title: Genomic, transcriptomic, and lipidomic profiling highlights the role of inflammation in individuals with low high-density lipoprotein cholesterol.
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).
  
  
  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.
authors: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Finland.
authors: Pirkka-Pekka
authors: PP
authors: Laurila
authors: Ida
authors: I
authors: Surakka
authors: Antti-Pekka
authors: AP
authors: Sarin
authors: Laxman
authors: L
authors: Yetukuri
authors: Tuulia
authors: T
authors: Hyötyläinen
authors: Sanni
authors: S
authors: Söderlund
authors: Jussi
authors: J
authors: Naukkarinen
authors: Jing
authors: J
authors: Tang
authors: Johannes
authors: J
authors: Kettunen
authors: Daniel B
authors: DB
authors: Mirel
authors: Jarkko
authors: J
authors: Soronen
authors: Terho
authors: T
authors: Lehtimäki
authors: Aimo
authors: A
authors: Ruokonen
authors: Christian
authors: C
authors: Ehnholm
authors: Johan G
authors: JG
authors: Eriksson
authors: Veikko
authors: V
authors: Salomaa
authors: Antti
authors: A
authors: Jula
authors: Olli T
authors: OT
authors: Raitakari
authors: Marjo-Riitta
authors: MR
authors: Järvelin
authors: Aarno
authors: A
authors: Palotie
authors: Leena
authors: L
authors: Peltonen
authors: Matej
authors: M
authors: Oresic
authors: Matti
authors: M
authors: Jauhiainen
authors: Marja-Riitta
authors: MR
authors: Taskinen
authors: Samuli
authors: S
authors: Ripatti
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood* / Q000235:genetics* / Q000276:immunology; D005260:Female; D005387:Finland; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D006680:HLA Antigens / Q000235:genetics; D006306:Health Surveys; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000235:genetics* / Q000276:immunology; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010955:Plasmalogens / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012307:Risk Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
chemical_list: D015415:Biomarkers; D008076:Cholesterol, HDL; D006680:HLA Antigens; D010955:Plasmalogens; D019010:Vascular Cell Adhesion Molecule-1