Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes

Brian Ference, Jennifer Robinson, Robert Brook, Alberico L. Catapano, John Chapman, David Neff, Szilard Voros, Robert Giugliano, George Davey Smith, Sergio Fazio, Marc S Sabatine

Research output: Contribution to journalArticle (Academic Journal)peer-review

452 Citations (Scopus)
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Background: Pharmacologic inhibitors of the proprotein convertase subtilisin-kexin type 9 (PCSK9) are in clinical trials for the treatment of coronary artery disease. The effect of lowering low-density lipoprotein cholesterol (LDL-C) by inhibiting PCSK9 on risk of cardiovascular events and risk of diabetes is unknown

Methods: We used genetic scores consisting of independently inherited variants in the PCSK9 and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) genes, respectively, as instruments to randomly allocate 112,772 persons (14,120 cardiovascular events; 10,635 cases of diabetes) from 14 studies to higher or lower LDL-C levels. (HMGCR is the target of statins.) We compared the effect of lower LDL-C mediated by variants in PCSK9, HMGCR or both on the risk of cardiovascular events and diabetes.
Results: Variants in PCSK9 (OR:0.811; 95%-CI:0.738-0.885) and HMGCR (OR:0.809; 95%-CI:0.722-0.903) were associated with nearly identical protective effects on the risk of cardiovascular events per 10 mg/dL lower LDL-C. Variants in PCSK9 (OR:1.112; 95%-CI:1.049-1.189) and HMGCR (OR:1.127; 95%-CI:1.060-1.198) also had very similar effects on the risk of diabetes per 10 mg/dL lower LDL-C. The increased risk of diabetes was limited to persons with impaired fasting glucose for both scores, and in magnitude, was less than (approximately 60% of) the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on both cardiovascular events and diabetes.
Conclusions: Variants in PCSK9 and HMGCR are associated with approximately the same effect on the risk of cardiovascular events and diabetes per unit lower LDL-C. These effects are independent and additive.
Original languageEnglish
Pages (from-to)2144-2153
Number of pages9
JournalNew England Journal of Medicine
Issue number22
Publication statusPublished - 1 Dec 2016


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