Academic literature on the topic 'PCSK1'
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Journal articles on the topic "PCSK1":
1
Parvaz, Najmeh, and Zahra Jalali. "Molecular evolution of PCSK family: Analysis of natural selection rate and gene loss." PLOS ONE 16, no. 10 (October 28, 2021): e0259085. http://dx.doi.org/10.1371/journal.pone.0259085.
Abstract:
Proprotein convertases subtilisin kexins are serine endoproteases, playing critical roles in the biological functions, including lipid, glucose, and bile acid metabolism, as well as cell proliferation, migration, and metastasis. Experimental studies have demonstrated the physiological functions of PCSKs and their association with diseases; however, studies on the evolutionary history and diversification of these proteins are missing. In the present research, a bioinformatics study was conducted on the molecular evolution of several PCSKs family members and gene loss events across placental mammalian. In order to detect evolutionary constraints and positive selection, the CodeML program of the PAML package was used. The results showed the positive selection to occur in PCSK1, PCSK3, PCSK5, and PCSK7. A decelerated rate of evolution was observed in PCSK7, PCSK3, and MBTPS1 in Carnivores compared to the rest of phylogeny, and an accelerated evolution of PCSK1, PCSK7, and MBTPS1 in Muridae family of rodents was found. Additionally, our results indicated pcsk9 gene loss in 12 species comprising Carnivores and bats (Chiroptera). Future studies are required to evaluate the functional relevance and selective evolutionary advantages associated with these modifications in PCSK proteins during evolution.
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Gagnon, Jeffrey, Janice Mayne, Majambu Mbikay, John Woulfe, and Michel Chrétien. "Expression of PCSK1 (PC1/3), PCSK2 (PC2) and PCSK3 (furin) in mouse small intestine." Regulatory Peptides 152, no. 1-3 (January 2009): 54–60. http://dx.doi.org/10.1016/j.regpep.2008.07.006.
3
Xu, Xu, Egor Volcotrub, and Svetlana B. Ten. "LBSUN131 Leptin Level, BMI And Genetics In Early Onset Obesity." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A5. http://dx.doi.org/10.1210/jendso/bvac150.009.
Abstract:
Abstract Objective To evaluate leptin level and its association with BMI and genetic predisposition in cases of early onset obesity. Methods 76 children (15.3 ± 10 yrs, 47 females) with morbid obesity (BMI of 41.7 ± 5.7 kg/m2) and 2 fathers and 5 mothers of these patients with BMI 47.8 ± 8.7 kg/m2 underwent genetic testing at the Prevention Genetics after obtaining consent. Leptin, Lipid profile, Glucose, Insulin, ALT, AST were measured. Results From 83 cases heterozygous polymorphism was found in 65 and in 18 genetic analysis was negative. | Patients were divided into 3 groups according to the leptin level. | 13 patients had leptin level less than 12 ng/ml (7.9 ± 2.5) (Group 1) (5 patients - no mutation, 8 with different combination of the genes: 1 with (BBS14 (CEP290) and BBS10), 2 BBS5, 2 SH2B1, 1 PLXNA3, 1 with (PCSK1 and ALMS1), 1 with BBS 20 (IFT172). Leptin didn't correlate with BMI in this group. | 6 patients had leptin elevated more than 50 ng/ml (74.5 ± 17.7) (Group 2). (1 patient – no mutation, 1 with KSR2, 1 with MCR4, 1 with SEMA3G, 1 with a combination of MCR4 and 2 different POMC, 1 with PLXNA4 and BBS15 (WDPCP). Leptin didn't correlate with BMI in this group. | 64 patients had leptin level (24.6 ± 9.4 ng/ml) expected for their BMI (42.7 ± 8.5 kg/m2) (Group 3). Leptin level correlated with BMI (r=0.37, P=0. 002). In group 3, Genetic analysis was negative in 12 patients, 1 gene was in 19 cases (KSR2 in 3, PCSK1 in 4, POMC in 2, others in 1: BBS 17(KZTFL1), BBS9, BBS21 (C8orf37), BBC20(IFT172), MCR4, MRAP2, PLXNA4, POMC, INPP5E, UCP3. | 2 genes in 25 cases: (BBS1, NTRK2), (BBS4, RAI1), (BBS4, PLXNA3) (BBS7, NTRK2), (BBS2, BBS9), (BBS9, MCR4),(BBS9, ADCY3), (BBS9, ALMS1), (BBS10, ALMS1), (BBS10, BBS22 (IFT74)), (BBS13 (MKS1), PCKS1), (BBS14 (CEP290), PCSK1), (BBS15 (WDPCP), PCSK1), (BBS18, POMC), (BBS20(IFT172), PCSK1), (BBS 22 (IFT74), SH2B1), (ALMS1,PCSK1), (ALMS1, BDNF), (SH2B1, NCOA1), (SH2B1, PCSK1), (SEMA3G, NTRK2), (SEMA3D, UCP3), (SIM1, NROB2), (KSR2, NTRK2), (MRAP2, RPGRIP1L). | 3 genes in 5 cases (BBS16 (SDCCAG8), BBS14 (CEP290), KIDINS220), (KSR2, ALMS1, PCNT), (KSR2, SEMA3G, NTRK2), (ALMS1, PCSK1, NCOA1), (BBS9, ALMS1, TRIM32)4 genes in 2 cases (BBS9, BBS11(TRIM32), ALMS1, POMC) and (BBS19 (IFT27), BBS 20 (IFT27), SEMA3B, PLXNA3). | 5 genes in 1 case (BBS12, BBS20 (IFT172), ALMS1, RPGRIP1L, SEMA3G). There were no differences in age, BMI, Hb A1c, SBP, DBP, Glucose, Insulin HOMA. ALT, AST, TG, and HDL levels between groups. Conclusion There is a high frequency of genes involved in cilia regulation like BBS and ALMS1 genes. Identifying patients with low leptin level for the degree of obesity can individualize treatment to decrease appetite and increase energy expenditure Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
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Clément, Karine, Martin Wabitsch, Erica Van den Akker, Jesús Argente, Ceclila Scimia, Madhura Srinivasan, Guojun Yuan, and Peter Kühnen. "ODP607 Long-term Efficacy of Setmelanotide in Patients With POMC or LEPR Deficiency Obesity." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A14—A15. http://dx.doi.org/10.1210/jendso/bvac150.030.
Abstract:
Abstract The melanocortin-4 receptor (MC4R) pathway in the brain is responsible for energy regulation, affecting appetite and body weight. Impairments of this pathway can result in hyperphagia (insatiable hunger) and obesity. The MC4R can be impacted by the POMC, PCSK1, or LEPR genes. Variants in these genes that are inherited from both parents (biallelic) can result in MC4R pathway signaling deficiencies. Setmelanotide is a drug that activates the MC4R. In earlier Phase 3 studies, setmelanotide was shown to improve hunger and reduce weight in patients with POMC, PCSK1, and LEPR biallelic deficiency. The present study aims to examine the long-term efficacy of ∼3 years of setmelanotide treatment in patients with POMC, PCSK1, and LEPR biallelic deficiency in a long-term extension after a previous trial. Setmelanotide treatment continued to provide sizable reductions in body weight and body mass index while being generally well tolerated. These findings provide strong support of the safe and effective long-term use of setmelanotide to treat obesity in patients with POMC, PCSK1, and LEPR biallelic deficiency. Presentation: No date and time listed
5
Aerts, Laetitia, Nathalie A. Terry, Nina N. Sainath, Clarivet Torres, Martín G. Martín, Bruno Ramos-Molina, and John W. Creemers. "Novel Homozygous Inactivating Mutation in the PCSK1 Gene in an Infant with Congenital Malabsorptive Diarrhea." Genes 12, no. 5 (May 10, 2021): 710. http://dx.doi.org/10.3390/genes12050710.
Abstract:
Proprotein convertase 1/3 (PC1/3), encoded by the PCSK1 gene, is expressed in neuronal and (entero)endocrine cell types, where it cleaves and hence activates a number of protein precursors that play a key role in energy homeostasis. Loss-of-function mutations in PCSK1 cause a recessive complex endocrinopathy characterized by malabsorptive diarrhea and early-onset obesity. Despite the fact that neonatal malabsorptive diarrhea is observed in all patients, it has remained understudied. The aim of this study was to investigate the enteroendocrine pathologies in a male patient with congenital PCSK1 deficiency carrying the novel homozygous c.1034A>C (p.E345A) mutation. This patient developed malabsorptive diarrhea and metabolic acidosis within the first week of life, but rapid weight gain was observed after total parenteral nutrition, and he displayed high proinsulin levels and low adrenocorticotropin. In vitro analysis showed that the p.E345A mutation in PC1/3 resulted in a (near) normal autocatalytic proPC1/3 processing and only partially impaired PC1/3 secretion, but the processing of a substrate in trans was completely blocked. Immunohistochemical staining did not reveal changes in the proGIP/GIP and proglucagon/GLP-1 ratio in colonic tissue. Hence, we report a novel PCSK1 deficient patient who, despite neonatal malabsorptive diarrhea, showed a normal morphology in the small intestine.
