R46L polymorphism in the PCSK9 gene: Relationship to lipid levels, subclinical vascular disease, and erectile dysfunction

Mostaza, José María; Lahoz, Carlos; Salinero-Fort, Miguel Á.; Dios, Olaya de; Castillo, Elisa; González-Alegre, Teresa; García-Iglesias, Francisca; Estirado, Eva; Laguna, Fernando Ballester; Sabín, Concesa; López, Silvia; Cornejo, Victor; Burgos, Carmen de; Sánchez, Vanesa; Garcés, Cármen; Puntero, Belén Fernández; Montesano, Luis; Linde, Pedro PatronConcepción Aguilera; Fernandez-Garcia, Pedro J.; Linde, Concepción Aguilera; Escolano, A; Sacristán, Patricio Alonso.; Otero, María‐José; Pérez, Paloma Arribas; Ruiz, Maria Luisa. Asensio; Díaz, Pablo; Ena, Begoña Berriatua; Varela, Ana Isabel Bezos; Triguero, María José Calatrava; García, Carlos Casanova; Llorente, Angeles Conde; Laso, Concepción Diaz; García, Emilia Elviro; Dueñas, Orlando Enríquez; Zapata, María Isabel Ferrer; Antuña, Froilán; Lazaro, Maria Isabel García; Rodríguez, Maria Teresa Gómez; Lucena, África Gómez; Hernández, Francisco Herrero; Viñals, Rosa Julián; Ogarrio, Gerardo López Ruiz; Manzano, María Del Carmen Lumbreras; López, Sonsoles Paloma Luquero; Peláez, Ana Martinez Cabrera; Candenas, Montserrat Nieto; Carrera, María Alejandra Rabanal; Rodríguez, Alonso Mateos; Castellanos, Ana López; García, Milagros Velazquez; Pacheco, Margarita Ruiz

doi:10.1016/j.jacl.2018.04.004

Cited by 13 publications

(11 citation statements)

References 26 publications

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“…26 Another meta-analysis on the PCSK9 rs11591147 polymorphism found the minor allele frequency (T) to be 0.25 in familial hypercholesterolemia patients. 11,27 Mostaza et al 28 reported that the adults with the T-allele had a lower intimamedia thickness in coronary arteries and erectile dysfunction compared to those with the G-allele. In our case-control study, we observed that approximately 5% of the CAD patients have the PCSK9 rs11591147 TT genotype and show a significantly protective effect against disease progression in co-dominant and recessive genetic models.…”

Section: Discussionmentioning

confidence: 99%

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

Shyamala

Gundapaneni

Galimudi

et al. 2021

The Journal of Gene Medicine

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Introduction: 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.Methods: 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. Results: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 lipoproteincholesterol levels than individuals with the GG genotype. Logistic regression analysis has shown that the GG and GT (p = 1.51 Â 10 -8 , p = 1.47 Â 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.

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Section: Discussionmentioning

confidence: 99%

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

Shyamala

Gundapaneni

Galimudi

et al. 2021

The Journal of Gene Medicine

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“…A study with a large sample size is needed to verify the results. Data from previous studies indicated that the variant of R46L is rare in both Caucasians and Asians [10,11]. Caucasians carriers of the minor allele had lower cardiovascular disease susceptibility and lower LDL-C levels [9].…”

Section: Introductionmentioning

confidence: 99%

Serum PCSK9 levels, but not PCSK9 polymorphisms, are associated with CAD risk and lipid profiles in southern Chinese Han population

