The biological relevance of PCSK9: when less is better…

Mbikay, Majambu; Chrétien, Michel

doi:10.1139/bcb-2021-0540

Cited by 4 publications

(3 citation statements)

References 94 publications

(110 reference statements)

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“…86 A significant correlation has been found between PCSK9 and glucose metabolism, 87 but studies linking PCSK9 LOF variants to the risk of developing diabetes are conflicting. 88,89 PCSK9 may also be involved in the pathogenesis of fatty liver disease. For example, PCSK9 rs11591147 (p.R46L) LOF has a protective effect on hepatic steatosis, NAFLD/NASH, and fibrosis.…”

Section: Structure and Function Of Pcsk9mentioning

confidence: 99%

“…PCSK9 also binds to CD36 to promote platelet activation and thrombosis and to reduce fatty acid uptake and TG accumulation in tissues 86 . A significant correlation has been found between PCSK9 and glucose metabolism, 87 but studies linking PCSK9 LOF variants to the risk of developing diabetes are conflicting 88,89 . PCSK9 may also be involved in the pathogenesis of fatty liver disease.…”

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

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Drug development advances in human genetics‐based targets

Zhang,

Yu,

et al. 2024

MedComm

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Drug development is a long and costly process, with a high degree of uncertainty from the identification of a drug target to its market launch. Targeted drugs supported by human genetic evidence are expected to enter phase II/III clinical trials or be approved for marketing more quickly, speeding up the drug development process. Currently, genetic data and technologies such as genome‐wide association studies (GWAS), whole‐exome sequencing (WES), and whole‐genome sequencing (WGS) have identified and validated many potential molecular targets associated with diseases. This review describes the structure, molecular biology, and drug development of human genetics‐based validated beneficial loss‐of‐function (LOF) mutation targets (target mutations that reduce disease incidence) over the past decade. The feasibility of eight beneficial LOF mutation targets (PCSK9, ANGPTL3, ASGR1, HSD17B13, KHK, CIDEB, GPR75, and INHBE) as targets for drug discovery is mainly emphasized, and their research prospects and challenges are discussed. In conclusion, we expect that this review will inspire more researchers to use human genetics and genomics to support the discovery of novel therapeutic drugs and the direction of clinical development, which will contribute to the development of new drug discovery and drug repurposing.

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Section: Structure and Function Of Pcsk9mentioning

confidence: 99%

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

Drug development advances in human genetics‐based targets

Zhang,

Yu,

et al. 2024

MedComm

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“…Indeed, Perrone et al reported the prognostic role of hypercholesterolemia in terms of overall survival and non-progression-free survival in patients treated with immune checkpoint inhibitors [49]. Recently, a research focus has been on proprotein convertase subtilisin/kexin-type 9 (PCSK9), a circulating negative regulator of LDL receptors that reduces blood Chol [50]. Genetic mutations responsible for amplification of PCSK9 activity are considered a potential cause of lethal familial hypercholesterolemia.…”

Section: Cholesterol Disorder In Cancermentioning

confidence: 99%

Hypercholesterolemia in Cancer and in Anorexia Nervosa: A Hypothesis for a Crosstalk

Gizzi

Cataldi

Mazzeschi

et al. 2022

IJMS

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The relationship between cholesterol and cancer has been widely demonstrated. Clinical studies have shown changes in blood cholesterol levels in cancer patients. In parallel, basic research studies have shown that cholesterol is involved in the mechanisms of onset and progression of the disease. On the other hand, anorexic patients have high cholesterol levels and a high susceptibility to cancer. In this review, we first present a brief background on the relations among nutrition, eating disorders and cancer. Using several notable examples, we then illustrate the changes in cholesterol in cancer and in anorexia nervosa, providing evidence for their important relationship. Finally, we show a new possible link between cholesterol disorder in cancer and in anorexia nervosa.

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Characterizing the pathogenicity of genetic variants: the consequences of context

Ciesielski,

Sirugo,

Iyengar

et al. 2024

npj Genom. Med.

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Beyond initial discovery of a pathogenic variant, establishing that a variant is recurrently associated with disease is important for understanding clinical impact and disease etiology. Disappointingly, our ability to characterize pathogenicity under varied circumstances is limited. Here we discuss the role of genetic and environmental background and how it affects variant penetrance and outcomes. Specifically, genetic and environmental settings determine penetrance, and we should expect lower penetrance where contexts are diverse. For example, when over 5000 ClinVar pathogenic and loss-of-function variants were assessed in two large biobanks, UK Biobank and BioMe, the mean penetrance was only 7%. This indicates that the participants in the family-based, clinical, and case-control studies that identified these variants were more homogenous and enriched for etiologic co-factors, and the winner’s curse was at play. We also emphasize that the outcome of interest can vary across conditions. The variant that causes hemoglobin S can increase the risk of death from sickling, lower the risk of death from malaria, or increase the risk of kidney disease, depending on the presence of other variants, the endemicity of malaria, and a suite of other factors. Overall, annotation on a single continuum from benign to pathogenic attempts to shoehorn a complex phenomenon into an overly simplistic framework. Variant effects often vary by context, and thus it is critical to assess potential pathogenicity in different settings. There is no panacea or easy fix, but we offer two recommendations for consideration. First, we need to routinely evaluate contexts such as sex and genetic ancestry by conducting stratified analyses and developing methods that can detect heterogenous effects (e.g. female-to-male allele proportion ratios). Second, we need to consistently document what we know about effect modifiers in our annotation databases. These are not the only possible approaches, but they begin to provide means to create robust annotations of pathogenicity.

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The biological relevance of PCSK9: when less is better…

Cited by 4 publications

References 94 publications

Drug development advances in human genetics‐based targets

Drug development advances in human genetics‐based targets

Hypercholesterolemia in Cancer and in Anorexia Nervosa: A Hypothesis for a Crosstalk

Characterizing the pathogenicity of genetic variants: the consequences of context

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