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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10079290/ https://www.ncbi.nlm.nih.gov/pubmed/36988189 http://dx.doi.org/10.7554/eLife.80560 |
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author | Park, Joshua K Bafna, Shantanu Forrest, Iain S Duffy, Áine Marquez-Luna, Carla Petrazzini, Ben O Vy, Ha My Jordan, Daniel M Verbanck, Marie Narula, Jagat Rosenson, Robert S Rocheleau, Ghislain Do, Ron |
author_facet | Park, Joshua K Bafna, Shantanu Forrest, Iain S Duffy, Áine Marquez-Luna, Carla Petrazzini, Ben O Vy, Ha My Jordan, Daniel M Verbanck, Marie Narula, Jagat Rosenson, Robert S Rocheleau, Ghislain Do, Ron |
author_sort | Park, Joshua K |
collection | PubMed |
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). |
format | Online Article Text |
id | pubmed-10079290 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-100792902023-04-07 Phenome-wide Mendelian randomization study of plasma triglyceride levels and 2600 disease traits Park, Joshua K Bafna, Shantanu Forrest, Iain S Duffy, Áine Marquez-Luna, Carla Petrazzini, Ben O Vy, Ha My Jordan, Daniel M Verbanck, Marie Narula, Jagat Rosenson, Robert S Rocheleau, Ghislain Do, Ron eLife Genetics and Genomics 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). eLife Sciences Publications, Ltd 2023-03-29 /pmc/articles/PMC10079290/ /pubmed/36988189 http://dx.doi.org/10.7554/eLife.80560 Text en © 2023, Park, Bafna et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Genetics and Genomics Park, Joshua K Bafna, Shantanu Forrest, Iain S Duffy, Áine Marquez-Luna, Carla Petrazzini, Ben O Vy, Ha My Jordan, Daniel M Verbanck, Marie Narula, Jagat Rosenson, Robert S Rocheleau, Ghislain Do, Ron Phenome-wide Mendelian randomization study of plasma triglyceride levels and 2600 disease traits |
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 | Genetics and Genomics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10079290/ https://www.ncbi.nlm.nih.gov/pubmed/36988189 http://dx.doi.org/10.7554/eLife.80560 |
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