Circulating PCSK9 is associated with liver biomarkers and hepatic steatosis

Paquette, Martine; Gauthier, Dany; Chamberland, Ann; Prat, Annik; Rolfe, Emanuella De Lucia; Rasmussen, Jeppe Nørgaard; Kaduka, Lydia; Seidah, Nabil G.; Bernard, Sophie; Christensen, Dirk L.; Baass, Alexis

doi:10.1016/j.clinbiochem.2020.01.003

Cited by 28 publications

(22 citation statements)

References 43 publications

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“…As for the association between PCSK9 and -GTP, Ruscica M, et al 36) suggested that circulating PCSK9 increases with hepatic fat accumulation and correlates with the severity of steatosis, independent of metabolic confounders and liver damage. Recently, Paquette M, et al 37) reported that circulating PCSK9 levels were strongly associated with all circulating liver biomarkers, as well as the presence of hepatic steatosis. These associations were independent of insulin resistance status, although the strength of the association between PCSK9 and hepatic steatosis decreased when corrected for HOMA-IR, BMI, and alcohol use.…”

Section: Associations Between Pcsk9 and Systolic Blood Pressure/ -Glutamyl Transferasementioning

confidence: 99%

Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Independently Associated with Insulin Resistance, Triglycerides, Lipoprotein(a) Levels but not Low-Density Lipoprotein Cholesterol Levels in a General Population

Hamamura

Adachi

Enomoto

et al. 2021

JAT

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as an important regulator of low-density lipoprotein (LDL) receptor processing. Evolocumab and alirocumab are PCSK9 inhibitors; however, little is known about the association between PCSK9 levels and lipid profiles in a general population. Because PCSK9 inhibitors have LDL-C lowering effects, we investigated whether there is a positive correlation between serum PCSK9 levels and LDL-C or lipoprotein(a) [Lp(a)]. Methods: In Uku town, 674 residents (mean age; 69.2 8.3 years) received health check-ups. The participants underwent a physical examination and blood tests, including PCSK9 and Lp(a). Serum PCSK9 and Lp(a) were measured by ELISA and Latex methods, respectively. HOMA-IR was calculated by fasting plasma glucose insulin levels/405. Results: The mean (range) of PCSK9 and Lp(a) were 211.2 (49-601) ng/mL and 60 (1-107) mg/dL, respectively. Because of a skewed distribution, the log-transformed values were used. With univariate linear regression analysis, PCSK9 levels were associated with Lp(a) (p 0.028), triglycerides (p 0.001), and HOMA-IR (p 0.001), but not with LDL-C (p 0.138) levels. Multiple stepwise regression analysis revealed that serum PCSK9 levels were independently associated with triglycerides (p 0.001), Lp(a) (p 0.033) and HOMA-IR (p 0.041). Conclusions: PCSK-9 is independently associated with triglycerides, Lp(a) levels, and HOMA-IR, but not LDL-C, in a relatively large general population sample.moting their degradation through the endosomal/ lysosomal pathway 1) .Data from clinical, in vivo, in vitro, and animal studies have associated PCSK9 with triglycerides 2) , triglycerides-rich lipoproteins 3) , high-density lipoprotein cholesterol (HDL-C) 4) , insulin, and insulin resistance 5,6) . Studies on the relationship between PCSK9 and the components of metabolic syndrome have been reported; however, the results are inconsistent 7,8) .

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Section: Associations Between Pcsk9 and Systolic Blood Pressure/ -Glutamyl Transferasementioning

confidence: 99%

Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Independently Associated with Insulin Resistance, Triglycerides, Lipoprotein(a) Levels but not Low-Density Lipoprotein Cholesterol Levels in a General Population

Hamamura

Adachi

Enomoto

et al. 2021

JAT

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“…PCSK9 has also been shown to be associated with metabolic factors other than lipoproteins. It is positively associated with albumin, liver enzymes (ALT, ALP, AST, GGT) and with hepatic steatosis, although whether this association is confounded by or mediated by LDL-C is still unclear (Paquette et al, 2020). Finally, PCSK9 is also expressed in the intestine, endocrine pancreas and brain, and non-lipid-lowering effects of PCSK9 inhibition could also be linked to platelet activation (Qi et al, 2021), cell proliferation and apoptosis (Macchi et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study

