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[Preprint]. 2025 Sep 9:2025.03.07.25323588.
doi: 10.1101/2025.03.07.25323588.

Using Mendelian randomization to assess long-term pleiotropic effects of potential novel triglyceride-lowering medications

Elliot Outland  1 , Yi Xin  1   2 , Alyson L Dickson  3 , Sergio Mundo  1 , Ran Tao  4 , Xue Zhong  3   5 , Gul Karakoc  3 , Sevim Serley  3 , Lan Jiang  3 , Nancy J Cox  3   5 , Wei-Qi Wei  1   2 , C Michael Stein  3   6 , QiPing Feng  1   3   5
Affiliations

Using Mendelian randomization to assess long-term pleiotropic effects of potential novel triglyceride-lowering medications

Elliot Outland et al. medRxiv. .

Abstract

Background: Drugs targeting triglyceride (TG)-associated genes have the potential to improve cardiovascular outcomes for patients with elevated TG levels. However, we know little regarding the potential additional benefits or deleterious effects of such targeting. Mendelian randomization and PheWAS approaches offer the opportunity to examine such effects.

Methods: In ancestry-specific cohorts of patients of European ancestry (EA) and patients of African ancestry (AA), we tested associations between measured TG levels and 11 functional variants previously associated with TG levels; for validated variants, we conducted PheWAS for previously reported potential effects and unspecified other potential effects. We replicated results in All of Us (AoU).

Findings: In the BioVU EA cohort (n=63,094), 9 of 10 validated SNPs had suggestive or significant associations with lipid and cardiovascular phenotypes. Results were largely consistent in AoU participants of EA (n=97,545). In the BioVU AA cohort (n=12,515) and AoU AA cohort (n=31,710), results were more limited; only 1 of 6 validated SNPs was significantly associated with a lipid or cardiovascular phenotype in either BioVU or AoU, and no suggestive or significant associations were consistent across both cohorts. We detected few secondary effects in either EA or AA BioVU patients, and none were replicated.

Interpretation: These results suggest that there may be limited additional benefits, but few deleterious effects, associated with targeting known TG-associated genes. However, these targets may not be as effective for mitigating cardiovascular risk among patients of AA.

Keywords: Triglycerides; drug side effects; mendelian randomization; phewas.

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Conflict of interest statement

Drs. Mundo and Zhong reported receiving support from National Institutes of Health (NIH) grants during the conduct of the study. Ms. Karakoc reported receiving support from the Vanderbilt Physician Scientist Development Award during the conduct of the study. Dr. Cox reported receiving an honorarium from the Endocrine Society during the conduct of the study. Dr. Stein reported receiving support from NIH grants, book royalties, and an honorarium for writing a textbook chapter during the conduct of the study. The remaining authors declared no competing interests for this work.

Figures

Figure 1.
Figure 1.. Study design.
TG = triglyceride. MR = Mendelian randomization. GWAS = genome-wide association study. MAF = minor allele frequency. EA = European ancestry. AA = African ancestry. PheWAS = phenome-wide association study. BioVU = Vanderbilt University Medical Center biobank. AoU = All of Us Research Program.
Figure 2.
Figure 2.. Significant associations between prespecified phenotypes and genetic variants in the BioVU European ancestry cohort, with All of Us replication indicated.
∘ = replicated in All of Us. Dark red = p<3.15×10−5 (0.05/1587) [logistic regression]; highly significantly increased risk associated with TG-increasing allele (full PheWAS Bonferroni-corrected). Medium red = p<0.0024 (0.05/21) [logistic regression]; significantly increased risk associated with TG-increasing allele (Bonferroni-corrected). Light red = p<0.05 [logistic regression]; suggestive significance of increased risk associated with TG-increasing allele. Light blue = p<0.05 [logistic regression]; suggestive significance of decreased risk associated with TG-increasing allele.
Figure 3.
Figure 3.. Significant associations between prespecified phenotypes and genetic variants in the BioVU African ancestry cohort, with All of Us replication indicated.
∘ = replicated in All of Us. Dark red = p<4.69×10−5 (0.05/1065) [logistic regression]; highly significantly increased risk associated with TG-increasing allele (full PheWAS Bonferroni-corrected). Medium red = p<0.0024 (0.05/21) [logistic regression]; significantly increased risk associated with TG-increasing allele (Bonferroni-corrected). Light red = p<0.05 [logistic regression]; suggestive significance of increased risk associated with TG-increasing allele. Light blue = p<0.05 [logistic regression; suggestive significance of decreased risk associated with TG-increasing allele.
See this image and copyright information in PMC

References

    1. The top 10 causes of death, https://test-cms.who.int/news-room/fact-sheets/detail/the-top-10-causes-... (accessed Aug 1, 2025).
    1. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and Cardiovascular Disease A Scientific Statement From the American Heart Association. Circulation 2011; 123: 2292–333. - PubMed
    1. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996; 3: 213–9. - PubMed
    1. Nichols GA, Philip S, Reynolds K, Granowitz CB, Fazio S. Increased Cardiovascular Risk in Hypertriglyceridemic Patients With Statin-Controlled LDL Cholesterol. The Journal of Clinical Endocrinology & Metabolism 2018; 103: 3019–27. - PubMed
    1. Mszar R, Bart S, Sakers A, Soffer D, Karalis DG. Current and Emerging Therapies for Atherosclerotic Cardiovascular Disease Risk Reduction in Hypertriglyceridemia. Journal of Clinical Medicine 2023; 12: 1382. - PMC - PubMed

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