Phenome-wide Mendelian randomization study of plasma triglyceride levels and 2600 disease traits
Background: Causality between plasma triglyceride (TG) levels and atherosclerotic cardiovascular disease (ASCVD) risk remains controversial despite more than four decades of study and two recent landmark trials, STRENGTH, and REDUCE-IT. Further unclear is the association between TG levels and non-at...
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eLife Sciences Publications Ltd
2023-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/80560 |
| _version_ | 1797829818097598464 |
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| author | Joshua K Park Shantanu Bafna Iain S Forrest Áine Duffy Carla Marquez-Luna Ben O Petrazzini Ha My Vy Daniel M Jordan Marie Verbanck Jagat Narula Robert S Rosenson Ghislain Rocheleau Ron Do |
| author_facet | Joshua K Park Shantanu Bafna Iain S Forrest Áine Duffy Carla Marquez-Luna Ben O Petrazzini Ha My Vy Daniel M Jordan Marie Verbanck Jagat Narula Robert S Rosenson Ghislain Rocheleau Ron Do |
| author_sort | Joshua K Park |
| collection | DOAJ |
| description | Background: Causality between plasma triglyceride (TG) levels and atherosclerotic cardiovascular disease (ASCVD) risk remains controversial despite more than four decades of study and two recent landmark trials, STRENGTH, and REDUCE-IT. Further unclear is the association between TG levels and non-atherosclerotic diseases across organ systems.
Methods: Here, we conducted a phenome-wide, two-sample Mendelian randomization (MR) analysis using inverse-variance weighted (IVW) regression to systematically infer the causal effects of plasma TG levels on 2600 disease traits in the European ancestry population of UK Biobank. For replication, we externally tested 221 nominally significant associations (p<0.05) in an independent cohort from FinnGen. To account for potential horizontal pleiotropy and the influence of invalid instrumental variables, we performed sensitivity analyses using MR-Egger regression, weighted median estimator, and MR-PRESSO. Finally, we used multivariable MR (MVMR) controlling for correlated lipid fractions to distinguish the independent effect of plasma TG levels.
Results: Our results identified seven disease traits reaching Bonferroni-corrected significance in both the discovery (p<1.92 × 10-5) and replication analyses (p<2.26 × 10-4), suggesting a causal relationship between plasma TG levels and ASCVDs, including coronary artery disease (OR 1.33, 95% CI 1.24–1.43, p=2.47 × 10-13). We also identified 12 disease traits that were Bonferroni-significant in the discovery or replication analysis and at least nominally significant in the other analysis (p<0.05), identifying plasma TG levels as a novel potential risk factor for nine non-ASCVD diseases, including uterine leiomyoma (OR 1.19, 95% CI 1.10–1.29, p=1.17 × 10-5).
Conclusions: Taking a phenome-wide, two-sample MR approach, we identified causal associations between plasma TG levels and 19 disease traits across organ systems. Our findings suggest unrealized drug repurposing opportunities or adverse effects related to approved and emerging TG-lowering agents, as well as mechanistic insights for future studies.
