Abstract 16324: Framingham Offspring Cohort Genome-Wide Association Study of Gamma' Fibrinogen Levels
γ′ fibrinogen is a newly-emerging biomarker that has been associated with CVD in small case-control studies. γ′ fibrinogen arises from an alternative splicing event in the mRNA from the γ chain gene FGG. However, the genetic determinants of γ′ fibrinogen levels are unknown. We therefore conducted a genome-wide association study (GWAS) on 3,042 participants of the Framingham Heart Study Offspring Cohort. A GWAS with 2.5 million SNPs was carried out for γ′ fibrinogen levels measured in the cycle 7 exam. 54 SNPs in or near the fibrinogen gene locus demonstrated genome-wide significance (P<5.0x10-8) for association with γ′ fibrinogen levels. The top-signal SNP was rs7681423 (P=9.97x10-110) explaining 13% total variance in natural-log γ′ fibrinogen levels and was located in the fibrinogen gene locus near FGG. Conditional on the top SNP, only SNP rs1049636 remained genome-wide significant (P=3.4x10-17, variance explained 1.8%). These findings are in contrast to those for total fibrinogen levels, which are associated with different genetic loci, particularly the gene for the fibrinogen Bβ chain, FGB. Unlike total fibrinogen levels, no other loci on other chromosomes reached the threshold for significance. Also in contrast to total fibrinogen levels, γ′ fibrinogen levels were associated with several SNPs in the PLRG1 locus adjacent to the fibrinogen gene locus. PLRG1 encodes pleiotropic regulator 1, a component of the spliceosome that affects alternative splice site choice. However, after adjusting for the top-signal SNP rs7681423 from the initial GWAS, these SNPs were no longer genome-wide significant. Associations between SNPs, γ′ fibrinogen levels, and prevalent CVD events were next examined using multiple logistic regression. The two SNPs associated with γ′ fibrinogen levels were not associated with prevalent CVD events. However, γ′ fibrinogen levels were associated with prevalent CVD (P=0.02). γ′ fibrinogen levels are therefore associated with SNPs exclusively in and near the fibrinogen gene locus and with prevalent CVD.
- Genome-wide association studies (GWAS)
- Cardiovascular disease
- Risk factors
- Blood coagulation
- © 2011 by American Heart Association, Inc.