Studying genetic resilience to improve human health.

Abstract

In 2015, for the first time in three decades, novel lipid-lowering drugs for the treatment of hypercholesterolemia were approved by the FDA in the US and EMA in Europe (US Food and Drug Administration 2015a, US Food and Drug Administration 2015b, European Medicines Agency 2015a, European Medicines Agency 2015b). Proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme encoded by the PCSK9 gene in humans, is the target of these novel therapeutics. In the early 2000s, PCSK9 was found to play a role in cholesterol homeostasis by promoting the degradation of the low-density lipoprotein (LDL) receptor in the liver, reducing its ability to remove LDL from circulation (Maxwell & Breslow, 2004, Park et al., 2004, Benjannet et al., 2004, Maxwell et al., 2005). At the same time, Dr. Helen H. Hobbs and Dr. Jonathan Cohen at UT-Southwestern had been studying people with very high and very low cholesterol. Based on its role in cholesterol metabolism, they sequenced the PCSK9 gene in people with very low cholesterol and found nonsense mutations that caused the PCSK9 enzyme to lose its function (Cohen et al., 2005). “Resilience” to hypercholesterolemia was conferred on individuals harboring loss-of-function mutations in the PCSK9 gene, opening the door for the development of drugs based on this novel mechanism of action. The pursuit of resilience through genome-wide analyses is now underway and will undoubtedly further our understanding of the biology of disease, provide promising therapeutic targets, and potentially improve human health and aging. This article is protected by copyright. All rights reserved.