Novel loci, including those related to Crohn disease, psoriasis, and inflammation, identified in a genome-wide association study of fibrinogen in 17 686 women: the Women's Genome Health Study

Abstract

Background: Fibrinogen is a multifunctional circulating glycoprotein involved in wound healing, thrombosis, platelet aggregation, and inflammation, and elevated levels predict vascular disease. Despite evidence of crucial biological function and moderate heritability, comprehensive analysis of the influence of genetic variation on fibrinogen is not available.

Methods and results: To address this issue, we undertook a genome-wide association study evaluating the potential relationships between 337 343 single-nucleotide polymorphisms (SNPs) and plasma fibrinogen levels among 17 686 apparently healthy women participating in the Women's Genome Health Study. As C-reactive protein is also an inflammatory marker known to predict cardiovascular diseases, we compared the determinants of fibrinogen levels with those of C-reactive protein. Four novel loci were identified, in addition to the fibrinogen gene cluster, which were associated with fibrinogen levels at genome-wide levels of significance (range of probability values from 8.82 x 10(-09) to 8.04 x 10(-39)). Two of the loci are related to common chronic inflammatory diseases: the first, at locus 5q31.1 (SLC22A5, SLC22A4, IRF1), lies immediately adjacent to a locus linked to Crohn disease (P value for lead SNP, 1.24 x 10(-12)) and the second, at locus 17q25.1 (CD300LF, SLC9A3R1, NAT9), has been associated with psoriasis (P value for lead SNP, 7.72 x 10(-11)). A third locus at 1q21.3 (IL6R) lies within the interleukin 6 receptor gene, a critical component of the inflammatory cascade (P value for lead SNP, 1.80 x 10(-11)). A novel locus at 2q34 (CPSI) participates in the urea cycle (P=8.82 x 10(-09)). The majority of implicated SNPs showed little evidence of dual association with C-reactive protein levels.

Conclusions: A genome-wide survey of the human genome identifies novel loci related to common chronic inflammatory diseases as genetic determinants of fibrinogen levels, in addition to loci that relate to the inflammatory cascade, the urea cycle, and the fibrinogen gene cluster.

Figure 1

The distribution of P-values for the association of individual SNPs with plasma fibrinogen levels according to chromosome number and position.

Figure 2

Genetic Context of Loci with Genome-Wide Significant Associations with Fibrinogen Data are presented that map each SNP according to its physical location at each of the 5 loci, as well a plot of the P-values in relation to the distance from known recombination hotspots according to HapMap. Top panel: genes from RefSeq release 25 are shown. Only one isoform is shown when multiple splicing variants are known. Lower panel: SNPs are shown according to their physical location and P-values (red dots). Also shown is the genetic distance in cM from the lowest P-value SNP (light grey line) along with the position of recombination hotspots (light grey vertical bars). Recombination rates and hotspots are based on HapMap data, as described by McVean et al.. The IL6R region is shown in Figure 2-A, the CPS1 region in Figure 2-B, the fibrinogen gene cluster (4q32.1) in Figure 3-C, the SLC22A5, SLC22A4, IRF1 locus (5q31.1) in Figure 2-D and the CD300LF, SLC9A3R1, NAT9 locus in Figure 2-E.

Figure 3

Quantile-Quantile Plot of Actual and Expected P-Values for Association with Fibrinogen