Proprotein Convertase Subtilisin/kexin Type 9 Gene Research Articles

Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study.

Pharmacological inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is an established therapeutic option to treat hypercholesterolemia, and plasma PCSK9 levels have been implicated in cardiovascular disease incidence. A number of genetic variants within the PCSK9 gene locus have been shown to modulate PCSK9 levels, but these only explain a very small percentage of the overall PCSK9 interindividual variation. Here we present data on the genetic association structure between PCSK9 levels and genom-wide genetic variation in a healthy sample from the general population. We performed a genome-wide association study of plasma PCSK9 levels in a sample of Brazilian individuals enrolled in the Estudo Longitudinal de Saude do Adulto cohort (n=810). Enrolled individuals were free from cardiovascular disease, diabetes and were not under lipid-lowering medication. Genome-wide genotyping was conducted using the Axiom_PMRA.r3 array, and imputation was performed using the TOPMED multi-ancestry sample panel as reference. Total PCSK9 plasma concentrations were determined using the Quantikine SPC900 ELISA kit. We observed two genome-wide significant loci and seven loci that reached the pre-defined value of p threshold of 1×10−6. Significant variants were near KCNA5 and KCNA1, and LINC00353. Genetic variation at the PCSK9 locus was able to explain approximately 4% of the overall interindividual variations in PCSK9 levels. Colocalization analysis using eQTL data suggested RWDD3, ATXN7L1, KCNA1, and FAM177A1 to be potential mediators of some of the observed associations. Our results suggest that PCSK9 levels may be modulated by trans genetic variation outside of the PCSK9 gene and this may have clinical implications. Understanding both environmental and genetic predictors of PCSK9 levels may help identify new targets for cardiovascular disease treatment and contribute to a better assessment of the benefits of long-term PCSK9 inhibition.

PCSK9 E670G (rs505151) Variant and Coronary Artery Disease Risk Among Diabetics.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme in the family of proprotein convertases implicated in lipid metabolism and is a significant genetic risk factor in cardiovascular diseases among various populations. Aim of the Study: This study explored the correlation between the alleles of the rs505151 (E670G) locus of the PCSK9 gene and its expression levels with coronary artery disease (CAD) risk in Egyptian patients with type 2 diabetes mellitus (T2DM). Subjects and Methods: A case-control study was performed on 112 lean subjects compared to 100 T2DM patients without CAD and 84 T2DM patients with CAD to investigate the relationships among PCSK9 expression levels, the E670G (rs505151) gene variant, lipid concentrations, and CAD risk in an Egyptian diabetic population. A restriction fragment length polymorphism-polymerase chain reaction (PCR) assay was used to assess the gene polymorphism, and PCSK9 mRNA expression was determined by quantitative real-time PCR. Results: The prevalence of the E670G (rs505151) AG genotype in diabetics with CAD was significantly greater than the other two groups. The PCSK9 gene expression levels in diabetics with CAD were significantly greater than the other two groups. G allele carriers (AG+GG) had a higher relative PCSK9 expression than A allele carriers. Conclusion: PCSK9 relative expression levels and the E670G (rs505151) AG genotype are CAD risk factors among Egyptian diabetics and are linked positively to the atherogenic index of plasma.

PCSK9 Gene Polymorphisms Associated With the Risk of Myocardial Infarction in Iranian Patients

