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

2021 ◽  
Vol 10 (7) ◽  
pp. 1399
Author(s):  
Cristiana-Elena Vlad ◽  
Liliana Georgeta Foia ◽  
Roxana Popescu ◽  
Ioana Popa ◽  
Ruxandra Aanicai ◽  
...  

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.

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 66
Author(s):  
Alexey Meshkov ◽  
Alexandra Ershova ◽  
Anna Kiseleva ◽  
Evgenia Zotova ◽  
Evgeniia Sotnikova ◽  
...  

Familial hypercholesterolemia (FH) is a common autosomal codominant disorder, characterized by elevated low-density lipoprotein cholesterol levels causing premature atherosclerotic cardiovascular disease. About 2900 variants of LDLR, APOB, and PCSK9 genes potentially associated with FH have been described earlier. Nevertheless, the genetics of FH in a Russian population is poorly understood. The aim of this study is to present data on the spectrum of LDLR, APOB, and PCSK9 gene variants in a cohort of 595 index Russian patients with FH, as well as an additional systematic analysis of the literature for the period of 1995–2020 on LDLR, APOB and PCSK9 gene variants described in Russian patients with FH. We used targeted and whole genome sequencing to search for variants. Accordingly, when combining our novel data and the data of a systematic literature review, we described 224 variants: 187 variants in LDLR, 14 variants in APOB, and 23 variants in PCSK9. A significant proportion of variants, 81 of 224 (36.1%), were not described earlier in FH patients in other populations and may be specific for Russia. Thus, this study significantly supplements knowledge about the spectrum of variants causing FH in Russia and may contribute to a wider implementation of genetic diagnostics in FH patients in Russia.


2019 ◽  
Vol 16 (6) ◽  
pp. 467-478
Author(s):  
Ye-Xuan Cao ◽  
Bing-Yang Zhou ◽  
Di Sun ◽  
Sha Li ◽  
Yuan-Lin Guo ◽  
...  

Aim: To investigated the potential differences between probable and definite heterozygous familial hypercholesterolemia (HeFH) patients diagnosed by Dutch Lipid Clinic Network criteria. Methods: Clinical characteristics, lipid profile, severity of coronary artery stenosis and gene mutations were compared. Kaplan–Meier curve was performed to evaluate the cardiovascular events. Results: Overall, 325 participants were included and divided into two groups: probable (n = 233) and definite HeFH (n = 92). Definite HeFH patients had higher low-density lipoprotein cholesterol (LDL-C), oxidized-LDL and proprotein convertase subtilisin/kexin 9 levels, and higher prevalence of tendon xanthomas. The incidence of genetic mutations was statistically higher in definite HeFH than probable HeFH patients. The coronary stenosis calculated by Gensini score was statistically severer in definite HeFH patients. The best LDL-C threshold for predicting mutations was 5.14 mmol/l. Definite HeFH had lower event-free survival rates. Conclusion: Definite HeFH patients had higher severity of phenotype and genotype, and higher risk of cardiovascular events.


2019 ◽  
Vol 23 (10) ◽  
pp. 33
Author(s):  
Hadeel A. Abdel-Razaak Al-daraji1 ◽  
Akeel H. Ali Al-Assie2 ◽  
Rada H. Hussien3

Familial Hypercholesterolemia (FH) is autosomal codominant disease Characterized by elevated LDL Cholesterol and Early Coronary Artery disease. (FH) is commonly caused by mutations in the three genes: The Low-Density Lipoprotein Receptor (LDLR), apolipoprotein B (apoB), Proprotein Convertase Subtilisin ⁄ Kexin type 9 (PCSK9). The current study aimed to identify mutations in people with homozygous genotypes that affect protein binding causing defects and to ensure that these conditions are diagnosed through important molecular tests through the early intervention of the apoptoprotein gene (apoB) for the R3500Q mutagenic of healthy individuals not associated with hypercholesterolemia (FH) in Sulaymaniyah through the conduct of the polymer chain reaction system and Restrication enzyme genotyping. The study included determination of the polymorphism of genes associated with familial hypercholesterolemia (FH). The molecular study included the genetic analysis of (50) samples of the R3500Q mutation of the apoB gene, after adding the ScaI enzyme, showed there three genotype: were four cases found Homozygous to be one bundle (S+ ⁄ S+) (143 bp), a one case compound heterozygous (S- ⁄ S+) model are two bundle ( 143 bp, 90 bp) and a fourty-five cases had mutant  Homozygous (S- ⁄ S-)  model  of  the  one  bundle  (90 bp), all the R3500Q mutations were found on the same allele.                                           the study also included the R3500Q mutation of the apoB gene and Its relation to the studied traits, there was a significant increase in the 0.01 for cholesterol, TG and LDL for patients with hypercholesterolemia was mean (235.61 mg ⁄ dl, 321.83 mg ⁄ dl and 330.90 mg ⁄ dl) respectively , compared to healthy pateints with mean (172.15 mg ⁄ dl , 109.88 mg ⁄ dl and 77.1 mg  ⁄ dl).   http://dx.doi.org/10.25130/tjps.23.2018.166


Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yexuan Cao ◽  
Ruixia Xu ◽  
Huiwen Zhang ◽  
Jinglu Jin ◽  
Huihui Liu ◽  
...  

Introduction: Visit-to-visit variability in lipid has been suggested as an predictor of major adverse cardiovascular events (MACEs). However, no evidence exists on the prognostic value of lipid variability in patients with familial hypercholesterolemia (FH). Hypothesis: This prospective cohort study aimed to investigate whether lipid variability affects future MACEs in patients with FH receiving standard lipid-lowering therapy. Methods: A total of 254 patients with FH were consecutively enrolled and followed for MACEs. Variability in triglyceride, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] were evaluated from 3 months after discharge using the standard deviation (SD), coefficient of variation (CV) and variability independent of the mean (VIM). Results: During a mean follow-up of 49 months, 22 (8.7%) events occurred. Visit-to-visit variability in Lp(a) was significantly higher in the MACE group compared to the non-MACE group. In multivariate Cox analysis, only Lp(a) variability parameters were independent predictors for MACEs. The hazard ratios and 95% confidence intervals of each 1-SD increase of SD, CV and VIM of Lp(a) were 1.42 (1.12-1.80), 1.50 (1.11-2.02) and 1.60 (1.16-2.22), respectively. Kaplan-Meier analysis revealed that patients with higher Lp(a) variability presented lower event-free survival (Log-rank p <0.05). The results were consistent in various subgroups. Conclusions: This is the first report to evaluate the prognostic value of lipid variability in real-world patients with FH and showed that Lp(a), but not LDL-C variability, was associated with MACEs, which emphasized the importance of regular lipid monitoring in patients with high risk.


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