6
Velazquez-Roman, Jorge, Uriel A. Angulo-Zamudio, Nidia Leon-Sicairos, Hector Flores-Villaseñor, Miriam Benitez-Baez, Ana Espinoza-Salomón, Alejandra Karam-León, et al. "Association of PCSK1 and PPARG1 Allelic Variants with Obesity and Metabolic Syndrome in Mexican Adults." Genes 14, no. 9 (September 8, 2023): 1775. http://dx.doi.org/10.3390/genes14091775.
Abstract:
Metabolic diseases, including obesity, diabetes, and metabolic syndrome, are among the most important public health challenges worldwide. Metabolic diseases are classified as multifactorial diseases in which genetic variants such as single-nucleotide polymorphisms (SNPs) may play an important role. The present study aimed to identify associations linking allelic variants of the PCSK1, TMEM18, GPX5, ZPR1, ZBTB16, and PPARG1 genes with anthropometric and biochemical traits and metabolic diseases (obesity or metabolic syndrome) in an adult population from northwestern Mexico. Methods: Blood samples were collected from 523 subjects, including 247 with normal weight, 276 with obesity, and 147 with metabolic syndrome. Anthropometric and biochemical characteristics were recorded, and single-nucleotide polymorphisms (SNPs) were genotyped by real-time PCR. Results: PCSK1 was significantly (p < 0.05) associated with BMI, weight, and waist-to-hip ratio; TMEM18 was significantly associated with systolic blood pressure and triglyceride levels; GPX5 was significantly associated with HDL cholesterol levels. In addition, PCSK1 was associated with obesity (p = 1.0 × 10−4) and metabolic syndrome (p = 3.0 × 10−3), whereas PPARG1 was associated with obesity (p = 0.044). Conclusions: The associations found in this study, mainly between allelic variants of PCSK1 and metabolic traits, obesity, and metabolic syndrome, may represent a risk for developing metabolic diseases in adult subjects from northwestern Mexico.
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Ayers, Kristin L., Benjamin S. Glicksberg, Alastair S. Garfield, Simonne Longerich, Joseph A. White, Pengwei Yang, Lei Du, et al. "Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment." Journal of Clinical Endocrinology & Metabolism 103, no. 7 (May 2, 2018): 2601–12. http://dx.doi.org/10.1210/jc.2018-00258.
Abstract:
AbstractContextThe hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), orMC4R genes, have been shown to cause early-onset severe obesity.MethodsThrough a comprehensive epidemiological analysis of known and predicted LoF variants in thePOMC, PCSK1, andLEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants.ResultsWe predict ~650α-melanocyte-stimulating hormone (MSH)/POMC, 8500PCSK1, and 3600LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway–deficient obese patients. Few of these variants have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants:β-MSH/POMC,PCSK1 N221D, and aPCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity, we tested associations between body mass index (BMI) and LoF mutation burden in thePOMC, PCSK1, andLEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway are predisposed to a higher BMI than noncarriers or heterozygous LoF carriers with a defect in only one gene.ConclusionsOur analysis represents a genetically rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness.
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Van Dijck, Evelien, Sigri Beckers, Sara Diels, Tammy Huybrechts, An Verrijken, Kim Van Hoorenbeeck, Stijn Verhulst, Guy Massa, Luc Van Gaal, and Wim Van Hul. "Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review." Genes 13, no. 10 (September 27, 2022): 1746. http://dx.doi.org/10.3390/genes13101746.
Abstract:
Recently, it was reported that heterozygous PCSK1 variants, causing partial PC1/3 deficiency, result in a significant increased risk for obesity. This effect was almost exclusively generated by the rare p.Y181H (rs145592525, GRCh38.p13 NM_000439.5:c.541T>C) variant, which affects PC1/3 maturation but not enzymatic capacity. As most of the identified individuals with the heterozygous p.Y181H variant were of Belgian origin, we performed a follow-up study in a population of 481 children and adolescents with obesity, and 486 lean individuals. We identified three obese (0.62%) and four lean (0.82%) p.Y181H carriers (p = 0.506) through sanger sequencing and high resulting melting curve analysis, indicating no association with obesity. Haplotype analysis was performed in 13 p.Y181H carriers, 20 non-carriers (10 with obesity and 10 lean), and two p.Y181H families, and showed identical haplotypes for all heterozygous carriers (p < 0.001). Likewise, state-of-the-art literature concerning the role of rare heterozygous PCSK1 variants implies them to be rarely associated with monogenic obesity, as first-degree carrier relatives of patients with PC1/3 deficiency are mostly not reported to be obese. Furthermore, recent meta-analyses have only indicated a robust association for scarce disruptive heterozygous PCSK1 variants with obesity, while clinical significance is less or sometimes lacking for most nonsynonymous variants.
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Morash, Michael G., Angela B. MacDonald, Roger P. Croll, and Younes Anini. "Molecular cloning, ontogeny and tissue distribution of zebrafish (Danio rerio) prohormone convertases: pcsk1 and pcsk2." General and Comparative Endocrinology 162, no. 2 (June 2009): 179–87. http://dx.doi.org/10.1016/j.ygcen.2009.03.013.
10
Sanders, SS. "PCSK1 variants: genetic risk factors for obesity." Clinical Genetics 75, no. 4 (April 2009): 318–19. http://dx.doi.org/10.1111/j.1399-0004.2009.01171_1.x.
Dissertations / Theses on the topic "PCSK1":
1
Choquet, Hélène. "Contribution du gène PCSK1 aux formes monogéniques et polygéniques d'obésité." Phd thesis, Université du Droit et de la Santé - Lille II, 2010. http://tel.archives-ouvertes.fr/tel-00576415.
Abstract:
Quatre études de liaison génome entier ont mis en évidence une région commune de5,6 Mb dans la région du chromosome 5q15 liée à des traits associés à l'obésité, cette région incluant le gène de la prohormone convertase 1 (PCSK1). Une mutation Pc1 chez la souris a été associée à l'obésité, l'hyperphagie et à une augmentation de l'efficacité du métabolisme. La déficience complète en PCSK1 a été associée à une forme récessive rare d'obésité chezl'homme, et depuis 1997 seuls trois patients présentant cette déficience ont été décrits dans la littérature. Les porteurs de mutations délétères PCSK1 présentent des phénotypes sévères,incluant l'obésité, des hypoglycémies post-prandiales et des problèmes intestinaux ethormonaux. Contrairement aux observations faites chez la souris, les membres des famillesporteurs hétérozygotes ont été considérés comme cliniquement sains. Toutes ces études ontdésigné PCSK1 comme un gène candidat important pour l'obésité.Dans un premier temps, la contribution du gène PCSK1 au risque d'obésitépolygénique a été évaluée chez 13,659 individus d'origine européenne issus de huit cohortescas contrôles ou familiales indépendantes. Neuf variants fréquents couvrant 92% de lavariabilité génétique du locus ont été génotypés. Les méta-analyses des huit études pour levariant commun rs6232 et pour le cluster rs6234-rs6235 ont montré une associationreproductible avec l'obésité chez l'adulte et chez l'enfant (P=7.27x10-8 et P=2.31x10-12respectivement). Le rs6232 était associé à une augmentation du risque d'obésité de 34%, alorsque le cluster rs6234-rs6235 augmentait le risque d'obésité de 22%. Les analysesfonctionnelles ont montré une diminution significative de 10,4% de l'activité catalytique de laprotéine PC1/3 pour le N221D, et une diminution non significative de l'activité catalytique dela protéine PC1/3 pour le cluster Q665E/S690T.L'implication du gène PCSK1 dans l'obésité monogénique a ensuite été entreprise parle séquençage des exons de PCSK1 chez 845 sujets obèses non-consanguins d'origineeuropéenne,. Huit nouvelles mutations non-synonymes ont été identifiées. L'étude des conséquences fonctionnelles des mutations détectées sur la protéine PC1/3 a montré que62.5% de ces mutations détectées étaient prédites délétères par les analyses in silico et 87.5%de ces mutations avaient un effet sur l'auto-activation ou sur l'activité enzymatique de PC1/3in vitro. Dans le but d'estimer le degré de pénétrance pour ces sept mutations pathogéniques,6,060 obèses et 6,274 sujets minces ont été génotypés, démontrant un enrichissement par sixde ces mutations PCSK1 chez les sujets obèses (P=0.007). Cette étude a mis en évidence pourla première fois une augmentation du risque d'obésité chez les porteurs hétérozygotes de mutations perte de fonction du gène PCSK1, confirmant un mode de transmission codominantde l'obésité avec une pénétrance incomplète. La pénétrance de l'obésité a été105estimée à 54.5% pour les porteurs hétérozygotes de mutations délétères PCSK1. Unedéficience partielle en PCSK1 pourrait expliquer environ 0.83% des formes extrêmesd'obésité et représenter la seconde forme la plus fréquente d'obésité monogénique après ladficience en MC4R.Pour conclure, en plus des formes syndromiques très rares d'obésité dues à unedéficience complète en PCSK1, ce travail a permis de démontrer le rôle des variants codantsfréquents non-synonymes dans le risque d'obésité, ainsi que l'importance longtempsinsoupçonné d'une déficience partielle en PCSK1 dans les formes monogéniques d'obésité.
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Choquet, Hélène. "Contribution du gène PCSK1 aux formes monogéniques et polygéniques d’obésité." Thesis, Lille 2, 2010. http://www.theses.fr/2010LIL2S012/document.
