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8. Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models

Author

Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B., De Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E. Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T., ‘t Hart, Leen M., Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N., Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W., Schwenk, Jochen M., Adamski, Jerzy, McCarthy, Mark I., Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, Brunak, Søren, Froguel, Philippe, Thomas, Cecilia Engel, Häussler, Ragna S., Beulens, Joline, Rutters, Femke, Nijpels, Giel, van Oort, Sabine, Groeneveld, Lenka, Elders, Petra, Giorgino, Toni, Rodriquez, Marianne, Nice, Rachel, Perry, Mandy, Bianzano, Susanna, Graefe-Mody, Ulrike, Hennige, Anita, Grempler, Rolf, Baum, Patrick, Stærfeldt, Hans Henrik, Shah, Nisha, Teare, Harriet, Ehrhardt, Beate, Tillner, Joachim, Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinevich, Iryna, Cabrelli, Louise, Loftus, Heather, Bizzotto, Roberto, Tura, Andrea, Dekkers, Koen, Allesøe, Rosa Lundbye, Lundgaard, Agnete Troen, Hernández Medina, Ricardo, Aguayo-Orozco, Alejandro, Johansen, Joachim, Nissen, Jakob Nybo, Brorsson, Caroline, Mazzoni, Gianluca, Niu, Lili, Biel, Jorge Hernansanz, Brasas, Valentas, Webel, Henry, Benros, Michael Eriksen, Pedersen, Anders Gorm, Chmura, Piotr Jaroslaw, Jacobsen, Ulrik Plesner, Mari, Andrea, Koivula, Robert, Mahajan, Anubha, Vinuela, Ana, Tajes, Juan Fernandez, Sharma, Sapna, Haid, Mark, Hong, Mun-Gwan, Musholt, Petra B., De Masi, Federico, Vogt, Josef, Pedersen, Helle Krogh, Gudmundsdottir, Valborg, Jones, Angus, Kennedy, Gwen, Bell, Jimmy, Thomas, E. Louise, Frost, Gary, Thomsen, Henrik, Hansen, Elizaveta, Hansen, Tue Haldor, Vestergaard, Henrik, Muilwijk, Mirthe, Blom, Marieke T., ‘t Hart, Leen M., Pattou, Francois, Raverdy, Violeta, Brage, Soren, Kokkola, Tarja, Heggie, Alison, McEvoy, Donna, Mourby, Miranda, Kaye, Jane, Hattersley, Andrew, McDonald, Timothy, Ridderstråle, Martin, Walker, Mark, Forgie, Ian, Giordano, Giuseppe N., Pavo, Imre, Ruetten, Hartmut, Pedersen, Oluf, Hansen, Torben, Dermitzakis, Emmanouil, Franks, Paul W., Schwenk, Jochen M., Adamski, Jerzy, McCarthy, Mark I., Pearson, Ewan, Banasik, Karina, Rasmussen, Simon, Brunak, Søren, Froguel, Philippe, Thomas, Cecilia Engel, Häussler, Ragna S., Beulens, Joline, Rutters, Femke, Nijpels, Giel, van Oort, Sabine, Groeneveld, Lenka, Elders, Petra, Giorgino, Toni, Rodriquez, Marianne, Nice, Rachel, Perry, Mandy, Bianzano, Susanna, Graefe-Mody, Ulrike, Hennige, Anita, Grempler, Rolf, Baum, Patrick, Stærfeldt, Hans Henrik, Shah, Nisha, Teare, Harriet, Ehrhardt, Beate, Tillner, Joachim, Dings, Christiane, Lehr, Thorsten, Scherer, Nina, Sihinevich, Iryna, Cabrelli, Louise, Loftus, Heather, Bizzotto, Roberto, Tura, Andrea, and Dekkers, Koen

Abstract

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities., Correction in DOI 10.1038/s41587-023-01805-9QC 20230626

Published
2023
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9. Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

