PCSK9 gene variations in the clinical setting of premature cardiovascular disease: A critical appraisal.

INTRODUCTION: Information about PCSK9 gene variations and its association with cardiovascular (CV) disease is controversial. We aimed to evaluate 3 reported polymorphisms in PSCK9 in a cohort of young patients with myocardial infarction with ST segment elevation (STEMI). METHODS: Retrospective study of consecutive patients with premature STEMI (2018-2023). 216 patients with STEMI due atherothrombotic coronary artery disease (CAD), confirmed by coronary angiogram, were included. We genotyped 3 polymorphisms in PCSK9 (rs12117661, rs2483205, rs505151) in 207 patients (DNA unavailable in 9) and a control group (N = 200). RESULTS: Mean age 49.4 ± 6,6 years (82.4% men). Genotypes frequencies distribution in patient's and control's cohorts did not deviate from the expected by Hardy-Weinberg equilibrium and there were no significant differences between patients and controls. Among patients, we did not find any association between PSCK9 genotypes and clinical variables (gender, age, CV risk factors, cholesterol levels, family history of premature CAD or number of coronary arteries affected). CONCLUSION: We did not find any association between PSCK9 genotypes (RS12117661, RS2483205 and RS505151) and any CV risk factors or the extent of CAD in a cohort of patients with premature STEMI. There were not differences in the genotype distribution between patients and controls.

Exploring PCSK9 Genetic Impact on Lipoprotein(a) via Dual Approaches: Association and Mendelian Randomization.

Previous investigations have suggested an association between the PCSK9 common polymorphism E670G and Lipoprotein(a) (Lp(a)) levels, as well as a link between plasma PCSK9 levels and Lp(a) concentrations. However, the causal relationship between plasma PCSK9 and Lp(a) levels remains uncertain. In this study, we explored the association between PCSK9 E670G polymorphism and Lp(a) levels in 614 healthy Taiwanese individuals. Employing a two-sample Mendelian randomization (MR) analysis using openly accessible PCSK9 and Lp(a) summary statistics from the genome-wide association studies (GWAS) and UK Biobank, we aimed to determine if a causal link exists between plasma PCSK9 levels and Lp(a) concentrations. Our findings reveal that the E670G G allele is independently associated with a decreased likelihood of developing elevated Lp(a) levels. This association persists even after adjusting for common cardiovascular risk factors and irrespective of lipid profile variations. The MR analysis, utilizing six PCSK9 GWAS-associated variants as instrumental variables to predict plasma PCSK9 levels, provides compelling evidence of a causal relationship between plasma PCSK9 levels and Lp(a) concentration. In conclusion, our study not only replicates the association between the PCSK9 E670G polymorphism and Lp(a) levels but also confirms a causative relationship between PCSK9 levels and Lp(a) concentrations through MR analysis.

Genetic Spectrum of Familial Hypercholesterolaemia in the Malaysian Community: Identification of Pathogenic Gene Variants Using Targeted Next-Generation Sequencing.

Familial hypercholesterolaemia (FH) is caused by mutations in lipid metabolism genes, predominantly in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin-type 9 (PCSK9) and LDL receptor adaptor protein 1 (LDLRAP1). The prevalence of genetically confirmed FH and the detection rate of pathogenic variants (PV) amongst clinically diagnosed patients is not well established. Targeted next-generation sequencing of LDLR, APOB, PCSK9 and LDLRAP1 was performed on 372 clinically diagnosed Malaysian FH subjects. Out of 361 variants identified, 40 of them were PV (18 = LDLR, 15 = APOB, 5 = PCSK9 and 2 = LDLRAP1). The majority of the PV were LDLR and APOB, where the frequency of both PV were almost similar. About 39% of clinically diagnosed FH have PV in PCSK9 alone and two novel variants of PCSK9 were identified in this study, which have not been described in Malaysia and globally. The prevalence of genetically confirmed potential FH in the community was 1:427, with a detection rate of PV at 0.2% (12/5130). About one-fourth of clinically diagnosed FH in the Malaysian community can be genetically confirmed. The detection rate of genetic confirmation is similar between potential and possible FH groups, suggesting a need for genetic confirmation in index cases from both groups. Clinical and genetic confirmation of FH index cases in the community may enhance the early detection of affected family members through family cascade screening.

