecther, Manuela Bergmann, Carlos Crespo, Jolanda M.A Boer, J. Ramon Quiros, Eric B Rimm, Dan G Blazer III, Jean-Pierre Dallongeville, Richard F Gillumn, Ian Ford Ford, Simon Thompson, Epidemiology, Wood, Angela M, Kaptoge, Stephen, Butterworth, Adam S, Willeit, Peter, Warnakula, Samantha, Bolton, Thoma, Paige, Ellie, Paul, Dirk S, Sweeting, Michael, Burgess, Stephen, Bell, Steven, Astle, William, Stevens, David, Koulman, Albert, Selmer, Randi M, Verschuren, W M Monique, Sato, Shinichi, Njølstad, Inger, Woodward, Mark, Salomaa, Veikko, Nordestgaard, Børge G, Yeap, Bu B, Fletcher, Astrid, Melander, Olle, Kuller, Lewis H, Balkau, Beverley, Marmot, Michael, Koenig, Wolfgang, Casiglia, Edoardo, Cooper, Cyru, Arndt, Volker, Franco, Oscar H, Wennberg, Patrik, Gallacher, John, de la Cámara, Agustín Gómez, Völzke, Henry, Dahm, Christina C, Dale, Caroline E, Bergmann, Manuela M, Crespo, Carlos J, van der Schouw, Yvonne T, Kaaks, Rudolf, Simons, Leon A, Lagiou, Pagona, Schoufour, Josje D, Boer, Jolanda M A, Key, Timothy J, Rodriguez, Beatriz, Moreno-Iribas, Conchi, Davidson, Karina W, Taylor, James O, Sacerdote, Carlotta, Wallace, Robert B, Quiros, J Ramon, Tumino, Rosario, Blazer, Dan G, Linneberg, Allan, Daimon, Makoto, Panico, Salvatore, Howard, Barbara, Skeie, Guri, Strandberg, Timo, Weiderpass, Elisabete, Nietert, Paul J, Psaty, Bruce M, Kromhout, Daan, Salamanca-Fernandez, Elena, Kiechl, Stefan, Krumholz, Harlan M, Grioni, Sara, Palli, Domenico, Huerta, José M, Price, Jackie, Sundström, Johan, Arriola, Larraitz, Arima, Hisatomi, Travis, Ruth C, Panagiotakos, Demosthenes B, Karakatsani, Anna, Trichopoulou, Antonia, Kühn, Tilman, Grobbee, Diederick E, Barrett-Connor, Elizabeth, van Schoor, Natasja, Boeing, Heiner, Overvad, Kim, Kauhanen, Jussi, Wareham, Nick, Langenberg, Claudia, Forouhi, Nita, Wennberg, Maria, Després, Jean-Pierre, Cushman, Mary, Cooper, Jackie A, Rodriguez, Carlos J, Sakurai, Masaru, Shaw, Jonathan E, Knuiman, Matthew, Voortman, Trudy, Meisinger, Christa, Tjønneland, Anne, Brenner, Hermann, Palmieri, Luigi, Dallongeville, Jean, Brunner, Eric J, Assmann, Gerd, Trevisan, Maurizio, Gillum, Richard F, Ford, Ian, Sattar, Naveed, Lazo, Mariana, Thompson, Simon G, Ferrari, Pietro, Leon, David A, Smith, George Davey, Peto, Richard, Jackson, Rod, Banks, Emily, Di Angelantonio, Emanuele, Danesh, John, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Internal Medicine and Rehabilitation, APH - Personalized Medicine, APH - Aging & Later Life, and Epidemiology and Data Science

Subjects
Male, FLOATING ABSOLUTE RISK, Alcohol abuse, BLOOD-PRESSURE, 030204 cardiovascular system & hematology, Alcohol Drinking/adverse effects, 0302 clinical medicine, Cardiovascular Disease, Prospective Studies, 030212 general & internal medicine, Myocardial infarction, Prospective cohort study, Human Nutrition & Health, media_common, Medicine(all), VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Research Support, Non-U.S. Gov't, Humane Voeding & Gezondheid, Hazard ratio, Substance Abuse, Public Health, Global Health, Social Medicine and Epidemiology, ASSOCIATION, General Medicine, Middle Aged, ddc, 3. Good health, Substance abuse, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, MENDELIAN RANDOMIZATION, Female, Risk assessment, STROKE, Human, Alcohol Drinking, Lower risk, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, US ADULTS, medicine, Journal Article, Life Science, Humans, media_common.cataloged_instance, CORONARY-HEART-DISEASE, ddc:610, Cardiovascular Diseases/etiology, European union, Beroendelära, METAANALYSIS, business.industry, MORTALITY, medicine.disease, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 3121 General medicine, internal medicine and other clinical medicine, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, business, Demography
Abstract

