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Genetic dissection of serum vaspin highlights its causal role in lipid metabolism

Breitfeld, Jana ; Horn, Katrin ; Le Duc, Diana ; Velluva, Akhil ; Marzi, Carola ; Grallert, Harald ; Friedrich, Nele ; Pietzner, Maik ; Völker, Uwe and Völzke, Henry , et al. (2023) In Obesity 31(11). p.2862-2874
Abstract

Objective: Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity-related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated. Methods: A meta-analysis of genome-wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype-Tissue Expression (GTEx) were analyzed,... (More)

Objective: Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity-related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated. Methods: A meta-analysis of genome-wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype-Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured. Results: A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p < 5×10−8, explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low-density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice. Conclusions: The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism.

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type
Contribution to journal
publication status
published
subject
in
Obesity
volume
31
issue
11
pages
2862 - 2874
publisher
Nature Publishing Group
external identifiers
  • scopus:85172085596
ISSN
1930-7381
DOI
10.1002/oby.23882
language
English
LU publication?
yes
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Funding Information: LIFE‐Heart and LIFE‐Adult are funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF), and by means of the Free State of Saxony within the framework of the excellence initiative. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403) and the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg‐West Pomerania and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (grant 03IS2061A). The University of Greifswald is a member of the “Center of Knowledge Interchange” program of the Siemens AG and the Caché Campus program of the InterSystems GmbH. Funding Information: We would like to thank Kerstin Wirkner for running the LIFE-Adult study center, Annegret Unger and Kay Olischer for recruitment of the LIFE-Heart study, and Sylvia Henger for data quality control of LIFE-Adult and LIFE-Heart. We thank all study participants of the LIFE studies for donating their blood and time. Genotyping of LIFE-Adult was performed at the Cologne Center for Genomics (University of Cologne, Peter Nürnberg and Mohammad R. Toliat). Genotype imputation was supported by the compute infrastructure of ScaDS (Dresden/Leipzig Competence Center for Scalable Data Services and Solutions). The SHIP authors are grateful to Mario Stanke for the opportunity to use his Server Cluster for the SNP imputation as well as to Holger Prokisch and Thomas Meitinger (Helmholtz Zentrum München) for the genotyping of the SHIP-TREND cohort. We thank Manuela Quandt and Eva Böge for excellent technical work and Noura Kabbani for proofreading the English language of the manuscript. Open Access funding enabled and organized by Projekt DEAL. Funding Information: We would like to thank Kerstin Wirkner for running the LIFE‐Adult study center, Annegret Unger and Kay Olischer for recruitment of the LIFE‐Heart study, and Sylvia Henger for data quality control of LIFE‐Adult and LIFE‐Heart. We thank all study participants of the LIFE studies for donating their blood and time. Genotyping of LIFE‐Adult was performed at the Cologne Center for Genomics (University of Cologne, Peter Nürnberg and Mohammad R. Toliat). Genotype imputation was supported by the compute infrastructure of ScaDS (Dresden/Leipzig Competence Center for Scalable Data Services and Solutions). Publisher Copyright: © 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.
id
36833027-71b0-4660-aa61-c66be3b331f5
date added to LUP
2023-11-15 10:31:42
date last changed
2024-04-13 00:21:14
@article{36833027-71b0-4660-aa61-c66be3b331f5,
  abstract     = {{<p>Objective: Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity-related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated. Methods: A meta-analysis of genome-wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype-Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured. Results: A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p &lt; 5×10<sup>−8</sup>, explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low-density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice. Conclusions: The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism.</p>}},
  author       = {{Breitfeld, Jana and Horn, Katrin and Le Duc, Diana and Velluva, Akhil and Marzi, Carola and Grallert, Harald and Friedrich, Nele and Pietzner, Maik and Völker, Uwe and Völzke, Henry and Ahlqvist, Emma and Aly, Dina Mansour and Tuomi, Tiinamaija and Baber, Ronny and Kratzsch, Jürgen and Thiery, Joachim and Isermann, Berend and Loeffler, Markus and Klöting, Nora and Blüher, Matthias and Stumvoll, Michael and Heiker, John T. and Tönjes, Anke and Scholz, Markus and Kovacs, Peter}},
  issn         = {{1930-7381}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{2862--2874}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Obesity}},
  title        = {{Genetic dissection of serum vaspin highlights its causal role in lipid metabolism}},
  url          = {{http://dx.doi.org/10.1002/oby.23882}},
  doi          = {{10.1002/oby.23882}},
  volume       = {{31}},
  year         = {{2023}},
}