Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in <i>PCSK9</i>

Schmidt, Amand F.; Holmes, Michael V.; Preiss, David; Swerdlow, Daniel I.; Denaxas, Spiros; Hemingway, Harry; Asselbergs, Folkert W.; Patel, Riyaz; Keating, Brendan J.; Sattar, Naveed; Houlston, Richard S.; Casas, JP; Hingorani, Aroon D.

doi:10.1101/329052

Cited by 11 publications

(13 citation statements)

References 32 publications

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“…Although there is no evidence on the effects of PCSK9 inhibitors in cancerous conditions, recent studies have shown that PCSK9 variants with LDL-lowering mutations mimicking PCSK9 inhibitors are associated with a lower risk and occurrence of cancer [36,54]. Such inconsistency between results of our study and others is probably due to different modalities of PCSK9 inhibition.…”

Section: Discussioncontrasting

confidence: 94%

Effects of immunisation against PCSK9 in mice bearing melanoma

Momtazi‐Borojeni¹,

Nik²,

Jaafari³

et al. 2020

aoms

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Introduction: Inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) is an established modality for the treatment of hypercholesterolaemia. However, the impact of PCSK9 inhibition in other situations such as cancer remains largely unknown. The current study was conducted to study the effects of PCSK9 inhibition on cancer endpoints in mice bearing melanoma. Material and methods: To generate antiPCSK9 antibody in vivo, a nanoliposomal antiPCSK9 vaccine adsorbed to 0.4% Alum adjuvant was subcutaneously injected in C57BL/6 mice four times with biweekly intervals. Two weeks after the last immunisation, mice were subcutaneously inoculated with B16F0 melanoma cells. After a tumour mass was palpable (approximately 10 mm 3), the mice were randomly divided into four groups and subjected to different treatment protocols: (1) PBS (untreated control), (2) vaccine group, (3) the combination of vaccine and a single dose of liposomal doxorubicin (Doxil ®), and (4) liposomal doxorubicin (positive control) group. To determine therapeutic efficacy, mouse body weight, tumour size, and survival were monitored every three days for 36 days. Results: The nanoliposomal antiPCSK9 vaccine was found to efficiently induce specific antibodies against PCSK9 in C57BL/6 mice, thereby reducing plasma levels and function of PCSK9. Tumour volumes in the vaccinated group were not significantly different from those in the liposomal doxorubicin, combination, and control groups. The time to reach endpoint (TTE) values of the vaccine (28 ±5 days), combination (30 ±6 days), liposomal doxorubicin (34 ±2 days), and control (31 ±2 days) groups were not significantly different, either. Furthermore, the tumour growth delay (TGD) values of the vaccine (-11.5 ±15.4%), liposomal doxorubicin (7.75 ±6.5%), combination (-6 ±20.77%), and control (0 ±7.5) groups were not significantly different. Finally, there was no significant difference between the median survival time and lifespan of the vaccinated versus other tested groups.

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Section: Discussioncontrasting

confidence: 94%

Effects of immunisation against PCSK9 in mice bearing melanoma

Momtazi‐Borojeni¹,

Nik²,

Jaafari³

et al. 2020

aoms

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“…The moderate anti-tumor effect of the tested anti-PCSK9 vaccine is underpinned by the recent Mendelian randomization study which revealed that LDL-lowering mutations of PCSK9 mimicking PCSK9 inhibitors were correlated with a lower risk of breast cancer occurrence, while PCSK9 with LDL-raising mutations has a causal correlation with a higher risk of breast cancer [26]. It is further supported by another human study analyzing a phenome-wide association of LDL-lowering genetic variants in the PCSK9 locus mimicking PCSK9 inhibitors, showing that these PCSK9 variants do not increase the risk of cancer [39]. However, a prospective, population-based cohort study showed that there is no association between LDL-lowering PCSK9 polymorphisms and the risk of cancer [25].…”

Section: Discussionmentioning

confidence: 79%

Potential anti-tumor effect of a nanoliposomal antiPCSK9 vaccine in mice bearing colorectal cancer

