Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels

Abbas Dehghan; Josée Dupuis; Maja Barbalic; Joshua C. Bis; Gudny Eiriksdottir; Chen Lu; Niina Pellikka; Henri Wallaschofski; Johannes Kettunen; Peter Henneman; Jens Baumert; David P. Strachan; Christian Fuchsberger; Veronique Vitart; James F. Wilson; Guillaume Paré; Silvia Naitza; Megan E. Rudock; Ida Surakka; Eco J.C. De Geus; Behrooz Z. Alizadeh; Jack Guralnik; Alan Shuldiner; Toshiko Tanaka; Robert Y.L. Zee; Renate B. Schnabel; Vijay Nambi; Maryam Kavousi; Samuli Ripatti; Matthias Nauck; Nicholas L. Smith; Albert V. Smith; Jouko Sundvall; Paul Scheet; Yongmei Liu; Aimo Ruokonen; Lynda M. Rose; Martin G. Larson; Ron C. Hoogeveen; Nelson B. Freimer; Alexander Teumer; Russell P. Tracy; Lenore J. Launer; Julie E. Buring; Jennifer F. Yamamoto; Aaron R. Folsom; Eric J.G. Sijbrands; James Pankow; Paul Elliott; John F. Keaney; Wei Sun; Antti Pekka Sarin; João D. Fontes; Sunita Badola; Brad C. Astor; Albert Hofman; Anneli Pouta; Karl Werdan; Karin H. Greiser; Oliver Kuss; Henriette E. Meyer Zu Schwabedissen; Joachim Thiery; Yalda Jamshidi; Ilja M. Nolte; Nicole Soranzo; Timothy D. Spector; Henry Völzke; Alexander N. Parker; Thor Aspelund; David Bates; Lauren Young; Kim Tsui; David S. Siscovick; Xiuqing Guo; Jerome I. Rotter; Manuela Uda; David Schlessinger; Igor Rudan; Andrew A. Hicks; Brenda W. Penninx; Barbara Thorand; Christian Gieger; Joe Coresh; Gonneke Willemsen; Tamara B. Harris; Andre G. Uitterlinden; Marjo Riitta Järvelin; Kenneth Rice; Dörte Radke; Veikko Salomaa; Ko Willems Van Dijk; Eric Boerwinkle; Ramachandran S. Vasan; Luigi Ferrucci; Quince D. Gibson; Stefania Bandinelli; Harold Snieder; Dorret I. Boomsma; Xiangjun Xiao; Harry Campbell; Caroline Hayward; Peter P. Pramstaller; Cornelia M. Van Duijn; Leena Peltonen; Bruce M. Psaty; Vilmundur Gudnason; Paul M. Ridker; Georg Homuth; Wolfgang Koenig; Christie M. Ballantyne; Jacqueline C.M. Witteman; Emelia J. Benjamin; Markus Perola; Daniel I. 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, Josée Dupuis, Maja Barbalic, Joshua C. Bis, Gudny Eiriksdottir, Chen Lu, Niina Pellikka, Henri Wallaschofski, Johannes Kettunen, Peter Henneman, Jens Baumert, David P. Strachan, Christian Fuchsberger, Veronique Vitart, James F. Wilson, Guillaume Paré, Silvia Naitza, Megan E. Rudock, Ida Surakka, Eco J.C. De GeusBehrooz Z. Alizadeh, Jack Guralnik, Alan Shuldiner, Toshiko Tanaka, Robert Y.L. Zee, Renate B. Schnabel, Vijay Nambi, Maryam Kavousi, Samuli Ripatti, Matthias Nauck, Nicholas L. Smith, Albert V. Smith, Jouko Sundvall, Paul Scheet, Yongmei Liu, Aimo Ruokonen, Lynda M. Rose, Martin G. Larson, Ron C. Hoogeveen, Nelson B. Freimer, Alexander Teumer, Russell P. Tracy, Lenore J. Launer, Julie E. Buring, Jennifer F. Yamamoto, Aaron R. Folsom, Eric J.G. Sijbrands, James Pankow, Paul Elliott, John F. Keaney, Wei Sun, Antti Pekka Sarin, João D. Fontes, Sunita Badola, Brad C. Astor, Albert Hofman, Anneli Pouta, Karl Werdan, Karin H. Greiser, Oliver Kuss, Henriette E. Meyer Zu Schwabedissen, Joachim Thiery, Yalda Jamshidi, Ilja M. Nolte, Nicole Soranzo, Timothy D. Spector, Henry Völzke, Alexander N. Parker, Thor Aspelund, David Bates, Lauren Young, Kim Tsui, David S. Siscovick, Xiuqing Guo, Jerome I. Rotter, Manuela Uda, David Schlessinger, Igor Rudan, Andrew A. Hicks, Brenda W. Penninx, Barbara Thorand, Christian Gieger, Joe Coresh, Gonneke Willemsen, Tamara B. Harris, Andre G. Uitterlinden, Marjo Riitta Järvelin, Kenneth Rice, Dörte Radke, Veikko Salomaa, Ko Willems Van Dijk, Eric Boerwinkle, Ramachandran S. Vasan, Luigi Ferrucci, Quince D. Gibson, Stefania Bandinelli, Harold Snieder, Dorret I. Boomsma, Xiangjun Xiao, Harry Campbell, Caroline Hayward, Peter P. Pramstaller, Cornelia M. Van Duijn, Leena Peltonen, Bruce M. Psaty, Vilmundur Gudnason, Paul M. Ridker, Georg Homuth, Wolfgang Koenig, Christie M. Ballantyne, Jacqueline C.M. Witteman, Emelia J. Benjamin, Markus Perola, Daniel I. Chasman