Abstract:
Quatre études de liaison génome entier ont mis en évidence une région commune de5,6 Mb dans la région du chromosome 5q15 liée à des traits associés à l’obésité, cette région incluant le gène de la prohormone convertase 1 (PCSK1). Une mutation Pc1 chez la souris a été associée à l’obésité, l’hyperphagie et à une augmentation de l’efficacité du métabolisme. La déficience complète en PCSK1 a été associée à une forme récessive rare d’obésité chezl’homme, et depuis 1997 seuls trois patients présentant cette déficience ont été décrits dans la littérature. Les porteurs de mutations délétères PCSK1 présentent des phénotypes sévères,incluant l’obésité, des hypoglycémies post-prandiales et des problèmes intestinaux ethormonaux. Contrairement aux observations faites chez la souris, les membres des famillesporteurs hétérozygotes ont été considérés comme cliniquement sains. Toutes ces études ontdésigné PCSK1 comme un gène candidat important pour l’obésité.Dans un premier temps, la contribution du gène PCSK1 au risque d’obésitépolygénique a été évaluée chez 13,659 individus d’origine européenne issus de huit cohortescas contrôles ou familiales indépendantes. Neuf variants fréquents couvrant 92% de lavariabilité génétique du locus ont été génotypés. Les méta-analyses des huit études pour levariant commun rs6232 et pour le cluster rs6234-rs6235 ont montré une associationreproductible avec l’obésité chez l’adulte et chez l’enfant (P=7.27x10-8 et P=2.31x10-12respectivement). Le rs6232 était associé à une augmentation du risque d’obésité de 34%, alorsque le cluster rs6234-rs6235 augmentait le risque d’obésité de 22%. Les analysesfonctionnelles ont montré une diminution significative de 10,4% de l’activité catalytique de laprotéine PC1/3 pour le N221D, et une diminution non significative de l’activité catalytique dela protéine PC1/3 pour le cluster Q665E/S690T.L’implication du gène PCSK1 dans l’obésité monogénique a ensuite été entreprise parle séquençage des exons de PCSK1 chez 845 sujets obèses non-consanguins d’origineeuropéenne,. Huit nouvelles mutations non-synonymes ont été identifiées. L’étude des conséquences fonctionnelles des mutations détectées sur la protéine PC1/3 a montré que62.5% de ces mutations détectées étaient prédites délétères par les analyses in silico et 87.5%de ces mutations avaient un effet sur l’auto-activation ou sur l’activité enzymatique de PC1/3in vitro. Dans le but d’estimer le degré de pénétrance pour ces sept mutations pathogéniques,6,060 obèses et 6,274 sujets minces ont été génotypés, démontrant un enrichissement par sixde ces mutations PCSK1 chez les sujets obèses (P=0.007). Cette étude a mis en évidence pourla première fois une augmentation du risque d’obésité chez les porteurs hétérozygotes de mutations perte de fonction du gène PCSK1, confirmant un mode de transmission codominantde l’obésité avec une pénétrance incomplète. La pénétrance de l’obésité a été105estimée à 54.5% pour les porteurs hétérozygotes de mutations délétères PCSK1. Unedéficience partielle en PCSK1 pourrait expliquer environ 0.83% des formes extrêmesd’obésité et représenter la seconde forme la plus fréquente d’obésité monogénique après ladficience en MC4R.Pour conclure, en plus des formes syndromiques très rares d’obésité dues à unedéficience complète en PCSK1, ce travail a permis de démontrer le rôle des variants codantsfréquents non-synonymes dans le risque d’obésité, ainsi que l’importance longtempsinsoupçonné d’une déficience partielle en PCSK1 dans les formes monogéniques d’obésitéFour whole genome studies basing on positional cloning approach revealed a region ofchromosome 5q linked to traits related to obesity, this region contained the gene coding forthe prohormone convertase 1 named PCSK1. Pc1 mutation in mice has been associated withobesity, hyperphagia and increased metabolic efficiency. In human, PCSK1 deficiency is amonogenic form of obesity. The first case of complete PCSK1 deficiency has been identifiedin 1997 and since two other cases were discovered. Deleterious PCSK1 mutations carrierswere either homozygous or compound heterozygous and presented severe phenotypes, such asobesity, intestinal troubles and endocrine disorders. Surprisingly, the family members whowere heterozygous for these mutations appeared clinically unaffected. Overall of these studieshighlighted PCSK1 as a candidate gene for obesity.We have therefore decided to assess the contribution of PCSK1 gene to polygenicobesity risk. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tagsingle nucleotide polymorphisms in a total of 13,659 European individuals from eightindependent case-control or family-based cohorts. The non-synonymous variants rs6232,encoding N221D, and cluster rs6234-rs6235, encoding the Q665E-S690T pair, wereconsistently associated with obesity in adults and children (P=7.27 x 10-8 and P=2.31 x 10-12,respectively). Functional analysis revealed a significant impairment of the N221D mutant onPC1/3 protein catalytic activity.In continuity of this study we decided to assess the involvement of PCSK1 gene inmonogenic obesity, knowing that only three cases of complete PCSK1 deficiency have beenreported up to now. The objectives of this study were to evaluate the prevalence of rarePCSK1 mutations contributing to human obesity and to investigate the mode of inheritance ofobesity in the context of PCSK1 deficiency. We sequenced exons of the PCSK1 gene in 845non-consanguineous extremely obese subjects of European origin and we identified eightnovel PCSK1 non-synonymous mutations in eight carriers, all heterozygous. Wecharacterized the functional consequences of the detected mutations on PC1/3 protein and wefound that 62.5% of mutations detected were predicted to be deleterious in silico and werevealed that 87.5% of mutations had an effect on the autoactivation or on the enzymaticactivity of PC1/3 in vitro. In order to estimate the degree of penetrance for the sevenpathogenic mutations, we genotyped 6,060 obese and 6,274 lean subjects. We assessed a 6-fold enrichment of these PCSK1 mutations in obese subjects (P = 0.007). We provided thefirst evidence of an increased obesity risk in heterozygous carriers of loss of functionmutations in PCSK1 gene, confirming a co-dominant mode of transmission of obesity withincomplete penetrance for this gene. The penetrance of obesity was estimated to 54.5% for108heterozygous carriers of deleterious PCSK1 mutations. Partial PCSK1 deficiency mightexplain ~ 0.83% of extreme obesity.To conclude, in addition of the syndromic forms of obesity due to a complete PCSK1deficiency, we provided the strong evidence of the contribution of common non-synonymousvariants in obesity risk and we highlighted that a partial PCSK1 deficiency is associated withan increased risk of obesity
3
Guerardel, Audrey. "Analyse de deux gènes candidats physiologiques et positionnels de l'obésité humaine CART et PCSK1." Lille 2, 2005. http://www.theses.fr/2005LIL2S012.
