Genetic and Metabolic Determinants of Plasma PCSK9 Levels

Lakoski, Susan G.; Lagace, Thomas A.; Cohen, Jonathan C.; Horton, Jay D.; Hobbs, Helen H.

doi:10.1210/jc.2009-0141

Cited by 463 publications

(449 citation statements)

References 25 publications

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“…Although positive correlations were observed between plasma PCSK9 and both FPG and HOMA-IR in the Dallas Heart Study [12], we did not find any associations between p.R46L and either FPG, HbA 1c , or markers of insulin resistance (HOMA-IR) or insulin secretion (HOMA-B). However, a non-clinically relevant tendency for a positive association between p.R46L and FPG was observed in MAGIC.…”

Section: Discussioncontrasting

confidence: 96%

The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

et al. 2015

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Aims/hypothesis Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a critical regulator of cholesterol homeostasis. PCSK9 inhibitors are being actively developed to lower LDL-cholesterol levels. However, there are conflicting data regarding the consequences of Pcsk9 deficiency on glucose homeostasis in mouse models. Here, we analysed in humans the association between the PCSK9 p.R46L loss-of-function (LOF) variant and (1) glucose homeostasis variables; (2) type 2 diabetes status; and (3) the risk of 9 year incident type 2 diabetes in a prospective study. Methods PCSK9 p.R46L was genotyped in 4630 French participants from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study and in 1342 French participants with type 2 diabetes. The association between p.R46L and metabolic traits or type 2 diabetes risk was assessed through linear or logistic regression models adjusted for age, sex and BMI. The association between p.R46L and incident type 2 diabetes was assessed using a Cox regression model adjusted for sex, age and BMI at baseline. Results Significant associations (p<10 −6 ) were found between p.R46L and lower total cholesterol (−0.394 mmol/l), LDL-cholesterol (−0.393 mmol/l) and apolipoprotein B concentrations (−0.099 g/l). However, no significant association was observed between p.R46L and markers of glucose homeostasis (including fasting glucose, fasting insulin, HbA 1c , HOMA-B, HOMA-IR) or type 2 diabetes risk. Furthermore, no significant association between p.R46L variant and risk of incident type 2 diabetes was observed in DESIR. Conclusions/interpretation The PCSK9 p.R46L LOF variant was not associated with impaired glucose homeostasis in Electronic supplementary material The online version of this article

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Section: Discussioncontrasting

confidence: 96%

The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

et al. 2015

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“…As observed in non-diabetic patients [17][18][19], we found that plasma PCSK9 levels positively correlated with TC, LDL-C, non-HDL-C, BMI, γGTP, insulin and HOMA-IR at baseline levels in subjects with impaired glucose tolerance or T2DM. On the other hand, fasting plasma glucose was negatively correlated with plasma PCSK9 levels in our study on impaired glucose tolerance or type 2 diabetes mellitus, which does not appear to be consistent with these reports on non-diabetic patients.…”

Section: Discussionsupporting

confidence: 81%

Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: Results from a crossover study

Noguchi¹,

Kobayashi²,

Yagi³

et al. 2011

Atherosclerosis

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“…119 In the multiethnic Dallas Heart Study of 3138 patients, plasma PCSK9 levels were significantly higher in women (n=1863) than in men (n=1489). This difference persisted after adjusting for most variables.. 120 In the same study, premenopausal women had considerably higher levels of plasma PCSK9 than postmenopausal women. Estrogen treatment did not significantly affect fasting PCSK9 levels in postmenopausal women.…”

Section: Physiological Modulation Of Pcsk9 Levels Variation With Agementioning

confidence: 83%

Pcsk9

Seidah

Awan

Chrétien³

et al. 2014

Circulation Research

502

197

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Genetic and Metabolic Determinants of Plasma PCSK9 Levels

Abstract: Multiple metabolic and genetic factors contribute to variation in plasma levels of PCSK9 in the general population. Although levels of PCSK9 correlate with plasma levels of LDL-C, they account for only a small proportion of the variation in the levels of this lipoprotein.

Cited by 463 publications

References 25 publications

The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis

Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: Results from a crossover study

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