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Original Investigation
September 12, 2017

Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk

Author Affiliations
  • 1Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit, Michigan
  • 2Institute for Advanced Studies, University of Bristol, Bristol, United Kingdom
  • 3Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  • 4Irving Institute for Clinical and Translational Research, Columbia University College of Physicians and Surgeons, New York, New York
  • 5National Institute for Health and Medical Research (INSERM), Pitie-Salpetriere University Hospital, Paris, France
  • 6South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia
  • 7Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom
  • 8Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
  • 9Department of Cardiology, University of Leipzig, Leipzig, Germany
  • 10Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor
  • 11MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 12National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom
  • 13Wellcome Trust Sanger Institute, Hinxton, United Kingdom
  • 14MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
  • 15Department of Pharmacological and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milano, Italy
  • 16Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA. 2017;318(10):947-956. doi:10.1001/jama.2017.11467
Key Points

Question  Does the clinical benefit of lowering low-density lipoprotein cholesterol (LDL-C) levels depend on how LDL-C is lowered?

Findings  In a mendelian randomization analysis of an individual-participant data meta-analysis that included 102 837 participants, combined exposure to variants related to the action of CETP inhibitors and statins was significantly associated with discordant reductions in LDL-C and apolipoprotein B levels; the corresponding association with cardiovascular events was proportional to the attenuated reduction in apolipoprotein B but less than expected per unit change in LDL-C.

Meaning  The clinical benefit of lowering LDL-C may be related to the corresponding absolute reduction in apolipoprotein B-containing lipoprotein particles and therefore may depend on how LDL-C is lowered.

Abstract

Importance  Some cholesteryl ester transfer protein (CETP) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered.

Objective  To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene.

Design, Setting, and Participants  Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189 539 participants from 48 studies conducted between 2011 and 2015.

Exposures  Differences in mean high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median.

Main Outcomes and Measures  Odds ratio (OR) for major cardiovascular events.

Results  The primary analysis included 102 837 participants (mean age, 59.9 years; 58% women) who experienced 13 821 major cardiovascular events. The validation analyses included 189 539 participants (mean age, 58.5 years; 39% women) with 62 240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955-1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P = .79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P < .001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB.

Conclusions and Relevance  Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles.

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