Bloomberg School of Public Health

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

359 Scopus citations

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<2.9×10). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈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.

Original language	English (US)
Pages (from-to)	731-738
Number of pages	8
Journal	Circulation
Volume	123
Issue number	7
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.110.948570
State	Published - Feb 22 2011

Keywords

genetics
genome-wide association study
inflammation
meta-analysis
myocardial infarction

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

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10.1161/CIRCULATIONAHA.110.948570

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Dehghan, A., Dupuis, J., Barbalic, M., Bis, J. C., Eiriksdottir, G., Lu, C., Pellikka, N., Wallaschofski, H., Kettunen, J., Henneman, P., Baumert, J., Strachan, D. P., Fuchsberger, C., Vitart, V., Wilson, J. F., Paré, G., Naitza, S., Rudock, M. E., Surakka, I., ... Chasman, D. I. (2011). Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation, 123(7), 731-738. https://doi.org/10.1161/CIRCULATIONAHA.110.948570

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, Paré, 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, Y, 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, A, Pouta, A, Werdan, K, Greiser, KH, Kuss, O, Meyer Zu Schwabedissen, HE, Thiery, J, Jamshidi, Y, Nolte, IM, Soranzo, N, Spector, TD, Völzke, H, Parker, AN, Aspelund, T, Bates, D, Young, L, Tsui, K, Siscovick, DS, Guo, X, Rotter, JI, Uda, M, Schlessinger, D, Rudan, I, Hicks, AA, Penninx, BW, Thorand, B, Gieger, C, Coresh, J, Willemsen, G, Harris, TB, Uitterlinden, AG, Järvelin, MR, Rice, K, Radke, D, Salomaa, V, Willems Van Dijk, K, Boerwinkle, E, Vasan, RS, Ferrucci, L, Gibson, QD, Bandinelli, S, Snieder, H, Boomsma, DI, Xiao, X, Campbell, H, Hayward, C, Pramstaller, PP, Van Duijn, CM, 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. 731-738. https://doi.org/10.1161/CIRCULATIONAHA.110.948570

