1. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.
- Author
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Huang J, Sabater-Lleal M, Asselbergs FW, Tregouet D, Shin SY, 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 FM, Dehghan A, Silbernagel G, Schrijvers EM, Smith S, Karakas M, Tofler GH, Silveira A, Navis GJ, Lohman K, Chen MH, 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 AC, 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 PE, Koenig W, Soranzo N, van der Harst P, Liu Y, O'Donnell CJ, and Hamsten A
- Subjects
- ARNTL Transcription Factors genetics, ATPases Associated with Diverse Cellular Activities, Adaptor Proteins, Signal Transducing genetics, Cell Line, Cell Line, Tumor, Cohort Studies, Coronary Artery Disease blood, Coronary Artery Disease genetics, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 genetics, Gene Expression Profiling, Gene Expression Regulation, Gene Frequency, Genotype, Humans, LIM Domain Proteins genetics, Meta-Analysis as Topic, Monocytes metabolism, Mucin-3 genetics, PPAR gamma genetics, Proteasome Endopeptidase Complex, RNA Interference, Transcription Factors genetics, Genome-Wide Association Study methods, Plasminogen Activator Inhibitor 1 blood, Plasminogen Activator Inhibitor 1 genetics, Polymorphism, Single Nucleotide
- 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.
- Published
- 2012
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