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 Palotie & 5 others Leena Peltonen, Matej Orešič, Matti Jauhiainen, Marja-Riitta Taskinen, Samuli Ripatti

Research output: Contribution to journalArticleScientificpeer-review

26 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

Fingerprint

LDL Cholesterol
HDL Cholesterol
Inflammation
Adipose Tissue
Plasmalogens
Single Nucleotide Polymorphism
Genes
Vascular Cell Adhesion Molecule-1
Information Storage and Retrieval
Quantitative Trait Loci
Plasma Cells
Population
Blood Vessels
Alleles
Genotype
Pathology
Phenotype

Keywords

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

Cite this

Laurila, Pirkka-Pekka ; Surakka, Ida ; Sarin, Antti-Pekka ; Yetukuri, Laxman ; Hyötyläinen, Tuulia ; Söderlund, Sanni ; Naukkarinen, Jussi ; Tang, Jing ; Kettunen, Johannes ; Mirel, Daniel B. ; Soronen, Jarkko ; Lehtimäki, Terho ; Ruokonen, Aimo ; Ehnholm, Christian ; Eriksson, Johan G. ; Salomaa, Veikko ; Jula, Antti ; Raitakari, Olli T. ; Järvelin, Marjo-Riitta ; Palotie, Aarno ; Peltonen, Leena ; Orešič, Matej ; Jauhiainen, Matti ; Taskinen, Marja-Riitta ; Ripatti, Samuli. / Genomic, transcriptomic, and lipidomic profiling highlights the role of inflammation in individuals with low high-density lipoprotein cholesterol. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2013 ; Vol. 33, No. 4. pp. 847-857.
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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). 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.",
keywords = "coronary artery disease, genome-wide association, genomics, HDL-cholesterol, inflammation, lipdomics, transcriptomics",
author = "Pirkka-Pekka Laurila and Ida Surakka and Antti-Pekka Sarin and Laxman Yetukuri and Tuulia Hy{\"o}tyl{\"a}inen and Sanni S{\"o}derlund and Jussi Naukkarinen and Jing Tang and Johannes Kettunen and Mirel, {Daniel B.} and Jarkko Soronen and Terho Lehtim{\"a}ki and Aimo Ruokonen and Christian Ehnholm and Eriksson, {Johan G.} and Veikko Salomaa and Antti Jula and Raitakari, {Olli T.} and Marjo-Riitta J{\"a}rvelin and Aarno Palotie and Leena Peltonen and Matej Orešič and Matti Jauhiainen and Marja-Riitta Taskinen and Samuli Ripatti",
year = "2013",
doi = "10.1161/ATVBAHA.112.300733",
language = "English",
volume = "33",
pages = "847--857",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
number = "4",

}

Laurila, P-P, Surakka, I, Sarin, A-P, Yetukuri, L, Hyötyläinen, T, Söderlund, S, Naukkarinen, J, Tang, J, Kettunen, J, Mirel, DB, Soronen, J, Lehtimäki, T, Ruokonen, A, Ehnholm, C, Eriksson, JG, Salomaa, V, Jula, A, Raitakari, OT, Järvelin, M-R, Palotie, A, Peltonen, L, Orešič, M, Jauhiainen, M, Taskinen, M-R & Ripatti, S 2013, 'Genomic, transcriptomic, and lipidomic profiling highlights the role of inflammation in individuals with low high-density lipoprotein cholesterol', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 4, pp. 847-857. https://doi.org/10.1161/ATVBAHA.112.300733

Genomic, transcriptomic, and lipidomic profiling highlights the role of inflammation in individuals with low high-density lipoprotein cholesterol. / Laurila, Pirkka-Pekka; Surakka, Ida; Sarin, Antti-Pekka; Yetukuri, Laxman; Hyötyläinen, Tuulia; Söderlund, Sanni; Naukkarinen, Jussi; Tang, Jing; Kettunen, Johannes; Mirel, Daniel B.; Soronen, Jarkko; Lehtimäki, Terho; Ruokonen, Aimo; Ehnholm, Christian; Eriksson, Johan G.; Salomaa, Veikko; Jula, Antti; Raitakari, Olli T.; Järvelin, Marjo-Riitta; Palotie, Aarno; Peltonen, Leena; Orešič, Matej; Jauhiainen, Matti; Taskinen, Marja-Riitta; Ripatti, Samuli (Corresponding Author).

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 33, No. 4, 2013, p. 847-857.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Genomic, transcriptomic, and lipidomic profiling highlights the role of inflammation in individuals with low high-density lipoprotein cholesterol

AU - Laurila, Pirkka-Pekka

AU - Surakka, Ida

AU - Sarin, Antti-Pekka

AU - Yetukuri, Laxman

AU - Hyötyläinen, Tuulia

AU - Söderlund, Sanni

AU - Naukkarinen, Jussi

AU - Tang, Jing

AU - Kettunen, Johannes

AU - Mirel, Daniel B.

AU - Soronen, Jarkko

AU - Lehtimäki, Terho

AU - Ruokonen, Aimo

AU - Ehnholm, Christian

AU - Eriksson, Johan G.

AU - Salomaa, Veikko

AU - Jula, Antti

AU - Raitakari, Olli T.

AU - Järvelin, Marjo-Riitta

AU - Palotie, Aarno

AU - Peltonen, Leena

AU - Orešič, Matej

AU - Jauhiainen, Matti

AU - Taskinen, Marja-Riitta

AU - Ripatti, Samuli

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - coronary artery disease

KW - genome-wide association

KW - genomics

KW - HDL-cholesterol

KW - inflammation

KW - lipdomics

KW - transcriptomics

U2 - 10.1161/ATVBAHA.112.300733

DO - 10.1161/ATVBAHA.112.300733

M3 - Article

VL - 33

SP - 847

EP - 857

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 4

ER -