Increased Carotid Intima-Media Thickness in Asymptomatic Individuals Is Associated with the PCSK9 (rs2149041) Gene Polymorphism in the Mexican Mestizo Population: Results of the GEA Cohort.

The increase in carotid intima-media thickness (CIMT) and coronary artery calcification (CAC) are features of subclinical atherosclerosis that might be determined by the genetic background of patients. Among the multiple risk factors, the proprotein convertase subtilisin kexin type 9 (PCSK9) has a great impact on atheroma development. Then, we focused on the potential association of the PCSK9 gene polymorphism (rs2149041) with the risk of an increased CIMT. We included 881 unrelated, asymptomatic individuals (732 normal CIMT and 149 increased CIMT) who lacked coronary calcification (CAC score = 0). Under the recessive inheritance model and adjusted by several cardiovascular risk factors, the rs2149041 polymorphism, determined by TaqMan genotyping assay, was associated with a high risk of increased CIMT (OR = 2.10, 95% IC = 1.26-3.47, P recessive = 0.004). Our results suggest that the rs2149041 polymorphism could be a risk marker for increased CIMT in asymptomatic individuals without coronary artery disease determined by the absence of a CAC score.

Common and Rare PCSK9 Variants Associated with Low-Density Lipoprotein Cholesterol Levels and the Risk of Diabetes Mellitus: A Mendelian Randomization Study.

PCSK9 is a candidate locus for low-density lipoprotein cholesterol (LDL-C) levels. The cause-effect relationship between LDL-C levels and diabetes mellitus (DM) has been suggested to be mechanism-specific. To identify the role of PCSK9 and genome-wide association study (GWAS)-significant variants in LDL-C levels and the risk of DM by using Mendelian randomization (MR) analysis, a total of 75,441 Taiwan Biobank (TWB) participants was enrolled for a GWAS to determine common and rare PCSK9 variants and their associations with LDL-C levels. MR studies were also conducted to determine the association of PCSK9 variants and LDL-C GWAS-associated variants with DM. A regional plot association study with conditional analysis of the PCSK9 locus revealed that PCSK9 rs10788994, rs557211, rs565436, and rs505151 exhibited genome-wide significant associations with serum LDL-C levels. Imputation data revealed that three rare nonsynonymous mutations-namely, rs151193009, rs768846693, and rs757143429-exhibited genome-wide significant association with LDL-C levels. A stepwise regression analysis indicated that seven variants exhibited independent associations with LDL-C levels. On the basis of two-stage least squares regression (2SLS), MR analyses conducted using weighted genetic risk scores (WGRSs) of seven PCSK9 variants or WGRSs of 41 LDL-C GWAS-significant variants revealed significant association with prevalent DM (p = 0.0098 and 5.02 × 10-7, respectively), which became nonsignificant after adjustment for LDL-C levels. A sensitivity analysis indicated no violation of the exclusion restriction assumption regarding the influence of LDL-C-level-determining genotypes on the risk of DM. Common and rare PCSK9 variants are independently associated with LDL-C levels in the Taiwanese population. The results of MR analyses executed using genetic instruments based on WGRSs derived from PCSK9 variants or LDL-C GWAS-associated variants demonstrate an inverse association between LDL-C levels and DM.

PCSK9 Gene Participates in the Development of Primary Dyslipidemias.

