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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
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
_version_ 1785020697123225600
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
work_keys_str_mv AT parkjoshuak phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits
AT bafnashantanu phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits
AT forrestiains phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits
AT duffyaine phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits
AT marquezlunacarla phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits
AT petrazzinibeno phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits
AT vyhamy phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits
AT jordandanielm phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits
AT verbanckmarie phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits
AT narulajagat phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits
AT rosensonroberts phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits
AT rocheleaughislain phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits
AT doron phenomewidemendelianrandomizationstudyofplasmatriglyceridelevelsand2600diseasetraits