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; DIAGRAM Consortium

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, DIAGRAM Consortium

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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.

Original language	English
Pages (from-to)	4873-81
Number of pages	9
Journal	Blood Reviews
Volume	120
Issue number	24
DOIs	https://doi.org/10.1182/blood-2012-06-436188
Publication status	Published - 6 Dec 2012

Keywords

ARNTL Transcription Factors
Polymorphism, Single Nucleotide
Gene Frequency
Humans
Cell Line, Tumor
Genome-Wide Association Study
Genotype
Gene Expression Profiling
Transcription Factors
Mucin-3
Adaptor Proteins, Signal Transducing
Cohort Studies
Diabetes Mellitus, Type 2
Plasminogen Activator Inhibitor 1
PPAR gamma
LIM Domain Proteins
Gene Expression Regulation
Monocytes
RNA Interference
Meta-Analysis as Topic
Cell Line
Coronary Artery Disease

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., ... DIAGRAM Consortium (2012). Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. Blood Reviews, 120(24), 4873-81. https://doi.org/10.1182/blood-2012-06-436188

@article{1f0f92aacc03436bafb91eac52b80039,

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 × 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.",

keywords = "ARNTL Transcription Factors, Polymorphism, Single Nucleotide, Gene Frequency, Humans, Cell Line, Tumor, Genome-Wide Association Study, Genotype, Gene Expression Profiling, Transcription Factors, Mucin-3, Adaptor Proteins, Signal Transducing, Cohort Studies, Diabetes Mellitus, Type 2, Plasminogen Activator Inhibitor 1, PPAR gamma, LIM Domain Proteins, Gene Expression Regulation, Monocytes, RNA Interference, Meta-Analysis as Topic, Cell Line, Coronary Artery Disease",

author = "Jie Huang and Maria Sabater-Lleal and Asselbergs, {Folkert W} and David Tregouet and So-Youn Shin 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 Ming-Huei Chen 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 {DIAGRAM Consortium}",

year = "2012",

month = dec,

day = "6",

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

language = "English",

volume = "120",

pages = "4873--81",

journal = "Blood Reviews",

number = "24",

}

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, Öhrvik, J, Taylor, K, Franzosi, MG, Seedorf, U & DIAGRAM Consortium 2012, 'Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation', Blood Reviews, vol. 120, no. 24, pp. 4873-81. 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, 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 - DIAGRAM Consortium

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 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.

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 × 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.

KW - ARNTL Transcription Factors

KW - Polymorphism, Single Nucleotide

KW - Gene Frequency

KW - Humans

KW - Cell Line, Tumor

KW - Genome-Wide Association Study

KW - Genotype

KW - Gene Expression Profiling

KW - Transcription Factors

KW - Mucin-3

KW - Adaptor Proteins, Signal Transducing

KW - Cohort Studies

KW - Diabetes Mellitus, Type 2

KW - Plasminogen Activator Inhibitor 1

KW - PPAR gamma

KW - LIM Domain Proteins

KW - Gene Expression Regulation

KW - Monocytes

KW - RNA Interference

KW - Meta-Analysis as Topic

KW - Cell Line

KW - Coronary Artery Disease

U2 - 10.1182/blood-2012-06-436188

DO - 10.1182/blood-2012-06-436188

M3 - Article (Academic Journal)

C2 - 22990020

VL - 120

SP - 4873

EP - 4881

JO - Blood Reviews

JF - Blood Reviews

IS - 24

ER -

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

Abstract

Keywords

UN SDGs

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