Author

Brown, Andrew A., Fernandez-Tajes, Juan J., Hong, Mun gwan, Brorsson, Caroline A., Koivula, Robert W., Davtian, David, Dupuis, Théo, Sartori, Ambra, Michalettou, Theodora Dafni, Forgie, Ian M., Adam, Jonathan, Allin, Kristine H., Caiazzo, Robert, Cederberg, Henna, De Masi, Federico, Elders, Petra J.M., Giordano, Giuseppe N., Haid, Mark, Hansen, Torben, Hansen, Tue H., Hattersley, Andrew T., Heggie, Alison J., Howald, Cédric, Jones, Angus G., Kokkola, Tarja, Laakso, Markku, Mahajan, Anubha, Mari, Andrea, McDonald, Timothy J., McEvoy, Donna, Mourby, Miranda, Musholt, Petra B., Nilsson, Birgitte, Pattou, Francois, Penet, Deborah, Raverdy, Violeta, Ridderstråle, Martin, Romano, Luciana, Rutters, Femke, Sharma, Sapna, Teare, Harriet, ‘t Hart, Leen, Tsirigos, Konstantinos D., Vangipurapu, Jagadish, Vestergaard, Henrik, Brunak, Søren, Franks, Paul W., Frost, Gary, Grallert, Harald, Jablonka, Bernd, McCarthy, Mark I., Pavo, Imre, Pedersen, Oluf, Ruetten, Hartmut, Walker, Mark, Adragni, Kofi, Allesøe, Rosa Lundbye L., Artati, Anna A., Arumugam, Manimozhiyan, Atabaki-Pasdar, Naeimeh, Baltauss, Tania, Banasik, Karina, Barnett, Anna L., Baum, Patrick, Bell, Jimmy D., Beulens, Joline W., Bianzano, Susanna B., Bizzotto, Roberto, Bonnefond, Amelie, Cabrelli, Louise, Dale, Matilda, Dawed, Adem Y., de Preville, Nathalie, Dekkers, Koen F., Deshmukh, Harshal A., Dings, Christiane, Donnelly, Louise, Dutta, Avirup, Ehrhardt, Beate, Engelbrechtsen, Line, Eriksen, Rebeca, Fan, Yong, Ferrer, Jorge, Fitipaldi, Hugo, Forman, Annemette, Fritsche, Andreas, Froguel, Philippe, Gassenhuber, Johann, Gough, Stephen, Graefe-Mody, Ulrike, Grempler, Rolf, Groeneveld, Lenka, Groop, Leif, Gudmundsdóttir, Valborg, Gupta, Ramneek, Hennige, Anita M.H., Hill, Anita V., Holl, Reinhard W., Hudson, Michelle, Jacobsen, Ulrik Plesner, Jennison, Christopher, Johansen, Joachim, Jonsson, Anna, Karaderi, Tugce, Kaye, Jane, Kennedy, Gwen, Klintenberg, Maria, Kuulasmaa, Teemu, Lehr, Thorsten, Loftus, Heather, Lundgaard, Agnete Troen T., Mazzoni, Gianluca, McRobert, Nicky, McVittie, Ian, Nice, Rachel, Nicolay, Claudia, Nijpels, Giel, Palmer, Colin N., Pedersen, Helle K., Perry, Mandy H., Pomares-Millan, Hugo, Prehn, Cornelia P., Ramisch, Anna, Rasmussen, Simon, Robertson, Neil, Rodriquez, Marianne, Sackett, Peter, Scherer, Nina, Shah, Nisha, Sihinevich, Iryna, Slieker, Roderick C., Sondertoft, Nadja B., Steckel-Hamann, Birgit, Thomas, Melissa K., Thomas, Cecilia Engel E., Thomas, Elizabeth Louise L., Thorand, Barbara, Thorne, Claire E., Tillner, Joachim, Tura, Andrea, Uhlen, Mathias, van Leeuwen, Nienke, van Oort, Sabine, Verkindt, Helene, Vogt, Josef, Wad Sackett, Peter W., Wesolowska-Andersen, Agata, Whitcher, Brandon, White, Margaret W., Adamski, Jerzy, Schwenk, Jochen M., Pearson, Ewan R., Dermitzakis, Emmanouil