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A meta-analysis of gene expression signatures of blood pressure and hypertension.
journal contribution
posted on 2018-01-25, 10:09 authored by Tianxiao Huan, Tõnu Esko, Marjolein J. Peters, Luke C. Pilling, Katharina Schramm, Claudia Schurmann, Brian H. Chen, Chunyu Liu, Roby Joehanes, Andrew D. Johnson, Chen Yao, Sai-xia Ying, Paul Courchesne, Lili Milani, Nalini Raghavachari, Richard Wang, Poching Liu, Eva Reinmaa, Abbas Dehghan, Albert Hofman, André G. Uitterlinden, Dena G. Hernandez, Stefania Bandinelli, Andrew Singleton, David Melzer, Andres Metspalu, Maren Carstensen, Harald Grallert, Christian Herder, Thomas Meitinger, Annette Peters, Michael Roden, Melanie Waldenberger, Marcus Dörr, Stephan B. Felix, Tanja Zeller, International Consortium for Blood Pressure GWAS (ICBP), Ramachandran Vasan, Christopher J. O'Donnell, Peter J. Munson, Xia Yang, Holger Prokisch, Uwe Völker, Joyce B. J. van Meurs, Luigi Ferrucci, Daniel LevyGenome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%-9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension.
Funding
The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. EGCUT is supported by targeted financing from the Estonian Ministry of Science and Education [SF0180142s08]; the Development Fund of the University of Tartu (grant SP1GVARENG); the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN; grant 3.2.0304.11-0312); and through FP7 grant 313010. AD is supported by NWO grant (veni, 916.12.154) and the EUR Fellowship. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The generation and management of RNA-expression array data for the Rotterdam Study was executed and funded by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The InCHIANTI study was supported in part by the Intramural Research Program, National Institute on Aging. DM was generously supported by a Wellcome Trust Institutional Strategic Support Award (WT097835MF). The KORA research platform and the KORA Augsburg studies are financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, which is funded by the B
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Citation
PLoS Genetics, 2015, 11 (3), e1005035Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular SciencesVersion
- VoR (Version of Record)
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PLoS GeneticsPublisher
Public Library of Scienceissn
1553-7390eissn
1553-7404Acceptance date
2015-01-28Available date
2018-01-25Publisher DOI
Publisher version
http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005035Notes
Data Availability: Raw data from gene expression profiling are available online (FHS [http://www.ncbi.nlm.nih.gov/gap; accession number phs000007], EGCUT [GSE48348], RS [GSE33828], InCHIANTI [GSE48152], KORA F4 [E-MTAB-1708] and SHIP-TREND [GSE36382]).Language
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