Dyslipidemias are a group of diseases, which are characterized by abnormal blood concentrations of cholesterol, triglycerides and/or low-density lipoprotein-cholesterol (LDL-c). Dyslipidemia is a determinant condition for the progress of an atherosclerotic plaque formation. The resulting atherogenicity is due to at least two mechanisms: first, to the accumulation in the plasma of lipid particles that have the capacity to alter the function of the endothelium and deposit at the atheromatous plaque, and second, at an insufficient concentration of multifactorial type of high density lipoprotein-cholesterol (HDL-c), whose function is to protect against the development of atherosclerosis. Its highest prevalence is encountered among individuals with diabetes, hypertension or overweight. Hyperlipidemia is one of the main predisposing factors for the development of cardiovascular disease. Hyperlipidemia can be the result of a genetic condition, the secondary expression of a primary process or the consequence of exogenous factors (food, cultural, socio-economic, etc.), all of which lead to the elevation of plasma lipid levels. The objective of this study was to carry out an analysis of the genes involved in the development of dyslipidemias that lead to cardiovascular disease with special emphasis on the proprotein convertase subtilin/kexin type 9 (PCSK9) gene. The PCSK9 gene participates in the development of primary dyslipidemias, mainly familial hypercholesterolemia, currently the pharmacological treatment of choice to reduce LDL-c are statins, however, it has been observed that these have been insufficient to eliminate cardiovascular risk, especially in subjects with primary forms of hypercholesterolemia related to genetic mutations, or statin intolerance.

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.

Major 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.

Patients With LDLR and PCSK9 Gene Variants Experienced Higher Incidence of Cardiovascular Outcomes in Heterozygous Familial Hypercholesterolemia.

Background Patients with familial hypercholesterolemia who harbored both low-density lipoprotein receptor (LDLR) and PCSK9 (proprotein convertase subtilisin/kexin type 9) gene variants exhibit severe phenotype associated with substantially high levels of low-density lipoprotein cholesterol. In this study, we investigated the cardiovascular outcomes in patients with both LDLR and PCSK9 gene variants. Methods and Results A total of 232 unrelated patients with LDLR and/or PCSK9 gene variants were stratified as follows: patients with LDLR and PCSK9 (LDLR/PCSK9) gene variants, patients with LDLR gene variant, and patients with PCSK9 gene variant. Clinical demographics and the occurrence of primary outcome (nonfatal myocardial infarction) were compared. The observation period of primary outcome started at the time of birth and ended at the time of the first cardiac event or the last visit. Patients with LDLR/PCSK9 gene variants were identified in 6% of study patients. They had higher levels of low-density lipoprotein cholesterol (P=0.04) than those with LDLR gene variants. On multivariate Cox regression model, they experienced a higher incidence of nonfatal myocardial infarction (hazard ratio, 4.62; 95% CI, 1.66-11.0; P=0.003 versus patients with LDLR gene variant). Of note, risk for nonfatal myocardial infarction was greatest in male patients with LDLR/PCSK9 gene variants compared with those with LDLR gene variant (86% versus 24%; P<0.001). Conclusions Patients with LDLR/PCSK9 gene variants were high-risk genotype associated with atherogenic lipid profiles and worse cardiovascular outcomes. These findings underscore the importance of genetic testing to identify patients with LDLR/PCSK9 gene variants, who require more stringent antiatherosclerotic management.

Familial Hypercholesterolemia in Russia: Three Decades of Genetic Studies.

The first studies of familial hypercholesterolemia (FH) in Russia go back to late 1980-ies. For more than 10 years the research in this field was carried out in Saint-Petersburg, the megapolis in the North-West Russia. Studies were focused on the search for causative mutations in low-density lipoprotein receptor gene (LDLR). Gradually the research was spread to Petrozavodsk in Karelia and in the XXI century two more centers contributed in investigations of genetics of FH, i.e., in Moscow and Novosibirsk. The best studied is the spectrum of mutations in LDLR, though genetic abnormalities in APOB and PCSK9 genes were also considered. Despite that some 40% mutations in LDLR found in Saint-Petersburg and Moscow are referred to as specific for Russian population, and this proportion is even higher in Karelia (ca. 70%), rapid introduction of NGS and intensifying genetic research all over the world result in continuous decrease of these numbers as "Slavic" mutations become documented in other countries. The samplings of genetically characterized patients in Russia were relatively small, which makes difficult to specify major mutations reflecting the national specificity of FH. Moreover, the majority of studies accomplished so far did not explore possible associations of certain mutations with ethnic origin of patients. By now the only exception is the study of Karelian population showing the absence of typical Finnish mutations in the region that borders on Finland. It can be concluded that the important primary research partly characterizing the mutation spectrum in FH patients both in the European and Siberian parts of Russia has been done. However, it seems likely that the most interesting and comprehensive genetic studies of FH in Russia, concerning various mutations in different genes and the variety of ethnic groups in this multi-national country, are still to be undertaken.

