ASSOCIATION OF LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A2 (LP-PLA2) WITH PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) IN FAMILIAL HYPERCHOLESTEROLEMIA

2019 ◽  
Keyword(s):  
Phospholipase A2 ◽  
Familial Hypercholesterolemia ◽  
Proprotein Convertase

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

Processes ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 283
Author(s):  
Nang Hoang Pham ◽  
Phuong Kim Truong ◽  
Thuan Duc Lao ◽  
Thuy Ai Huyen Le
Keyword(s):  
Familial Hypercholesterolemia ◽  
Hot Spot ◽  
Meta Analysis ◽  
Critical Role ◽  
Random Effect ◽  
Random Effect Model ◽  
Weighted Average ◽  
Atherosclerotic Cardiovascular Disease ◽  
Proprotein Convertase ◽  
Ldl Receptors

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.

Plasma Lipoprotein-associated Phospholipase A2 Is Inversely Correlated with Proprotein Convertase Subtilisin-kexin Type 9

2012 ◽  
Vol 43 (1) ◽  
pp. 11-14 ◽  
Author(s):  
Alexander Constantinides ◽  
Paul J.W.H. Kappelle ◽  
Gilles Lambert ◽  
Robin P.F. Dullaart
Keyword(s):  
Phospholipase A2 ◽  
Plasma Lipoprotein ◽  
Proprotein Convertase

Abstract 490: Distribution of Oxidized Phospholipids and Lipoprotein-Associated Phospholipase A2 in Plasma, Density Gradient Fractions and Individual Lipoproteins in Patients with Familial Hypercholesterolemia: Effect of LDL Apheresis

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Kiyohito Arai ◽  
Alexina Orsoni ◽  
Elizabeth R Miller ◽  
Ziad Mallat ◽  
Alain Tedgui ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Familial Hypercholesterolemia ◽  
Genetic Risk ◽  
Oxidized Phospholipids ◽  
Ldl Apheresis ◽  
Direct Plating ◽  
Density Fraction ◽  
Density Fractions ◽  
Additive Risk ◽  
Antibody Capture

Objectives: Lipoprotein(a)[Lp(a)] is a causal, genetic risk factor for cardiovascular disease(CVD) and is enriched in pro-inflammatory oxidized phospholipids(OxPL) and lipoprotein-associated phospholipase A2(Lp-PLA2). Epidemiologic outcome studies have shown that the OxPL, Lp(a) and Lp-PLA2 collectively mediate additive risk for CVD. Methods: To derive insights into the relationships between Lp(a), OxPL and Lp-PLA2, 18 patients with familial hypercholesterolemia(FH) and Low(<10mg/dl), Intermediate (∼50mg/dl) or High(>100mg/dl) Lp(a) levels on chronic LDL apheresis were evaluated. Twenty-five isopycnic density fractions(density <1.015 to >1.189 g/ml) were isolated from pre and post apheresis plasma(n=50 fractions per patient). OxPL and Lp-PLA2 mass and activity were quantitated with a variety of techniques under 3 conditions: in plasma, in each density fraction with direct plating techniques and on individual lipoproteins within each density fraction by using antibody capture assays to apoB-100(OxPL/apoB and Lp-PLA2/apoB), Lp(a)[OxPL/apo(a) and Lp-PLA2/apo(a)] and apoA-I(OxPL/apoA-I and Lp-PLA2/apoA-I)(total of 900 fractions per measure) and detecting OxPL and Lp-PLA2 with monoclonal antibodies E06 and 4B4, respectively. Results: In whole density gradients by direct plating techniques, OxPL were almost exclusively detected in the Lp(a) containing fractions(density 1.059-1.094 g/ml) and Lp-PLA2 mass and activity were present between the apoB and Lp(a) density fractions. In lipoprotein capture assays, OxPL/apoB and OxPL/apo(a) increased proportionally with increasing Lp(a) levels; Lp-PLA2/apoB and Lp-PLA2/apoA-I levels were highest in patients with Low Lp(a) but decreased proportionally with increasing Lp(a) levels; Lp-PLA2/apo(a) was lowest in patients with Low Lp(a) levels and increased proportionally with increasing Lp(a) levels. LDL apheresis significantly reduces levels of OxPL and Lp-PLA2 on apoB and Lp(a), particularly in patients with high Lp(a) levels Conclusions: This study documents that OxPL are primarily present on Lp(a) and Lp-PLA2 primarily on apoB, but the proportion of each increases on Lp(a) and decreases on apoB as plasma Lp(a) levels increase. These data suggest a pathophysiological relationship between Lp(a), OxPL and Lp-PLA2 and provide a rationale for understanding how they collectively mediate CVD in humans.

