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

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

crossref(2020)

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摘要
AbstractPharmacological 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-definedpvalue threshold of 1 × 10−6. Significant variants were nearKCNA5andKCNA1, andLINC00353. Genetic variation at thePCSK9locus was able to explain approximately 4% of the overall interindividual variation in PCSK9 levels. Colocalization analysis using eQTL data suggestedRWDD3,ATXN7L1,KCNA1, andFAM177A1to be potential mediators of some of the observed associations.Our results suggest that PCSK9 levels may be modulated bytransgenetic variation outside of thePCSK9gene 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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