T., Viñuela, Ana, Brown, Andrew A., Fernandez-Tajes, Juan J., Hong, Mun gwan, Brorsson, Caroline A., Koivula, Robert W., Davtian, David, Dupuis, Théo, Sartori, Ambra, Michalettou, Theodora Dafni, Forgie, Ian M., Adam, Jonathan, Allin, Kristine H., Caiazzo, Robert, Cederberg, Henna, De Masi, Federico, Elders, Petra J.M., Giordano, Giuseppe N., Haid, Mark, Hansen, Torben, Hansen, Tue H., Hattersley, Andrew T., Heggie, Alison J., Howald, Cédric, Jones, Angus G., Kokkola, Tarja, Laakso, Markku, Mahajan, Anubha, Mari, Andrea, McDonald, Timothy J., McEvoy, Donna, Mourby, Miranda, Musholt, Petra B., Nilsson, Birgitte, Pattou, Francois, Penet, Deborah, Raverdy, Violeta, Ridderstråle, Martin, Romano, Luciana, Rutters, Femke, Sharma, Sapna, Teare, Harriet, ‘t Hart, Leen, Tsirigos, Konstantinos D., Vangipurapu, Jagadish, Vestergaard, Henrik, Brunak, Søren, Franks, Paul W., Frost, Gary, Grallert, Harald, Jablonka, Bernd, McCarthy, Mark I., Pavo, Imre, Pedersen, Oluf, Ruetten, Hartmut, Walker, Mark, Adragni, Kofi, Allesøe, Rosa Lundbye L., Artati, Anna A., Arumugam, Manimozhiyan, Atabaki-Pasdar, Naeimeh, Baltauss, Tania, Banasik, Karina, Barnett, Anna L., Baum, Patrick, Bell, Jimmy D., Beulens, Joline W., Bianzano, Susanna B., Bizzotto, Roberto, Bonnefond, Amelie, Cabrelli, Louise, Dale, Matilda, Dawed, Adem Y., de Preville, Nathalie, Dekkers, Koen F., Deshmukh, Harshal A., Dings, Christiane, Donnelly, Louise, Dutta, Avirup, Ehrhardt, Beate, Engelbrechtsen, Line, Eriksen, Rebeca, Fan, Yong, Ferrer, Jorge, Fitipaldi, Hugo, Forman, Annemette, Fritsche, Andreas, Froguel, Philippe, Gassenhuber, Johann, Gough, Stephen, Graefe-Mody, Ulrike, Grempler, Rolf, Groeneveld, Lenka, Groop, Leif, Gudmundsdóttir, Valborg, Gupta, Ramneek, Hennige, Anita M.H., Hill, Anita V., Holl, Reinhard W., Hudson, Michelle, Jacobsen, Ulrik Plesner, Jennison, Christopher, Johansen, Joachim, Jonsson, Anna, Karaderi, Tugce, Kaye, Jane, Kennedy, Gwen, Klintenberg, Maria, Kuulasmaa, Teemu, Lehr, Thorsten, Loftus, Heather, Lundgaard, Agnete Troen T., Mazzoni, Gianluca, McRobert, Nicky, McVittie, Ian, Nice, Rachel, Nicolay, Claudia, Nijpels, Giel, Palmer, Colin N., Pedersen, Helle K., Perry, Mandy H., Pomares-Millan, Hugo, Prehn, Cornelia P., Ramisch, Anna, Rasmussen, Simon, Robertson, Neil, Rodriquez, Marianne, Sackett, Peter, Scherer, Nina, Shah, Nisha, Sihinevich, Iryna, Slieker, Roderick C., Sondertoft, Nadja B., Steckel-Hamann, Birgit, Thomas, Melissa K., Thomas, Cecilia Engel E., Thomas, Elizabeth Louise L., Thorand, Barbara, Thorne, Claire E., Tillner, Joachim, Tura, Andrea, Uhlen, Mathias, van Leeuwen, Nienke, van Oort, Sabine, Verkindt, Helene, Vogt, Josef, Wad Sackett, Peter W., Wesolowska-Andersen, Agata, Whitcher, Brandon, White, Margaret W., Adamski, Jerzy, Schwenk, Jochen M., Pearson, Ewan R., Dermitzakis, Emmanouil T., and Viñuela, Ana

