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

Jie Huang; Maria Sabater-Lleal; Folkert W. Asselbergs; David Tregouet; So Youn Shin; Jingzhong Ding; Jens Baumert; Tiphaine Oudot-Mellakh; Lasse Folkersen; Andrew D. Johnson; Nicholas L. Smith; Scott M. Williams; Mohammad A. Ikram; Marcus E. Kleber; Diane M. Becker; Vinh Truong; Josyf C. Mychaleckyj; Weihong Tang; Qiong Yang; Bengt Sennblad; Jason H. Moore; Frances M K Williams; Abbas Dehghan; Günther Silbernagel; Elisabeth M C Schrijvers; Shelly Smith; Mahir Karakas; Geoffrey H. Tofler; Angela Silveira; Gerjan J. Navis; Kurt Lohman; Ming Huei Chen; Annette Peters; Anuj Goel; Jemma C. Hopewell; John C. Chambers; Danish Saleheen; Per Lundmark; Bruce M. Psaty; Rona J. Strawbridge; Bernhard O. Boehm; Angela M. Carter; Christa Meisinger; John F. Peden; Joshua C. Bis; Barbara McKnight; John Öhrvik; Kent Taylor; Maria Grazia Franzosi; Udo Seedorf; Rory Collins; Anders Franco-Cereceda; Ann Christine Syvänen; Alison H. Goodall; Lisa R. Yanek; Mary Cushman; Martina Müller-Nurasyid; Aaron R. Folsom; Saonli Basu; Nena Matijevic; Wiek H. Van Gilst; Jaspal S. Kooner; Albert Hofman; John Danesh; Robert Clarke; James B. Meigs; Sekar Kathiresan; Muredach P. Reilly; Norman Klopp; Tamara B. Harris; Bernhard R. Winkelmann; Peter J. Grant; Hans L. Hillege; Hugh Watkins; Timothy D. Spector; Lewis C. Becker; Russell P. Tracy; Winfried März; Andre G. Uitterlinden; Per Eriksson; Francois Cambien; Pierre Emmanuel Morange; Wolfgang Koenig; Nicole Soranzo; Pim Van Der Harst; Yongmei Liu; Christopher J. O'Donnell; Anders Hamsten

doi:10.1182/blood-2012-06-436188

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

Jie Huang, Maria Sabater-Lleal, Folkert W. Asselbergs, David Tregouet, So Youn Shin, Jingzhong Ding, Jens Baumert, Tiphaine Oudot-Mellakh, Lasse Folkersen, Andrew D. Johnson, Nicholas L. Smith, Scott M. Williams, Mohammad A. Ikram, Marcus E. Kleber, Diane M. Becker, Vinh Truong, Josyf C. Mychaleckyj, Weihong Tang, Qiong Yang, Bengt SennbladJason H. Moore, Frances M K Williams, Abbas Dehghan, Günther Silbernagel, Elisabeth M C Schrijvers, Shelly Smith, Mahir Karakas, Geoffrey H. Tofler, Angela Silveira, Gerjan J. Navis, Kurt Lohman, Ming Huei Chen, Annette Peters, Anuj Goel, Jemma C. Hopewell, John C. Chambers, Danish Saleheen, Per Lundmark, Bruce M. Psaty, Rona J. Strawbridge, Bernhard O. Boehm, Angela M. Carter, Christa Meisinger, John F. Peden, Joshua C. Bis, Barbara McKnight, John Öhrvik, Kent Taylor, Maria Grazia Franzosi, Udo Seedorf, Rory Collins, Anders Franco-Cereceda, Ann Christine Syvänen, Alison H. Goodall, Lisa R. Yanek, Mary Cushman, Martina Müller-Nurasyid, Aaron R. Folsom, Saonli Basu, Nena Matijevic, Wiek H. Van Gilst, Jaspal S. Kooner, Albert Hofman, John Danesh, Robert Clarke, James B. Meigs, Sekar Kathiresan, Muredach P. Reilly, Norman Klopp, Tamara B. Harris, Bernhard R. Winkelmann, Peter J. Grant, Hans L. Hillege, Hugh Watkins, Timothy D. Spector, Lewis C. Becker, Russell P. Tracy, Winfried März, Andre G. Uitterlinden, Per Eriksson, Francois Cambien, Pierre Emmanuel Morange, Wolfgang Koenig, Nicole Soranzo, Pim Van Der Harst, Yongmei Liu, Christopher J. O'Donnell, Anders Hamsten

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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 metaanalysis 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.

Original language	English (US)
Pages (from-to)	4873-4881
Number of pages	9
Journal	Blood
Volume	120
Issue number	24
DOIs	https://doi.org/10.1182/blood-2012-06-436188
State	Published - Dec 6 2012

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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., ... Hamsten, A. (2012). Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. Blood, 120(24), 4873-4881. https://doi.org/10.1182/blood-2012-06-436188

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, FMK, Dehghan, A, Silbernagel, G, Schrijvers, EMC, 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 & Hamsten, A 2012, 'Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation', Blood, vol. 120, no. 24, pp. 4873-4881. https://doi.org/10.1182/blood-2012-06-436188

