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Genomic, transcriptomic, and lipidomic profiling highlights the role of inflammation in individuals with low high-density lipoprotein cholesterol
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.
VTT Technical Research Centre of Finland, Espoo, Finland.
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2013 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 33, no 4, p. 847-857Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Low high-density lipoprotein cholesterol (HDL-C) is associated with cardiometabolic pathologies. In this study, we investigate the biological pathways and individual genes behind low HDL-C by integrating results from 3 high-throughput data sources: adipose tissue transcriptomics, HDL lipidomics, and dense marker genotypes from Finnish individuals with low or high HDL-C (n=450).

APPROACH AND RESULTS: In the pathway analysis of genetic data, we demonstrate that genetic variants within inflammatory pathways were enriched among low HDL-C associated single-nucleotide polymorphisms, and the expression of these pathways upregulated in the adipose tissue of low HDL-C subjects. The lipidomic analysis highlighted the change in HDL particle quality toward putatively more inflammatory and less vasoprotective state in subjects with low HDL-C, as evidenced by their decreased antioxidative plasmalogen contents. We show that the focal point of these inflammatory pathways seems to be the HLA region with its low HDL-associated alleles also associating with more abundant local transcript levels in adipose tissue, increased plasma vascular cell adhesion molecule 1 (VCAM1) levels, and decreased HDL particle plasmalogen contents, markers of adipose tissue inflammation, vascular inflammation, and HDL antioxidative potential, respectively. In a population-based look-up of the inflammatory pathway single-nucleotide polymorphisms in a large Finnish cohorts (n=11 211), no association of the HLA region was detected for HDL-C as quantitative trait, but with extreme HDL-C phenotypes, implying the presence of low or high HDL genes in addition to the population-genomewide association studies-identified HDL genes.

CONCLUSIONS: Our study highlights the role of inflammation with a genetic component in subjects with low HDL-C and identifies novel cis-expression quantitative trait loci (cis-eQTL) variants in HLA region to be associated with low HDL-C.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2013. Vol. 33, no 4, p. 847-857
National Category
Cardiac and Cardiovascular Systems Medical Genetics
Identifiers
URN: urn:nbn:se:oru:diva-63677DOI: 10.1161/ATVBAHA.112.300733ISI: 000316110400027PubMedID: 23413431Scopus ID: 2-s2.0-84875372535OAI: oai:DiVA.org:oru-63677DiVA, id: diva2:1169242
Note

Funding agencies:

Finnish Foundation for Cardiovascular Research

Novo Nordisk Foundation

Helsinki University Central Hospital Research Foundation

Emil Aaltonen Foundation

Finnish Medical Foundation

Biomedicum Helsinki Foundation

Aarne Koskelo Foundation

Finska Lakaresallskapet

Research Council for the Health

Academy of Finland 132625

Paavo Nurmi Foundation

Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-05-29Bibliographically approved

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Hyötyläinen, TuuliaOresic, Matej

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