Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease · SciRah

^aDepartments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
^bINSERM UMR 1166 ICAN, Université Pierre et Marie Curie Paris 6, Hôpital de la Pitié, Paris, France
^cCardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
^dCentre for Non-Communicable Diseases, Karachi, Pakistan
^eDepartment of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
^fDepartment of Cardiology, Leiden University Medical Center, Leiden, Netherlands
^gDepartment of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands
^hThe Interuniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands
ⁱWellcome Trust Sanger Institute, Genome Campus, Hinxton, UK
^jInstitute of Cardiovascular and Medical Sciences, British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
^kRobertson Center for Biostatistics, University of Glasgow, Glasgow, UK
^lGlasgow Clinical Research Facility, Western Infirmary, Glasgow, UK
^mNational Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Dhaka, Bangladesh
ⁿInternational Centre for Diarrhoeal Disease Research, Mohakhali, Dhaka, Bangladesh
^oCenter for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
^pInstitute for Integrative and Experimental Genomics, University of Lübeck, Lübeck 23562, Germany
^qDepartment of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
^rCopenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
^sDepartment of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark
^tDepartment of Health, National Institute for Health and Welfare, Helsinki, Finland
^uDepartment of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
^vInstitute of Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland
✉Corresponding author

Abstract

A scavenger that protects the heart Coronary heart disease is a tale of two forms of plasma cholesterol. In contrast to the well-established effects of “bad” cholesterol (LDL-C), the role of “good” cholesterol (HDL-C) is mysterious. Elevated HDL-C correlates with a lower risk of heart disease, yet drugs that raise HDL-C levels do not reduce risk. Zanoni et al. found that some people with exceptionally high levels of HDL-C carry a rare sequence variant in the gene encoding the major HDL-C receptor, scavenger receptor BI. This variant destroys the receptor's ability to take up HDL-C. Interestingly, people with this variant have a higher risk of heart disease despite having high levels of HDL-C. Science, this issue p. 1166 A human genetics study sheds light on how HDL (good) cholesterol protects against cardiovascular disease. Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

TL;DRA human genetics study sheds light on how HDL (good) cholesterol protects against cardiovascular disease by identifying a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI (Semantic Scholar)

Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

Abstract

Plain-language summary

Discussion