Meta-Analysis of Genome-Wide Association Studies in > 80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels

Abbas Dehghan; J Dupuis; M Barbalic; JC Bis; G Eiriksdottir; C Lu; N Pellikka; H Wallaschofski; J Kettunen; Peter Henneman; J Baumert; DP Strachan; C Fuchsberger; V Vitart; JF Wilson; G Pare; S Naitza; ME Rudock; I Surakka; EJC de Geus; BZ Alizadeh; J Guralnik; A Shuldiner; T Tanaka; RYL Zee; RB Schnabel; V Nambi; Maryam Kavousi; S Ripatti; M Nauck; NL Smith; AV Smith; J Sundvall; P Scheet; YM Liu; A Ruokonen; LM Rose; MG Larson; RC Hoogeveen; NB Freimer; A Teumer; RP Tracy; LJ (Lenore) Launer; JE Buring; JF Yamamoto; AR Folsom; E.J.G. Sijbrands; J Pankow; P Elliott; JF Keaney; W Sun; AP Sarin; JD Fontes; S Badola; BC Astor; Bert Hofman; A Pouta; K Werdan; KH Greiser; O Kuss; HEMZ Schwabedissen; J Thiery; Y Jamshidi; IM (Ilja) Nolte; N Soranzo; TD Spector; H Volzke; AN Parker; T Aspelund; D Bates; L Young; K Tsui; DS Siscovick; XQ Guo; JI Rotter; M Uda; D Schlessinger; I Rudan; AA Hicks; BW Penninx; B Thorand; C Gieger; J Coresh; G Willemsen; TB Harris; André Uitterlinden; MR Jarvelin; K Rice; D Radke; V Salomaa; KW van Dijk; E Boerwinkle; RS Vasan; L Ferrucci; QD Gibson; S Bandinelli; H Snieder; DI Boomsma; XJ Xiao; H Campbell; C Hayward; PP Pramstaller; Cornelia Duijn; L Peltonen; BM Psaty; V Gudnason; PM Ridker; G Homuth; W Koenig; CM Ballantyne; JCM Witteman; EJ Benjamin; M Perola; DI Chasman

doi:10.1161/CIRCULATIONAHA.110.948570

Meta-Analysis of Genome-Wide Association Studies in > 80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels

Abbas Dehghan, J Dupuis, M Barbalic, JC Bis, G Eiriksdottir, C Lu, N Pellikka, H Wallaschofski, J Kettunen, Peter Henneman, J Baumert, DP Strachan, C Fuchsberger, V Vitart, JF Wilson, G Pare, S Naitza, ME Rudock, I Surakka, EJC de GeusBZ Alizadeh, J Guralnik, A Shuldiner, T Tanaka, RYL Zee, RB Schnabel, V Nambi, Maryam Kavousi, S Ripatti, M Nauck, NL Smith, AV Smith, J Sundvall, P Scheet, YM Liu, A Ruokonen, LM Rose, MG Larson, RC Hoogeveen, NB Freimer, A Teumer, RP Tracy, LJ (Lenore) Launer, JE Buring, JF Yamamoto, AR Folsom, E.J.G. Sijbrands, J Pankow, P Elliott, JF Keaney, W Sun, AP Sarin, JD Fontes, S Badola, BC Astor, Bert Hofman, A Pouta, K Werdan, KH Greiser, O Kuss, HEMZ Schwabedissen, J Thiery, Y Jamshidi, IM (Ilja) Nolte, N Soranzo, TD Spector, H Volzke, AN Parker, T Aspelund, D Bates, L Young, K Tsui, DS Siscovick, XQ Guo, JI Rotter, M Uda, D Schlessinger, I Rudan, AA Hicks, BW Penninx, B Thorand, C Gieger, J Coresh, G Willemsen, TB Harris, André Uitterlinden, MR Jarvelin, K Rice, D Radke, V Salomaa, KW van Dijk, E Boerwinkle, RS Vasan, L Ferrucci, QD Gibson, S Bandinelli, H Snieder, DI Boomsma, XJ Xiao, H Campbell, C Hayward, PP Pramstaller, Cornelia Duijn, L Peltonen, BM Psaty, V Gudnason, PM Ridker, G Homuth, W Koenig, CM Ballantyne, JCM Witteman, EJ Benjamin, M Perola, DI Chasman

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

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Abstract

Background-C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. Methods and Results-We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P < 2.9 x 10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained approximate to 5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. Conclusions-We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation. (Circulation. 2011; 123: 731-738.)