Polygenic Hypercholesterolemia and Cardiovascular Disease Risk.

PURPOSE OF THE REVIEW: Identification of loci and common single-nucleotide polymorphisms (SNPs) that have modest effects on plasma lipids have been used to confirm or refute the causal role of lipid traits in the development of coronary heart disease (CHD), and as tools to identify individuals with polygenic hypercholesterolemia. RECENT FINDINGS: Several groups have reported on the use of SNP scores in distinguishing individuals with a clinical diagnosis of familial hypercholesterolemia (FH) with a monogenic or polygenic etiology. We review evidence that those with monogenic FH have worse prognosis and discuss the possible mechanisms for this and their management. Individuals with a clinical phenotype of FH and a monogenic cause are at greater risk of CHD than those where no causative mutation can be found. The patients with polygenic hypercholesterolemia would not require elaborate cascade screening or secondary care input for their management.

The study of familial hypercholesterolemia in Italy: A narrative review.

In this review we outline our experience in the clinical and molecular diagnosis of familial hypercholesterolemia (FH), built up over more than three decades. We started our work by selecting FH patients on the basis of stringent clinical criteria, including extensive family studies. In most patients we confirmed the clinical diagnosis by showing a reduced LDLR activity in skin fibroblasts. After the isolation of LDLR cDNA and the characterization of the corresponding gene by the Dallas group, we started a systematic molecular investigation of our patients first using Southern blotting, and, subsequently Sanger sequencing. Up to now we have been able to identify 260 mutations of LDLR gene in more than 1000 genotyped FH patients, including 68 homozygotes. During this survey we identified 13 mutation clusters located in different geographical districts, which gave us the chance to compare the phenotype of patients carrying the most common mutations. We also found that mutations in APOB and PCSK9 genes were a rare cause of FH in our cohort. Despite our efforts, we failed to identify mutations in candidate genes in ∼20% of cases of definite FH. An exome-wide study, conducted within the context of an international collaboration, excluded the presence of other major genes in our unexplained FH cases. Recently, we have adopted sequencing technology of the next generation (NGS) with the parallel sequencing of a panel of FH targeted genes as a way of obtaining a more comprehensive picture of the gene variants potentially involved in the disease.

Genetic Architecture of Familial Hypercholesterolaemia.

PURPOSE OF REVIEW: Familial hypercholesterolaemia (FH) is an inherited disorder of low-density lipoprotein cholesterol (LDL-C) which is characterised by a raised cholesterol level from birth and a high risk of premature coronary heart disease. In this paper, we review the genetic basis of FH and its impact on the clinical presentation. RECENT FINDINGS: Mutations in any of three genes (LDLR, APOB and PCSK9) are known to cause autosomal dominant FH, but a mutation can be found in only ∼40% of patients with a clinical diagnosis of FH. In the remainder, a polygenic aetiology is most likely, due to the co-inheritance of common LDL-C-raising variants. The cardiovascular presentation and management of FH will differ between patients based on their underlying genetic factors. New genotyping methods such as next-generation sequencing will provide us with better understanding of the genetic architecture of FH.

