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March 10, 2016ViewOpen Access

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

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Why the study?

Does the SCARB1 P376L loss-of-function variant increase HDL-C levels and the risk of coronary heart disease?

Population

328 individuals with extremely high plasma HDL-C levels, large population-based cohorts, and preclinical…

Comparison

Presence of the SCARB1 P376L loss-of-function… vs Non-carriers of the SCARB1 P376L variant.

Design

Cohort

Authors

PZPaolo ZanoniUniversity of ZurichSKSumeet A. KhetarpalHarvard UniversityDLDaniel B. LarachVanderbilt University

Discussion

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Overview

P376L carriers may face higher CHD risk despite elevated HDL-C; challenges HDL-C protective role and leaves causality open.

Key Points

  • To determine the role of the primary high-density lipoprotein receptor, scavenger receptor BI (SR-BI encoded by SCARB1), in human HDL metabolism and coronary heart disease risk.
  • Targeted sequencing of coding regions across lipid-modifying genes was conducted in 328 individuals with extremely high plasma HDL cholesterol levels.
  • Posttranslational processing and selective HDL cholesterol uptake of the identified SCARB1 P376L variant were evaluated in transfected cells, subject-derived induced pluripotent stem cell hepatocytes, and mouse models.
  • Genotype-phenotype associations between heterozygous P376L carrier status, circulating lipid levels, and coronary heart disease were evaluated in large population cohorts.
  • A homozygous loss-of-function P376L variant in SCARB1 impaired posttranslational receptor processing and abrogated selective HDL cholesterol uptake across cellular and animal models.
  • Heterozygous carriers of the P376L variant exhibited significantly increased plasma HDL cholesterol levels alongside a significantly increased risk of coronary heart disease (odds ratio = 1.79).

Structured PICO

Does the SCARB1 P376L loss-of-function variant increase HDL-C levels and the risk of coronary heart disease?

P
Population
328 individuals with extremely high plasma HDL-C levels, large population-based cohorts, and preclinical models (transfected cells, iPSC-derived hepatocyte-like cells, mice).
I
Intervention
Presence of the SCARB1 P376L loss-of-function variant.
C
Comparator
Non-carriers of the SCARB1 P376L variant.
O
Outcome
Plasma HDL-C levels and risk of coronary heart disease (CHD).hard clinical

The SCARB1 P376L variant paradoxically increases both HDL-C levels and the risk of coronary heart disease, challenging the assumption that higher HDL-C is always cardioprotective.

Cite This Study

Zanoni et al. (2016) studied this question.

synapsesocial.com/papers/6a7e14d7693a82ae6737ec0bhttps://doi.org/10.1126/science.aad3517
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Also Consider

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  4. 4Highly Efficient Generation of Human Hepatocyte–Like Cells From Induced Pluripotent Stem Cells2009 · 1,303 citations
  5. 5Relationship between Expression Levels and Atherogenesis in Scavenger Receptor Class B, Type I Transgenics2000 · 166 citations