Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels
Authors: Dehghan Abbas , Dupuis Josée , Barbalic Maja , Bis Joshua C. , Eiriksdottir Gudny , Lu Chen , Pellikka Niina , Wallaschofski Henri , Kettunen Johannes , Henneman Peter , Baumert Jens , Strachan David P. , Fuchsberger Christian , Vitart Veronique , Wilson James F. , Paré Guillaume , Naitza Silvia , Rudock Megan E. , Surakka Ida , de Geus Eco J.C. , Alizadeh Behrooz Z. , Guralnik Jack , Shuldiner Alan , Tanaka Toshiko , Zee Robert Y.L. , Schnabel Renate B. , Nambi Vijay , Kavousi Maryam , Ripatti Samuli , Nauck Matthias , Smith Nicholas L. , Smith Albert V. , Sundvall Jouko , Scheet Paul , Liu Yongmei , Ruokonen Aimo , Rose Lynda M. , Larson Martin G. , Hoogeveen Ron C. , Freimer Nelson B. , Teumer Alexander , Tracy Russell P. , Launer Lenore J. , Buring Julie E. , Yamamoto Jennifer F. , Folsom Aaron R. , Sijbrands Eric J.G. , Pankow James , Elliott Paul , Keaney John F. , Sun Wei , Sarin Antti-Pekka , Fontes João D. , Badola Sunita , Astor Brad C. , Hofman Albert , Pouta Anneli , Werdan Karl , Greiser Karin H. , Kuss Oliver , Meyer zu Schwabedissen Henriette E. , Thiery Joachim , Jamshidi Yalda , Nolte Ilja M. , Soranzo Nicole , Spector Timothy D. , Völzke Henry , Parker Alexander N. , Aspelund Thor , Bates David , Young Lauren , Tsui Kim , Siscovick David S. , Guo Xiuqing , Rotter Jerome I. , Uda Manuela , Schlessinger David , Rudan Igor , Hicks Andrew A. , Penninx Brenda W. , Thorand Barbara , Gieger Christian , Coresh Joe , Willemsen Gonneke , Harris Tamara B. , Uitterlinden Andre G. , Järvelin Marjo-Riitta , Rice Kenneth , Radke Dörte , Salomaa Veikko , Willems van Dijk Ko , Boerwinkle Eric , Vasan Ramachandran S. , Ferrucci Luigi , Gibson Quince D. , Bandinelli Stefania , Snieder Harold , Boomsma Dorret I. , Xiao Xiangjun , Campbell Harry , Hayward Caroline , Pramstaller Peter P. , van Duijn Cornelia M. , Peltonen Leena , Psaty Bruce M. , Gudnason Vilmundur , Ridker Paul M. , Homuth Georg , Koenig Wolfgang , Ballantyne Christie M. , Witteman Jacqueline C.M. , Benjamin Emelia J. , Perola Markus , Chasman Daniel I. 
Published: February 2011

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
−6
). 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.