Abstract:
L'obésité commune est une maladie multifactorielle, dont l'émergence récente comme maladie de masse, est liée à l'occidentalisation du mode de vie. Elle est la conséquence d'une diminution de l'activité physique et d'un accès illimité à une alimentation calorique. Néanmoins, les facteurs génétiques influencent la prédisposition individuelle, comme l'attestent des études familiales et l'identification de formes monogéniques d'obésité. Les déterminants des formes polygéniques fréquentes (95%) sont encore peu caractérisés, même si des études récentes ont montré notamment le rôle de certains gènes dans la signalisation de l'insuline (ENPP1) et les voies métaboliques de neurotransmetteurs (GABA, sérotonine), qui prédisposeraient à l'obésité dans un environnement peu favorable. L'implication des facteurs génétiques dans les maladies polygéniques tel que l'obésité est abordée par des approches directes d'analyses de gènes candidats physiologiques et indirectes par l'étude de gènes candidats positionnels localisés dans des régions chromosomiques de liaison à des traits phénotypiques. Deux études " génome entier " sur des familles caucasiennes françaises ont permis de souligner l'importance du locus 5cen-q comme région de susceptibilité à la variation du taux de leptine et à l'obésité. Parmi les nombreux gènes localisés dans cette région ; les gènes CART (5q12-q13) et PCSK1 (5q15-q21) sont exprimés au niveau du système nerveux central dans des régions impliquées dans le contrôle de la prise alimentaire et le maintien de l'homéostasie énergétique et sont des acteurs de la voie de la leptine. L'analyse de 5,4 kb du gène CART (Cocaine and Amphetamine Regulated Transcript), a permis l'identification d'un SNP de la région promotrice (SNP-3608T>C) qui pourrait être un composant des déterminants génétiques de l'obésité polygénique. Ce polymorphisme se révèle également être associé, dans une population générale, avec les sous-fractions de cholestérol et les apolipoprotéines plasmatiques suggérant une implication du gène CART dans l'athérogénèse. Ce SNP aurait également un effet dans le remodelage de la masse osseuse corticale dans une population de femmes danoises. Le gène PCSK1 (Proprotein Convertase Subtilisin/kexin type 1) code une endoprotéase à sérine de type subtilisine, impliquée dans la maturation de pro-hormones et de neuropeptides précurseurs tels que la proinsuline et POMC. Des mutations du gène PCSK1 responsables d'une forme monogénique rare d'obésité sévère de l'enfant ont été décrites. L'analyse de ce gène dans un contexte polygénique a permis l'identification de SNP fréquents (dont une mutation exonique non-synonyme) associés à l'obésité adulte et/ou infantile. L'approche génétique a validé des hypothèses physiologiques et a amélioré notre compréhension des voies métaboliques impliquées en suggérant l'effet de ces deux gènes dans l'obésité polygénique et le rôle pléiotropique du gène CARTCommon obesity is a multifactorial disease, whose recent increase, is related to the modernization of life. This epidemic is the consequence of a physical inactivity and an unlimited access to over-nutrition and consumption of caloric food. Nevertheless, many familial studies and the identification of monogenic forms of obesity indicate that genetic factors are also involved. All determinants of the polygenic forms are still unknown, recent studies show the role of genes in the signalling of insulin (ENPP1) and metabolic pathways of neurotransmitters (GABA, serotonin) which would predispose to obesity in a sedentary, high calorie lifestyle. The identification of genetic factors in the polygenic diseases such as obesity is assessed by direct studies of physiological genes and by indirect analyses with positional candidate genes located in chromosomal regions of linkage to phenotype traits. Two genome wide-scans on French Caucasian families show the importance of the locus 5cen-q. Among many genes located in this region ; CART (5q12-q13) and PCSK1 (5q15-q21) genes are expressed in the central nervous system (principally in the hypothalamus) and are involved in the control of food intake and the regulation of energy homeostasis. The analysis of a 5,4 Kb region of the CART gene (Cocaine and Amphetamine Regulated Transcript), including the promoter, 3 exons, introns and the 3'UTR, resulted in the identification of a promoter SNP (SNP-3608T>C) which is associated with the polygenic obesity. In a general population, this polymorphism is also associated, with subfractions of plasma cholesterol and apolipoproteins which suggests that the CART gene maybe implicated in lipid metabolism and atherogenesis. Within a Danish study of menopausal women, the SNP-3608T>C was shown to effect remodelling of the bone mass (on arm BMD). PCSK1 (Proprotein Convertase Subtilisin/kexin type 1) Gene code for a neuroendocrine member of the family of subtilisin-like proprotein convertases and is important for the maturation of pro-hormones and neuropeptides precursors such as the proinsulin and POMC. PCSK1 gene mutations are responsible for a number of rare monogenic forms of severe obesity. The analysis of this gene in a polygenic context enabled the identification of frequent mutations including a non-synonymous exonic variant which is associated with adult and/or childhood polygenic obesity. The genetic approach validates physiological hypotheses and improves current understanding of metabolic pathways, and suggests a pleiotropic effect of the CART gene and that the CART and PCSK1 genes are implicated in polygenic obesity
4
Folon, Lise. "Étude de l'impact des variants génétiques rares sur l'obésité monogénique." Electronic Thesis or Diss., Université de Lille (2022-....), 2023. https://pepite-depot.univ-lille.fr/ToutIDP/EDBSL/2023/2023ULILS059.pdf.
Abstract:
L'obésité est une maladie multifactorielle complexe avec une forte composante génétique. Contrairement à l'obésité commune qui est une maladie polygénique, les formes d'obésité monogénique sont causées par un seul variant génétique rare avec un effet fort et délétère. Ces formes sont rares, précoces et généralement sévères, affectant environ 5% des individus atteints d'obésité. La plupart des mutations rares liées aux formes monogéniques de l'obésité ont été identifiées dans les gènes de la voie leptine-mélanocortine, qui est essentielle pour la régulation de la prise alimentaire. L'identification de ces gènes est cruciale dans la compréhension de la physiopathologie de l'obésité et l'élaboration de nouveaux traitements.J'ai tout d'abord étudié les variants rares hétérozygotes du gène PCSK1 qui code l'enzyme prohormone convertase 1 (PC1/3). PC1/3 est impliqué dans la voie leptine-mélanocortine. Les mutations bialléliques de PCSK1 causent une obésité précoce avec une endocrinopathie sévère. Les patients déficients en PCSK1 (hétérozygotes ou homozygotes) peuvent dorénavant être traités avec des injections de setmélanotide pour perdre du poids. Or l'impact des variants rares hétérozygotes de PCSK1 sur l'obésité, et leur pertinence en médecine de précision sont encore mal définis. Dans l'étude RaDiO incluant 9320 participants, 65 variants rares hétérozygotes de PCSK1 ont été identifiés et analysés in vitro. Ces variants ont été classés en cinq groupes suivant la sévérité de leur impact sur l'activité enzymatique de PC1/3. Les résultats d'analyses d'association ont révélé que les variants rares induisant une perte totale de fonction augmentaient fortement le risque d'obésité et l'indice de masse corporelle (IMC) alors que les variants des autres groupes avec un effet partiel ou neutre sur l'activité de PC1/3 n'avaient aucun effet sur l'adiposité. Nous avons observé que les outils de prédiction in silico étaient peu fiables pour détecter les mutations entraînant une perte totale de fonction.Dans un second temps, je me suis intéressée aux variants rares du gène DYRK1B. Bien que ce gène ne soit pas impliqué dans la voie leptine-mélanocortine, des variants pathogènes de DYRK1B ont été décrits chez plusieurs patients avec une obésité centrale, un diabète de type 2 (DT2) et une maladie des artères coronaires. Cependant, l'impact des variants rares de DYRK1B n'a pas été évalué à grande échelle. A partir de l'étude RaDiO incluant 9353 participants, 65 variants rares dans DYRK1B ont été détectés. Après une analyse in vitro de chaque variant, nous avons identifié 20 variants pathogènes ou probablement pathogènes (P/LP) d'après les critères de l'American College of Medical Genetics and Genomics. Parmi ces variants P/LP, six montraient un effet entrainant une perte totale de fonction de DYRK1B (P/LP-full). Les analyses d'association ont montré que les variants P/LP-full de DYRK1B étaient fortement associés à une augmentation de l'IMC et de la glycémie à jeun, et à un risque accru d'obésité et de DT2, alors que les variants P/LP n'avaient qu'un effet modeste sur l'adiposité et aucun impact sur l'homéostasie glucidique.En conclusion, l'utilisation de la génétique fonctionnelle a permis de mettre en évidence que seuls les variants hétérozygotes de PCSK1 et DYRK1B avec une perte de fonction totale causaient une obésité monogénique. Pour DYRK1B, l'obésité est en plus associée à un DT2. Ces résultats soulignent l'importance cruciale de déterminer in vitro l'impact fonctionnel des mutations en vue du diagnostic génétique et de l'éventuel choix d'un traitement approprié. Nous avons démontré que les tests de prédiction in silico ne sont pour l'heure pas assez précisObesity is a complex multifactorial disease with a strong genetic component. Unlike common obesity, which is a polygenic disease, monogenic forms of obesity are caused by a single rare genetic variant with a strong and deleterious effect. These monogenic forms are rare, early-onset and generally very severe, affecting around 5% of individuals with obesity. Most rare mutations associated with monogenic obesity are found in genes within the leptin-melanocortin pathway, which is crucial for the regulation of food intake. Identifying these genes is crucial for understanding the pathophysiology of obesity and developing new treatments.I initially studied rare heterozygous variants of the PCSK1 gene, which encodes the prohormone convertase 1 (PC1/3) enzyme. PC1/3 is involved in the leptin-melanocortin pathway. Biallelic mutations in PCSK1 cause early-onset obesity with severe endocrinopathy. Patients with PCSK1 deficiency (heterozygous or homozygous) can now be treated with setmelanotide injections to promote weight loss. However, the impact of rare heterozygous variants of PCSK1 on obesity and their relevance in precision medicine are still not well-defined. In the RaDiO study, which included 9,320 participants, 65 rare heterozygous variants of PCSK1 were identified and assessed in vitro. These variants were classified into five groups based on the severity of their impact on the enzymatic activity of PC1/3. Association analysis results revealed that rare variants inducing a complete loss of function significantly increased the risk of obesity and body mass index (BMI), whereas variants in other groups with partial or neutral effects on PC1/3 activity had no impact on adiposity. We observed that in silico prediction tools were unreliable in detecting mutations leading to a complete loss of function.Subsequently, I focused on rare variants of the DYRK1B gene. Although this gene is not directly involved in the leptin-melanocortin pathway, pathogenic variants of DYRK1B have been described in several patients with central obesity, type 2 diabetes (T2D), and coronary artery disease. However, the impact of rare DYRK1B variants has not been assessed on a large scale. In the RaDiO study, which included 9,353 participants, 65 rare variants in DYRK1B were detected. Following in vitro analysis of each variant, we identified 20 pathogenic or likely pathogenic variants (P/LP) according to the criteria of the American College of Medical Genetics and Genomics. Among these P/LP variants, six showed an effect leading to a complete loss of function of DYRK1B (P/LP-full). Association analyses showed that P/LP-full variants of DYRK1B were strongly associated with increased BMI and fasting glucose levels, as well as a heightened risk of obesity and T2D, whereas P/LP variants had only a modest effect on adiposity and no impact on glucose homeostasis.In conclusion, the use of functional genetics has demonstrated that only heterozygous variants of PCSK1 and DYRK1B with a complete loss of function cause monogenic obesity. For DYRK1B, obesity is additionally associated with T2D. These results underscore the critical significance of assessing the functional impact of mutations in vitro for genetic diagnosis and the potential selection of appropriate treatments. We have demonstrated that in silico prediction tests are currently not precise enough
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Bhat, Mamatha. "Expression of PCSK9 in Hepatocellular Carcinoma." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106271.