Abstract

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.

Published
2023

10. Inflammation and heart failure: a two-sample Mendelian randomization study

Author

Remmelzwaal, Sharon, van Oort, Sabine, Handoko, M. Louis, van Empel, Vanessa, Heymans, Stephane R. B., Beulens, Joline W. J., Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Epidemiology and Data Science, General practice, APH - Health Behaviors & Chronic Diseases, APH - Methodology, ACS - Diabetes & metabolism, Cardiology, ACS - Heart failure & arrhythmias, APH - Personalized Medicine, and ACS - Pulmonary hypertension & thrombosis

Subjects
RISK, Science & Technology, Cardiac & Cardiovascular Systems, heart failure, NECROSIS-FACTOR-ALPHA, General Medicine, C-REACTIVE PROTEIN, DOUBLE-BLIND, MARKERS, inflammation, ATRIAL-FIBRILLATION, Cardiovascular System & Cardiology, Mendelian randomization, GENOME-WIDE ASSOCIATION, CARDIOVASCULAR EVENTS, OLDER-ADULTS, ROSUVASTATIN, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine
Abstract

BACKGROUND: It is hypothesized that inflammation leads to heart failure. Results from observational studies thus far have been inconsistent and it is unclear whether inflammation is causally associated with new-onset heart failure. Mendelian randomization analyses are less prone to biases common in observational studies such as reverse causation and unmeasured confounding. The aim of this study was to investigate the causal relation between various inflammatory biomarkers with risk of new-onset heart failure by using a two-sample Mendelian randomization approach. METHODS: Ten inflammatory biomarkers with available genome-wide association studies (GWAS) among individuals of European ancestry were identified and included C-reactive protein (CRP), immunoglobulin E, tumour necrosis factor (TNF), toll-like receptor 4, interleukin 1 receptor antagonist, interleukin 2 receptor subunit α, interleukin 6 receptor subunit α, interleukin 16, 17 and 18. For the associations between the identified SNPs and heart failure, we used the largest GWAS meta-analysis performed by the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium with 47 309 participants with heart failure and 930 014 controls. For our main analyses, we used the inverse-variance weighted method. RESULTS: We included 63 SNPs. CRP, TNF, interleukin 2, 16 and 18 were not associated with heart failure with odds ratios (ORs) of 1.01 [95% confidence interval (95% CI: 0.94-1.09), 1.11 (95% CI: 0.80-1.48), 0.97 (95% CI: 0.93-1.02), 0.99 (95% CI: 0.96-1.03) and 1.01 (95% CI: 0.97-1.06), respectively. The other biomarkers were also not associated with the risk of heart failure and suffered from weak instrument bias. CONCLUSION: This Mendelian randomization study could not determine a causal relationship between inflammation and risk of heart failure. However, some biomarkers suffered from weak instrument bias. ispartof: JOURNAL OF CARDIOVASCULAR MEDICINE vol:23 issue:11 pages:728-735 ispartof: location:United States status: published

Published
2022
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12. Modifiable cardiovascular risk factors and lifestyle behaviours in relation to cardiometabolic health: Opportunities for prevention

Author

van Oort, Sabine, Beulens, J.W.J., Grobbee, D.E., van Ballegooijen, Adriana Johanne, Schrieks, Ilse, VUmc - School of Medical Sciences, Beulens, Joline, van Ballegooijen, Hanne, VU University medical center, General practice, ACS - Diabetes & metabolism, and APH - Health Behaviors & Chronic Diseases

Subjects
lifestyle, diabetes, cardiovascular disease, alcohol consumption, Mendelian randomization
Abstract

