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Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.
Tuesday,2013-10-01 10:18 America/Los_Angeles — poolea2
| Title | Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. |
| Publication Type | Journal Article |
| Year of Publication | 2012 |
| 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, 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 Authors | DIAGRAM Consortium, CARDIoGRAM consortium, C4D Consortium, Cardiogenics consortium, |
| Journal | Blood |
| Volume | 120 |
| Issue | 24 |
| Pagination | 4873-81 |
| Date Published | 2012 Dec 06 |
| ISSN | 1528-0020 |
| Keywords | Adaptor 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> |
| DOI | 10.1182/blood-2012-06-436188 |
| Alternate Journal | Blood |
| PubMed ID | 22990020 |
| PubMed Central ID | PMC3520624 |
| Grant List | N02-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 R01-HL-087641 / HL / NHLBI NIH HHS / United States R01 HL095603 / HL / NHLBI NIH HHS / United States N01AG62101 / AG / NIA NIH HHS / United States N01-HC-95163 / HC / NHLBI NIH HHS / United States G0700931 / / Medical Research Council / United Kingdom N01-HC-55016 / HC / NHLBI NIH HHS / United States 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 1R01AG032098-01A1 / AG / NIA NIH HHS / United States / / Department of Health / United Kingdom N01 HC095166 / HC / NHLBI NIH HHS / United States AG-20098 / AG / NIA NIH HHS / United States HHSN268200625226C / / PHS HHS / United States N01-HC-95165 / HC / NHLBI NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States N01-HC-55021 / HC / NHLBI NIH HHS / United States MC_U137686857 / / Medical Research Council / United Kingdom R01HL071252 / HL / NHLBI NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States R01HL071205 / HL / NHLBI NIH HHS / United States AG-027058 / AG / NIA NIH HHS / United States N01-HC-85082 / HC / NHLBI NIH HHS / United States R01-HL-59367 / HL / NHLBI NIH HHS / United States / / Intramural NIH HHS / United States N01-HC-35129 / HC / NHLBI NIH HHS / United States RR018787 / RR / NCRR NIH HHS / United States N01 HC-55222 / HC / NHLBI NIH HHS / United States N01-HC-55019 / HC / NHLBI NIH HHS / United States N01-HC-55015 / HC / NHLBI NIH HHS / United States N01-HC-95169 / HC / NHLBI NIH HHS / United States N01-HC-95164 / HC / NHLBI NIH HHS / United States R01 LM010098 / LM / NLM NIH HHS / United States K24 DK080140 / DK / NIDDK NIH HHS / United States N01-HC-85083 / HC / NHLBI NIH HHS / United States 090532 / / Wellcome Trust / United Kingdom N01-HC-75150 / HC / NHLBI NIH HHS / United States N01-HC-55020 / HC / NHLBI NIH HHS / United States N01-HC-85080 / HC / NHLBI NIH HHS / United States N01-HC-95160 / HC / NHLBI NIH HHS / United States N01 HC-15103 / HC / NHLBI NIH HHS / United States U01 HL072518 / HL / NHLBI NIH HHS / United States R01 HL59684 / HL / NHLBI NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States N01-HC-45133 / HC / NHLBI NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States N01-HC-95161 / HC / NHLBI NIH HHS / United States N01AG62103 / AG / NIA NIH HHS / United States HHSN268201200036C / / PHS HHS / United States HHSN268200782096C / / PHS HHS / United States HL080295 / HL / NHLBI NIH HHS / United States N01AG62106 / AG / NIA NIH HHS / United States R01HL071259 / HL / NHLBI NIH HHS / United States N01-HC-85239 / HC / NHLBI NIH HHS / United States AG-023629 / AG / NIA NIH HHS / United States R01HL071251 / HL / NHLBI NIH HHS / United States N01-HC-55018 / HC / NHLBI NIH HHS / United States N01-HC-95166 / HC / NHLBI NIH HHS / United States U01-HG-004402 / HG / NHGRI NIH HHS / United States 1U01 HL072518 / HL / NHLBI NIH HHS / United States R01HL071258 / HL / NHLBI NIH HHS / United States M01 RR00052 / RR / NCRR NIH HHS / United States R01HL071051 / HL / NHLBI NIH HHS / United States / / Wellcome Trust / United Kingdom R01HL071250 / HL / NHLBI NIH HHS / United States N01-HC-85084 / HC / NHLBI NIH HHS / United States N01-HC-95167 / HC / NHLBI NIH HHS / United States LM010098 / LM / NLM NIH HHS / United States |