LDLR and PCSK9 Are Associated with the Presence of Antiphospholipid Antibodies and the Development of Thrombosis in aPLA Carriers

Ochoa, Eguzkine; Iriondo, Mikel; Manzano, Carmen; Fullaondo, Asier; Villar, Irama; Ruiz‐Irastorza, Guillermo; Zubiaga, Ana M.; Estonba, Andone

doi:10.1371/journal.pone.0146990

Cited by 26 publications

(12 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that two variants of the LDLR strongly influenced the LDL-C and TC levels. The rs1003723 and rs6413504 in LDLR are mainly associated with hypercholesterolemia, which is consistent with several studies [29,30,31,32]. Both rs1003723 and rs6413504 in the LDLR can affect the expression of LDLR .…”

Section: Discussionsupporting

confidence: 90%

Polymorphisms in PCSK9, LDLR, BCMO1, SLC12A3, and KCNJ1 Are Associated with Serum Lipid Profile in Chinese Han Population

Zhao

Tan

et al. 2019

IJERPH

View full text Add to dashboard Cite

Unfavorable serum lipid levels are the most important risk factors for coronary artery disease (CAD), cerebral infarction, and other cardiovascular and cerebrovascular diseases. This study included 2323 Han Chinese in southern China. We collected medical reports, lifestyle details, and blood samples of individuals and used the polymerase chain reaction-ligase detection reaction method to genotype single-nucleotide polymorphisms (SNPs). Two SNPs showed a strong evidence of association with total cholesterol (TC): rs1003723 and rs6413504 in the low-density lipoproteins receptor (LDLR). Two SNPs in LDLR showed a strong evidence of association with low-density lipoprotein cholesterol (LDL-C), rs1003723 and rs6413504. Two SNPs showed a strong evidence of association with triglycerides (TG), namely, rs662145 in pro-protein convertase subtilisin-kexin type 9 (PCSK9) and rs11643718 in the solute carrier family 12 member 3 (SLC12A3). For the TC, LDL-C, and TG levels, these SNPs generated strong combined effects on these lipid levels. For each additional dangerous gene, TC increased by 0.085 mmol/L (p = 7.00 × 10−6), and LDL-C increased by 0.075 mmol/L (p = 9.00 × 10−6). The TG increased by 0.096 mmol/L (p = 2.90 × 10−5). Compared with those bearing no risk alleles, the risk of hypertriglyceridemia, hypercholesterolemia, and dyslipidemia increased in those with two or more risk alleles and one risk gene. Polymorphisms of PCSK9, LDLR, and SLC12A3 were associated with the plasma lipid levels in people in southern China. These results provide a theoretical basis for gene screening and the prevention of dyslipidemia.

show abstract

Section: Discussionsupporting

confidence: 90%

Polymorphisms in PCSK9, LDLR, BCMO1, SLC12A3, and KCNJ1 Are Associated with Serum Lipid Profile in Chinese Han Population

Zhao

Tan

et al. 2019

IJERPH

View full text Add to dashboard Cite

show abstract

“…In fact, plasma levels of TF, a pro-coagulant glycoprotein triggering thrombin formation and playing a central role in atherothrombosis, 57 positively correlated with plasma PCSK9 in patients with CAD and T2DM. 58 Moreover, single nucleotide polymorphisms of the PCSK9 gene were shown to be associated with the development of thrombosis in carriers of anti-phospholipid antibodies, 59 subjects characterized by a hypercoagulabe state and in vivo platelet activation, 60,61 confirming a link between PCSK9, platelets and blood coagulation.…”

Section: Studies In Humansmentioning

confidence: 99%

PCSK9 in Haemostasis and Thrombosis: Possible Pleiotropic Effects of PCSK9 Inhibitors in Cardiovascular Prevention