The research described in this thesis addresses the association of several traditional and novel cardiovascular risk factors and lifestyle behaviours with cardiometabolic diseases. This was further specified into two research objectives: I. What are potential mechanisms of the relationship between the modifiable lifestyle factor alcohol consumption and cardiometabolic diseases? II. What is the causal role of modifiable cardiovascular and lifestyle-related risk factors in the development of cardiometabolic diseases? Potential mechanisms of the relation between alcohol consumption and cardiometabolic diseases In Chapters 2 and 3, cardiac function and structure, insulin sensitivity and adiposity were investigated as potential underlying mechanisms in the relation of alcohol consumption with cardiometabolic diseases. Chapter 2 showed that higher levels of alcohol consumption were linearly associated with a decrease in left ventricular ejection fraction, a measure of systolic function, in a prospective study of 404 participants. No association was observed between alcohol consumption and left atrial volume index, which is a measure of diastolic function, or left ventricular mass index, a measure of cardiac structure. These findings suggest that alcohol consumption might play a role in the pathophysiology of heart failure with reduced ejection fraction. Chapter 3 showed that heavy drinking was associated with higher liver fat in a cross-sectional study on 787 men with prediabetes, and central adiposity seemed to explain part of this association. Moderate amounts of alcohol consumption appeared to be associated with a decrease in liver fat in the prospective analysis, but the definitive shape of this association warrants investigation in larger and more long-term follow-up studies. Altogether, heavy alcohol consumption is harmful for preclinical aspects of cardiometabolic health, but whether there is a safe drinking threshold for moderate amounts of alcohol consumption remains a point of discussion. The causal role of modifiable cardiovascular and lifestyle-related risk factors in the development of cardiometabolic diseases In Chapter 4, a systematic review of the current evidence from Mendelian randomization (MR) studies on the association between alcohol consumption and cardiometabolic diseases, mortality and cardiovascular risk factors was conducted. There was large heterogeneity in the methodological quality of the MR studies on this topic so far. It was not possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. Recent developments in MR reporting guidelines and methodology including instrument selection and non-linearity are expected to improve evidence from future MR studies. In Chapters 5, 6 and 7, the two-sample MR method was used to investigate the potential causal association of several cardiovascular risk factors and lifestyle behaviours with risk of hypertension, heart failure and longevity, respectively. These MR studies confirmed the causal role of several traditional risk factors in the development of cardiometabolic diseases, with for example genetically predicted smoking initiation being detrimentally associated with hypertension, heart failure and longevity, and genetically predicted higher body mass index being harmful for hypertension and longevity. A genetically predicted higher educational level was associated with a reduced risk of hypertension and increased life expectancy. The MR studies implied that sleep might be an important novel risk factor for cardiometabolic health, with a genetically predicted longer sleep duration being associated with a lower heart failure risk en a potentially lower hypertension risk, and genetically predicted insomnia increasing the risk of hypertension and possibly reducing life expectancy. For lifestyle factors including physical activity, sedentary behaviour and coffee consumption, the precision was low in the majority of the MR analyses, making it not possible to draw causal conclusions for these factors.

Published
2022

13. Alcohol consumption in relation to cardiovascular diseases and mortality : a systematic review of Mendelian randomization studies

Author

van de Luitgaarden, Inge A T, van Oort, Sabine, Bouman, Emma J, Schoonmade, Linda J, Schrieks, Ilse C, Grobbee, Diederick E, van der Schouw, Yvonne T, Larsson, Susanna C., Burgess, Stephen, van Ballegooijen, Adriana J, Onland-Moret, N Charlotte, Beulens, Joline W J, van de Luitgaarden, Inge A T, van Oort, Sabine, Bouman, Emma J, Schoonmade, Linda J, Schrieks, Ilse C, Grobbee, Diederick E, van der Schouw, Yvonne T, Larsson, Susanna C., Burgess, Stephen, van Ballegooijen, Adriana J, Onland-Moret, N Charlotte, and Beulens, Joline W J

Abstract

The causal effects of alcohol-in-moderation on cardiometabolic health are continuously debated. Mendelian randomization (MR) is an established method to address causal questions in observational studies. We performed a systematic review of the current evidence from MR studies on the association between alcohol consumption and cardiometabolic diseases, all-cause mortality and cardiovascular risk factors. We performed a systematic search of the literature, including search terms on type of design and exposure. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. We additionally looked at exploration of non-linearity. We reported the direction of the studied associations. Our search yielded 24 studies that were eligible for inclusion. A full instrumental variable analysis was performed in 17 studies (71%) and 13 out of 24 studies (54%) validated all three key assumptions. Five studies (21%) assessed potential non-linearity. In general, null associations were reported for genetically predicted alcohol consumption with the primary outcomes cardiovascular disease (67%) and diabetes (75%), while the only study on all-cause mortality reported a detrimental association. Considering the heterogeneity in methodological quality of the included MR studies, it is not yet possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. As MR is a rapidly evolving field, we expect that future MR studies, especially with recent developments regarding instrument selection and non-linearity methodology, will further substantiate this discussion.