et al. 2018

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BackgroundGenetic and environment factors affect the occurrence and development of coronary artery disease (CAD). Proprotein convertase subtilisin/kexin type 9 (PCSK9), has been investigated extensively in the field of lipid metabolism and CAD. We performed this case-control study to investigate the relationship between serum PCSK9 levels and PCSK9 polymorphisms and lipid levels and CAD risk in a southern Chinese population.MethodsA hospital-based case-control study with 1, 096 subjects, including 626 CAD patients and 470 controls, were conducted. Genotyping of PCSK9 polymorphisms was performed using polymerase chain reaction-ligase detection reaction (PCR-LDR) method.ResultsThe frequencies of the AA, AG and GG genotypes of PCSK9 E670G polymorphism were 90.58, 9.27, and 0.16% in the CAD patients, compared with 88.72, 10.85 and 0.43% in the controls, respectively. No R46L variant was detected in this population. There were no significant differences in genotype and allele frequencies of PCSK9E670G polymorphism between the CAD group and the controls. Serum lipid levels were not significantly different in carriers with the G allele and those with the AA genotype. The median (QR) of PCSK9 concentration was 1205.00 ng/l (577.28–1694.13 ng/l) in cases and 565.87 ng/l (357.17–967.50 ng/l) in controls, respectively. Compared with controls, CAD patients had significantly higher PCSK9 levels (z = 4.559, P < 0.001). After adjusting for age, gender, essential hypertension, diabetic mellitus, smoking and lipid profiles, PCSK9 levels remain significantly associated with increased CAD susceptibility (OR = 1.002, 95% CI = 1.001–1.002, P < 0.001). The correlation analyses showed that serum PCSK9 levels were positively associated with triglyceride (TG), Apo B and atherogenic index of plasma (AIP) levels in controls. No significant association between the PCSK9 E670G polymorphism and serum PCSK9 levels was observed in the CAD group and the controls.ConclusionsThe present study shows that serum PCSK9 levels, but not PCSK9 polymorphisms, are associated with CAD risk in Southern Chinese Han population, and that serum PCSK9 levels are positively associated with AIP.Electronic supplementary materialThe online version of this article (10.1186/s12944-018-0859-5) contains supplementary material, which is available to authorized users.

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“…Mostaza et al analyzed the association of rs11591147 polymorphism with lipid levels and subclinical vascular disease in 1188 individuals free of cardiovascular disease. They found a significant association with SA; however, no association with lipid levels was found [ 11 ]. Recently, Qiu et al performed a meta-analysis of rs505151 and rs11591147 polymorphisms of PCSK9 and found an association of these polymorphisms with cardiovascular risk and high lipid levels [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…Up to now, there is only one study that has indicated an association of PCSK9 gene polymorphisms with SA [ 11 ]. However, associations of PCSK9 gene polymorphisms with CAD and comorbidities, such as type 2 diabetes mellitus, have been reported in different populations with inconsistent results [ 8 , 12 , 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Variants of PCSK9 Gene Are Associated with Subclinical Atherosclerosis and Cardiometabolic Parameters in Mexicans. The GEA Project

et al. 2021

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Background: Coronary artery disease (CAD) is a chronic, inflammatory, and complex disease associated with vascular risk factors. Nowadays, the coronary artery calcium (CAC) is a specific marker of the presence and extent of atherosclerosis. Additionally, CAC is a predictor of future coronary events in asymptomatic individuals diagnosed with subclinical atherosclerosis (CAC > 0). In this study, our aim is to evaluate the participation of two polymorphisms of the PCSK9 gene as genetic markers for developing subclinical atherosclerosis and cardiometabolic risk factors in asymptomatic individuals. Methods: We analyzed two PCSK9 polymorphisms (rs2479409 and rs615563) in 394 individuals with subclinical atherosclerosis and 1102 healthy controls using real time- polymerase chain reaction (PCR). Results: Under various inheritance models adjusted for different confounding factors, the rs2479409 polymorphism was associated with an increased risk of developing subclinical atherosclerosis (OR = 1.53, P recessive = 0.041). Both polymorphisms were significantly associated with several cardiometabolic parameters. Conclusions: Our data suggest that rs2479409 polymorphism could be envisaged as a risk marker for subclinical atherosclerosis.

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R46L polymorphism in the PCSK9 gene: Relationship to lipid levels, subclinical vascular disease, and erectile dysfunction

Cited by 13 publications

References 26 publications

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

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

Serum PCSK9 levels, but not PCSK9 polymorphisms, are associated with CAD risk and lipid profiles in southern Chinese Han population

Variants of PCSK9 Gene Are Associated with Subclinical Atherosclerosis and Cardiometabolic Parameters in Mexicans. The GEA Project

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