Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study
- PMID: 25770315
- PMCID: PMC6101243
- DOI: 10.1016/j.jacc.2015.02.020
Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study
Abstract
Background: Considerable uncertainty exists as to whether lowering low-density lipoprotein cholesterol (LDL-C) by inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) receptor with ezetimibe, either alone or in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (statin), will reduce the risk of coronary heart disease (CHD).
Objectives: This study evaluated the effect of naturally random allocation to lower LDL-C mediated by polymorphisms in the NPC1L1 gene (target of ezetimibe), the HMGCR gene (target of statins), or both (target of combination therapy) on the risk of CHD.
Methods: We constructed NPC1L1 and HMGCR genetic LDL-C scores to naturally randomize participants into 4 groups: reference, lower LDL-C mediated by NPC1L1 polymorphisms, lower LDL-C mediated by HMGCR polymorphisms, or lower LDL-C mediated by polymorphisms in both NPC1L1 and HMGCR. We compared the risk of CHD (fatal or nonfatal myocardial infarction) among each group using a 2 × 2 factorial mendelian randomization study design.
Results: A total of 108,376 persons (10,464 CHD events) from 14 studies were included. There were no significant differences in baseline characteristics among the 4 groups, thus confirming that allocation was random. Compared to the reference group, the NPC1L1 group had 2.4 mg/dl lower LDL-C and 4.8% lower risk of CHD (odds ratio [OR]: 0.952, 95% confidence interval [CI]: 0.920 to 0.985); whereas the HMGCR group had 2.9 mg/dl lower LDL-C and a similar 5.3% lower risk of CHD (OR: 0.947, 95% CI: 0.909 to 0.986). The group with lower LDL-C mediated by both NPC1L1 and HMGCR polymorphisms had 5.8 mg/dl additively lower LDL-C and a 10.8% log-linearly additive lower risk of CHD (OR: 0.892, 95% CI: 0.854 to 0.932).
Conclusions: The effect of lower LDL-C on the risk of CHD mediated by polymorphisms in NPC1L1, HMGCR, or both is approximately the same per unit lower LDL-C and log-linearly proportional to the absolute exposure to lower LDL-C.
Keywords: PCSK9; ezetimibe; genetic association; statins.
Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Figures
![FIGURE 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6101243/bin/nihms984847f1.gif)
![FIGURE 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6101243/bin/nihms984847f2.gif)
![FIGURE 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6101243/bin/nihms984847f3.gif)
![FIGURE 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6101243/bin/nihms984847f4.gif)
![CENTRAL ILLUSTRATION](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6101243/bin/nihms984847f5.gif)
Comment in
-
Developing medicines that mimic the natural successes of the human genome: lessons from NPC1L1, HMGCR, PCSK9, APOC3, and CETP.J Am Coll Cardiol. 2015 Apr 21;65(15):1562-6. doi: 10.1016/j.jacc.2015.02.049. J Am Coll Cardiol. 2015. PMID: 25881938 No abstract available.
-
Genetic Variation in NPC1L1 and Risk of Gallstone Disease.J Am Coll Cardiol. 2015 Sep 1;66(9):1086. doi: 10.1016/j.jacc.2015.05.076. J Am Coll Cardiol. 2015. PMID: 26314540 No abstract available.
-
Reply: Genetic Variation in NPC1L1 and Risk of Gallstone Disease.J Am Coll Cardiol. 2015 Sep 1;66(9):1086-8. doi: 10.1016/j.jacc.2015.06.1311. J Am Coll Cardiol. 2015. PMID: 26314541 No abstract available.
Similar articles
-
Association Between Genetically Proxied Inhibition of HMG-CoA Reductase and Epithelial Ovarian Cancer.JAMA. 2020 Feb 18;323(7):646-655. doi: 10.1001/jama.2020.0150. JAMA. 2020. PMID: 32068819 Free PMC article.
-
Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis.JAMA. 2016 Oct 4;316(13):1383-1391. doi: 10.1001/jama.2016.14568. JAMA. 2016. PMID: 27701660 Free PMC article.
-
Mendelian randomization studies: using naturally randomized genetic data to fill evidence gaps.Curr Opin Lipidol. 2015 Dec;26(6):566-71. doi: 10.1097/MOL.0000000000000247. Curr Opin Lipidol. 2015. PMID: 26780009 Review.
-
The effects of age and gender on the relationship between HMGCR promoter-911 SNP (rs33761740) and serum lipids in patients with coronary heart disease.Gene. 2013 Oct 10;528(2):93-8. doi: 10.1016/j.gene.2013.07.056. Epub 2013 Aug 8. Gene. 2013. PMID: 23933271
-
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis.J Am Coll Cardiol. 2012 Dec 25;60(25):2631-9. doi: 10.1016/j.jacc.2012.09.017. Epub 2012 Oct 17. J Am Coll Cardiol. 2012. PMID: 23083789 Review.
Cited by
-
Effects of genetically proxied lipid-lowering drugs on acute myocardial infarction: a drug-target mendelian randomization study.Lipids Health Dis. 2024 Jun 3;23(1):163. doi: 10.1186/s12944-024-02133-w. Lipids Health Dis. 2024. PMID: 38831433 Free PMC article.
-
Causal association of plasma circulating metabolites with nephritis: a Mendelian randomization study.Front Nutr. 2024 May 3;11:1364841. doi: 10.3389/fnut.2024.1364841. eCollection 2024. Front Nutr. 2024. PMID: 38765814 Free PMC article.
-
Evaluating the causal association between bronchiectasis and different types of inflammatory bowel disease: a two-sample Mendelian randomization study.Front Immunol. 2024 Apr 4;15:1365108. doi: 10.3389/fimmu.2024.1365108. eCollection 2024. Front Immunol. 2024. PMID: 38638444 Free PMC article.
-
Pharmacogenomics-based systematic review of coronary artery disease based on personalized medicine procedure.Heliyon. 2024 Mar 29;10(7):e28983. doi: 10.1016/j.heliyon.2024.e28983. eCollection 2024 Apr 15. Heliyon. 2024. PMID: 38601677 Free PMC article.
-
Causal association between lipoproteins and risk of coronary artery disease-a systematic review and meta-analysis of Mendelian randomization studies.Clin Res Cardiol. 2024 Feb 26. doi: 10.1007/s00392-024-02420-7. Online ahead of print. Clin Res Cardiol. 2024. PMID: 38407584 Review.
References
-
- Prospective Studies Collaboration. Lewington S, Whitlock G, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007;370:1829–39. - PubMed
-
- Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012;60:2631–9. - PubMed
-
- AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous