Genomic, transcriptomic, and lipidomic profiling highlights the role of inflammation in individuals with low high-density lipoprotein cholesterol

Pirkka-Pekka Laurila, Ida Surakka, Antti-Pekka Sarin, Laxman Yetukuri, Tuulia Hyötyläinen, Sanni Söderlund, Jussi Naukkarinen, Jing Tang, Johannes Kettunen, Daniel B. Mirel, Jarkko Soronen, Terho Lehtimäki, Aimo Ruokonen, Christian Ehnholm, Johan G. Eriksson, Veikko Salomaa, Antti Jula, Olli T. Raitakari, Marjo-Riitta Järvelin, Aarno PalotieLeena Peltonen, Matej Orešič, Matti Jauhiainen, Marja-Riitta Taskinen, Samuli Ripatti

Research output: Contribution to journalArticleScientificpeer-review

29 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)847-857
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number4
DOIs
Publication statusPublished - 2013
MoE publication typeA1 Journal article-refereed

Keywords

  • coronary artery disease
  • genome-wide association
  • genomics
  • HDL-cholesterol
  • inflammation
  • lipdomics
  • transcriptomics

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