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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Huang, J; Sabater-Lleal, M; Asselbergs, FW; Tregouet, D; Shin, S-Y; Ding, J; Baumert, J; Oudot-Mellakh, T; Folkersen, L; Johnson, AD; Smith, NL; Williams, SM; Ikram, MA; Kleber, ME; Becker, DM; Truong, V; Mychaleckyj, JC; Tang, W; Yang, Q; Sennblad, B; Moore, JH; Williams, FMK; Dehghan, A; Silbernagel, G; Schrijvers, EMC; Smith, S; Karakas, M; Tofler, GH; Silveira, A; Navis, GJ; Lohman, K; Chen, M-H; Peters, A; Goel, A; Hopewell, JC; Chambers, JC; Saleheen, D; Lundmark, P; Psaty, BM; Strawbridge, RJ; Boehm, BO; Carter, AM; Meisinger, C; Peden, JF; Bis, JC; McKnight, B; Öhrvik, J; Taylor, K; Franzosi, MG; Seedorf, U; Collins, R; Franco-Cereceda, A; Syvänen, A-C; Goodall, AH; Yanek, LR; Cushman, M; Müller-Nurasyid, M; Folsom, AR; Basu, S; Matijevic, N; van Gilst, WH; Kooner, JS; Hofman, A; Danesh, J; Clarke, R; Meigs, JB; DIAGRAM Consortium, ; Kathiresan, S; Reilly, MP; CARDIoGRAM Consortium, ; Klopp, N; Harris, TB; Winkelmann, BR; Grant, PJ; Hillege, HL; Watkins, H; C4D Consortium, ; Spector, TD; Becker, LC; Tracy, RP; März, W; Uitterlinden, AG; Eriksson, P; Cambien, F; CARDIOGENICS Consortium, ; Morange, P-E; Koenig, W; Soranzo, N; van der Harst, P; Liu, Y; O'Donnell, CJ; Hamsten, A

Published Date

  • December 6, 2012

Published In

Volume / Issue

  • 120 / 24

Start / End Page

  • 4873 - 4881

PubMed ID

  • 22990020

Pubmed Central ID

  • 22990020

Electronic International Standard Serial Number (EISSN)

  • 1528-0020

Digital Object Identifier (DOI)

  • 10.1182/blood-2012-06-436188

Language

  • eng

Conference Location

  • United States