et al. 2021

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Pharmacological inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is an established therapeutic option to treat hypercholesterolemia, and plasma PCSK9 levels have been implicated in cardiovascular disease incidence. A number of genetic variants within the PCSK9 gene locus have been shown to modulate PCSK9 levels, but these only explain a very small percentage of the overall PCSK9 interindividual variation. Here we present data on the genetic association structure between PCSK9 levels and genom-wide genetic variation in a healthy sample from the general population. We performed a genome-wide association study of plasma PCSK9 levels in a sample of Brazilian individuals enrolled in the Estudo Longitudinal de Saude do Adulto cohort (n=810). Enrolled individuals were free from cardiovascular disease, diabetes and were not under lipid-lowering medication. Genome-wide genotyping was conducted using the Axiom_PMRA.r3 array, and imputation was performed using the TOPMED multi-ancestry sample panel as reference. Total PCSK9 plasma concentrations were determined using the Quantikine SPC900 ELISA kit. We observed two genome-wide significant loci and seven loci that reached the pre-defined value of p threshold of 1×10−6. Significant variants were near KCNA5 and KCNA1, and LINC00353. Genetic variation at the PCSK9 locus was able to explain approximately 4% of the overall interindividual variations in PCSK9 levels. Colocalization analysis using eQTL data suggested RWDD3, ATXN7L1, KCNA1, and FAM177A1 to be potential mediators of some of the observed associations. Our results suggest that PCSK9 levels may be modulated by trans genetic variation outside of the PCSK9 gene and this may have clinical implications. Understanding both environmental and genetic predictors of PCSK9 levels may help identify new targets for cardiovascular disease treatment and contribute to a better assessment of the benefits of long-term PCSK9 inhibition.

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“…It has also been shown to be associated with metabolic factors other than lipoproteins. It is positively associated with albumin, liver enzymes (ALT, ALP, AST, GGT) and with hepatic steatosis, although whether this association is confounded by or mediated by LDL-C is still unclear [18]. Another important point to be considered is that there is great interindividual variation in both PCSK9 levels and response to PCSK9 inhibitors [8,19,20].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) plasma levels in the ELSA-Brasil study

Padilha

Lima

Santos

et al. 2020

Preprint

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Pharmacological inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is an established therapeutic option to treat hypercholesterolemia and plasma PCSK9 levels have been implicated in cardiovascular disease incidence. A number of genetic variants within the PCSK9 gene locus have been shown to modulate PCSK9 levels, but these only explain a very small percentage of the overall PCSK9 interindividual variation. Here we present data on the genetic association structure between PCSK9 levels and genome-wide genetic variation in a healthy sample from the general population.We performed a genome-wide association study of plasma PCSK9 levels in a sample of Brazilian individuals enrolled in the ELSA-Brasil cohort (n=810). Enrolled individuals were free from cardiovascular disease, diabetes and were not under lipid-lowering medication. Genome-wide genotyping was conducted using the Axiom_PMRA.r3 array and imputation used the TOPMED multi-ancestry sample panel. Total PCSK9 plasma concentrations were determined using the Quantikine SPC900 ELISA kit.We observed two genome-wide significant loci and seven loci that reached the pre-defined p value threshold of 1 × 10−6. Significant variants were near KCNA5 and KCNA1, and LINC00353. Genetic variation at the PCSK9 locus was able to explain approximately 4% of the overall interindividual variation in PCSK9 levels. Colocalization analysis using eQTL data suggested RWDD3, ATXN7L1, KCNA1, and FAM177A1 to be potential mediators of some of the observed associations.Our results suggest that PCSK9 levels may be modulated by trans genetic variation outside of the PCSK9 gene and this may have clinical implications. Understanding both environmental and genetic predictors of PCSK9 levels may help identifying new targets for cardiovascular disease treatment and contribute to a better assessment of the benefits of long-term PCSK9 inhibition.

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Circulating PCSK9 is associated with liver biomarkers and hepatic steatosis

Cited by 28 publications

References 43 publications

Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Independently Associated with Insulin Resistance, Triglycerides, Lipoprotein(a) Levels but not Low-Density Lipoprotein Cholesterol Levels in a General Population

Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Independently Associated with Insulin Resistance, Triglycerides, Lipoprotein(a) Levels but not Low-Density Lipoprotein Cholesterol Levels in a General Population

Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study

Genome-wide association of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) plasma levels in the ELSA-Brasil study

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