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LDLR activity in patients with homozygous Familial Hypercholesterolaemia in Portugal
Session:
Posters (Sessão 6 - Écran 5) - Risco Cardiovascular
Speaker:
Ana Catarina Alves
Congress:
CPC 2023
Topic:
J. Preventive Cardiology
Theme:
28. Risk Factors and Prevention
Subtheme:
28.14 Risk Factors and Prevention - Other
Session Type:
Pósters Electrónicos
FP Number:
---
Authors:
Ana Catarina Alves; Ana Margarida Medeiros; Rafael Graça; Mafalda Bourbon
Abstract
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Background: Homozygous Familial Hypercholesterolemia (HoFH) is a rare disorder, affecting 1/300,000 to 1/1,000,000 people in the general population. In more than 90% of cases, FH is caused by mutations in both alleles of the LDLR gene. Other less frequent genes are<em> APOB</em> or <em>PCSK9</em>. Clinically HoFH is characterized by extremely high LDL-C levels, in general >500 mg/dL or >300 mg/dL under classical lipid lowering treatment, cutaneous xanthomas, abnormalities of aortic valve and supra-valvar region of aortic root and multi-vessel atherosclerotic cardiovascular disease (ASCVD). Recent evidence, however, suggests that HoFH phenotype is more heterogeneous than previously thought and this has been attributed to the severity of the molecular defects that cause the disease. </span></span><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Methods: The Portuguese Familial Hypercholesterolemia Study (PFHS) was created in 1999 and since then 1005 index-cases with clinical diagnosis to FH have been received for genetic study. Since 2017, genetic diagnosis is performed with an NGS panel with 8 genes. To evaluate LDLR activity different LDLR mutants were generated by site-directed mutagenesis and expressed in CHO–ldlA7 cells lacking endogenous expression of LDLR. To determine the effects of the different variants on LDLR function, binding, uptake and expression of FITC-LDL was assessed by flow cytometry. </span></span><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Results and discussion: A total of 12 HoFH and 2 double heterozygous (<em>LDLR/APOB</em>) were genetically confirmed. Among the homozygous individuals, 4 are true homozygous and 8 are compound heterozygous. In total 19 variants were found (16 in <em>LDLR,</em> 2 in <em>PCSK9</em> and 1 in <em>APOB</em>). All variants, except 2 in <em>LDLR</em>, have already been functionally characterized, 11 in our lab. The functional study of the remaining variants is ongoing. All true homozygous have a defective variant (LDLR activity 15-70%); 5/8 compound heterozygous have a null and defective variant (LDLR activity < 10%; LDLR activity 20-65%, respectively); 1 individual has two defective variants (LDLR activity 35%) and in 2 the activity is under study. In the group of null-defective, 3/5 already have CVD (60%) compared to 1/5 (20%) in defective-defective group. </span></span><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Conclusions: It is important to functionally characterise FH variants for the elucidation of the mechanism of disease so a correct FH diagnosis is achieved. Moreover, LDLR activity determination can contribute to personalize treatment according to patient metabolism improving patient prognosis, especially in homozygous individuals.</span></span></p>
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