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A genome-wide expression quantitative trait loci analysis of proprotein convertase subtilisin/kexin enzymes identifies a novel regulatory gene variant for FURIN expression and blood pressure

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Abstract

Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave and convert their immature substrates into biologically active forms. Polymorphisms in the PCSK genes have been reported to associate with human diseases and phenotypes, including hypercholesterolemia and blood pressure (BP), and targeting PCSKs is considered a promising future form of drug therapy. PCSK processing is readily induced upon upregulation of the enzyme, but the genetic factors contributing to PCSK expression have not been thoroughly characterized. To gain a comprehensive understanding of the genetic regulation of PCSK expression, we performed, for the first time, a genome-wide expression quantitative trait loci (eQTL) analysis using mRNA expression in >1400 human peripheral blood samples from the Cardiovascular Risk in Young Finns Study and ca. ten million single-nucleotide polymorphisms (SNPs). The expression data showed clear expression for FURIN, PCSK5, PCSK7 and MBTPS1 (membrane-bound transcription factor peptidase, site 1) mRNAs in virtually all tested samples. A discovery analysis demonstrated a genome-wide significant (p < 5 × 10−8) association with the selected PCSK probes for 1024 variants, which were located at ten independent loci. Of these loci, 5/10 could be confirmed to regulate PCSK expression in two additional and independent sample sets. Finally, a phenotypic analysis demonstrated that a novel cis-eQTL SNP rs4702 for FURIN is strongly associated with both diastolic (p = 0.012) and systolic (p = 0.035) BP levels, as well as peripheral vascular resistance (p = 0.003). These findings indicate that the expression of the PCSK enzymes is regulated by genetic factors, which have biological roles in health and disease.

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Abbreviations

eQTL:

Expression quantitative trait loci

GWAS:

Genome-wide association analysis

GWE:

Genome-wide expression

PCSK:

Proprotein convertase subtilisin/kexin

SNP:

Single-nucleotide polymorphism

TVS:

Tampere Vascular Study

YFS:

Young Finns Study

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Acknowledgments

This work was supported by the Academy of Finland (Projects 128623 and 135980 to MP and 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi) to The Cardiovascular Risk in Young Finns Study), Emil Aaltonen Foundation (to MP, TL, NO), Sigrid Jusélius Foundation (to MP), Tampere Tuberculosis Foundation (to MP, TL, MK, The Cardiovascular Risk in Young Finns Study), Competitive Research Funding of the Tampere University Hospital (Grants 9M080, 9N056, 9S051 to MP and 9N035, X51001 to TL), the European Union 7th Framework Program (Grant 201668, Atheroremo), the Finnish Angiology Association (NO), Maire Taponen Foundation (NO), Paavo Nurmi Foundation (NO, The Cardiovascular Risk in Young Finns Study), the Social Insurance Institution of Finland (The Cardiovascular Risk in Young Finns Study), Kuopio, Tampere and Turku University Hospital Medical Funds (The Cardiovascular Risk in Young Finns Study), Juho Vainio Foundation (The Cardiovascular Risk in Young Finns Study), Finnish Foundation of Cardiovascular Research (The Cardiovascular Risk in Young Finns Study) and Finnish Cultural Foundation (The Cardiovascular Risk in Young Finns Study).

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Correspondence to Hannu Turpeinen.

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T. Lehtimäki and M. Pesu equally contributed.

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439_2015_1546_MOESM1_ESM.pdf

Supplementary Figure 1. PCSK gene expression in peripheral blood mononuclear cells in the YFS samples. Probe IDs are given next to the gene names. Expression levels on the X-axis are arbitrary. Supplementary Figure 2. Manhattan and QQ-plots of the discovery genome-wide eQTL analyses. Probe IDs are given next to the gene names. Supplementary Figure 3. Regional plots of the genome-wide significant loci in YFS. Probe IDs are given next to the gene names. LD reference in these plots is the 1000 Genomes EUR sample (March 2012). Supplementary Figure 4. Linkage disequilibrium observed in the FURIN +-15 kb region in the HapMap II CEU and Young Finns Study samples (PDF 2086 kb)

439_2015_1546_MOESM2_ESM.xlsx

Supplementary Table 1. Genetic variants statistically significantly (p < 5 × 10−8) associated with the expression of PCSK genes in peripheral blood (XLSX 178 kb)

439_2015_1546_MOESM3_ESM.xlsx

Supplementary Table 2. Background information on variants statistically significantly (p < 5 × 10−8) associated with the expression of PCSK genes in peripheral blood (XLSX 1698 kb)

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Turpeinen, H., Seppälä, I., Lyytikäinen, LP. et al. A genome-wide expression quantitative trait loci analysis of proprotein convertase subtilisin/kexin enzymes identifies a novel regulatory gene variant for FURIN expression and blood pressure. Hum Genet 134, 627–636 (2015). https://doi.org/10.1007/s00439-015-1546-5

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