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

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 metaanalysis 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.",

author = "Jie Huang and Maria Sabater-Lleal and Asselbergs, {Folkert W.} and David Tregouet and Shin, {So Youn} and Jingzhong Ding and Jens Baumert and Tiphaine Oudot-Mellakh and Lasse Folkersen and Johnson, {Andrew D.} and Smith, {Nicholas L.} and Williams, {Scott M.} and Ikram, {Mohammad A.} and Kleber, {Marcus E.} and Becker, {Diane M.} and Vinh Truong and Mychaleckyj, {Josyf C.} and Weihong Tang and Qiong Yang and Bengt Sennblad and Moore, {Jason H.} and Williams, {Frances M K} and Abbas Dehghan and G{\"u}nther Silbernagel and Schrijvers, {Elisabeth M C} and Shelly Smith and Mahir Karakas and Tofler, {Geoffrey H.} and Angela Silveira and Navis, {Gerjan J.} and Kurt Lohman and Chen, {Ming Huei} and Annette Peters and Anuj Goel and Hopewell, {Jemma C.} and Chambers, {John C.} and Danish Saleheen and Per Lundmark and Psaty, {Bruce M.} and Strawbridge, {Rona J.} and Boehm, {Bernhard O.} and Carter, {Angela M.} and Christa Meisinger and Peden, {John F.} and Bis, {Joshua C.} and Barbara McKnight and John {\"O}hrvik and Kent Taylor and Franzosi, {Maria Grazia} and Udo Seedorf and Rory Collins and Anders Franco-Cereceda and Syv{\"a}nen, {Ann Christine} and Goodall, {Alison H.} and Yanek, {Lisa R.} and Mary Cushman and Martina M{\"u}ller-Nurasyid and Folsom, {Aaron R.} and Saonli Basu and Nena Matijevic and {Van Gilst}, {Wiek H.} and Kooner, {Jaspal S.} and Albert Hofman and John Danesh and Robert Clarke and Meigs, {James B.} and Sekar Kathiresan and Reilly, {Muredach P.} and Norman Klopp and Harris, {Tamara B.} and Winkelmann, {Bernhard R.} and Grant, {Peter J.} and Hillege, {Hans L.} and Hugh Watkins and Spector, {Timothy D.} and Becker, {Lewis C.} and Tracy, {Russell P.} and Winfried M{\"a}rz and Uitterlinden, {Andre G.} and Per Eriksson and Francois Cambien and Morange, {Pierre Emmanuel} and Wolfgang Koenig and Nicole Soranzo and {Van Der Harst}, Pim and Yongmei Liu and O'Donnell, {Christopher J.} and Anders Hamsten",

year = "2012",

month = dec,

day = "6",

doi = "10.1182/blood-2012-06-436188",

language = "English (US)",

volume = "120",

pages = "4873--4881",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "24",

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TY - JOUR

T1 - Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

AU - Huang, Jie

AU - Sabater-Lleal, Maria

AU - Asselbergs, Folkert W.

AU - Tregouet, David

AU - Shin, So Youn

AU - Ding, Jingzhong

AU - Baumert, Jens

AU - Oudot-Mellakh, Tiphaine

AU - Folkersen, Lasse

AU - Johnson, Andrew D.

AU - Smith, Nicholas L.

AU - Williams, Scott M.

AU - Ikram, Mohammad A.

AU - Kleber, Marcus E.

AU - Becker, Diane M.

AU - Truong, Vinh

AU - Mychaleckyj, Josyf C.

AU - Tang, Weihong

AU - Yang, Qiong

AU - Sennblad, Bengt

AU - Moore, Jason H.

AU - Williams, Frances M K

AU - Dehghan, Abbas

AU - Silbernagel, Günther

AU - Schrijvers, Elisabeth M C

AU - Smith, Shelly

AU - Karakas, Mahir

AU - Tofler, Geoffrey H.

AU - Silveira, Angela

AU - Navis, Gerjan J.

AU - Lohman, Kurt

AU - Chen, Ming Huei

AU - Peters, Annette

AU - Goel, Anuj

AU - Hopewell, Jemma C.

AU - Chambers, John C.

AU - Saleheen, Danish

AU - Lundmark, Per

AU - Psaty, Bruce M.

AU - Strawbridge, Rona J.

AU - Boehm, Bernhard O.

AU - Carter, Angela M.

AU - Meisinger, Christa

AU - Peden, John F.

AU - Bis, Joshua C.

AU - McKnight, Barbara

AU - Öhrvik, John

AU - Taylor, Kent

AU - Franzosi, Maria Grazia

AU - Seedorf, Udo

AU - Collins, Rory

AU - Franco-Cereceda, Anders

AU - Syvänen, Ann Christine

AU - Goodall, Alison H.

AU - Yanek, Lisa R.

AU - Cushman, Mary

AU - Müller-Nurasyid, Martina

AU - Folsom, Aaron R.

AU - Basu, Saonli

AU - Matijevic, Nena

AU - Van Gilst, Wiek H.

AU - Kooner, Jaspal S.

AU - Hofman, Albert

AU - Danesh, John

AU - Clarke, Robert

AU - Meigs, James B.

AU - Kathiresan, Sekar

AU - Reilly, Muredach P.

AU - Klopp, Norman

AU - Harris, Tamara B.

AU - Winkelmann, Bernhard R.

AU - Grant, Peter J.

AU - Hillege, Hans L.

AU - Watkins, Hugh

AU - Spector, Timothy D.

AU - Becker, Lewis C.

AU - Tracy, Russell P.

AU - März, Winfried

AU - Uitterlinden, Andre G.

AU - Eriksson, Per

AU - Cambien, Francois

AU - Morange, Pierre Emmanuel

AU - Koenig, Wolfgang

AU - Soranzo, Nicole

AU - Van Der Harst, Pim

AU - Liu, Yongmei

AU - O'Donnell, Christopher J.

AU - Hamsten, Anders

PY - 2012/12/6

Y1 - 2012/12/6

N2 - 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 metaanalysis 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.

AB - 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 metaanalysis 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.

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U2 - 10.1182/blood-2012-06-436188

DO - 10.1182/blood-2012-06-436188

M3 - Article

C2 - 22990020

AN - SCOPUS:84870738355

SN - 0006-4971

VL - 120

SP - 4873

EP - 4881

JO - Blood

JF - Blood

IS - 24

ER -

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

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