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

Huang, J. et al. (2012) Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. Blood, 120(24), pp. 4873-4881. (doi:10.1182/blood-2012-06-436188) (PMID:22990020) (PMCID:PMC3520624)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Strawbridge, Dr Rona
Authors: Huang, J., Sabater-Lleal, M., Asselbergs, F. W., Tregouet, D., Shin, S.-Y., Ding, J., Baumert, J., Oudot-Mellakh, T., Folkersen, L., Johnson, A. D., Smith, N. L., Williams, S. M., Ikram, M. A., Kleber, M. E., Becker, D. M., Truong, V., Mychaleckyj, J. C., Tang, W., Yang, Q., Sennblad, B., Moore, J. H., Williams, F. M. K., Dehghan, A., Silbernagel, G., Schrijvers, E. M. C., Smith, S., Karakas, M., Tofler, G. H., Silveira, A., Navis, G. J., Lohman, K., Chen, M.-H., Peters, A., Goel, A., Hopewell, J. C., Chambers, J. C., Saleheen, D., Lundmark, P., Psaty, B. M., Strawbridge, R.J., Boehm, B. O., Carter, A. M., Meisinger, C., Peden, J. F., Bis, J. C., McKnight, B., Ohrvik, J., Taylor, K., Franzosi, M. G., Seedorf, U., Collins, R., Franco-Cereceda, A., Syvanen, A.-C., Goodall, A. H., Yanek, L. R., Cushman, M., Muller-Nurasyid, M., Folsom, A. R., Basu, S., Matijevic, N., van Gilst, W. H., Kooner, J. S., Hofman, A., Danesh, J., Clarke, R., Meigs, J. B., Kathiresan, S., Reilly, M. P., Klopp, N., Harris, T. B., Winkelmann, B. R., Grant, P. J., Hillege, H. L., Watkins, H., Spector, T. D., Becker, L. C., Tracy, R. P., Marz, W., Uitterlinden, A. G., Eriksson, P., Cambien, F., Morange, P.-E., Koenig, W., Soranzo, N., van der Harst, P., Liu, Y., O'Donnell, C. J., and Hamsten, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Published Online:06 December 2012

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