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies.FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Published
2018

45. Causal Associations of Adiposity and Body Fat Distribution With Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus: A Mendelian Randomization Analysis

Author

Helen R. Warren, Bradford B. Worrall, Jorgen Engmann, Tom R. Gaunt, David Prieto-Merino, Usha Menon, Dennis O. Mook-Kanamori, Aroon D. Hingorani, Meena Kumari, Mika Kivimäki, Ang Zhou, Michael V. Holmes, Aleksandra Gentry-Maharaj, Barbara J. Jefferis, Delilah Zabaneh, Mark J. Caulfield, Reecha Sofat, Renée de Mutsert, Chris Power, Yoav Ben-Shlomo, J. Wouter Jukema, Tom Palmer, Richard W Morris, Tina Shah, Juan P. Casas, Diana Kuh, Max Moldovan, Debbie A Lawlor, Jacqueline F. Price, Andrew Wong, Raymond Noordam, Caroline Dale, Steve E. Humphries, Naveed Sattar, Stella Trompet, Jon White, Stela McLachlan, George Davey Smith, Frank Dudbridge, Patricia B. Munroe, Andy Ryan, Elina Hyppönen, Ghazaleh Fatemifar, Dale, Caroline E, Fatemifar, Ghazaleh, Palmer, Tom M, White, Jon, Hyppönen, Elina, Zhou, Ang, and Casas, Juan P

Subjects
0301 basic medicine, medicine.medical_specialty, Mendelian randomization analysis, body fat distribution, body mass index, Coronary Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Waist–hip ratio, Physiology (medical), Internal medicine, Diabetes mellitus, Mendelian randomization, medicine, Body Fat Distribution, Humans, Longitudinal Studies, Prospective Studies, Stroke, Adiposity, adiposity, business.industry, Type 2 Diabetes Mellitus, Odds ratio, Mendelian Randomization Analysis, medicine.disease, stroke, Observational Studies as Topic, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Cardiology, waist-hip ratio, Cardiology and Cardiovascular Medicine, business, Body mass index, coronary artery disease, Bristol Population Health Science Institute
Abstract

Background: The implications of different adiposity measures on cardiovascular disease etiology remain unclear. In this article, we quantify and contrast causal associations of central adiposity (waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) and general adiposity (body mass index [BMI]) with cardiometabolic disease. Methods: Ninety-seven independent single-nucleotide polymorphisms for BMI and 49 single-nucleotide polymorphisms for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with coronary heart disease (CHD) data from CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics; combined total 66 842 cases), stroke from METASTROKE (12 389 ischemic stroke cases), type 2 diabetes mellitus from DIAGRAM (Diabetes Genetics Replication and Meta-analysis; 34 840 cases), and lipids from GLGC (Global Lipids Genetic Consortium; 213 500 participants) consortia. Primary outcomes were CHD, type 2 diabetes mellitus, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits. Results: Each one standard deviation (SD) higher WHRadjBMI (1 SD≈0.08 U) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD, 1.48; 95% confidence interval [CI], 1.28–1.71), similar to findings for BMI (1 SD≈4.6 kg/m 2 ; OR for CHD, 1.36; 95% CI, 1.22–1.52). Only WHRadjBMI increased risk of ischemic stroke (OR, 1.32; 95% CI, 1.03–1.70). For type 2 diabetes mellitus, both measures had large effects: OR, 1.82 (95% CI, 1.38–2.42) and OR, 1.98 (95% CI, 1.41–2.78) per 1 SD higher WHRadjBMI and BMI, respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95% CI, 9%–77% per 1 SD). Conclusions: Both general and central adiposity have causal effects on CHD and type 2 diabetes mellitus. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity.

Published
2017

46. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data

Author

Holmes, Michael, Dale, Caroline E, Zuccolo, Luisa, Silverwood, Richard J, Hypponen, Elina Tuulikki, Casas, Juan P, The InterAct Consortium, and IMPROVE Study Group

Subjects
single nucleotide, adult, genotype, Mendelian randomization analysis, alcohol dehydrogenase, coronary disease, alcohol drinking, stroke, polymorphism, aged, models, female, male, middle aged, genetic markers, humans, statistical, biological markers
Abstract

Refereed/Peer-reviewed

Published
2014

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