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulatory protein in lipid metabolism and a candidate gene in the etiology of cardiovascular diseases. The present study aimed to evaluate the prevalence and significance of PCSK9 rs505151 and rs11591147 variants with myocardial infarction (MI) risk in the Iranian population. Patients and Methods: The frequency of the PCSK9 rs505151 and rs11591147 variants were compared between 600 cases of MI and 600 healthy age- and sex-matched individuals. Tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS PCR) was used for rs505151, and amplification refractory mutation system-polymerase chain (ARMS-PCR) was utilized to detect the rs11591147 polymorphism. Finally, SPSS and SHEsis software were applied for data analysis. Results: Carriers of the GG genotype of rs505151 polymorphism (OR: 1.57, 95% CI: 1.05–2.35, P = 0.02; age-adjusted; OR: 1.54, 95% CI: 1.03–2.32, P = 0.03) and at least one G-allele including GG+AG vs. AA (OR: 1.54, 95% CI: 1.04–2.28, P = 0.03; age-adjusted; OR: 1.51, 95% CI: 1.01–2.24, P = 0.04) have an increased risk of MI. No association between PCSK9 rs505151 alleles and MI risk was observed. The ratio of individuals with the rs11591147GT variant was higher in healthy individuals vs. patients with MI (48.6% vs. 41.7%), indicating a reduced risk of developing MI (OR: 0.75; 95% CI: 0.59–0.95; P = 0.01; age-adjusted; OR: 0.74; 95% CI: 0.58–0.95; P = 0.01). The carriers of at least one T allele (TT+GT vs. GG) (OR: 0.78; 95% CI: 0.62–0.98; P = 0.03; age-adjusted; OR: 0.78; 95% CI: 0.62–0.98; P = 0.03) showed a significant reduction in MI risk. The allelic frequencies at this polymorphic site did not differ between MI patients and healthy counterparts. No association was found between the haplotypes constructed from the alleles of these two polymorphisms. Conclusion: Our study provides the first evidence that PCSK9 gene polymorphisms may serve as independent prognostic markers for MI patients in Iran.

Protective lipid-lowering variants in healthy older individuals without coronary heart disease

ObjectiveGenetic variants that disrupt the function of the PCSK9 (proprotein convertase subtilisin kexin type 9) and APOB (apolipoprotein B)genes result in lower serum low-density lipoprotein cholesterol (LDL-C) levels and subsequently...

PCSK9 genetic (rs11591147) and epigenetic (DNA methylation) modifications associated with PCSK9 expression and serum proteins in CAD patients.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) genetic polymorphisms play a significant role in cholesterol homeostasis. Therefore, we aimed to investigate the association of PCSK9 genetic variations NM_174936.3:c.137G>T (R46L, rs11591147) and NM_174936.3:c.1120G>T (D374Y, rs137852912), as well as promoter DNA methylation status, with mRNA expression and circulating serum protein levels in coronary artery disease (CAD) patients. The present study includes 300 CAD cases and 300 controls from South India. Biochemical assays were performed using commercially available kits. PCSK9 rs11591147 and rs137852912 polymorphisms were analyzed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method, whereas promoter DNA methylation status and gene expression were determined using methylation specific PCR and quantitative PCR respectively. The genotypic distribution of PCSK9 rs11591147 revealed that individuals with the TT-genotype and T-allele have a reduced risk for CAD. Furthermore, patients with the PCSK9 rs11591147 TT genotype have a significantly lower total cholesterol and low-density lipoprotein-cholesterol levels and also higher high-density lipoprotein-cholesterol levels than individuals with the GG genotype. Logistic regression analysis has shown that the GG and GT (p =1.51 × 10-8 , p =1.47 × 10-9 ) genotypes predicted the risk for CAD with an odds ratio of 5.8 and 7.3 respectively. In addition, individuals with the TT genotype were hypermethylated at promoter DNA of PCSK9, resulting in lower mRNA expression and circulating serum proteins than in individuals with the GG genotype. In silico analyses revealed that rs11591147 T-allele has protein destabilizing capacity. In conclusion, the present study indicates that the PCSK9 gene expression and circulating serum protein levels are not only associated with rs11591147 genotype, but also with promoter DNA methylation. Furthermore, the findings with respect to both single nucleotide polymorphism and promoter DNA methylation may open avenues for novel treatment possibilities targeting PCSK9 for CAD management.

PCSK9 and the Gut-Liver-Brain Axis: A Novel Therapeutic Target for Immune Regulation in Alcohol Use Disorder.

Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to control or stop alcohol intake and is associated with organ damage including alcohol-associated liver disease (ALD) and progressive neurodegeneration. The etiology of AUD is complex, but organ injury due to chronic alcohol use can be partially attributed to systemic and local inflammation along the gut-liver-brain axis. Excessive alcohol use can result in translocation of bacterial products into circulation, increased expression of pro-inflammatory cytokines, and activation of immune cells, including macrophages and/or microglia in the liver and brain. One potential mediator of this alcohol-induced inflammation is proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is primarily known for its regulation of plasma low-density lipoprotein cholesterol but has more recently been shown to influence inflammatory responses in the liver and brain. In rodent and post-mortem brain studies, chronic alcohol use altered methylation of the PCSK9 gene and increased expression of PCSK9 in the liver and cerebral spinal fluid. Additionally, PCSK9 inhibition in a rat model of ALD attenuated liver inflammation and steatosis. PCSK9 may play an important role in alcohol-induced pathologies along the gut-liver-brain axis and may be a novel therapeutic target for AUD-related liver and brain inflammation.

Molecular Genetic Approach and Evaluation of Cardiovascular Events in Patients with Clinical Familial Hypercholesterolemia Phenotype from Romania.

This study identifies the genetic background of familial hypercholesterolemia (FH) patients in Romania and evaluates the association between mutations and cardiovascular events. We performed a prospective observational study of 61 patients with a clinical diagnosis of FH selected based on Dutch Lipid Clinic Network (DLCN) and Simon Broome score between 2017 and 2020. Two techniques were used to identify mutations: multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. The mutation rate was 37.7%, i.e., 23 patients with mutations were identified, of which 7 subjects had pathogenic mutations and 16 had polymorphisms. Moreover, 10 variants of the low-density lipoprotein receptor (LDLR) gene were identified in 22 patients, i.e., one variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in six patients, and one variant of the apolipoprotein B (APOB) gene in three patients. Of the LDLR gene variants, four were LDLR pathogenic mutations (c.81C > G, c.502G > A, c.1618G > A mutations in exon 2, exon 4, exon 11, and exon 13–15 duplication). The PCSK9 and APOB gene variants were benign mutations. The pathogenic LDLR mutations were significant predictors of the new cardiovascular events, and the time interval for new cardiovascular events occurrence was significantly decreased, compared to FH patients without mutations. In total, 12 variants were identified, with four pathogenic variants identified in the LDLR gene, whereas 62.3% of the study population displayed no pathological mutations.

Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993–2020

Background and aimsIn this study, we present the status regarding molecular genetic testing for mutations in the genes encoding the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) as causes of autosomal dominant hypercholesterolemia (ADH) in Norway. MethodsWe have extracted data from the laboratory information management system at Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital for the period 1993–2020. This laboratory is the sole laboratory performing molecular genetic testing for ADH in Norway. ResultsA total of 29,449 unrelated hypercholesterolemic patients have been screened for mutations in the LDLR gene, in the APOB gene and in the PCSK9 gene. Of these, 2818 (9.6%) were heterozygotes and 11 were homozygotes or compound heterozygotes. Most of the 264 different mutations identified were found in the LDLR gene. Only two and three mutations were found in the APOB gene or in the PCSK9 gene, respectively. Several founder mutations were identified. After testing of 14,230 family members, a total of 8811 heterozygous patients have been identified. Of these, 94.0% had a mutation in the LDLR gene, 5.4% had a mutation in the APOB gene and 0.6% had a mutation in the PCSK9 gene. ConclusionsA large proportion of Norwegian ADH patients have been provided with a molecular genetic diagnosis. Norway is probably only second to the Netherlands in this respect. A molecular genetic diagnosis may form the basis for starting proper preventive measures and for identifying affected family members by cascade genetic screening.