Original language	Undefined/Unknown
Pages (from-to)	731-U151
Journal	Circulation
Volume	123
Issue number	7
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.110.948570
Publication status	Published - 2011

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EMC COEUR-09
EMC MM-01-25-01
EMC MM-01-39-09-A
EMC NIHES-01-64-01
EMC NIHES-01-64-02

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

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10.1161/CIRCULATIONAHA.110.948570

Cite this

Dehghan, A., Dupuis, J., Barbalic, M., Bis, JC., Eiriksdottir, G., Lu, C., Pellikka, N., Wallaschofski, H., Kettunen, J., Henneman, P., Baumert, J., Strachan, DP., Fuchsberger, C., Vitart, V., Wilson, JF., Pare, G., Naitza, S., Rudock, ME., Surakka, I., ... Chasman, DI. (2011). Meta-Analysis of Genome-Wide Association Studies in > 80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels. Circulation, 123(7), 731-U151. https://doi.org/10.1161/CIRCULATIONAHA.110.948570

@article{5aab035341e04b9d84c62fd5f3875ead,

title = "Meta-Analysis of Genome-Wide Association Studies in > 80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels",

abstract = "Background-C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. Methods and Results-We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P < 2.9 x 10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained approximate to 5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. Conclusions-We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation. (Circulation. 2011; 123: 731-738.)",

author = "Abbas Dehghan and J Dupuis and M Barbalic and JC Bis and G Eiriksdottir and C Lu and N Pellikka and H Wallaschofski and J Kettunen and Peter Henneman and J Baumert and DP Strachan and C Fuchsberger and V Vitart and JF Wilson and G Pare and S Naitza and ME Rudock and I Surakka and {de Geus}, EJC and BZ Alizadeh and J Guralnik and A Shuldiner and T Tanaka and RYL Zee and RB Schnabel and V Nambi and Maryam Kavousi and S Ripatti and M Nauck and NL Smith and AV Smith and J Sundvall and P Scheet and YM Liu and A Ruokonen and LM Rose and MG Larson and RC Hoogeveen and NB Freimer and A Teumer and RP Tracy and Launer, {LJ (Lenore)} and JE Buring and JF Yamamoto and AR Folsom and E.J.G. Sijbrands and J Pankow and P Elliott and JF Keaney and W Sun and AP Sarin and JD Fontes and S Badola and BC Astor and Bert Hofman and A Pouta and K Werdan and KH Greiser and O Kuss and HEMZ Schwabedissen and J Thiery and Y Jamshidi and Nolte, {IM (Ilja)} and N Soranzo and TD Spector and H Volzke and AN Parker and T Aspelund and D Bates and L Young and K Tsui and DS Siscovick and XQ Guo and JI Rotter and M Uda and D Schlessinger and I Rudan and AA Hicks and BW Penninx and B Thorand and C Gieger and J Coresh and G Willemsen and TB Harris and Andr{\'e} Uitterlinden and MR Jarvelin and K Rice and D Radke and V Salomaa and {van Dijk}, KW and E Boerwinkle and RS Vasan and L Ferrucci and QD Gibson and S Bandinelli and H Snieder and DI Boomsma and XJ Xiao and H Campbell and C Hayward and PP Pramstaller and Cornelia Duijn and L Peltonen and BM Psaty and V Gudnason and PM Ridker and G Homuth and W Koenig and CM Ballantyne and JCM Witteman and EJ Benjamin and M Perola and DI Chasman",

year = "2011",

doi = "10.1161/CIRCULATIONAHA.110.948570",

language = "Undefined/Unknown",

volume = "123",

pages = "731--U151",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams & Wilkins",

number = "7",

}

Dehghan, A, Dupuis, J, Barbalic, M, Bis, JC, Eiriksdottir, G, Lu, C, Pellikka, N, Wallaschofski, H, Kettunen, J, Henneman, P, Baumert, J, Strachan, DP, Fuchsberger, C, Vitart, V, Wilson, JF, Pare, G, Naitza, S, Rudock, ME, Surakka, I, de Geus, EJC, Alizadeh, BZ, Guralnik, J, Shuldiner, A, Tanaka, T, Zee, RYL, Schnabel, RB, Nambi, V, Kavousi, M, Ripatti, S, Nauck, M, Smith, NL, Smith, AV, Sundvall, J, Scheet, P, Liu, YM, Ruokonen, A, Rose, LM, Larson, MG, Hoogeveen, RC, Freimer, NB, Teumer, A, Tracy, RP, Launer, LJ, Buring, JE, Yamamoto, JF, Folsom, AR, Sijbrands, EJG, Pankow, J, Elliott, P, Keaney, JF, Sun, W, Sarin, AP, Fontes, JD, Badola, S, Astor, BC, Hofman, B, Pouta, A, Werdan, K, Greiser, KH, Kuss, O, Schwabedissen, HEMZ, Thiery, J, Jamshidi, Y, Nolte, IM, Soranzo, N, Spector, TD, Volzke, H, Parker, AN, Aspelund, T, Bates, D, Young, L, Tsui, K, Siscovick, DS, Guo, XQ, Rotter, JI, Uda, M, Schlessinger, D, Rudan, I, Hicks, AA, Penninx, BW, Thorand, B, Gieger, C, Coresh, J, Willemsen, G, Harris, TB, Uitterlinden, A, Jarvelin, MR, Rice, K, Radke, D, Salomaa, V, van Dijk, KW, Boerwinkle, E, Vasan, RS, Ferrucci, L, Gibson, QD, Bandinelli, S, Snieder, H, Boomsma, DI, Xiao, XJ, Campbell, H, Hayward, C, Pramstaller, PP, Duijn, C, Peltonen, L, Psaty, BM, Gudnason, V, Ridker, PM, Homuth, G, Koenig, W, Ballantyne, CM, Witteman, JCM, Benjamin, EJ, Perola, M & Chasman, DI 2011, 'Meta-Analysis of Genome-Wide Association Studies in > 80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels', Circulation, vol. 123, no. 7, pp. 731-U151. https://doi.org/10.1161/CIRCULATIONAHA.110.948570