Abstract:
Hepatocellular carcinoma (HCC) is an often fatal condition due to late diagnosis, resistance to existing anticancer agents, as well as underlying liver disease that can limit the use of hepatotoxic chemotherapy. Proprotein convertases (PCs) are serine proteases that convert a variety of growth factors, cell surface glycoproteins, receptors and metalloproteinases into their active forms, thus regulating the biological activity of these proteins. PCs have been found to be upregulated in various malignancies. Growth factors implicated in HCC, such as IGF-1, HGF, VEGF and PDGF, have all been shown to be converted into their active forms by PCs. In this study, I explored the hypothesis that expression of proprotein convertases, specifically PCSK9, furin and PC5, is elevated in HCC. This was evaluated through construction of a Tissue Microarray and staining for these proteins. We found that PCSK9 expression was significantly downregulated in HCC tumours associated with poorer survival. PCSK9 is upregulated in the context of liver regeneration and has been involved in cholesterol metabolism, with development of monoclonal antibodies against PCSK9 to treat hypercholesterolemia. Its altered expression in aggressive HCC tumours potentially indicates that HCC is able to modulate its local microenvironment to enable a constant energy supply. There has recently been a move in oncology research to study suppression of suppress tumour growth by modifying energy supply and metabolism (for eg, metformin in prostate and breast cancer). Further confirmation at the mRNA level is required to confirm the altered expression of PCSK9, however this appears to be a promising finding and potential chemotherapeutic target.Contexte et hypothèses: Le carcinome hépatocellulaire (CHC) est le 5e cancer le plus courant dans le monde entier et la 3ème cause de décès par cancer dans le monde entier, avec une survie médiane à 5 ans de 8,9%. La reconnaissance tardive en raison du manque de biomarqueurs pour détecter la maladie résécable, une résistance aux agents anticancéreux, ainsi qu'une maladie du foie sous-jacente limitant l'utilisation de chimiothérapie hépatotoxique sont des facteurs qui diminuent le taux de survie. Les proprotéines convertases (PCs) sont des sérine-protéases qui convertissent une variété de facteurs de croissance, glycoprotéines de surface cellulaire, les récepteurs, et les métalloprotéinases à leurs formes actives, contrôlant ainsi l'activité biologique de ces protéines. On a démontré l'expression augmentée de PCs dans de diverses tumeurs malignes. On a prouvé que les facteurs de croissance impliqués dans le CHC, tels que l'IGF-1, HGF, VEGF et PDGF, sont convertis à leurs forme actives par les PC. Notre hypothèse est que l'expression de proprotéines convertases est élevée dans le CHC, permettant l'activation de différentes protéines essentielles dans le développement et la progression du CHC. L'objectif de recherche était d'évaluer l'expression des PCs PCSK9, furine et PC5 dans le CHC par rapport aux stroma environnant, zones péri-cirrhotiques, et foie normal afin de déterminer si un gradient d'expression existe. PCSK9 en particulier est connu comme étant plus exprimé chez le foie régénérateur post-hepatectomie. Les diapositives de pathologie de CHC stockés dans le département de pathologie du CUSM ont été examinés par une pathologiste, et les zones appropriées (tumeur de CHC, interface de tumeur et du foie, le foie cirrhotique, et d'autres échantillons d'hépatite et de foie normal) dans les blocs de tissu correspondants ont été creusés et ont été incorporées dans un microarray de tissu (TMA). Des lignes cellulaires de CHC etablies, dont le HepG2 et le Huh7, avec des profils d'expression de PC connus, ont été incorporées sous forme de pastilles de cellules dans la TMA, afin de servir de témoins positifs et négatifs. La TMA a été sectionnée en diapositives, qui ont été colorées avec des anticorps de la PCSK9, furine et PC5. On a découvert que le niveau d'expression de PCSK9 était diminuée dans les CHC avec un pire prognostique. L'expression augmentée de PCSK9 dans les CHC plus aggressifs pourrait indiquer un rôle du PCSK9 dans la tumorigenèse, directement ou indirectement. Il se peut que les CHCs plus aggressifs sont capables de modifier l'environnement local pour apprivoiser l'énergie métabolique, et que le PCSK9 permet que le cholestérol soit utilisé comme source d'énergie. La confirmation de son importance fonctionnelle avec mRNA pourrait potentiellement mener au développement de chimiothérapie ciblée avec des anticorps contre le PCSK9 (stratégie en étude pour l'hypercholestérolémie). Compte tenu des options chimiothérapeutiques actuellement limitées pour le CHC, une telle constatation pourrait améliorer la prise en charge clinique du CHC.
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DA, DALT LORENZO. "IMPACT OF PCSK9 ON EXTRAHEPATIC TISSUES." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/813080.
Abstract:
Introduzione e scopo: la proproteina convertasi subtilisina kexin tipo 9 (PCSK9) è una glicoproteina di 692 amminoacidi che appartiene alla famiglia delle proproteine convertasi. È prodotta principalmente dal fegato dal quale viene secreta nel torrente circolatorio. PCSK9 interagisce con diversi recettori della famiglia dell’LDLr, inclusi VLDLr, LRP1 ma anche con CD36, e guida la loro degradazione lisosomiale. La mancanza di PCSK9 determina quindi una maggiore espressione dei recettori della famiglia LDLr e favorisce l'accumulo di lipidi nei tessuti extraepatici. L’eccesso di lipidi cellulari è associato a disfunzione mitocondriale e danni tissutali in diversi organi, tra cui il pancreas e il cuore. Per questo motivo ci siamo chiesti se la mancanza di PCSK9 circolante e localmente prodotto possa influenzare l'accumulo di lipidi nei tessuti extraepatici come il pancreas e il cuore influenzandone la funzionalità.
Metodi: Animali WT, Pcsk9 KO, albumin CRE PCSK9LoxP / LoxP KO condizionali (privi di PCSK9 selettivamente nel fegato e quindi non presentando proteina PCSK9 rilevabile in circolazione) e topi maschi Doppi KO LDLr-Pcsk9 di 2 mesi sono stati nutriti per 20 settimane con SFD o HFD. I livelli plasmatici di GTT, ITT, insulina e peptide C, morfologia del pancreas e accumulo di colesterolo nelle isole pancreatiche sono stati studiati nei diversi modelli animali. Inoltre su questi topi sono state eseguite analisi ecocardiografiche del cuore e test funzionali. La respirazione mitocondriale è stata studiata in condizioni di riposo e in seguito a condizioni massime di accoppiamento e disaccoppiamento in tutti i modelli di topo, seguite da caratterizzazione delle proteine mitocondriali mediante western blot e analisi di metabolomica approfondita.
Risultati: Il metabolismo glucidico è significativamente ridotto nei topi Pcsk9 KO alimentati sia con una dieta standard che con una dieta ricca di grassi per 20 settimane rispetto agli animali WT; la sensibilità all'insulina, tuttavia, non viene alterata. Un'analisi dettagliata della morfologia del pancreas dei topi Pcsk9 KO rispetto ai controlli ha rivelato isole più grandi con un maggiore accumulo di esteri del colesterolo, che si associa ad aumentati livelli intracellulari di insulina e alla diminuzione dei livelli plasmatici di insulina e C-peptide. Questo fenotipo è stato completamente ripristinato nei topi Pcsk9 / Ldlr DKO, il che implica che l’aumentata espressione di LDLr potrebbe spiegare il fenotipo osservato. Da notare che i topi privi di PCSK9 circolante non presentavano un fenotipo alterato, indicando così che PCSK9 circolante e di origine epatica non influisce sulla funzione delle cellule beta e sulla secrezione di insulina. In parallelo, una caratterizzazione dettagliata della funzionalità cardiaca, ha rivelato che i topi Pcsk9 KO mostrano un fenotipo caratteristico dello scompenso cardiaco con frazione di eiezione conservata. Inoltre, i topi Pcsk9 KO presentano una ridotta resistenza alla corsa senza difetti muscolari accoppiata a importanti adattamenti nel metabolismo cardiaco e nella funzionalità mitocondriale dovuti all'accumulo di colesterolo cardiaco. Un fenotipo simile è stato osservato negli LDLr Doppi KO confermando un effetto indipendente dall'espressione dell’LDLr. Il fenotipo cardiaco risulta completamente ristabilito nel modello KO selettivo del fegato escludendo così il coinvolgimento del PCSK9 circolante nello sviluppo dell'insufficienza cardiaca con frazione di eiezione conservata. Studi traslazionali hanno mostrato che i soggetti umani portatori del polimorfismo di perdita di funzione R46L mostravano un aumento della massa ventricolare sinistra senza alterazioni nella frazione di eiezione rispetto ai controlli con BMI R46R abbinati.