Funding: RD is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (R35-GM124836) and the National Heart, Lung, and Blood Institute of the NIH (R01-HL139865 and R01-HL155915). |
| first_indexed | 2024-04-09T13:27:06Z |
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| last_indexed | 2024-04-09T13:27:06Z |
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| spelling | doaj.art-12127af73513498d96d6ca12833158042023-05-10T07:46:12ZengeLife Sciences Publications LtdeLife2050-084X2023-03-011210.7554/eLife.80560Phenome-wide Mendelian randomization study of plasma triglyceride levels and 2600 disease traitsJoshua K Park0https://orcid.org/0000-0002-1719-3537Shantanu Bafna1Iain S Forrest2Áine Duffy3Carla Marquez-Luna4Ben O Petrazzini5Ha My Vy6Daniel M Jordan7Marie Verbanck8Jagat Narula9Robert S Rosenson10Ghislain Rocheleau11https://orcid.org/0000-0002-9989-7553Ron Do12https://orcid.org/0000-0002-3144-3627Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States; Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, United StatesCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United StatesCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States; Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, United StatesCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United StatesCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United StatesCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United StatesCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United StatesCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United StatesUniversité Paris Cité, Paris, FranceDepartment of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; Cardiovascular Imaging Program, Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, United StatesDepartment of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; Metabolism and Lipids Unit, Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, United StatesCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United StatesCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United StatesBackground: Causality between plasma triglyceride (TG) levels and atherosclerotic cardiovascular disease (ASCVD) risk remains controversial despite more than four decades of study and two recent landmark trials, STRENGTH, and REDUCE-IT. Further unclear is the association between TG levels and non-atherosclerotic diseases across organ systems. Methods: Here, we conducted a phenome-wide, two-sample Mendelian randomization (MR) analysis using inverse-variance weighted (IVW) regression to systematically infer the causal effects of plasma TG levels on 2600 disease traits in the European ancestry population of UK Biobank. For replication, we externally tested 221 nominally significant associations (p<0.05) in an independent cohort from FinnGen. To account for potential horizontal pleiotropy and the influence of invalid instrumental variables, we performed sensitivity analyses using MR-Egger regression, weighted median estimator, and MR-PRESSO. Finally, we used multivariable MR (MVMR) controlling for correlated lipid fractions to distinguish the independent effect of plasma TG levels. Results: Our results identified seven disease traits reaching Bonferroni-corrected significance in both the discovery (p<1.92 × 10-5) and replication analyses (p<2.26 × 10-4), suggesting a causal relationship between plasma TG levels and ASCVDs, including coronary artery disease (OR 1.33, 95% CI 1.24–1.43, p=2.47 × 10-13). We also identified 12 disease traits that were Bonferroni-significant in the discovery or replication analysis and at least nominally significant in the other analysis (p<0.05), identifying plasma TG levels as a novel potential risk factor for nine non-ASCVD diseases, including uterine leiomyoma (OR 1.19, 95% CI 1.10–1.29, p=1.17 × 10-5). Conclusions: Taking a phenome-wide, two-sample MR approach, we identified causal associations between plasma TG levels and 19 disease traits across organ systems. Our findings suggest unrealized drug repurposing opportunities or adverse effects related to approved and emerging TG-lowering agents, as well as mechanistic insights for future studies. Funding: RD is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (R35-GM124836) and the National Heart, Lung, and Blood Institute of the NIH (R01-HL139865 and R01-HL155915).https://elifesciences.org/articles/80560Mendelian randomizationtriglyceridescardiovascular diseaseUK BiobankFinnGenlipid metabolism |
| spellingShingle | Joshua K Park Shantanu Bafna Iain S Forrest Áine Duffy Carla Marquez-Luna Ben O Petrazzini Ha My Vy Daniel M Jordan Marie Verbanck Jagat Narula Robert S Rosenson Ghislain Rocheleau Ron Do Phenome-wide Mendelian randomization study of plasma triglyceride levels and 2600 disease traits eLife Mendelian randomization triglycerides cardiovascular disease UK Biobank FinnGen lipid metabolism |
| title | Phenome-wide Mendelian randomization study of plasma triglyceride levels and 2600 disease traits |
| title_full | Phenome-wide Mendelian randomization study of plasma triglyceride levels and 2600 disease traits |
| title_fullStr | Phenome-wide Mendelian randomization study of plasma triglyceride levels and 2600 disease traits |
| title_full_unstemmed | Phenome-wide Mendelian randomization study of plasma triglyceride levels and 2600 disease traits |
| title_short | Phenome-wide Mendelian randomization study of plasma triglyceride levels and 2600 disease traits |
| title_sort | phenome wide mendelian randomization study of plasma triglyceride levels and 2600 disease traits |
| topic | Mendelian randomization triglycerides cardiovascular disease UK Biobank FinnGen lipid metabolism |
| url | https://elifesciences.org/articles/80560 |
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