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Meta-Analysis
. 2009 Apr;2(2):125-33.
doi: 10.1161/CIRCGENETICS.108.825224.

Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts

Abbas Dehghan  1 , Qiong Yang, Annette Peters, Saonli Basu, Joshua C Bis, Alicja R Rudnicka, Maryam Kavousi, Ming-Huei Chen, Jens Baumert, Gordon D O Lowe, Barbara McKnight, Weihong Tang, Moniek de Maat, Martin G Larson, Susana Eyhermendy, Wendy L McArdle, Thomas Lumley, James S Pankow, Albert Hofman, Joseph M Massaro, Fernando Rivadeneira, Melanie Kolz, Kent D Taylor, Cornelia M van Duijn, Sekar Kathiresan, Thomas Illig, Yurii S Aulchenko, Kelly A Volcik, Andrew D Johnson, Andre G Uitterlinden, Geoffrey H Tofler, Christian Gieger; Wellcome Trust Case Control Consortium; Bruce M Psaty, David J Couper, Eric Boerwinkle, Wolfgang Koenig, Christopher J O'Donnell, Jacqueline C Witteman, David P Strachan, Nicholas L Smith, Aaron R Folsom
Collaborators, Affiliations
Meta-Analysis

Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts

Abbas Dehghan et al. Circ Cardiovasc Genet. 2009 Apr.

Abstract

Background: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.

Methods and results: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)).

Conclusions: Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.

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Figures

Figure 1
Figure 1
QQ-plot for the meta-analysis results. Quantile-quantile plot of the observed and the expected distribution of p-values for all 2,661,766 SNPs and their association with fibrinogen levels based on meta-analyzed data.
Figure 2
Figure 2
−Log plot for the meta-analysis. −Log p-values for each of the 2,661,766 tests performed as part of the genome-wide association analysis of fibrinogen levels. The grey dashed horizontal lines correspond to the p-value threshold of 5×10−8 and the grey solid line corresponds to 5×10−6.
Figure 3
Figure 3
Regional plots of loci associated with fibrinogen. (a-d). The association p-values (−log10 transformed, indicated by the left y-axis) for SNPs in a 60kb region of each of the four loci (FGB, IRF1, PCCB, NLRP3) are plotted against their chromosome positions (NCBI build 36) on x-axis. Each diamond represents a SNP with the color indicating the linkage disequilibrium (estimated using HapMap CEU sample) between the SNP and the top associated SNP that is plotted by a red diamond with size larger than all other diamonds, and with the SNP name displayed on the top, and p-value on the right. Shown in light blue are the estimated recombination rates in HapMap with values indicated by the right y-axis. The bottom panel displays the genes in the region based on the UCSC Genome Browser March 2006 assembly, with the arrow to right (left) indicate indicating +(−) strand. The grey horizontal line corresponds to the p-value threshold of genome-wide significance, 5×10−8.
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