DNA methylation analysis identifies novel genetic loci associated with circulating fibrinogen levels in blood.

Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined by inter-individual differences in DNA methylation at CpG sites, and vice versa.
Methods: We performed an epigenome-wide association study (EWAS) of circulating fibrinogen levels in 18,037 White, Black, American Indian, and Hispanic participants representing 14 studies from the CHARGE consortium. Circulating leukocyte DNA methylation was measured in 12,904 participants using the Illumina 450K array, and in 5,133 participants using the EPIC array. Each study performed an EWAS of fibrinogen using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without C-reactive protein (CRP) adjustment to examine the role of inflammation.
Results: We identified 208 and 87 significant CpG sites associated with fibrinogen from the 450K (p-value<1.03×10 ^-7 ) and EPIC arrays (p-value<5.78×10 ^-8 ), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for the overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. Examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations for all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant.
Conclusion: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.
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