Effect of PCSK9 E670G and R46L Polymorphisms on Major Adverse Cardio-Cerebrovascular Events in Patients with ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

AbstractMajor adverse cardio-cerebrovascular events (MACCE) in ST-segment elevation myocardial infarction (STEMI) are still high, although there have been advances in pharmacology and interventional procedures. Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a serine protease regulating lipid metabolism associated with inflammation in acute coronary syndrome. The MACCE is possibly related to polymorphisms in PCSK9. A prospective cohort observational study was designed to confirm the association between polymorphism of E670G and R46L in the PCSK9 gene with MACCE in STEMI. The Cox proportional hazards model and Spearman correlation were utilized in the study. The Genotyping of PCSK9 and ELISA was assayed.Sixty-five of 423 STEMI patients experienced MACCE in 6 months. The E670G polymorphism in PCSK9 was associated with MACCE (hazard ratio = 45.40; 95% confidence interval: 5.30–390.30; p = 0.00). There was a significant difference of PCSK9 plasma levels in patients with previous statin consumption (310 [220–1,220] pg/mL) versus those free of any statins (280 [190–1,520] pg/mL) (p = 0.001).E670G polymorphism of PCSK9 was associated with MACCE in STEMI within a 6-month follow-up. The plasma PCSK9 level was higher in statin users.

The Cholesterol-Lowering Effect of Capsella Bursa-Pastoris Is Mediated via SREBP2 and HNF-1α-Regulated PCSK9 Inhibition in Obese Mice and HepG2 Cells

The objective of the present study was to investigate the mechanism by which capsella bursa-pastoris ethanol extract (CBE), containing 17.5 milligrams of icaritin per kilogram of the extract, and icaritin, mediate hypocholesterolemic activity via the low-density lipoprotein receptor (LDLR) and pro-protein convertase subtilisin/kexin type 9 (PCSK9) in obese mice and HepG2 cells. CBE significantly attenuated serum total and LDL cholesterol levels in obese mice, which was associated with significantly decreased PCSK9 gene expression. HepG2 cells were cultured using delipidated serum (DLPS), and CBE significantly reduced PCSK9 and maintained the LDLR level. CBE co-treatment with rosuvastatin attenuated statin-mediated PCSK9 expression, and further increased LDLR. The icaritin contained in CBE decreased intracellular PCSK9 and LDLR levels by suppressing transcription factors SREBP2 and HNF-1α. Icaritin also significantly suppressed the extracellular PCSK9 level, which likely contributed to post-translational stabilization of LDLR in the HepG2 cells. PCSK9 inhibition by CBE is actively attributed to icaritin, and the use of CBE and icaritin could be an alternative therapeutic approach in the treatment of hypercholesterolemia.

Proprotein Convertase Subtilisin/Kexin Type 9 Gene Variants in Familial Hypercholesterolemia: A Systematic Review and Meta-Analysis

Proprotein Convertase Subtilisin Kexin type 9 (PCSK9), comprises 12 exons, encoded for an enzyme which plays a critical role in the regulation of circulating low density lipoprotein. The gain-of-function (GOF) mutations aggravate the degradation of LDL receptors, resulting in familial hypercholesterolemia (FH), while loss-of-function (LOF) mutations lead to higher levels of the LDL receptors, lower the levels of LDL cholesterol, and preventing from cardiovascular diseases. It is noted that, previous publications related to the mutations of PCSK9 were not always unification. Therefore, this study aims to present the spectrum and distribution of PCSK9 gene mutations by a meta-analysis. A systematic literature analysis was conducted based on previous studies published by using different keywords. The weighted average frequency of PCSK9 mutation was calculated and accessed by MedCalc®. A total of 32 cohort studies, that included 19,725 familial hypercholesterolemia blood samples, were enrolled in the current study. The analysis results indicated that, based on the random-effect model, the weighted prevalence of PCSK9 mutation was 5.67% (95%CI = 3.68–8.05, p < 0.0001). The prevalence of PCSK9 GOF mutations was 3.57% (95%CI = 1.76–5.97, p < 0.0001) and PCSK9 LOF mutations was 6.05% (95%CI = 3.35–9.47, p < 0.0001). Additionally, the first and the second exon were identified as the hot spot of mutation occurred in PCSK9. Both GOF and LOF mutations have a higher proportion in Asia and Africa compared with other regions. The GOF PCSK9 p.(Glu32Lys) and LOF PCSK9 p.(Leu21dup/tri) were dominant in the Asia region with the proportion as 6.58% (95%CI = 5.77–7.47, p = 0.62) and 16.20% (95%CI = 6.91–28.44, p = 0.0022), respectively. This systematic analysis provided scientific evidence to suggest the mutation of PCSK9 was related to the metabolism of lipoprotein and atherosclerotic cardiovascular disease.

