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

J Huang; M Sabater-Lleal; FW Asselbergs; D Tregouet; SY Shin; JZ (Jing Zhong) Ding; J Baumert; T Oudot-Mellakh; L Folkersen; AD Johnson; NL Smith; SM Williams; Arfan Ikram; ME Kleber; DM Becker; V Truong; JC Mychaleckyj; WH Tang; Q Yang; B Sennblad; JH Moore; FMK Williams; Abbas Dehghan; G Silbernagel; Elisabeth Schrijvers; S Smith; M Karakas; GH Tofler; A Silveira; GJ Navis; K Lohman; MH Chen; A Peters; A Goel; JC Hopewell; JC Chambers; D Saleheen; P Lundmark; BM Psaty; RJ Strawbridge; BO Boehm; AM Carter; C Meisinger; JF Peden; JC Bis; B McKnight; J Ohrvik; K Taylor; MG Franzosi; U Seedorf; R Collins; A Franco-Cereceda; AC Syvanen; AH Goodall; LR Yanek; M Cushman; M Muller-Nurasyid; AR Folsom; S (Sanjay) Basu; N Matijevic; WH van Gilst; JS Kooner; Bert Hofman; J Danesh; R Clarke; JB Meigs; S Kathiresan; MP Reilly; N Klopp; TB Harris; BR Winkelmann; PJ Grant; HL Hillege; H Watkins; TD Spector; LC Becker; RP Tracy; W Marz; André Uitterlinden; P Eriksson; F Cambien; PE Morange; W Koenig; N Soranzo; P van der Harst; YM Liu; CJ O'Donnell; A Hamsten

doi:10.1182/blood-2012-06-436188

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

J Huang, M Sabater-Lleal, FW Asselbergs, D Tregouet, SY Shin, JZ (Jing Zhong) Ding, J Baumert, T Oudot-Mellakh, L Folkersen, AD Johnson, NL Smith, SM Williams, Arfan Ikram, ME Kleber, DM Becker, V Truong, JC Mychaleckyj, WH Tang, Q Yang, B SennbladJH Moore, FMK Williams, Abbas Dehghan, G Silbernagel, Elisabeth Schrijvers, S Smith, M Karakas, GH Tofler, A Silveira, GJ Navis, K Lohman, MH Chen, A Peters, A Goel, JC Hopewell, JC Chambers, D Saleheen, P Lundmark, BM Psaty, RJ Strawbridge, BO Boehm, AM Carter, C Meisinger, JF Peden, JC Bis, B McKnight, J Ohrvik, K Taylor, MG Franzosi, U Seedorf, R Collins, A Franco-Cereceda, AC Syvanen, AH Goodall, LR Yanek, M Cushman, M Muller-Nurasyid, AR Folsom, S (Sanjay) Basu, N Matijevic, WH van Gilst, JS Kooner, Bert Hofman, J Danesh, R Clarke, JB Meigs, S Kathiresan, MP Reilly, N Klopp, TB Harris, BR Winkelmann, PJ Grant, HL Hillege, H Watkins, TD Spector, LC Becker, RP Tracy, W Marz, André Uitterlinden, P Eriksson, F Cambien, PE Morange, W Koenig, N Soranzo, P van der Harst, YM Liu, CJ O'Donnell, A Hamsten

Research output: Contribution to journal › Article › Academic › peer-review

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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 x 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 x 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 x 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, dis-covery P = 2.9 x 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. (Blood. 2012;120(24):4873-4881)

Original language	Undefined/Unknown
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
Publication status	Published - 2012

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10.1182/blood-2012-06-436188

http://hdl.handle.net/1765/66508

Cite this

Huang, J., Sabater-Lleal, M., Asselbergs, FW., Tregouet, D., Shin, SY., Ding, JZ., Baumert, J., Oudot-Mellakh, T., Folkersen, L., Johnson, AD., Smith, NL., Williams, SM., Ikram, A., Kleber, ME., Becker, DM., Truong, V., Mychaleckyj, JC., Tang, WH., 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

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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 meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 x 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 x 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 x 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, dis-covery P = 2.9 x 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. (Blood. 2012;120(24):4873-4881)",

author = "J Huang and M Sabater-Lleal and FW Asselbergs and D Tregouet and SY Shin and Ding, {JZ (Jing Zhong)} and J Baumert and T Oudot-Mellakh and L Folkersen and AD Johnson and NL Smith and SM Williams and Arfan Ikram and ME Kleber and DM Becker and V Truong and JC Mychaleckyj and WH Tang and Q Yang and B Sennblad and JH Moore and FMK Williams and Abbas Dehghan and G Silbernagel and Elisabeth Schrijvers and S Smith and M Karakas and GH Tofler and A Silveira and GJ Navis and K Lohman and MH Chen and A Peters and A Goel and JC Hopewell and JC Chambers and D Saleheen and P Lundmark and BM Psaty and RJ Strawbridge and BO Boehm and AM Carter and C Meisinger and JF Peden and JC Bis and B McKnight and J Ohrvik and K Taylor and MG Franzosi and U Seedorf and R Collins and A Franco-Cereceda and AC Syvanen and AH Goodall and LR Yanek and M Cushman and M Muller-Nurasyid and AR Folsom and Basu, {S (Sanjay)} and N Matijevic and {van Gilst}, WH and JS Kooner and Bert Hofman and J Danesh and R Clarke and JB Meigs and S Kathiresan and MP Reilly and N Klopp and TB Harris and BR Winkelmann and PJ Grant and HL Hillege and H Watkins and TD Spector and LC Becker and RP Tracy and W Marz and Andr{\'e} Uitterlinden and P Eriksson and F Cambien and PE Morange and W Koenig and N Soranzo and {van der Harst}, P and YM Liu and CJ O'Donnell and A Hamsten",