Conclusione / Discussione: PCSK9 prodotto localmente nel pancreas e nel cuore limita l'accumulo di lipidi in modo dipendente da LDLr nel pancreas e in modo LDLr indipendente nel cuore contribuendo così a mantenere l'omeostasi dei tessuti. La carenza genetica di PCSK9 porta allo sviluppo di intolleranza al glucosio e insufficienza cardiaca con frazione di eiezione conservata nei modelli murini e nell'uomo.Background and Aim: Proprotein convertase subtilisin Kexin type 9 (PCSK9) is a 692-amino acid glycoprotein that belongs to the family of proprotein convertases. It is produced mainly by the liver and secreted into the circulation. PCSK9 interacts with several receptors of the LDLr family, including VLDLr, LRP1 but also with CD36, and drives their degradation in the lysosome. As a consequence, PCSK9 deficiency results in increased expression of LDLr family receptors and favors lipid accumulation in extrahepatic tissues. Lipids overload is associated with mitochondrial dysfunction and tissue damage in different organs including the pancreas and the heart. We wondered whether the lack of both circulating and locally produced PCSK9 may affect lipid accumulation on extrahepatic tissues such as the pancreas and the heart those affecting their functionality. Methods: 2-months old WT, Pcsk9 KO, Albumin CRE PCSK9LoxP/LoxP conditional KO (lacking PCSK9 production selectively in the liver and thus presenting undetectable PCSK9 protein in the circulation) and Double KO LDLr-Pcsk9 male mice were fed for 20 weeks with SFD or HFD. GTT, ITT, insulin and C-peptide plasma levels, pancreas morphology, and cholesterol accumulation in pancreatic islets were studied in the different animal models. Moreover, echocardiographic analysis of the heart and functional tests were performed on these mice. Mitochondrial respiration was investigated under resting conditions and following maximal coupling and uncoupling conditions in all mice models followed by mitochondrial protein profiling by western blotting and extensive metabolomic analysis. Results: Glucose clearance was significantly reduced in Pcsk9 KO mice fed with a standard or a high-fat diet for 20 weeks compared with WT animals; insulin sensitivity, however, was not affected. A detailed analysis of pancreas morphology of Pcsk9 KO mice vs. controls revealed larger islets with increased accumulation of cholesteryl esters, paralleled by increased insulin intracellular levels and decreased plasma insulin, and C-peptide levels. This phenotype was completely reverted in Pcsk9/Ldlr DKO mice implying that increased LDLR could explain the phenotype observed. Of note mice lacking circulating PCSK9 did not present an impaired phenotype, thus indicating that circulating, liver-derived PCSK9 does not impact beta-cell function and insulin secretion. In parallel, a detailed characterization of heart function revealed that Pcsk9 KO displays a phenotype characteristic of heart failure with preserved ejection fraction. Moreover, PCSK9 KO mice present a reduced running resistance without muscular defects coupled to major adaptations in cardiac metabolism and mitochondrial functionality due to heart cholesterol accumulation. A similar phenotype was observed in LDLr Double KO confirming an effect independent of LDLr expression. The cardiac phenotype is completed reverted in the liver selective KO model thus excluding the involvement of circulating PCSK9 in the development of Heart Failure with preserved Ejection Fraction. Translational studies showed that human subjects carrying the R46L loss of function polymorphism displayed increased left ventricular mass without alterations in ejection fraction compared to R46R BMI-matched controls. Conclusion/Discussion: PCSK9 locally produced in the pancreas and the heart affects limits lipid accumulation in an LDLr dependent manner in the pancreas and an LDLr independent manner in the heart thus contributing to maintaining tissue homeostasis. Genetic PCSK9 deficiency leads to the development of glucose intolerance and heart failure with preserved ejection fraction in mice models and humans.
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Stefan, Elias. "Familjär hyperkolesterolemi (FH) – analys av prevalens i Stockholm och hälsoekonomiska konsekvenser av tidigdiagnostik och behandling." Thesis, Uppsala universitet, Institutionen för farmaci, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-434844.
Abstract:
Background: Familial hypercholesterolemia (FH) is a genetic disorder estimated to affect 0,4 % of the world's population (1 in 250). Patients with FH have abnormally high LDL-cholesterol. Aim: The aim of this study was to estimate the prevalence of FH in Stockholm County and to evaluate the health economic impact of diagnosing people with FH early in life. Methods: Two algorithms were used to estimate the number of people with high LDLcholesterol. The first method applied data on cholesterol measurements from patients in Stockholm County between 2006-2008 and a modified version of Dutch Lipid Clinic Network. The second method was based on dispensed prescriptions of ezetimibe, lomitapide, evolucumab and alirocumab during 2019. A health economic model was created to estimate the economical outcome of diagnosing and treating patients early before undergoing a cardiovascular event. Results: The prevalence of FH in Stockholm County was estimated to 0.63 %, corresponding to a total of 12 000 individuals. The accumulated costs over 20 years for FH is estimated to be more than 1,1 billion SEK for diagnosed and treated patients, and 1,7 billion SEK for undiagnosed and untreated patients. Conclusions: The prevalence of FH in Stockholm County is probably higher than previously suggested. Early diagnosis and treatment is an investment for society and necessary for the patients to prevent cardiovascular events and improve quality of life.
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Giunzioni, I. "MACROPHAGE EXPRESSION OF PCSK9 INFLUENCES ATHEROSCLEROSIS DEVELOPMENT." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/229332.
Abstract:
Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) regulates low‐density lipoprotein (LDL) cholesterol
levels by binding and degrading hepatic LDL receptor (LDLR), thus promoting atherosclerosis. Little is known
of PCSK9 effect in macrophages and whether this contributes to the development of the atheroma.
To test the effect of human (h) PCSK9 expression on atherosclerosis we developed transgenic mice
expressing hPCSK9 on wild type (WT), LDLR‐/‐ or apoE‐/‐ background. We first demonstrated that both
mPCSK9 and hPCSk9 are expressed at the mRNA level and secreted in the culture medium by MPM. As in
hepatocytes, hPCSK9 reduced LDLR levels in the murine macrophage cell line J774A.1 and in inflammatory
MPM. On the contrary, hPCSK9 did not reduce LRP1 expression, another member of the LDL‐R gene family
involved in the development of atherosclerosis through its effects on macrophage inflammatory responses
and promotion of cell survival. To test the effects of PCSK9 in the atheroma, we fed our transgenic mice a
high fat diet for 8 weeks. As expected, serum cholesterol levels were increased by 2 fold in hPCSK9tg
compared to WT mice (325±64 vs. 158±44 mg/dl, respectively, p<0.05) and hPCSK9 was detected in
atherosclerotic plaques of hPCSK9 tg. In contrast, there was no effect of PCSK9 expression in apoE‐/‐ mice
on serum cholesterol levels compared with apoE‐/‐ controls (1066±161 vs. 964±188 mg/dl, respectively, NS).
Surprisingly, hPCSK9 expressing apoE‐/‐ mice showed increased proximal aorta lesion area. Lesion
composition analysis revealed that lesions of PCSK9/apoE‐/‐ mice have a higher content of Ly6Chigh positive
cells (6.7±0.2%) compared to apoE‐/‐ controls (5.7±0.4%). Moreover, analysis of spleen lysates revealed an
increase in the percentage of Ly6Chigh positive cells in hPCSK9tg compared to control apoE‐/‐, suggesting a
direct effect of PCSK9 in macrophage inflammation and plaque development. On the contrary, despite an
increase in both cholesterol levels and lesion size in hPCSK9 tg/LDLR‐/‐ compared to LDLR‐/‐, no differences
in Ly6Chigh positive cells were found between the two groups. To study the effect of macrophage PCSK9 in
the atheroma, bone marrow cells from PCSK9/apoE‐/‐ or apoE‐/‐ mice were transplanted into apoE‐/‐
recipients. hPCSK9 was detected in serum and lesions from PCSK9/apoE‐/‐ mice but there was no effect of
PCSK9 expression on serum cholesterol levels compared with apoE‐/‐ controls. Interestingly, lesion
composition analysis showed significantly higher levels of Ly6Chigh positive cells in recipients of
hPCSK9/apoE‐/‐ bone marrow cells compared to controls (7.4±1.5% vs. 5.6±1.1%, respectively, p<0.05). To
test whether the effects of hPCSK9 on inflammation were dependent on binding and degradation of LDLR in
macrophages, we transplanted bone marrow cells from PCSK9/LDLR‐/‐ or LDLR‐/‐ mice into LDLR‐/‐ recipients.
We observed that, despite a large amount of PCSK9 accumulated in the serum of transgenic mice, nearly
undetectable levels were found in the plaque. No differences were found between the two groups in terms
of cholesterol levels, lesion size and Ly6Chigh positive cells between the two groups.
Our results show for first time that human PCSK9 expression in macrophages directly influences
atherosclerotic plaque composition in the absence of changes in serum cholesterol levels, suggesting a
direct effect of PCSK9 in macrophage inflammation and plaque development. The effect on inflammation is
dependent on LDLR since no effects in lesion composition were found in its absence.
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Kourimate, Sanae. "Pcsk9 : régulation et implication dans le syndrome métabolique." Nantes, 2008. https://archive.bu.univ-nantes.fr/pollux/show/show?id=4ac185ba-f999-45ff-9241-4278a9699b5c.