Case report: Prevention of apheresis reactions with icatibant

The familial hyperlipidemias are genetic disorders that are characterized by marked elevations of low-density lipoprotein cholesterol (LDL-C) in the serum.1 Patients with these disorders are at very high risk for coronary artery disease and xanthomas. In addition to specific diets and weight loss, treatment of these disorders usually consists of statins, aspirin, ezetimibe (an inhibitor of absorption of cholesterol from the small intestine) and evolocomab (a monoclonal antibody that inhibits the PCSK9 (pro-protein convertase subtilisin/kexin type 9) gene.

Association of the rs562556 PCSK9 Gene Polymorphism with Reduced Mortality in Severe Malaria among Malian Children.

Recent evidence suggests that proprotein convertase subtilisin/kexin type 9 (PCSK9), a downmodulator of cellular uptake of blood cholesterol, also negatively impacts host immune response to microbial infection. In this study, we investigated whether carrying the loss-of-function (LOF) rs562556 (c.1420 A > G; p.I474 V) PCSK9 single nucleotide polymorphism (SNP) affected the outcome of severe malaria in children. Archival DNA of a cohort of 207 Malian children suffering from severe malaria was genotyped for the rs562556 SNP. Sixty-four children were either heterozygous or homozygous for the minor G allele (carriers); 143 children were homozygous for the common A allele (noncarriers). Among carriers, there was one mortality case (1.6%), compared to 15 cases (10.5%) among noncarriers (p=0.0251), suggesting that the G allele is associated with better survival in severe malaria. Intriguingly, this allele did not negatively segregate with any of the clinical symptoms linked to mortality in this cohort. Studies are needed to determine whether PCSK9 inactivation promotes a protective immune response to malaria infection.

Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9: The Role of STAT3

In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokine levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of STAT3. In HepG2 cells, leptin and resistin up-regulated PCSK9 gene and protein expression, as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knockdown of STAT3 did not affect the expression of leptin and resistin receptors or that of PCSK9. The analysis of the human PCSK9 promoter region showed that the two adipokines raised PCSK9 promoter activity via the involvement of a sterol regulatory element motif. In healthy males, a positive association between circulating leptin and PCSK9 levels was found only when the body mass index was <25 kg/m2. In conclusion, this study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9.

Effect of Modified Aspirin and Isoxsuprine Analogs on Ischemic Heart Disease

Ischemic heart disease (IHD) or coronary artery disease (CAD) is one of the largest death-causing reasons in developing countries. Approximately, every year 15 million deaths due to IHD are reported worldwide. PLG (Plasminogen), PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9), CXCL12 (C-X-C Motif Chemokine Ligand 12), and EDNRA (Endothelin Receptor type A) genes were selected for the study due to their higher rate of mutations in IHD. Drugs that are being used to cure IHD were reformulated by structurally modifying them for repurposing. Reformulated drugs were further analyzed for side effects, toxicity, and ADMET (Absorption, Distribution, Metabolism, Excreation, Toxicity) properties. Molecular docking studies of reformulated drugs with selected genes were performed to determine their efficacy to cure IHD. Interacting amino acid residues in the docked complex of aspirin were identified as Aspartic acid, Arginine, Tyrosine, Proline, Valine, Alanine, Threonine, Iso Leusine, Lysine, Triptophan, Aspargine, Histadine, Cystine. Similarly, for isoxsuprine the residues were Valine, Aspargine, Leucine, Argining, Iso Leucine, Glutamic acid, Lysine, Glycine, Proline, Threonine, Aspartic acid, Histadine and Arginine. In reformulated compounds, the addition of sulfur in the aspirin compound reduced the toxicity from class 3 to class 5 and in isoxsuprine, the addition of nitrogen hydrogen bond in the second aromatic ring reduced its toxicity from class 3 to class 4. It is suggested that both aspirin and isoxsuprine analogs are more effective having least predicted side effects and toxicities than already existing aspirin and isoxsuprine. In the future, these drugs can be used as potential drugs for the treatment of IHD than original drugs because of their low toxicity and side effects. This study can be validated in vitro to confirm its efficacy.