2019

View full text Add to dashboard Cite

Since increased cholesterol levels are crucial in determining the development of atheroma, their reduction represents a mainstay in primary and secondary cardiovascular prevention. The most recent spectacular advancement in cholesterol-lowering therapy is represented by proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors. Although their benefit over currently available treatments has been ascribed primarily to their strong low-density lipoprotein (LDL)-cholesterol reducing action, several clues suggest that PCSK9 inhibitors may also influence platelet function and blood coagulation. PCSK9 knockout mice develop less venous and arterial thrombosis and show reduced in vivo platelet activation upon arterial injury. In patients with acute coronary syndromes (ACSs) treated with P2Y12 inhibitors, a direct association between PCSK9 serum levels and residual platelet reactivity was found. A direct correlation between urinary excretion of 11-dehydro-thromboxane-B2, a marker of in vivo platelet activation, and circulating PCSK9 levels was reported in patients with atrial fibrillation. Moreover, recombinant human PCSK9 added in vitro to human platelets potentiated activation induced by weak agonists. Finally, blood clotting factor VIII (FVIII), which is associated with stroke and ACS risk, is cleared from the circulation by members of the LDL receptor (LDLR) family. Given that PCSK9 degrades LDLR, it is conceivable that PCSK9 inhibitors by enhancing the expression of LDLR may slightly decrease circulating FVIII, in this way contributing to the prevention of cardiovascular events. This review aims to discuss the possible and hypothetical interactions between PCSK9 and the haemostatic system and to examine the possible pleiotropic effects of PCSK9 inhibitors in cardiovascular prevention.

show abstract

“…However, the distributions of rs562556 variants in Japanese subjects with MI were not different from those in the control population, although this SNP was associated with cholesterol level [27]. An association between polymorphism rs562556, the presence of anti-phospholipid antibodies, and development of thrombosis (the risk factor of MI) was revealed in subjects carrying these antibodies [28]. The association of other PCSK9 gene variants (namely, rs11206510 [29] and rs11591147 [30]) with MI was demonstrated in different populations.…”

Section: Discussionmentioning

confidence: 84%

Multilocus Analysis of Genetic Susceptibility to Myocardial Infarction in Russians: Replication Study

Kukava¹,

Titov²,

Osmak³

et al. 2017

Acta Naturae

View full text Add to dashboard Cite

In search of genetic markers of myocardial infarction (MI) risk, which have prognostic significance for Russians, we performed a replication study of MI association with genetic variants of PCSK9 (rs562556), APOE (epsilon polymorphism, rs7412 and rs429358), LPL (rs320), MTHFR (rs1801133), eNOS (rs2070744), and the 9p21 region (rs1333049) in 405 patients with MI and 198 controls. Significant MI association was observed with variants of the lipid metabolism genes (PCSK9, APOE and LPL), and of eNOS. The SNPs in the MTHFR gene and the 9p21 region were not significantly associated with MI one by one but were included in several different MI-associated allelic combinations identified by multilocus analysis. Since we have not revealed nonlinear epistatic interactions between the components of the identified combinations, we postulate that the cumulative effect of genes that form а combination arises from the summation of their small independent contributions. The prognostic significance of the additive composite model built from the PCSK9, APOE, LPL, and eNOS genes as genetic markers was assessed using ROC analysis. After we included these markers in the previously published composite model of individual genetic risk of MI, the prognostic efficacy in our sample reached AUC = 0.676. However, the results obtained in this study certainly need to be replicated in an independent sample of Russians. KEYWORDS myocardial infarction, Russians, genes, allelic polymorphism, multilocus analysis, genetic markers ABBREVIATIONS AUC -area under curve in ROC analysis; GWAS -genome-wide association study; NO -nitrogen oxide; ROC -receiver operating characteristic; SNP -single nucleotide polymorphism; CI -confidence interval; CAD -coronary artery disease; MI -myocardial infarction; OR -odds ratio; PCR -polymerase chain reaction; PCR-SSP -polymerase chain reaction using allele-specific primers; CVD -cardiovascular disease, m. a. -mean age.

show abstract

LDLR and PCSK9 Are Associated with the Presence of Antiphospholipid Antibodies and the Development of Thrombosis in aPLA Carriers

Cited by 26 publications

References 49 publications

Polymorphisms in PCSK9, LDLR, BCMO1, SLC12A3, and KCNJ1 Are Associated with Serum Lipid Profile in Chinese Han Population

Polymorphisms in PCSK9, LDLR, BCMO1, SLC12A3, and KCNJ1 Are Associated with Serum Lipid Profile in Chinese Han Population

PCSK9 in Haemostasis and Thrombosis: Possible Pleiotropic Effects of PCSK9 Inhibitors in Cardiovascular Prevention

Multilocus Analysis of Genetic Susceptibility to Myocardial Infarction in Russians: Replication Study

Contact Info

Product

Resources

About