Abstract:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) est une serine protéase, jouant un rôle important dans la régulation des niveaux de cholestérol circulant. Les mutations gains de fonctions de PCSK9 sont associées à une hypercholestérolémie autosomale dominante due à une élévation des concentrations en Low Density Lipoprotein associées au cholestérol (LDLc). A l'inverse, des mutations perte de fonction de PCSK9, sont associées à une diminution de ces concentrations et à une réduction de 88% du risque d'apparition de maladies coronariennes. Dans le réticulum endoplasmique, Pro-PCSK9 subit un autoclivage indispensable à sa maturation et à sa sécrétion. PCSK9 circulante se lie au domaine EGF-A du récepteur aux LDL (LDLR) et entraîne sa dégradation lysosomale. Tout comme le LDLR, PCSK9 est positivement régulé par les statines via le Sterol Responsive element Binding Protein -2 (SREBP2). Les statines sont très utilisées en clinique pour leurs effets hypocholestérolémiants, ajouter des inhibiteurs de PCSK9 pourrait améliorer leur efficacité. Le premier objectif a été de caractériser la régulation négative de PCSK9 par le récepteur nucléaire Peroxisome Proliferator Activated Receptor alpha (PPARα) et ses agonistes synthétiques : les fibrates. Les résultats obtenus in vitro sur des lignées d’hépatocytes humains révèlent que l’activation de PPARα réprime la transcription de PCSK9 -via une répression de son promoteur- suppriment son activation par les statines, et potentialise l’effet des statines sur l’activité du LDLR. De plus, ces résultats révélèrent que la furine et PC5/6A -deux protéines convertases qui dégradent PCSK9- sont également régulées positivement par PPARα. Au-delà de PCSK9, cette étude a permis d’identifier une nouvelle famille d’enzyme régulée par les fibrates : les pro-protéines convertases. La deuxième partie de mes travaux de thèse a porté sur la mise au point d’un test flurorométrique de dosage de l’activité autocatalytique de PCSK9. La spécificité de notre approche a été de considérer non pas la protéine recombinante purifiée, qui semble dépourvue d’activité pour une raison inconnue, mais la forme endogène des hépatocytes. Après avoir validé ce test sur des hépatocytes primaires de souris PCSK9-/-, je l’ai appliqué à l’étude de divers mutants de PCSK9. Enfin, suite aux travaux du laboratoire sur la régulation de PCSK9 par l'insuline, j’ai également caractérisé l’expression de PCSK9 dans divers modèles animaux de diabète et d’insulinorésistance. PCSK9 est une cible thérapeutique sérieuse pour diminuer le LDL-c. D'après ces résultats, l’inhibition transcriptionnelle de PCSK9 par les fibrates semble être très prometteuse. Cependant, en clinique les fibrates sont préférentiellement utilisés pour leurs propriétés hypotriglycéridémiantes, puisque leurs effets sur le cholestérol restent limités. Existerait-il in vivo un mécanisme inhibiteur de cette voie? L'identifier serait une des perspectives qu'ouvre cette thèseProprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the serine protease family. Gain of function mutations within PCSK9 are associated with dominant forms of familial hypercholesterolemia. Inversely, humans harbouring loss of function mutations have a significant plasma LDLc reduction and a 88% decrease of the risk of coronary heart disease. In the endoplasmic reticulum Pro-PCSK9 undergoes an autocalytique clivage that is crucial for its secretion. Then, this secreted protein binds to the EGF-A domain of the LDLR and targets it to the lysosomes rather than to the cell surface. Both PCSK9 and the LDLR are up-regulated by statins via SREBP2. Using PCSK9 inhibitors may optimize the effects of this hypocholesterolemic drug. The first aim of my thesis was to investigate in vitro the mechanisms of PCSK9 repression by the fibrates which are PPARα synthetic agonists. Activation of PPARα down-regulates PCSK9 transcription at the promoter level and increase the expression of two others Proprotein convertases: furin and PC5/6A which are known to degrade PCSK9. Fibrates counteracts PCSK9 induction by statins and amplifies the effects of this hypocholesterolemic drugs on the LDLR acitivity. The second part of my studies was based on measuring the endogenous cleavage activity of PCSK9, using a fluorogenic peptide corresponding to the cleavage site of Pro-PCSK9. After validation of the specificity of this assay on mice primary hepatocytes from PCSK9-/-, I applied it to the test of several PCSK9 variants. The final part of my studies dealt about the characterisation of PCSK9 expression in diabetic and insulin resistant animal models. PCSK9 is an attractive therapeutic target for lowering plasma LDLc levels. This study clearly showed that PCSK9 transcriptional inhibition by fibrates might be envisaged in combination with statins. However, in vivo, in humans, the fibrates are rather known for their hypotriglyceridemic properties. The limited effect of fibrates on lowering LDLc might be explained by a counteracting pathway. Identifying this pathway is one of the promising perspectives of this thesis
10
CANCLINI, LAURA. "PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 PREFERENTIALLY ASSOCIATES WITH A SPECIFIC LDL SUBFRACTION: A DETAILED CHARACTERIZATION AND STUDY OF THE EFFECTS OF ANTI-PCSK9 MABS TREATMENT." Doctoral thesis, Università degli Studi di Milano, 2022. https://hdl.handle.net/2434/947250.
Abstract:
BACKGROUND AND AIM: Proprotein Convertase Subtilysin/Kexin Type 9 is a key regulator of LDL-C levels. Nevertheless, its physiological modulation is not fully understood. It is unclear whether PCSK9 has biological effects other than degrading the LDLR; consensus is lacking also on how PCSK9 is transported in the bloodstream, and whether this influences PCSK9 function. There are several conflicting data about PCSK9’s possible association with different lipoprotein subtypes. The biological function of the lipoprotein-bound PCSK9, also, is still a matter of debate. Due to its role in modulating plasma cholesterol levels, several approaches have been developed to modulate PCSK9 activity. Anti-PCSK9 mAbs represent the most advanced clinical available strategy for PCSK9 pharmacological inhibition, followed by the siRNA approach which seems promising. In this context, our aims were: 1) to establish a valid experimental procedure for the study of the possible association between PCSK9 and plasma lipoproteins. This would help us reach a clear idea about PCSK9’s lipoprotein compartmentation. 2) To characterize the lipoprotein fraction that binds PCSK9; 3) to address whether anti-PCSK9 mAbs therapy interferes with the PCSK9-LPs association, with resulting biological consequences. The capacity of PCSK9 to bind different lipoproteins raises the possibility that changes in the lipoprotein compartmentalization could regulate PCSK9 activity, and mAbs possible effects on such interaction may have biological consequences thus affecting their own pharmacological action. The study of such regulatory mechanisms could represent a potential avenue for developing new cholesterol-lowering drugs. METHODS: To reach our first aim, we compared several well-established methods in the lipoprotein isolation technique to clarify whether PCSK9 associates differently with circulating lipoproteins. The lipoprotein fractions collected were quantified for their cholesterol, triglycerides, PCSK9, apoB, apo AI and Lp(a) content using clinical grade reactives or ELISA. They were further characterized through immunoblotting, agarose gel electrophoresis, transmission electron microscopy (TEM), lipidomic and mass spectrometry. Following this, we analyzed PCSK9’s lipoprotein distribution among OptiPrep UC-isolated lipoproteins, obtained from anti-PCSK9 mAbs treated subjects before therapy (T0), and 1 (T1), 3 (T3) and 6 (T6) months after the beginning of treatment. The collected lipoprotein fractions were further characterized as described above. RESULTS AND CONCLUSION: Based on our results, the PCSK9-LDL association exists and is sensitive to high salt concentrations. OptiPrep UC and FPLC are both suitable methods for the study of this association. We believe that PCSK9 circulates mostly as a free type of protein, and partially (approx. 10-20% of total recovered PCSK9) associated through its active form with a light LDL subfraction resembling an IDL. We believe that this association originates in the circulation, as we did not find PCSK9 in the VLDL-containing fractions. PCSK9 did not associate with Lp(a) or HDL. Anti-PCSK9 mAbs administration induced a large decrease in LDL-C levels, - from 140,3±64,8 mg/dL to 51,5±35,6 mg/dL before and after treatment, respectively - parallel with a drastic increase in PCSK9 plasma levels - from 409,4±123,3 ng/mL to 3802,3±1001,0 ng/mL (n=22); despite this, they did not affect the PCSK9-LDL association but instead induce a more than 10-fold increase in the absolute quantity of LDL-bound PCSK9. Interestingly, the amount of PCSK9 recovered in the LDL fractions after therapy was about 242,3±164,8 ng/mL, like that of plasma of untreated subjects; this suggested that the LDL-bound PCSK9 may be inactive. Preliminary data obtained from Inclisiran-treated subjects suggest that the PCSK9- LDL association is maintained also when reducing both LDL and PCSK9 levels, therefore reinforcing the idea that the PCSK9-LDL association might be biologically meaningful.
Books on the topic "PCSK1":
1
Gessner-Ulrich, Katrin. Untersuchungen zur Expression und Funktion des linearen, mitochondrialen Plasmides pC1K1 von Claviceps purpurea. Berlin: J. Cramer, 1992.
2
Xu, Weiming. New Cardiovascular Research: PCSK9 As a New Therapeutic Target for Cardiovascular Disease. Independently Published, 2021.