Published
2022
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14. Alcohol consumption in relation to cardiovascular diseases and mortality: a systematic review of Mendelian randomization studies

Author

Global Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 10, Circulatory Health, Cardiovasculaire Epi Team 1, Cardiovasculaire Epi Team 3, van de Luitgaarden, Inge A.T., van Oort, Sabine, Bouman, Emma J., Schoonmade, Linda J., Schrieks, Ilse C., Grobbee, Diederick E., van der Schouw, Yvonne T., Larsson, Susanna C., Burgess, Stephen, van Ballegooijen, Adriana J., Onland-Moret, N. Charlotte, Beulens, Joline W.J., Global Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 10, Circulatory Health, Cardiovasculaire Epi Team 1, Cardiovasculaire Epi Team 3, van de Luitgaarden, Inge A.T., van Oort, Sabine, Bouman, Emma J., Schoonmade, Linda J., Schrieks, Ilse C., Grobbee, Diederick E., van der Schouw, Yvonne T., Larsson, Susanna C., Burgess, Stephen, van Ballegooijen, Adriana J., Onland-Moret, N. Charlotte, and Beulens, Joline W.J.

Published
2022

15. Inferring causal pathways between metabolic processes and liver fat accumulation: an IMI DIRECT study

Author

Atabaki-Pasdar, Naeimeh, primary, Pomares-Millan, Hugo, additional, Koivula, Robert W, additional, Tura, Andrea, additional, Brown, Andrew, additional, Viñuela, Ana, additional, Agudelo, Leandro, additional, Coral, Daniel, additional, van Oort, Sabine, additional, Allin, Kristine, additional, Chabanova, Elizaveta, additional, Cederberg, Henna, additional, De Masi, Federico, additional, Elders, Petra, additional, Tajes, Juan Fernandez, additional, Forgie, Ian M, additional, Hansen, Tue H, additional, Heggie, Alison, additional, Jones, Angus, additional, Kokkola, Tarja, additional, Mahajan, Anubha, additional, McDonald, Timothy J, additional, McEvoy, Donna, additional, Tsirigos, Konstantinos, additional, Teare, Harriet, additional, Vangipurapu, Jagadish, additional, Vestergaard, Henrik, additional, Adamski, Jerzy, additional, Beulens, Joline WJ, additional, Brunak, Søren, additional, Dermitzakis, Emmanouil, additional, Hansen, Torben, additional, Hattersley, Andrew T, additional, Laakso, Markku, additional, Pedersen, Oluf, additional, Ridderstråle, Martin, additional, Ruetten, Hartmut, additional, Rutters, Femke, additional, Schwenk, Jochen M, additional, Walker, Mark, additional, Giordano, Giuseppe N, additional, Ohlsson, Mattias, additional, Gupta, Ramneek, additional, Mari, Andrea, additional, McCarthy, Mark I, additional, Thomas, E Louise, additional, Bell, Jimmy D, additional, Pavo, Imre, additional, Pearson, Ewan R, additional, and Franks, Paul W, additional

Published
2021
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16. Alcohol consumption in relation to cardiovascular diseases and mortality: a systematic review of Mendelian randomization studies

Author

van de Luitgaarden, Inge A. T., primary, van Oort, Sabine, additional, Bouman, Emma J., additional, Schoonmade, Linda J., additional, Schrieks, Ilse C., additional, Grobbee, Diederick E., additional, van der Schouw, Yvonne T., additional, Larsson, Susanna C., additional, Burgess, Stephen, additional, van Ballegooijen, Adriana J., additional, Onland-Moret, N. Charlotte, additional, and Beulens, Joline W. J., additional

Published
2021
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17. Cardiovascular risk factors and lifestyle behaviours in relation to longevity : a Mendelian randomization study.

Author

van Oort, Sabine, Beulens, J W J, van Ballegooijen, A J, Burgess, S, Larsson, Susanna C., van Oort, Sabine, Beulens, J W J, van Ballegooijen, A J, Burgess, S, and Larsson, Susanna C.