TY - JOUR

T1 - Meta-Analysis of Genome-Wide Association Studies in > 80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels

AU - Dehghan, Abbas

AU - Dupuis, J

AU - Barbalic, M

AU - Bis, JC

AU - Eiriksdottir, G

AU - Lu, C

AU - Pellikka, N

AU - Wallaschofski, H

AU - Kettunen, J

AU - Henneman, Peter

AU - Baumert, J

AU - Strachan, DP

AU - Fuchsberger, C

AU - Vitart, V

AU - Wilson, JF

AU - Pare, G

AU - Naitza, S

AU - Rudock, ME

AU - Surakka, I

AU - de Geus, EJC

AU - Alizadeh, BZ

AU - Guralnik, J

AU - Shuldiner, A

AU - Tanaka, T

AU - Zee, RYL

AU - Schnabel, RB

AU - Nambi, V

AU - Kavousi, Maryam

AU - Ripatti, S

AU - Nauck, M

AU - Smith, NL

AU - Smith, AV

AU - Sundvall, J

AU - Scheet, P

AU - Liu, YM

AU - Ruokonen, A

AU - Rose, LM

AU - Larson, MG

AU - Hoogeveen, RC

AU - Freimer, NB

AU - Teumer, A

AU - Tracy, RP

AU - Launer, LJ (Lenore)

AU - Buring, JE

AU - Yamamoto, JF

AU - Folsom, AR

AU - Sijbrands, E.J.G.

AU - Pankow, J

AU - Elliott, P

AU - Keaney, JF

AU - Sun, W

AU - Sarin, AP

AU - Fontes, JD

AU - Badola, S

AU - Astor, BC

AU - Hofman, Bert

AU - Pouta, A

AU - Werdan, K

AU - Greiser, KH

AU - Kuss, O

AU - Schwabedissen, HEMZ

AU - Thiery, J

AU - Jamshidi, Y

AU - Nolte, IM (Ilja)

AU - Soranzo, N

AU - Spector, TD

AU - Volzke, H

AU - Parker, AN

AU - Aspelund, T

AU - Bates, D

AU - Young, L

AU - Tsui, K

AU - Siscovick, DS

AU - Guo, XQ

AU - Rotter, JI

AU - Uda, M

AU - Schlessinger, D

AU - Rudan, I

AU - Hicks, AA

AU - Penninx, BW

AU - Thorand, B

AU - Gieger, C

AU - Coresh, J

AU - Willemsen, G

AU - Harris, TB

AU - Uitterlinden, André

AU - Jarvelin, MR

AU - Rice, K

AU - Radke, D

AU - Salomaa, V

AU - van Dijk, KW

AU - Boerwinkle, E

AU - Vasan, RS

AU - Ferrucci, L

AU - Gibson, QD

AU - Bandinelli, S

AU - Snieder, H

AU - Boomsma, DI

AU - Xiao, XJ

AU - Campbell, H

AU - Hayward, C

AU - Pramstaller, PP

AU - Duijn, Cornelia

AU - Peltonen, L

AU - Psaty, BM

AU - Gudnason, V

AU - Ridker, PM

AU - Homuth, G

AU - Koenig, W

AU - Ballantyne, CM

AU - Witteman, JCM

AU - Benjamin, EJ

AU - Perola, M

AU - Chasman, DI

PY - 2011

Y1 - 2011

N2 - Background-C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. Methods and Results-We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P < 2.9 x 10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained approximate to 5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. Conclusions-We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation. (Circulation. 2011; 123: 731-738.)

AB - Background-C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. Methods and Results-We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P < 2.9 x 10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained approximate to 5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. Conclusions-We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation. (Circulation. 2011; 123: 731-738.)

U2 - 10.1161/CIRCULATIONAHA.110.948570

DO - 10.1161/CIRCULATIONAHA.110.948570

M3 - Article

C2 - 21300955

SN - 0009-7322

VL - 123

SP - 731-U151

JO - Circulation

JF - Circulation

IS - 7

ER -