Momtazi‐Borojeni¹,

Nik²,

Jaafari³

et al. 2019

aoms

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Introduction: Inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) is an effective therapeutic tool for lowering low-density lipoprotein cholesterol (LDL-C). There is no available evidence on the efficacy and safety of PCSK9 inhibitors in non-cardiovascular diseases, particularly cancer. The present study aimed to evaluate the effect of PCSK9 inhibition on cancer endpoints in mice bearing colon carcinoma, using a nanoliposomal antiPCSK9 vaccine. Material and methods: The prepared nanoliposomal antiPCSK9 vaccine was subcutaneously inoculated in BALB/c mice four times with a biweekly interval. Two weeks after the last booster, the vaccinated and unvaccinated mice were subcutaneously inoculated with CT26 colon cancer cells into the right flank. After the tumor mass became palpable, the mice were randomly divided into three groups: (1) PBS (untreated control), (2) vaccine group, and (3) pegylated liposomal doxorubicin (PLD; positive control) group. Body weight, tumor size and survival of mice were monitored for 50 days. Results: The nanoliposomal antiPCSK9 vaccine could efficiently provoke specific antibodies against PCSK9 in BALB/c mice and thereby reduced the plasma level and function of PCSK9. Tumor volume was 77% and 87.7% lower (p < 0.0001) in the vaccinated mice when compared with Doxil (liposomal doxorubicin) and control mice, respectively. Tumor size analysis showed that time to reach the endpoint of the vaccine group (47 ±11 days) was slightly but not significantly higher than PLD (46 ±2.6 days) and the control (43 ±12 days) groups. The tumor growth rates in the vaccine and PLD groups were reduced by 9.3% and 7.3, respectively, when compared with the control group. The vaccinated mice survived slightly but not significantly longer than PLD and the control mice. The median survival of the vaccine, PLD and control groups were 51, 45, and 41 days, respectively. The vaccinated mice's life was prolonged by 24.4% as compared with the control mice, while it was increased by 9.8% in the PLD group. Preparation of immunogenic peptide The Immunogenic Fused PCSK9-Tetanus (IFPT) peptide with a purity grade of > 95% was synthe-Conclusions: Our results revealed that PCSK9 inhibition not only exerted no harmful effects but also could moderately inhibit tumor growth, and improve lifespan and survival in mice bearing colon cancer.

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“…Understanding which proteins influence which diseases is a fundamental problem in biomedical science since proteins are the major biological effector molecules. Proteins are also the targets of most medicines, so interest has emerged in the use of MR approaches to identify and validate drug targets [21][22][23][24] . Moreover, recent technological developments enable measurement of hundreds or thousands of proteins on an -omics scale in a single biological sample 8 .…”

Section: Introductionmentioning

confidence: 99%

Genetic drug target validation using Mendelian randomization

Schmidt

Finan

Gordillo-Marañón

et al. 2019

Preprint

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Mendelian randomisation analysis has emerged as an important tool to elucidate the causal relevance of a range of environmental and biological risk factors for human disease. However, inference on cause is undermined if the genetic variants used to instrument a risk factor of interest also associate with other traits that open alternative pathways to the disease (horizontal pleiotropy). We show how the 'no horizontal pleiotropy assumption' in MR analysis is strengthened when proteins are the risk factors of interest. Proteins are the proximal effectors of biological processes encoded in the genome, and are becoming assayable on an -omics scale.Moreover, proteins are the targets of most medicines, so Mendelian randomization (MR) studies of drug targets are becoming a fundamental tool in drug development. To enable such studies we introduce a formal mathematical framework that contrasts MR analysis of proteins with that of risk factors located more distally in the causal chain from gene to disease. Finally, we illustrate key model decisions and introduce an analytical framework for maximizing power and elucidating the robustness of drug target MR analyses.

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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Abstract: Background

Cited by 11 publications

References 32 publications

Effects of immunisation against PCSK9 in mice bearing melanoma

Effects of immunisation against PCSK9 in mice bearing melanoma

Potential anti-tumor effect of a nanoliposomal antiPCSK9 vaccine in mice bearing colorectal cancer

Genetic drug target validation using Mendelian randomization

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