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

Research output: Contribution to journalArticle

333 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 languageEnglish (US)
Pages (from-to)731-738
Number of pages8
JournalCirculation
Volume123
Issue number7
DOIs
StatePublished - Feb 22 2011

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Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

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