Abstract

BACKGROUND: The American Heart Association introduced the Life's Simple 7 initiative to improve cardiovascular health by modifying cardiovascular risk factors and lifestyle behaviours. It is unclear whether these risk factors are causally associated with longevity. OBJECTIVES: This study aimed to investigate causal associations of Life's Simple 7 modifiable risk factors, as well as sleep and education, with longevity using the two-sample Mendelian randomization design. METHODS: Instrumental variables for the modifiable risk factors were obtained from large-scale genome-wide association studies. Data on longevity beyond the 90th survival percentile were extracted from a genome-wide association meta-analysis with 11,262 cases and 25,483 controls whose age at death or last contact was ≤ the 60th survival percentile. RESULTS: Risk factors associated with a lower odds of longevity included the following: genetic liability to type 2 diabetes (OR 0.88; 95% CI: 0.84;0.92), genetically predicted systolic and diastolic blood pressure (per 1-mmHg increase: 0.96; 0.94;0.97 and 0.95; 0.93;0.97), body mass index (per 1-SD increase: 0.80; 0.74;0.86), low-density lipoprotein cholesterol (per 1-SD increase: 0.75; 0.65;0.86) and smoking initiation (0.75; 0.66;0.85). Genetically increased high-density lipoprotein cholesterol (per 1-SD increase: 1.23; 1.08;1.41) and educational level (per 1-SD increase: 1.64; 1.45;1.86) were associated with a higher odds of longevity. Fasting glucose and other lifestyle factors were not significantly associated with longevity. CONCLUSION: Most of the Life's Simple 7 modifiable risk factors are causally related to longevity. Prevention strategies should focus on modifying these risk factors and reducing education inequalities to improve cardiovascular health and longevity.

Published
2020
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18. Urinary Ethyl Glucuronide as Measure of Alcohol Consumption and Risk of Cardiovascular Disease : A Population-Based Cohort Study

Author

van de Luitgaarden, Inge A T, Schrieks, Ilse C, Kieneker, Lyanne M, Touw, Daan J, van Ballegooijen, Adriana J, van Oort, Sabine, Grobbee, Diederick E, Mukamal, Kenneth J, Kootstra-Ros, Jenny E, Muller Kobold, Anneke C, Bakker, Stephan J L, Beulens, Joline W J, van de Luitgaarden, Inge A T, Schrieks, Ilse C, Kieneker, Lyanne M, Touw, Daan J, van Ballegooijen, Adriana J, van Oort, Sabine, Grobbee, Diederick E, Mukamal, Kenneth J, Kootstra-Ros, Jenny E, Muller Kobold, Anneke C, Bakker, Stephan J L, and Beulens, Joline W J

Published
2020

19. Urinary Ethyl Glucuronide as Measure of Alcohol Consumption and Risk of Cardiovascular Disease: A Population-Based Cohort Study

Author

Global Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Circulatory Health, Cardiovasculaire Epi Team 1, van de Luitgaarden, Inge A T, Schrieks, Ilse C, Kieneker, Lyanne M, Touw, Daan J, van Ballegooijen, Adriana J, van Oort, Sabine, Grobbee, Diederick E, Mukamal, Kenneth J, Kootstra-Ros, Jenny E, Muller Kobold, Anneke C, Bakker, Stephan J L, Beulens, Joline W J, Global Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Circulatory Health, Cardiovasculaire Epi Team 1, van de Luitgaarden, Inge A T, Schrieks, Ilse C, Kieneker, Lyanne M, Touw, Daan J, van Ballegooijen, Adriana J, van Oort, Sabine, Grobbee, Diederick E, Mukamal, Kenneth J, Kootstra-Ros, Jenny E, Muller Kobold, Anneke C, Bakker, Stephan J L, and Beulens, Joline W J

Published
2020

20. Moderate and heavy alcohol consumption are prospectively associated with decreased left ventricular ejection fraction: The Hoorn Study

Author

Global Health, Cardiovasculaire Epi Team 10, Cardiovasculaire Epi Team 1, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 9, van Oort, Sabine, Beulens, Joline W, van der Heijden, Amber A W A, Elders, Petra J M, Stehouwer, Coen D A, van de Luitgaarden, Inge A T, Schrieks, Ilse C, Grobbee, Diederick E, van Ballegooijen, Adriana J, Global Health, Cardiovasculaire Epi Team 10, Cardiovasculaire Epi Team 1, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 9, van Oort, Sabine, Beulens, Joline W, van der Heijden, Amber A W A, Elders, Petra J M, Stehouwer, Coen D A, van de Luitgaarden, Inge A T, Schrieks, Ilse C, Grobbee, Diederick E, and van Ballegooijen, Adriana J

Published
2020

21. Urinary Ethyl Glucuronide as Measure of Alcohol Consumption and Risk of Cardiovascular Disease: A Population‐Based Cohort Study

Author

van de Luitgaarden, Inge A. T., primary, Schrieks, Ilse C., additional, Kieneker, Lyanne M., additional, Touw, Daan J., additional, van Ballegooijen, Adriana J., additional, van Oort, Sabine, additional, Grobbee, Diederick E., additional, Mukamal, Kenneth J., additional, Kootstra‐Ros, Jenny E., additional, Muller Kobold, Anneke C., additional, Bakker, Stephan J. L., additional, and Beulens, Joline W. J., additional

