Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

Jie Huang, Maria Sabater-Lleal, Folkert W Asselbergs, David Tregouet, So-Youn Shin, Jingzhong Ding, Jens Baumert, Tiphaine Oudot-Mellakh, Lasse Folkersen, Andrew D Johnson, Nicholas L Smith, Scott M Williams, Mohammad A Ikram, Marcus E Kleber, Diane M Becker, Vinh Truong, Josyf C Mychaleckyj, Weihong Tang, Qiong Yang, Bengt SennbladJason H Moore, Frances M K Williams, Abbas Dehghan, Günther Silbernagel, Elisabeth M C Schrijvers, Shelly Smith, Mahir Karakas, Geoffrey H Tofler, Angela Silveira, Gerjan J Navis, Kurt Lohman, Ming-Huei Chen, Annette Peters, Anuj Goel, Jemma C Hopewell, John C Chambers, Danish Saleheen, Per Lundmark, Bruce M Psaty, Rona J Strawbridge, Bernhard O Boehm, Angela M Carter, Christa Meisinger, John F Peden, Joshua C Bis, Barbara McKnight, John Öhrvik, Kent Taylor, Maria Grazia Franzosi, Udo Seedorf, DIAGRAM Consortium

Research output: Contribution to journalArticle (Academic Journal)

47 Citations (Scopus)

Abstract

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P <5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P <.05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
Original languageEnglish
Pages (from-to)4873-81
Number of pages9
JournalBlood Reviews
Volume120
Issue number24
DOIs
Publication statusPublished - 6 Dec 2012

Keywords

  • ARNTL Transcription Factors
  • Polymorphism, Single Nucleotide
  • Gene Frequency
  • Humans
  • Cell Line, Tumor
  • Genome-Wide Association Study
  • Genotype
  • Gene Expression Profiling
  • Transcription Factors
  • Mucin-3
  • Adaptor Proteins, Signal Transducing
  • Cohort Studies
  • Diabetes Mellitus, Type 2
  • Plasminogen Activator Inhibitor 1
  • PPAR gamma
  • LIM Domain Proteins
  • Gene Expression Regulation
  • Monocytes
  • RNA Interference
  • Meta-Analysis as Topic
  • Cell Line
  • Coronary Artery Disease

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