Effects of gypenosides on PCSK9 gene expression and blood lipids lowered by simvastatin / 中国病理生理杂志

AIM:To explore the effect of gypenosides ( GPs) on PCSK9 gene expression in hyperlipidemic rat liver and the blood lipids lowered by simvastatin .METHODS: Healthy male SD rats ( n=60 ) were randomized into 5 groups:normal control group , hyperlipidemic model group , simvastatin group , GPs group and GPs combined with simvasta-tin group ( combined group ) .The rats in all groups were fed high-fat diet except normal control group which were fed with ordinary diet.The rats in control group and hyperlipidemic model group were gavaged with 0.3%CMC-Na every day.The rats in GPs group were gavaged with GPs at 160 mg? kg-1? d-1 .The rats in simvastatin group were gavaged with simvas-tatin at 5 mg? kg-1? d-1 .The rats in combined group were gavaged with GPs and simvastatin .The experiment lasted for 8 weeks.The rats were anesthetized with chloral hydrate , and abdominal arterial blood samples were collected to detect the total cholesterol ( TC) , triglyceride ( TG) , low-density lipoprotein cholesterol ( LDL-C) and high-density lipoprotein cho-lesterol ( HDL-C) .The body weight and the wet weight of the livers were measured , and the liver index was calculated . The pathological changes of the livers were observed under microscope with HE staining .The expression of PCSK9 and low-density lipoprotein receptor ( LDLR) at mRNA and protein levels was determined by real-time PCR and Western blot .RE-SULTS:The model of hyperlipidemia rats was established successfully .Compared with model group , the levels of TC , TG and LDL-C in simvastatin group, GPs group and combined group were obviously decreased (P<0.05), and the HDL-C levels were obviously upregulated (P<0.05).Compared with model group, the liver indexes in simvastatin group, GPs group and combined group were obviously decreased (P<0.05).The pathological changes of the liver tissues showed that hepatic adipose appeared in model group , and that in simvastatin group and GPs group had different degrees of relief , espe-cially in combined group .Compared with model group , the mRNA expression levels of PCSK 9 and LDLR in simvastatin group were obviously increased , while the mRNA expression levels of PCSK 9 in GPs group and combined group were obvi-ously decreased (P<0.05), and the mRNA expression of LDLR in combined group was obviously increased (P<0.05). Compared with model group , the protein expression of PCSK 9 and LDLR in simvastatin group was obviously increased , while the protein expression levels of PCSK 9 in GPs group and combined group were obviously reduced , and the LDLR pro-tein levels were obviously increased (P<0.05).CONCLUSION:Gypenosides inhibit the expression of PCSK9 and in-crease the expression of LDLR in the liver .The combination of gypenosides and simvastatin promotes the lipid-lowering effect of simvastatin and attenuates hepatic steatosis , which may be related to inhibiting the expression of PCSK 9 in the liv-er.

E670G polymorphism of PCSK9 gene of patients with coronary heart disease among Han population in Hainan and three provinces in the northeast of China.

OBJECTIVE: To investigate the correlation between E670G polymorphism of proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and coronary heart disease (CHD), and contrastively study the regional differences of E670G polymorphism of PCSK9 gene between patients with CHD among the Han population in Hainan and three provinces in the northeast of China (TPNC), providing scientific basis for prevention and treatment of patients with CHD in different regions. METHODS: A total of 233 cases of patients with CHD were selected from the Han population in Hainan and TPNC as the experimental group (118 cases from Hainan, 115 cases from TPNC), and 239 cases with non-CHD were selected among the Han population also in the two regions as control group (125 cases from Hainan, 114 cases from TPNC). The triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol and low density lipoprotein cholesterol (LDL-C) levels of plasma were tested and PCR-RFLP method was used to test the E670G polymorphism of PCSK9 gene. The statistical software package SPSS 21.0 was used for the statistical analysis and P < 0.05 was considered as statistically significant. RESULTS: The levels of systolic pressure, diastolic blood pressure, fasting blood sugar, TC, TG, and LDL-C of patients in CHD group were significantly higher than those in non-CHD group, while the high density lipoprotein cholesterol level was lower than that in non-CHD group (P < 0.05). In CHD group, the frequencies of AG, GG genotypes of PCSK9 gene and G allele were higher than those in non-CHD group (P < 0.05), and in CHD group, the frequencies of AG, GG genotypes and G allele of patients both in Hainan and TPNC were higher than those in control group (P < 0.05). Among the patients with CHD, the frequencies of GG genotype and G allele of patients in Hainan were lower than those in TPNC (P < 0.05), and in CHD group, the levels of TG, TC and LDL-C of GG genotype were higher than those of AA genotype (P < 0.05). While in non-CHD group, there were no significant differences between the frequencies of GG genotype and G allele of patients in Hainan and TPNC (P > 0.05). CONCLUSIONS: There was a close correlation between the E670G polymorphism of PCSK9 gene and CHD with serum lipid level. Among Han population in Hainan and TPNC, the E670G polymorphism of PCSK9 gene of patients with CHD exhibited regional differences.