3
Atta-ur-Rahman and M. Iqbal Choudhary, eds. Frontiers in Cardiovascular Drug Discovery: Volume 4. BENTHAM SCIENCE PUBLISHERS, 2019. http://dx.doi.org/10.2174/97816810839951180401.
Abstract:
Frontiers in Cardiovascular Drug Discovery is an eBook series devoted to publishing the latest advances in cardiovascular drug design and discovery. Each volume brings reviews on the biochemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships of molecules used in cardiovascular therapy. The eBook series should prove to be of great interest to all medicinal chemists and pharmaceutical scientists involved in preclinical and clinical research in cardiology. The fourth volume of the series covers the following topics: -Aspirin administration -Adenosine receptor targeting for cardiovascular therapy -Drug treatment of patients with coronary stenting -Immunosuppressive drugs in heart transplantation -PCSK9 inhibition for lowering LDL-C levels.
Book chapters on the topic "PCSK1":
1
Choquet, Hélène, Pieter Stijnen, and John W. M. Creemers. "Genetic and Functional Characterization of PCSK1." In Methods in Molecular Biology, 247–53. Totowa, NJ: Humana Press, 2011. http://dx.doi.org/10.1007/978-1-61779-204-5_13.
2
Wright, R. Scott. "PCSK9 Inhibiting siRNA." In Stroke Revisited: Dyslipidemia in Stroke, 135–43. Singapore: Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-16-3923-4_12.
3
Ahmed, Zain, Prerak Juthani, Megan Lee, and Nihar R. Desai. "PCSK9 Inhibiting Monoclonal Antibodies." In Stroke Revisited: Dyslipidemia in Stroke, 125–33. Singapore: Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-16-3923-4_11.
4
Desnick, Robert J., Orlando Guntinas-Lichius, George W. Padberg, Gustav Schonfeld, Xiaobo Lin, Maurizio Averna, Pin Yue, et al. "FHBL due to Defective PCSK9." In Encyclopedia of Molecular Mechanisms of Disease, 653. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-29676-8_8889.
5
Wang, Zuo, Zhi-Han Tang, Yun-Chen Lv, Lu-Shan Liu, and Zhi-Sheng Jiang. "Bioinformatic Analysis of PCSK9 Related Caspase3 Activation." In Recent Advances in Computer Science and Information Engineering, 527–33. Berlin, Heidelberg: Springer Berlin Heidelberg, 2012. http://dx.doi.org/10.1007/978-3-642-25778-0_73.
6
Ooi, Teik Chye, and Hussein Abujrad. "PCSK9 as a Biomarker of Cardiovascular Disease." In Biomarkers in Cardiovascular Disease, 125–51. Dordrecht: Springer Netherlands, 2016. http://dx.doi.org/10.1007/978-94-007-7678-4_20.
7
Ooi, Teik Chye, and Hussein Abujrad. "PCSK9 as a Biomarker of Cardiovascular Disease." In Biomarkers in Cardiovascular Disease, 1–27. Dordrecht: Springer Netherlands, 2015. http://dx.doi.org/10.1007/978-94-007-7741-5_20-1.
8
Farnier, Michel. "Statins and PCSK9 Inhibitors: Defining the Correct Patients." In Combination Therapy In Dyslipidemia, 99–117. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-20433-8_9.
9
Innocenti, Francesca, Valentina Di Maria, Alice Poggi, and Riccardo Pini. "Biomarkers of Sepsis and a Focus on PCSK9." In Biomarkers in Trauma, Injury and Critical Care, 1–28. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-87302-8_40-1.
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Innocenti, Francesca, Valentina Di Maria, Alice Poggi, and Riccardo Pini. "Biomarkers of Sepsis and a Focus on PCSK9." In Biomarkers in Trauma, Injury and Critical Care, 785–812. Cham: Springer International Publishing, 2023. http://dx.doi.org/10.1007/978-3-031-07395-3_40.
Conference papers on the topic "PCSK1":
1
Sha, Xiangtong, and Yueqiang Wang. "PCSK1 Variants and Obesity: Relationship in Different Population." In 2021 International Conference on Public Art and Human Development ( ICPAHD 2021). Paris, France: Atlantis Press, 2022. http://dx.doi.org/10.2991/assehr.k.220110.187.
2
Vistica, David T., Susan Kenney, Dominic A. Scudiero, Russell A. Reinhart, Michael H. Selby, Donna O. Butcher, and Robert H. Shoemaker. "Abstract 1621: The proprotein convertase PCSK1 is a novel drug target in alveolar soft part sarcoma (ASPS)." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-1621.
3
Tent, Michiel. "Oral PCSK9 inhibitor significantly lowers LDL-C." In ACC 2023 Scientific Session, edited by Marc Bonaca. Baarn, the Netherlands: Medicom Medical Publishers, 2023. http://dx.doi.org/10.55788/629cbf29.
4
Martin Plagaro, Cesar, Kepa B. Uribe, Asier Benito Vicente, Rocio Alonso Estraba, Unai Galicia Garcia, Shifa Jebari Benslaiman, and Asier Larrea Sebal. "Hiperkolesterolemia Familiarra: PCSK9 aldaeren karakterizazioa tratamendu pertsonalizaturako." In III. Ikergazte. Nazioarteko ikerketa euskaraz. Bilbao: UEU arg, 2019. http://dx.doi.org/10.26876/ikergazte.iii.04.10.
5
Niemann, B., L. Li, F. Knapp, R. Schulz, and S. Rohrbach. "Modifying Epicardial PCSK9 Expression to Protect Cardiac Function?" In 48th Annual Meeting German Society for Thoracic, Cardiac, and Vascular Surgery. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1678923.
6
Ferrer Machín, A., S. Martin Rodriguez, J. Vilar Rodriguez, MDLA Padron Garcia, M. Vera Cabrera, J. Arias Blaco, and MDC Villastrigo Garcia. "4CPS-178 Effect of pcsk9 inhibitors on hypercholesterolemia." In 28th EAHP Congress, Bordeaux, France, 20-21-22 March 2024. British Medical Journal Publishing Group, 2024. http://dx.doi.org/10.1136/ejhpharm-2024-eahp.282.
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Lecis, M., E. Viglione, S. Strobino, and G. Ceravolo. "5PSQ-017 PCSK-9 inhibitors: real world effectiveness." In 25th EAHP Congress, 25th–27th March 2020, Gothenburg, Sweden. British Medical Journal Publishing Group, 2020. http://dx.doi.org/10.1136/ejhpharm-2020-eahpconf.334.
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Martin, V. Merino, MP Ortega-Garcia, P. Blasco-Segura, J. Sanfeliu Garcia, A. Lopez Carrasco, R. del Rio San Cristobal, and I. Toledo Guasp. "4CPS-035 Effectiveness and safety of monoclonal antibody pcsk9 inhibitors." In Abstract Book, 23rd EAHP Congress, 21st–23rd March 2018, Gothenburg, Sweden. British Medical Journal Publishing Group, 2018. http://dx.doi.org/10.1136/ejhpharm-2018-eahpconf.126.
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Ly, Kévin, Anna Kwiatkowska, Sophie Routhier, Roxane Desjardins, Monika Lewandowska, Adam Prahl, Josée Hamelin, Nabil G. Seidah, Yves Dory, and Robert Day. "Development of Peptide Inhibitors Disrupting PCSK9-LDLR Protein-Protein Interactions." In The Twenty-Third American and the Sixth International Peptide Symposium. Prompt Scientific Publishing, 2013. http://dx.doi.org/10.17952/23aps.2013.110.
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Sáez Rodríguez, MI, JJ Arenas Villafranca, B. Montero Salgado, PA Chinchurreta Capote, and B. Tortajada Goitia. "4CPS-119 Real-world experience with PCSK9 inhibitors protocol for hypercholesterolaemia." In 26th EAHP Congress, Hospital pharmacists – changing roles in a changing world, 23–25 March 2022. British Medical Journal Publishing Group, 2022. http://dx.doi.org/10.1136/ejhpharm-2022-eahp.146.
Reports on the topic "PCSK1":
1
Zhang, Lingnan, Fang Zhang, Xinwei Jia, Junmin Xie, Yeran Zhu, Xiaozhe Zhou, and Chang Meng. Targeting PCSK9 in Heterozygous familial hypercholesterolemia: a meta-analysis of randomized controlled trials. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, March 2024. http://dx.doi.org/10.37766/inplasy2024.3.0095.
2
Yu, Yani, Lei Chen, Honghong Zhang, Zihao Fu, Qi Liu, Haijing Zhao, Yuqi Liu, and Yundai Chen. Racial differences in the safety and efficacy of PCSK9 inhibitors in the treatment of hyperlipidemia：A Systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, November 2021. http://dx.doi.org/10.37766/inplasy2021.11.0047.
3
Niu, Xiaowei, and Shuwen Hu. Efficacy and safety of PCSK9 inhibitors and statin lipid-lowering therapy in coronary atherosclerosis: A meta-analysis of randomized trials. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, December 2022. http://dx.doi.org/10.37766/inplasy2022.12.0019.
4
Sun, Jing-Chao. The intense lipid-lowering strategies of PCSK9 inhibitor or ezetimibe for cardiovascular events in patients with coronary heart disease: a systemic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, April 2023. http://dx.doi.org/10.37766/inplasy2023.4.0040.