PCSK9 Inhibitors and Cardiovascular Disease: Impact on Cardiovascular Outcomes.

Cardiovascular Disease (CVD) remains the leading cause of morbidity and mortality in the western world. Hypolipidemic drugs have long been used for the primary and secondary prevention of heart disease. However, the high frequency of recurrent events in patients despite hypolipidemic therapy has increased the need for new more targeted therapeutic approaches. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are monoclonal antibodies to the PCSK9 gene and represent a new class of drugs that have been shown to further decrease LDL-C when administered as a monotherapy or in combination with statins. In addition to LDL reduction, PCSK9 inhibitors are shown to decrease apolipoprotein B and lipoprotein (a) levels without major adverse effects. Whether or not PCSK9 inhibitors can actually reduce the incidence of cardiovascular events and ameliorate CVD prognosis is yet to be clarified. This review summarizes recent literature on the safety and efficacy of PCSK9 inhibitors on CVD outcome and its potential role in the management of patients with high-risk cardiovascular disease.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in the Brain and Relevance for Neuropsychiatric Disorders.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has long been studied in the liver due to its regulation of plasma low-density lipoprotein cholesterol (LDL-C) and its causal role in familial hypercholesterolemia. Although PCSK9 was first discovered in cerebellar neurons undergoing apoptosis, its function in the central nervous system (CNS) is less clear. PCSK9 has been shown to be involved in neuronal differentiation, LDL receptor family metabolism, apoptosis, and inflammation in the brain, but in vitro and in vivo studies offer contradictory findings. PCSK9 expression in the adult brain is low but is highly upregulated during disease states. Cerebral spinal fluid (CSF) PCSK9 concentrations are correlated with neural tube defects and neurodegenerative diseases in human patients. Epigenetic studies reveal that chronic alcohol use may modulate methylation of the PCSK9 gene and genetic studies show that patients with gain-of-function PCSK9 variants have higher LDL-C and an increased risk of ischemic stroke. Early safety studies of the PCSK9 inhibitors evolocumab and alirocumab, used to treat hypercholesterolemia, hinted that PCSK9 inhibition may negatively impact cognition but more recent, longer-term clinical trials found no adverse neurocognitive events. The purpose of this review is to elucidate the role of PCSK9 in the brain, particularly its role in disease pathogenesis.

The benign c.344G > A: p.(Arg115His) variant in the LDLR gene interpreted from a pedigree-based genetic analysis of familial hypercholesterolemia

BackgroundWe previously identified the c.344G > A: p.(Arg115His) variant in the low-density lipoprotein receptor (LDLR) gene, which was interpreted as “conflicting interpretations of pathogenicity” in ClinVar, based on a genetic analysis of patients with familial hypercholesterolemia (FH). However, whether this variant affects the pathophysiology of FH remains unclear. Therefore, our aim was to annotate the c.344G > A: p.(Arg115His) variant in the LDLR gene in FH. We present 2 families harboring the c.344G > A: p.(Arg115His) variant in the LDLR gene.MethodsGenetic analyses were performed for the coding regions and the exon-intron boundary sequence of the LDLR and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes in 2 FH families. Next, the family without pathogenic variants in the LDLR and PCSK9 genes was screened by whole-exome sequencing. Detailed clinical and biochemical data were gathered from family members.ResultsIn one family, the index case had biallelic c.1567G > A: p.(Val523Met) and c.344G > A: p.(Arg115His) variants in the LDLR gene, while the sibling had only the c.1567G > A: p.(Val523Met) variant in the LDLR gene. There was no difference in the FH phenotype between the siblings. In another family, the index case and the sibling had no pathogenic variants in the LDLR, PCSK9, and apolipoprotein B (APOB) genes, but the sibling’s wife with nonFH had the c.344G > A: p.(Arg115His) variant in the LDLR gene. The sibling and his wife had 4 children, including an unaffected child and an affected child who had the c.344G > A: p.(Arg115His) variant in the LDLR gene. In addition, the allele frequency of the c.344G > A: p.(Arg115His) variant (0.0023–0.0043) in Japanese and East Asian populations is relatively high compared with that of the other LDLR pathogenic variants (0.0001–0.0008).ConclusionsThe c.344G > A: p.(Arg115His) variant in the LDLR gene is interpreted as benign in individuals with FH.

