Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein

Symen Ligthart, Paul S. De Vries, André G. Uitterlinden, Albert Hofman, Oscar H. Franco, Daniel I. Chasman, 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 VitartJames F. Wilson, Guillaume Paré, Silvia Naitza, Megan E. Rudock, Ida Surakka, Eco J C De Geus, Behrooz Z. Alizadeh, Jack M D 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, Anneli Pouta, Karl Werda, 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, 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 Mvan 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.

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38 Scopus citations

Abstract

Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP) is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic background of inflammation and cardiometabolic phenotypes using published genome-wide association studies (GWAS). We also evaluated whether the pleiotropic effects of such loci were biological or mediated in nature. First, we examined whether 283 common variants identified for 10 cardiometabolic phenotypes in GWAS are associated with CRP level. Second, we tested whether 18 variants identified for serum CRP are associated with 10 cardiometabolic phenotypes. We used a Bonferroni corrected p-value of 1.1×10-04 (0.05/463) as a threshold of significance. We evaluated the independent pleiotropic effect on both phenotypes using individual level data from the Women Genome Health Study. Evaluating the genetic overlap between inflammation and cardiometabolic phenotypes, we found 13 pleiotropic regions. Additional analyses showed that 6 regions (APOC1, HNF1A, IL6R, PPP1R3B, HNF4A and IL1F10) appeared to have a pleiotropic effect on CRP independent of the effects on the cardiometabolic phenotypes. These included loci where individuals carrying the risk allele for CRP encounter higher lipid levels and risk of type 2 diabetes. In addition, 5 regions (GCKR, PABPC4, BCL7B, FTO and TMEM18) had an effect on CRP largely mediated through the cardiometabolic phenotypes. In conclusion, our results show genetic pleiotropy among inflammation and cardiometabolic phenotypes. In addition to reverse causation, our data suggests that pleiotropic genetic variants partially underlie the association between CRP and cardiometabolic phenotypes.

Original languageEnglish (US)
Article numbere0118859
JournalPloS one
Volume10
Issue number3
DOIs
StatePublished - Mar 13 2015

Bibliographical note

Publisher Copyright:
© 2015 Ligthart et al.

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