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

TitleGenome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.
Publication TypeJournal Article
Year of Publication2012
AuthorsHuang, 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, Ohrvik, 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, Kathiresan, S, Reilly, MP, Klopp, N, Harris, TB, Winkelmann, BR, Grant, PJ, Hillege, HL, Watkins, H, Spector, TD, Becker, LC, Tracy, RP, März, W, Uitterlinden, AG, Eriksson, P, Cambien, F, Morange, P-E, Koenig, W, Soranzo, N, van der Harst, P, Liu, Y, O'Donnell, CJ, Hamsten, A
Corporate/Institutional AuthorsDIAGRAM Consortium, CARDIoGRAM consortium, C4D Consortium, Cardiogenics consortium,
JournalBlood
Volume120
Issue24
Pagination4873-81
Date Published2012 Dec 06
ISSN1528-0020
KeywordsAdaptor Proteins, Signal Transducing, ARNTL Transcription Factors, ATPases Associated with Diverse Cellular Activities, Cell Line, Cell Line, Tumor, Cohort Studies, Coronary Artery Disease, Diabetes Mellitus, Type 2, Gene Expression Profiling, Gene Expression Regulation, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, LIM Domain Proteins, Meta-Analysis as Topic, Monocytes, Mucin-3, Plasminogen Activator Inhibitor 1, Polymorphism, Single Nucleotide, PPAR gamma, Proteasome Endopeptidase Complex, RNA Interference, Transcription Factors
Abstract<p>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.</p>
DOI10.1182/blood-2012-06-436188
Alternate JournalBlood
PubMed ID22990020
PubMed Central IDPMC3520624
Grant ListN02-HL-6-4278 / HL / NHLBI NIH HHS / United States
HL67466 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
N01 HC085086 / HC / NHLBI NIH HHS / United States
P20 GM103534 / GM / NIGMS NIH HHS / United States
N01-HC-95162 / HC / NHLBI NIH HHS / United States
R01-HL-086694 / HL / NHLBI NIH HHS / United States
/ / British Heart Foundation / United Kingdom
R01-HL59367 / HL / NHLBI NIH HHS / United States
HL65234 / HL / NHLBI NIH HHS / United States
N01-HC-85085 / HC / NHLBI NIH HHS / United States
UL1-RR-025005 / RR / NCRR NIH HHS / United States
T32 GM080178 / GM / NIGMS NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-85081 / HC / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
RR-024156 / RR / NCRR NIH HHS / United States
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G0700931 / / Medical Research Council / United Kingdom
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N01-HC-95168 / HC / NHLBI NIH HHS / United States
RG/08/014/24067 / / British Heart Foundation / United Kingdom
AG-15928 / AG / NIA NIH HHS / United States
/ / Medical Research Council / United Kingdom
/ / Biotechnology and Biological Sciences Research Council / United Kingdom
N01-HC-95159 / HC / NHLBI NIH HHS / United States
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/ / Department of Health / United Kingdom
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MC_U137686857 / / Medical Research Council / United Kingdom
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090532 / / Wellcome Trust / United Kingdom
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/ / Wellcome Trust / United Kingdom
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