year = "2012",

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

language = "Undefined/Unknown",

volume = "120",

pages = "4873--4881",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "24",

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Huang, J, Sabater-Lleal, M, Asselbergs, FW, Tregouet, D, Shin, SY, Ding, JZ, Baumert, J, Oudot-Mellakh, T, Folkersen, L, Johnson, AD, Smith, NL, Williams, SM, Ikram, A, Kleber, ME, Becker, DM, Truong, V, Mychaleckyj, JC, Tang, WH, Yang, Q, Sennblad, B, Moore, JH, Williams, FMK, Dehghan, A, Silbernagel, G, Schrijvers, E, 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, Ohrvik, J, Taylor, K, Franzosi, MG, Seedorf, U, Collins, R, Franco-Cereceda, A, Syvanen, AC, Goodall, AH, Yanek, LR, Cushman, M, Muller-Nurasyid, M, Folsom, AR, Basu, S, Matijevic, N, van Gilst, WH, Kooner, JS, Hofman, B, 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, Marz, W, Uitterlinden, A, Eriksson, P, Cambien, F, Morange, PE, Koenig, W, Soranzo, N, van der Harst, P, Liu, YM, 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

TY - JOUR

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

AU - Huang, J

AU - Sabater-Lleal, M

AU - Asselbergs, FW

AU - Tregouet, D

AU - Shin, SY

AU - Ding, JZ (Jing Zhong)

AU - Baumert, J

AU - Oudot-Mellakh, T

AU - Folkersen, L

AU - Johnson, AD

AU - Smith, NL

AU - Williams, SM

AU - Ikram, Arfan

AU - Kleber, ME

AU - Becker, DM

AU - Truong, V

AU - Mychaleckyj, JC

AU - Tang, WH

AU - Yang, Q

AU - Sennblad, B

AU - Moore, JH

AU - Williams, FMK

AU - Dehghan, Abbas

AU - Silbernagel, G

AU - Schrijvers, Elisabeth

AU - Smith, S

AU - Karakas, M

AU - Tofler, GH

AU - Silveira, A

AU - Navis, GJ

AU - Lohman, K

AU - Chen, MH

AU - Peters, A

AU - Goel, A

AU - Hopewell, JC

AU - Chambers, JC

AU - Saleheen, D

AU - Lundmark, P

AU - Psaty, BM

AU - Strawbridge, RJ

AU - Boehm, BO

AU - Carter, AM

AU - Meisinger, C

AU - Peden, JF

AU - Bis, JC

AU - McKnight, B

AU - Ohrvik, J

AU - Taylor, K

AU - Franzosi, MG

AU - Seedorf, U

AU - Collins, R

AU - Franco-Cereceda, A

AU - Syvanen, AC

AU - Goodall, AH

AU - Yanek, LR

AU - Cushman, M

AU - Muller-Nurasyid, M

AU - Folsom, AR

AU - Basu, S (Sanjay)

AU - Matijevic, N

AU - van Gilst, WH

AU - Kooner, JS

AU - Hofman, Bert

AU - Danesh, J

AU - Clarke, R

AU - Meigs, JB

AU - Kathiresan, S

AU - Reilly, MP

AU - Klopp, N

AU - Harris, TB

AU - Winkelmann, BR

AU - Grant, PJ

AU - Hillege, HL

AU - Watkins, H

AU - Spector, TD

AU - Becker, LC

AU - Tracy, RP

AU - Marz, W

AU - Uitterlinden, André

AU - Eriksson, P

AU - Cambien, F

AU - Morange, PE

AU - Koenig, W

AU - Soranzo, N

AU - van der Harst, P

AU - Liu, YM

AU - O'Donnell, CJ

AU - Hamsten, A

PY - 2012

Y1 - 2012

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 meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 x 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 x 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 x 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, dis-covery P = 2.9 x 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. (Blood. 2012;120(24):4873-4881)

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 meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 x 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 x 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 x 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, dis-covery P = 2.9 x 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. (Blood. 2012;120(24):4873-4881)

U2 - 10.1182/blood-2012-06-436188

DO - 10.1182/blood-2012-06-436188

M3 - Article

VL - 120

SP - 4873

EP - 4881

JO - Blood

JF - Blood

SN - 0006-4971

IS - 24

ER -