E670G polymorphism of PCSK9 gene of patients with coronary heart disease among Han population in Hainan and three provinces in the northeast of China

OBJECTIVE@#To investigate the correlation between E670G polymorphism of proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and coronary heart disease (CHD), and contrastively study the regional differences of E670G polymorphism of PCSK9 gene between patients with CHD among the Han population in Hainan and three provinces in the northeast of China (TPNC), providing scientific basis for prevention and treatment of patients with CHD in different regions.@*METHODS@#A total of 233 cases of patients with CHD were selected from the Han population in Hainan and TPNC as the experimental group (118 cases from Hainan, 115 cases from TPNC), and 239 cases with non-CHD were selected among the Han population also in the two regions as control group (125 cases from Hainan, 114 cases from TPNC). The triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol and low density lipoprotein cholesterol (LDL-C) levels of plasma were tested and PCR-RFLP method was used to test the E670G polymorphism of PCSK9 gene. The statistical software package SPSS 21.0 was used for the statistical analysis and P  0.05).@*CONCLUSIONS@#There was a close correlation between the E670G polymorphism of PCSK9 gene and CHD with serum lipid level. Among Han population in Hainan and TPNC, the E670G polymorphism of PCSK9 gene of patients with CHD exhibited regional differences.

E670G polymorphism of PCSK9 gene of patients with coronary heart disease among Han population in Hainan and three provinces in the northeast of China

Objective: To investigate the correlation between E670G polymorphism of proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and coronary heart disease (CHD), and contrastively study the regional differences of E670G polymorphism of PCSK9 gene between patients with CHD among the Han population in Hainan and three provinces in the northeast of China (TPNC), providing scientific basis for prevention and treatment of patients with CHD in different regions. Methods: A total of 233 cases of patients with CHD were selected from the Han population in Hainan and TPNC as the experimental group (118 cases from Hainan, 115 cases from TPNC), and 239 cases with non-CHD were selected among the Han population also in the two regions as control group (125 cases from Hainan, 114 cases from TPNC). The triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol and low density lipoprotein cholesterol (LDL-C) levels of plasma were tested and PCR-RFLP method was used to test the E670G polymorphism of PCSK9 gene. The statistical software package SPSS 21.0 was used for the statistical analysis and P 0.05). Conclusions: There was a close correlation between the E670G polymorphism of PCSK9 gene and CHD with serum lipid level. Among Han population in Hainan and TPNC, the E670G polymorphism of PCSK9 gene of patients with CHD exhibited regional differences.

Pharmacological treatment of a Sardinian patient affected by Autosomal Recessive Hypercholesterolemia (ARH).