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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<2.9×10). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈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.",

keywords = "genetics, genome-wide association study, inflammation, meta-analysis, myocardial infarction",

author = "Abbas Dehghan and Jos{\'e}e Dupuis and Maja Barbalic and Bis, {Joshua C.} and Gudny Eiriksdottir and Chen Lu and Niina Pellikka and Henri Wallaschofski and Johannes Kettunen and Peter Henneman and Jens Baumert and Strachan, {David P.} and Christian Fuchsberger and Veronique Vitart and Wilson, {James F.} and Guillaume Par{\'e} and Silvia Naitza and Rudock, {Megan E.} and Ida Surakka and {De Geus}, {Eco J.C.} and Alizadeh, {Behrooz Z.} and Jack Guralnik and Alan Shuldiner and Toshiko Tanaka and Zee, {Robert Y.L.} and Schnabel, {Renate B.} and Vijay Nambi and Maryam Kavousi and Samuli Ripatti and Matthias Nauck and Smith, {Nicholas L.} and Smith, {Albert V.} and Jouko Sundvall and Paul Scheet and Yongmei Liu and Aimo Ruokonen and Rose, {Lynda M.} and Larson, {Martin G.} and Hoogeveen, {Ron C.} and Freimer, {Nelson B.} and Alexander Teumer and Tracy, {Russell P.} and Launer, {Lenore J.} and Buring, {Julie E.} and Yamamoto, {Jennifer F.} and Folsom, {Aaron R.} and Sijbrands, {Eric J.G.} and James Pankow and Paul Elliott and Keaney, {John F.} and Wei Sun and Sarin, {Antti Pekka} and Fontes, {Jo{\~a}o D.} and Sunita Badola and Astor, {Brad C.} and Albert Hofman and Anneli Pouta and Karl Werdan and Greiser, {Karin H.} and Oliver Kuss and {Meyer Zu Schwabedissen}, {Henriette E.} and Joachim Thiery and Yalda Jamshidi and Nolte, {Ilja M.} and Nicole Soranzo and Spector, {Timothy D.} and Henry V{\"o}lzke and Parker, {Alexander N.} and Thor Aspelund and David Bates and Lauren Young and Kim Tsui and Siscovick, {David S.} and Xiuqing Guo and Rotter, {Jerome I.} and Manuela Uda and David Schlessinger and Igor Rudan and Hicks, {Andrew A.} and Penninx, {Brenda W.} and Barbara Thorand and Christian Gieger and Joe Coresh and Gonneke Willemsen and Harris, {Tamara B.} and Uitterlinden, {Andre G.} and J{\"a}rvelin, {Marjo Riitta} and Kenneth Rice and D{\"o}rte Radke and Veikko Salomaa and {Willems Van Dijk}, Ko and Eric Boerwinkle and Vasan, {Ramachandran S.} and Luigi Ferrucci and Gibson, {Quince D.} and Stefania Bandinelli and Harold Snieder and Boomsma, {Dorret I.} and Xiangjun Xiao and Harry Campbell and Caroline Hayward and Pramstaller, {Peter P.} and {Van Duijn}, {Cornelia M.} and Leena Peltonen and Psaty, {Bruce M.} and Vilmundur Gudnason and Ridker, {Paul M.} and Georg Homuth and Wolfgang Koenig and Ballantyne, {Christie M.} and Witteman, {Jacqueline C.M.} and Benjamin, {Emelia J.} and Markus Perola and Chasman, {Daniel I.}",

year = "2011",

month = feb,

day = "22",

doi = "10.1161/CIRCULATIONAHA.110.948570",

language = "English (US)",

volume = "123",

pages = "731--738",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "7",

}

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, Josée

AU - Barbalic, Maja

AU - Bis, Joshua C.

AU - Eiriksdottir, Gudny

AU - Lu, Chen

AU - Pellikka, Niina

AU - Wallaschofski, Henri

AU - Kettunen, Johannes

AU - Henneman, Peter

AU - Baumert, Jens

AU - Strachan, David P.

AU - Fuchsberger, Christian

AU - Vitart, Veronique

AU - Wilson, James F.

AU - Paré, Guillaume

AU - Naitza, Silvia

AU - Rudock, Megan E.

