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

Isabela Bensenor,Itamar S Santos,Jose E Krieger,Alessandra C Goulart,Paulo A Lotufo,Jose G Mill,Isabella Ramos Lima,Stéphane Ramin-Mangata,Kallyandra Padilha,Alexandre C Pereira,Raul Dias Santos,Marcio S Bittencourt,Gilles Lambert

doi:10.3389/fgene.2021.728526

Abstract

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.

Highlights

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key modulator of LDL receptor (LDLR) degradation and, LDL-cholesterol (LDL-C) serum levels
Plasma PCSK9 levels were associated with Total cholesterol (TC) (p = 0.0006), TG (p = 0.003), and LDL-C (p = 0.003; Table 1)
It is not known whether PCSK9 has other actions independent of plasmatic LDL-C levels (Cesaro et al, 2020), and the association between PCSK9 inhibition and inflammatory markers has not been as consistent as its association to lipid levels (Ruscica et al, 2019)

Summary

Introduction

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key modulator of LDL receptor (LDLR) degradation and, LDL-cholesterol (LDL-C) serum levels. Gain-offunction mutations in PCSK9 have been shown to cause familial hypercholesterolemia and increased cardiovascular risk (Hopkins et al, 2015). Loss-of-function variants have been shown to associate with low LDL-C levels and reduced cardiovascular risk (Kent et al, 2017). Plasma PCSK9 has been independently associated with other components of the lipid profile (Leander et al, 2016; Brumpton et al, 2019). Understanding the factors that modulate interindividual variability of PCSK9 plasma levels is important for the better understanding of individual responses to treatment as well as the identification of new targets for cardiovascular disease treatment. The use of unbiased genetic approaches has the potential to contribute to increase our understanding of the two

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Conclusion