BACKGROUND AND AIM: Previous studies have shown that patients with autosomal recessive hypercholesterolemia (ARH) resulting from mutations in LDLRAP1 gene have a less severe cardiovascular involvement than familial hypercholesterolemia homozygotes, lower levels of low-density lipoprotein cholesterol (LDL-C), and higher levels of high-density lipoprotein cholesterol (HDL-C). In addition, ARH patients seem to be more responsive to the lipid-lowering drugs. The aim was to test the effect of a combined drug treatment in an ARH patient in the absence of plasmapheresis. METHODS AND RESULTS: Here we report the lipid-lowering effect of rosuvastatin (60 mg/day) associated with ezetimibe (10 mg/day) in a single ARH patient. The sequencing of LDLRAP1 gene showed that the patient was homozygous for the c.432insA mutation. During a 6-month treatment, we observed an 80% reduction of LDL-C and a significant increase of HDL-C and ApoA-I. Some sequence variations in PCSK9 and NPC1L1 genes found in this patient may have contributed to the success of drug treatment. CONCLUSIONS: Our findings, although limited to a single case, suggest that in many ARH patients the LDL-C goal may be reached with the more potent statins associated with ezetimibe in the absence of extracorporeal procedures.

PCSK9 polymorphism in a Tunisian cohort: identification of a new allele, L8, and association of allele L10 with reduced coronary heart disease risk.

The c.61_63dupCTG (L10) allele of rs72555377 polymorphism in PCSK9 has been reported to be associated with low-density lipoprotein-cholesterol (LDL-C) levels and with a decreased risk of coronary artery disease (CAD). We investigated the effect of two known alleles for rs72555377, L10 and L11, on the risk of CAD in a Tunisian cohort (218 patients diagnosed by angiography and 125 control subjects). Two subgroups of patients were defined by their level of stenosis: ≥50% for CAD and <50% for no-CAD. The genotypes were obtained by the size measurement of fluorescent-labeled PCR products. We identified a novel allele for the rs72555377 polymorphism: an in-frame deletion, c.61_63delCTG (L8). The frequency of the L10 allele was significantly higher in the no-CAD subgroup than in the CAD subgroup (0.210 vs 0.114, p = 0.045), and than in the subgroup of CAD patients presenting a stenosis ≥50% in two or three major coronary arteries (0.210 vs 0.125, p = 0.028). Multiple regression analysis showed that the L10 allele was significantly associated with a reduced risk of CAD (p = 0.049, OR = 0.51[0.26-1.00]), and with its reduced severity (p = 0.045, OR = 0.44[0.20-0.98]). The L10 allele is associated with a reduced risk and severity of CAD, seemingly independently of its LDL-lowering effect, suggesting a direct effect of PCSK9 on atherogenesis.

Dongguan Han patients with coronary artery PCSK9 gene SNP and its prognosis / 国际检验医学杂志

Objective To investigate the gene E670G SNP loci with coronary heart disease and its relationship Dongguan Han PCSK9 prognosis .Methods In our hospital 100 patients with coronary heart disease and 100 cases of non‐coronary heart disease patients for the study ,patients taking blood ,DNA was extracted and analyzed gene PCSK9 E670G SNP locus by PCR ,using gene sequencing validation .Lipid levels in patients using enzymatic detection and follow‐up of patients with coronary heart disease chan‐ges in serum lipid levels after statin therapy ,the incidence of cardiovascular events .Results CAD group TC ,LDL‐C levels were sig‐nificantly higher than the healthy control group ,HDL‐C was significantly lower than the healthy control group ,the difference was statistically significant (P<0 .05) .AA genotype that was mainly 298 bp and 152 bp of homozygotes ,followed by AG that was 450 bp and 298 bp ,152 bp heterozygotes ,had not been detected 450 bp GG homozygous genotype ,allele frequency distributions in Har‐dy‐Weinberg equilibrium .LDL‐C levels in patients with CAD patients was significantly lower than AA genotype AG genotype , HDL‐C levels were significantly higher in patients with AG genotype (P<0 .05) .Number of cardiovascular patients were followed up six months totaled 27 cases ,AA genotype accounted for 66 .7% ,AG genotype accounted for 33 .3% ,Gallele and the average number of cases of cardiovascular disease events count a statistically significant difference (P<0 .05) .Conclusion PCSK9 E670G polymorphism and LDL‐C ,HDL‐C levels and CAD severity gene‐related ,CAD patients carrying G allele may increase the risk of disease and the risk of again .