Published
2020
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22. Urinary Ethyl Glucuronide Can Be Used as a Biomarker of Habitual Alcohol Consumption in the General Population

Author

van de Luitgaarden, Inge A.T., Beulens, Joline W.J., Schrieks, Ilse C., Kieneker, Lyanne M., Touw, Daan J., van Ballegooijen, Adriana J., van Oort, Sabine, Grobbee, Diederick E., Bakker, Stephan J.L., van de Luitgaarden, Inge A.T., Beulens, Joline W.J., Schrieks, Ilse C., Kieneker, Lyanne M., Touw, Daan J., van Ballegooijen, Adriana J., van Oort, Sabine, Grobbee, Diederick E., and Bakker, Stephan J.L.

Published
2019

23. Urinary Ethyl Glucuronide Can Be Used as a Biomarker of Habitual Alcohol Consumption in the General Population

Author

Global Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 1, Circulatory Health, Cardiovasculaire Epi Team 10, Cardiovasculaire Epi Team 9, Affectieve & Psychotische Med., van de Luitgaarden, Inge A.T., Beulens, Joline W.J., Schrieks, Ilse C., Kieneker, Lyanne M., Touw, Daan J., van Ballegooijen, Adriana J., van Oort, Sabine, Grobbee, Diederick E., Bakker, Stephan J.L., Global Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 1, Circulatory Health, Cardiovasculaire Epi Team 10, Cardiovasculaire Epi Team 9, Affectieve & Psychotische Med., van de Luitgaarden, Inge A.T., Beulens, Joline W.J., Schrieks, Ilse C., Kieneker, Lyanne M., Touw, Daan J., van Ballegooijen, Adriana J., van Oort, Sabine, Grobbee, Diederick E., and Bakker, Stephan J.L.

Published
2019

24. Alcohol consumption in relation to cardiovascular diseases and mortality: a systematic review of Mendelian randomization studies

Author

Adriana J. van Ballegooijen, N. Charlotte Onland-Moret, Yvonne T. van der Schouw, Sabine van Oort, Joline W. J. Beulens, Diederick E. Grobbee, Inge A. T. van de Luitgaarden, Emma J. Bouman, Linda J. Schoonmade, Stephen Burgess, Susanna C. Larsson, Ilse C. Schrieks, van de Luitgaarden, Inge AT [0000-0002-4997-6376], van Oort, Sabine [0000-0002-0756-2730], Burgess, Stephen [0000-0001-5365-8760], and Apollo - University of Cambridge Repository

Subjects
medicine.medical_specialty, Alcohol Drinking, Epidemiology, Cardiovascular risk factors, Disease, Mendelian randomization, Medicine, Humans, Alcohol consumption, Mortality, business.industry, Public health, Instrumental variable, Diabetes, Public Health, Global Health, Social Medicine and Epidemiology, Mendelian Randomization Analysis, Cardiovascular disease, Causality, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Cardiovascular Diseases, Research Design, Systematic review, Observational study, business, Clinical psychology, Genome-Wide Association Study
Abstract

The causal effects of alcohol-in-moderation on cardiometabolic health are continuously debated. Mendelian randomization (MR) is an established method to address causal questions in observational studies. We performed a systematic review of the current evidence from MR studies on the association between alcohol consumption and cardiometabolic diseases, all-cause mortality and cardiovascular risk factors. We performed a systematic search of the literature, including search terms on type of design and exposure. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. We additionally looked at exploration of non-linearity. We reported the direction of the studied associations. Our search yielded 24 studies that were eligible for inclusion. A full instrumental variable analysis was performed in 17 studies (71%) and 13 out of 24 studies (54%) validated all three key assumptions. Five studies (21%) assessed potential non-linearity. In general, null associations were reported for genetically predicted alcohol consumption with the primary outcomes cardiovascular disease (67%) and diabetes (75%), while the only study on all-cause mortality reported a detrimental association. Considering the heterogeneity in methodological quality of the included MR studies, it is not yet possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. As MR is a rapidly evolving field, we expect that future MR studies, especially with recent developments regarding instrument selection and non-linearity methodology, will further substantiate this discussion.

Published
2022
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