Lipidology

Recent advances in ABCG5 and ABCG8 variants Purpose of review In this review, we summarize the genetics and mechanisms of sitosterolemia and sterol trafficking, and provide an update on the understanding of the prevalence of ABCG5 and ABCG8 variants and their role in human disease. Recent findings Defects in ABCG5/G8 result in the accumulation of xenosterols. It had been previously thought that near total LoF of one of the proteins was required to cause pathology. However, recently there was the first report of a patient with Sitosterolemia who was heterozygous for mutations in both genes. Moreover, large population studies have demonstrated the even simple heterozygous carriers are associated with altered lipid profiles and cardiovascular risk. Broader screening has added to the rapidly growing list of gene variants indicating that the prevalence of ABCG5/G8 variants is higher than previous thought, especially in patients with hypercholesterolemia. Summary These findings support a strategy of measuring xenosterol levels in patients with hypercholesterolemia to screen for ABCG5/G8 variants, and then tailoring treatment with a sterol absorption inhibitor, like ezetimibe, where indicated. Xenosterol trafficking affects remnant clearance and maybe pathogenically linked to the increased risk of atherosclerosis. Correspondence to Shailendra B. Patel, BM, ChB, DPhil, University of Cincinnati College of Medicine, Division of Endocrinology, Diabetes and Metabolism, 231 Albert Sabin Way, MSB 7168, Cincinnati, Ohio 45267, USA. Tel: +513 588 4444; e-mail: sbpatel@uc.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Polygenic scores for dyslipidemia: the emerging genomic model of plasma lipoprotein trait inheritance Purpose of review Contemporary polygenic scores, which summarize the cumulative contribution of millions of common single-nucleotide variants to a phenotypic trait, can have effects comparable to monogenic mutations. This review focuses on the emerging use of 'genome-wide' polygenic scores for plasma lipoproteins to define the etiology of clinical dyslipidemia, modify the severity of monogenic disease, and inform therapeutic options. Recent findings Polygenic scores for low-density lipoprotein cholesterol (LDL-C), triglycerides, and high-density lipoprotein cholesterol are associated with severe hypercholesterolemia, hypertriglyceridemia, or hypoalphalipoproteinemia, respectively. These polygenic scores for LDL-C or triglycerides associate with risk of incident coronary artery disease (CAD) independent of polygenic scores designed specifically for CAD and may identify individuals that benefit most from lipid-lowering medication. Additionally, the severity of hypercholesterolemia and CAD associated with familial hypercholesterolemia—a common monogenic disorder—is modified by these polygenic factors. The current focus of polygenic scores for dyslipidemia is to design predictive polygenic scores for diverse populations and determining how these polygenic scores could be implemented and standardized for use in the clinic. Summary Polygenic scores have shown early promise for the management of dyslipidemias, but several challenges need to be addressed before widespread clinical implementation to ensure that potential benefits are robust and reproducible, equitable, and cost-effective. Correspondence to Liam R. Brunham, MSc, Centre for Heart Lung Innovation, Room 166-1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6. Tel: +604 682 2344 x63929; fax: +604 806 9274; e-mail: liam.brunham@ubc.ca Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Apolipoprotein genetic variants and hereditary amyloidosis Purpose of review Amyloidosis is caused by the deposition of misfolded aggregated proteins called amyloid fibrils that in turn cause organ damage and dysfunction. In this review, we aim to summarize the genetic, clinical, and histological findings In apolipoprotein-associated hereditary amyloidosis and the growing list of mutations and apolipoproteins associated with this disorder. We also endeavor to summarize the features of apolipoproteins that have led them to be overrepresented among amyloidogenic proteins. Additionally, we aim to distinguish mutations leading to amyloidosis from those that lead to inherited dyslipidemias. Recent findings Apolipoproteins are becoming increasingly recognized in hereditary forms of amyloidosis. Although mutations in APOA1 and APOA2 have been well established in hereditary amyloidosis, new mutations are still being detected, providing further insight into the pathogenesis of apolipoprotein-related amyloidosis. Furthermore, amyloidogenic mutations in APOC2 and APOC3 have more recently been described. Although no hereditary mutations in APOE or APOA4 have been described to date, both protein products are amyloidogenic and frequently found within amyloid deposits. Summary Understanding the underlying apolipoprotein mutations that contribute to hereditary amyloidosis may help improve understanding of this rare but serious disorder and could open the door for targeted therapies and the potential development of new treatment options. Correspondence to Amanda J. Berberich, MD, FRCPC, Cert. Endo, Department of Medicine, Saint Joseph's Healthcare London, 268 Grosvenor St. London, Ontario, Canada, N6A 4V2. e-mail: Amanda.Berberich@sjhc.london.on.ca Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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