Statin therapy and secretory phospholipase A2 in children with heterozygous familial hypercholesterolemia

2013 ◽  
Vol 229 (2) ◽  
pp. 404-407 ◽  
Author(s):  
Marjet J.A.M. Braamskamp ◽  
Sotirios Tsimikas ◽  
Albert Wiegman ◽  
John J.P. Kastelein ◽  
Barbara A. Hutten
Keyword(s):  
Phospholipase A2 ◽  
Statin Therapy ◽  
Familial Hypercholesterolemia ◽  
Secretory Phospholipase A2 ◽  
Secretory Phospholipase ◽  
Heterozygous Familial Hypercholesterolemia

Lipoprotein Apheresis and Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors in Patients With Heterozygous Familial Hypercholesterolemia: A One Center Study

2020 ◽  
Vol 26 (1) ◽  
pp. 51-58
Author(s):  
Vana Kolovou ◽  
Niki Katsiki ◽  
Stamatis Makrygiannis ◽  
Sophie Mavrogieni ◽  
Nikoletta Karampetsou ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Proprotein Convertase ◽  
Low Density Lipoprotein Cholesterol ◽  
Lipoprotein Apheresis ◽  
Heterozygous Familial Hypercholesterolemia ◽  
Previously Treated

Aim: We evaluated the lipid-lowering (LL) effect of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with heterozygous familial hypercholesterolemia (HeFH) treated with LL-drugs and lipoprotein apheresis (LA). Patients and Methods: The PCSK9i treatment (evolocumab 420 mg/4 weeks, alirocumab 150 mg/2 weeks, or alirocumab 75 mg/2 weeks: 9, 6, and 2 patients, respectively) was initiated in patients with HeFH (n = 17; aged 35-69 years, 10 men, previously treated with statins + ezetimibe ± colesevelam and LA sessions for 2-12 years). A lipid profile was obtained before and immediately after the LA session and before, 1 and 2 months after switching to PCSK9i treatment. The duration of PCSK9i therapy ranged from 3 to 18 months. Results: Median total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) levels before LA were 268, 198, 46, and 126 mg/dL, respectively, and decreased (at the end of the LA session) to 117, 50, 40, and 51 mg/dL, respectively ( P < .001 for TC and P = .001 for all other comparisons). The median time-averaged LDL-C levels following LA were 155 (121, 176; median [25th, 75th percentile]) mg/dL. Median TC, LDL-C, and TG levels before PCSK9i therapy were 269, 190, and 127 mg/dL and decreased to 152, 100, and 95 mg/dL, respectively ( P = .002, P < .002, and P < .03, respectively). Steady LDL-C levels with PCSK9i treatment were significantly lower compared with time-averaged LDL-C levels following LA (median value: 100 vs 155 mg/dL; P = .008). With PCSK9i, from 13 patients with CHD, 6 (46.1%) patients achieved LDL-C <70 mg/dL, and 2 patients (15.4%) achieved LDL-C <100 mg/dL. Lipoprotein apheresis was discontinued in all patients except for 2 who continued once monthly. Conclusions: PCSK9i can reduce LDL-C more consistently over time compared with a transient decrease following LA in HeFH patients. PCSK9i therapy may reduce the frequency of LA. Larger trials are required to establish the clinical implications of PCSK9i in patients previously on LA.

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