AU - Surakka, Ida

AU - De Geus, Eco J.C.

AU - Alizadeh, Behrooz Z.

AU - Guralnik, Jack

AU - Shuldiner, Alan

AU - Tanaka, Toshiko

AU - Zee, Robert Y.L.

AU - Schnabel, Renate B.

AU - Nambi, Vijay

AU - Kavousi, Maryam

AU - Ripatti, Samuli

AU - Nauck, Matthias

AU - Smith, Nicholas L.

AU - Smith, Albert V.

AU - Sundvall, Jouko

AU - Scheet, Paul

AU - Liu, Yongmei

AU - Ruokonen, Aimo

AU - Rose, Lynda M.

AU - Larson, Martin G.

AU - Hoogeveen, Ron C.

AU - Freimer, Nelson B.

AU - Teumer, Alexander

AU - Tracy, Russell P.

AU - Launer, Lenore J.

AU - Buring, Julie E.

AU - Yamamoto, Jennifer F.

AU - Folsom, Aaron R.

AU - Sijbrands, Eric J.G.

AU - Pankow, James

AU - Elliott, Paul

AU - Keaney, John F.

AU - Sun, Wei

AU - Sarin, Antti Pekka

AU - Fontes, João D.

AU - Badola, Sunita

AU - Astor, Brad C.

AU - Hofman, Albert

AU - Pouta, Anneli

AU - Werdan, Karl

AU - Greiser, Karin H.

AU - Kuss, Oliver

AU - Meyer Zu Schwabedissen, Henriette E.

AU - Thiery, Joachim

AU - Jamshidi, Yalda

AU - Nolte, Ilja M.

AU - Soranzo, Nicole

AU - Spector, Timothy D.

AU - Völzke, Henry

AU - Parker, Alexander N.

AU - Aspelund, Thor

AU - Bates, David

AU - Young, Lauren

AU - Tsui, Kim

AU - Siscovick, David S.

AU - Guo, Xiuqing

AU - Rotter, Jerome I.

AU - Uda, Manuela

AU - Schlessinger, David

AU - Rudan, Igor

AU - Hicks, Andrew A.

AU - Penninx, Brenda W.

AU - Thorand, Barbara

AU - Gieger, Christian

AU - Coresh, Joe

AU - Willemsen, Gonneke

AU - Harris, Tamara B.

AU - Uitterlinden, Andre G.

AU - Järvelin, Marjo Riitta

AU - Rice, Kenneth

AU - Radke, Dörte

AU - Salomaa, Veikko

AU - Willems Van Dijk, Ko

AU - Boerwinkle, Eric

AU - Vasan, Ramachandran S.

AU - Ferrucci, Luigi

AU - Gibson, Quince D.

AU - Bandinelli, Stefania

AU - Snieder, Harold

AU - Boomsma, Dorret I.

AU - Xiao, Xiangjun

AU - Campbell, Harry

AU - Hayward, Caroline

AU - Pramstaller, Peter P.

AU - Van Duijn, Cornelia M.

AU - Peltonen, Leena

AU - Psaty, Bruce M.

AU - Gudnason, Vilmundur

AU - Ridker, Paul M.

AU - Homuth, Georg

AU - Koenig, Wolfgang

AU - Ballantyne, Christie M.

AU - Witteman, Jacqueline C.M.

AU - Benjamin, Emelia J.

AU - Perola, Markus

AU - Chasman, Daniel I.

PY - 2011/2/22

Y1 - 2011/2/22

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<2.9×10). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈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.

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<2.9×10). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈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.

KW - genetics

KW - genome-wide association study

KW - inflammation

KW - meta-analysis

KW - myocardial infarction

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UR - http://www.scopus.com/inward/citedby.url?scp=79952069515&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.110.948570

DO - 10.1161/CIRCULATIONAHA.110.948570

M3 - Article

C2 - 21300955

AN - SCOPUS:79952069515

SN - 0009-7322

VL - 123

SP - 731

EP - 738

JO - Circulation

JF - Circulation

IS - 7

ER -

Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels

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