Changes in PCSK9 and LDL cholesterol concentrations by everolimus treatment and their effects on polymorphisms in PCSK9 and mTORC1.

The purpose of this study was to evaluate the effects of concentrations of proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein (LDL) cholesterol by the mammalian target of rapamycin (mTOR) inhibitor everolimus and their effects on genetic polymorphisms in the PCSK9 and mTORC1 genes in 53 renal transplant recipients. Prior to and on day 15 after everolimus administration, the concentrations of everolimus in blood and PCSK9 and LDL cholesterol in plasma were evaluated. Additionally, mTORC1 (rs2536T>C and rs2295080T>G) and PCSK9 (rs505151G>A, rs562556G>A, and rs11593680C>T) polymorphisms were analyzed. Mean PCSK9 plasma concentrations on day 15 after everolimus treatment were significantly higher than those before treatment (295 versus 214ng/mL, respectively; p = 0.004). Significant correlations between the area under the blood concentration-time curves (AUC)0-12 on day 15 of everolimus treatment and the change rate in PCSK9 concentrations were found (r = 0.316, p = 0.021). However, there were no significant correlations between the change rate in PCSK9 and LDL cholesterol concentrations. The change rate in PCSK9 concentrations by everolimus treatment was significantly greater in patients with the mTORC1 rs2295080G allele than the T/T genotype (p = 0.006); however, there were no significant differences between PCSK9 rs505151G>A and rs11583680C>T genotypes. In multivariate analyses, patients with mTORC1 rs2295080G (p = 0.010), higher everolimus AUC0-12 (p = 0.006), and female sex (p = 0.029) showed higher change rates of PCSK9 following everolimus therapy. Administration of everolimus significantly elevated plasma PCSK9 concentrations, potentially causing everolimus-induced hyperlipidemia.

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9): A Narrative Review

Coronary artery disease (CAD), the most common type of heart disease, is the leading reason for mortality in both developing and developed countries. Increased cholesterol and fatty deposits (called plaques) may cause hardening or narrowing of the arteries which supply blood to heart muscles. Triglycerides, low density lipoproteins (LDL), high density lipoproteins (HDL) are different types of cholesterols found in the blood and LDL is the main target for lipid modifying therapy, with the aim of improving long term CAD prognosis. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is one of the candidate genes with expression of PCSK9 protein and PCSK9 inhibitors are coming up as newer lipid lowering therapy. This narrative review highlights the journey of drug development from recognition of PCSK9 gene to the recent approvals of PCSK9 targeting LDL lowering pharmacotherapy. A bibliographic survey was made with titles PCSK9, PCSK9 inhibitors and coronary artery disease in different search engines from year 2000 to 2019 and filtered with review, preclinical and clinical studies. Retrieved articles were revisited and it was observed that PCSK9 is expressed mainly in hepatocytes and to some extent in mesenchymal cells of kidney, intestinal ileum, colon epithelia and in telencephalon neurons of embryonic brain. In hepatocytes, loss-of function mutations of PCSK9 leads to higher levels of LDL receptors. These receptors make LDL receptor-LDL cholesterol complex, which is directed to the lysosome for degradation of LDL in hepatocytes and lowers LDL cholesterol levels, ultimately resulting in protection from CAD. Gain-of-function mutations hamper LDL degradation. PCSK9 research has proposed an exciting new area for cholesterol management and CAD risk reduction. Different PCSK9 inhibitors with different therapeutic targets for CAD are evolving day by day from bench to bedside. This review could be valuable for helping researchers acquire a deeper insight for PCSK9 and its Inhibitors.